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Elobixibat

• Molecular FormulaC₃₆H₄₅N₃O₇S₂
• Average mass695.888 Da

Elobixibat hydrate

Approved 2018/1/19 Japan pmda

TRADE NAME Goofice  to EA Pharma

C₃₆H₄₅N₃O₇S₂▪H₂O : 713.9
[1633824-78-8] CAS OF HYDRATE

Gooffice ® tablet 5 mg (hereinafter referred to as Gooffice ® ) is an oral chronic constipation remedy drug containing as active ingredient Erobi vat having bile acid transporter inhibitory action. It is the world’s first bile acid transporter inhibitor.

Elobixibat is an inhibitor of the ileal bile acid transporter (IBAT),^[1] undergoing development in clinical trials for the treatment of chronic constipation and irritable bowel syndrome with constipation (IBS-C).

Mechanism of action

IBAT is the bile acid:sodium symporter responsible for the reuptake of bile acids in the ileum which is the initial step in the enterohepatic circulation. By inhibiting the uptake of bile acids, elobixibat increases the bile acid concentration in the gut, and this accelerates intestinal passage and softens the stool. Following several phase II studies, it is now undergoing phase III trials.^[2]

Drug development

The drug was developed by Albireo AB, who licensed it to Ferring Pharmaceuticals for further development and marketing.^[3] Albireo has partnered with Ajinomoto Pharmaceuticals, giving the Japan-based company the rights to further develop the drug and market it throughout Asia.^[4]

• OriginatorAstraZeneca
• DeveloperAlbireo Pharma; EA Pharma
• Class2 ring heterocyclic compounds; Amides; Carboxylic acids; Laxatives; Small molecules; Sulfides; Sulfones; Thiazepines
• Mechanism of ActionSodium-bile acid cotransporter-inhibitors

• Orphan Drug StatusNo
• New Molecular EntityYes

Highest Development Phases

• RegisteredConstipation
• DiscontinuedDyslipidaemias; Irritable bowel syndrome

Most Recent Events

Approved 2018/1/19 japan pmda

• 24 Jan 2018Elobixibat is still in phase II trials for Constipation in Indonesia, South Korea, Taiwan, Thailand and Vietnam (Albireo pipeline, January 2018)
• 24 Jan 2018Discontinued – Phase-II for Irritable bowel syndrome in USA and Europe (PO) (Alberio pipeline, January 2018)
• 19 Jan 2018Registered for Constipation in Japan (PO) – First global approval
• In 2012, the compound was licensed to Ajinomoto (now EA Pharma) by Albireo for exclusive development and commercialization rights in several Asian countries. At the same year, the product was licensed to Ferring by Albireo worldwide, except Japan and a small number of Asian markets, for development and marketing. However, in 2015, this license between Ferring and Albireo was terminated and Albireo is seeking partner for in the U.S. and Europe. In 2016, Ajinomoto and Mochida signed an agreement on codevelopment and comarketing of the product in Japan.

Elobixibat

Elobixibat is an IBAT inhibitor approved in Japan for the treatment of chronic constipation, the first IBAT inhibitor to be approved anywhere in the world.  EA Pharma Co., Ltd., a company formed via a 2016 combination of Eisai’s GI business with Ajinomoto Pharmaceuticals and focused on the gastrointestinal disease space, is the exclusive licensee of elobixibat for the treatment of gastrointestinal disorders in Japan and other select countries in Asia (not including China) and is expected to co-market elobixibat in Japan with Mochida Pharmaceutical Co., Ltd., and to co-promote elobixibat in Japan with Eisai, under the trade name GOOFICE®.

We also believe that elobixibat has potential benefit in the treatment of NASH based on findings on relevant parameters in clinical trials of elobixibat that we previously conducted in patients with chronic constipation and in patients with elevated cholesterol and findings on other parameters relevant to NASH from nonclinical studies that we previously conducted with elobixibat or a different IBAT inhibitor. In particular, in a clinical trial in dyslipidemia patients, elobixibat given for four weeks reduced low-density lipoprotein (LDL) cholesterol, with the occurrence of diarrhea being substantially the same as the placebo group. Also, in other clinical trials in constipated patients, elobixibat given at various doses and for various durations reduced LDL-cholesterol and, in one trial, increased levels of glucagon-like peptide 1 (GLP-1). Moreover, A4250 (an IBAT inhibitor) showed significant improvement (p < 0.05) on the nonalcoholic fatty liver disease activity score in an established model of NASH in mice known as the STAM™ model and improvement in liver inflammation and fibrosis in another preclinical mouse model. We are considering conducting a Phase 2 clinical trial of elobixibat in NASH

These benzothiazepines possess ileal bile acid transport (IBAT) inhibitory activity and accordingly have value in the treatment of disease states associated with hyperlipidaemic conditions and they are useful in methods of treatment of a warm-blooded animal, such as man. The invention also relates to processes for the manufacture of said benzothiazepine derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments to inhibit IBAT in a warm-blooded animal, such as man.
It is well-known that hyperlipidaemic conditions associated with elevated
concentrations of total cholesterol and low-density lipoprotein cholesterol are major risk factors for cardiovascular atherosclerotic disease (for instance “Coronary Heart Disease: Reducing the Risk; a Worldwide View” Assman G., Carmena R. Cullen P. et al; Circulation 1999, 100, 1930-1938 and “Diabetes and Cardiovascular Disease: A Statement for Healthcare Professionals from the American Heart Association” Grundy S, Benjamin I., Burke G., et al; Circulation, 1999, 100, 1134-46). Interfering with the circulation of bile acids within the lumen of the intestinal tracts is found to reduce the level of cholesterol. Previous established therapies to reduce the concentration of cholesterol involve, for instance, treatment with HMG-CoA reductase inhibitors, preferably statins such as simvastatin and fluvastatin, or treatment with bile acid binders, such as resins. Frequently used bile acid binders are for instance cholestyramine and cholestipol. One recently proposed therapy (“Bile Acids and Lipoprotein Metabolism: a Renaissance for Bile Acids in the Post Statin Era” Angelin B, Eriksson M, Rudling M; Current Opinion on Lipidology, 1999, 10, 269-74) involved the treatment with substances with an IBAT inhibitory effect.
Re-absorption of bile acid from the gastro-intestinal tract is a normal physiological process which mainly takes place in the ileum by the IBAT mechanism. Inhibitors of EBAT can be used in the treatment of hypercholesterolaemia (see for instance “Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolaemic properties”, Biochemica et Biophysica Acta, 1210 (1994) 255- 287). Thus, suitable compounds having such inhibitory IBAT activity are also useful in the treatment of hyperlipidaemic conditions.

Compounds possessing such IBAT inhibitory activity have been described, see for instance the compounds described in WO 93/16055, WO 94/18183, WO 94/18184, WO 96/05188, WO 96/08484, WO 96/16051, WO 97/33882, WO 98/38182, WO 99/35135, WO 98/40375, WO 99/35153, WO 99/64409, WO 99/64410, WO 00/01687, WO 00/47568, WO 00/61568, WO 01/68906, DE 19825804, WO 00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO 00/38729, WO 01/68906, WO 01/66533, WO 02/50051 and EP 0 864 582.
A further aspect of this invention relates to the use of the compounds of the invention in the treatment of dyslipidemic conditions and disorders such as hyperlipidaemia, hypertrigliceridemia, hyperbetalipoproteinemia (high LDL), hyperprebetalipoproteinemia (high VLDL), hyperchylomicronemia, hypolipoproteinemia, hypercholesterolemia, hyperlipoproteinemia and hypoalphalipoproteinemia (low HDL). In addition, these compounds are expected to be useful for the prevention and treatment of different clinical conditions such as atherosclerosis, arteriosclerosis, arrhythmia, hyper-thrombotic conditions, vascular dysfunction, endothelial dysfunction, heart failure, coronary heart diseases, cardiovascular diseases, myocardial infarction, angina pectoris, peripheral vascular diseases, inflammation of cardiovascular tissues such as heart, valves, vasculature, arteries and veins, aneurisms, stenosis, restenosis, vascular plaques, vascular fatty streaks, leukocytes, monocytes and/or macrophage infiltration, intimal thickening, medial thinning, infectious and surgical trauma and vascular thrombosis, stroke and transient ischaemic attacks.

PATENTS

WO 2002050051

https://patentscope.wipo.int/search/en/detail.jsf%3Bjsessionid=4E054324A28B9E2E7C3C73102D1560EC.wapp1?docId=WO2002050051&recNum=237&office=&queryString=&prevFilter=%26fq%3DOF%3AWO%26fq%3DICF_M%3A%22A61K%22%26fq%3DPAF_M%3A%22ASTRAZENECA+AB%22&sortOption=Relevance&maxRec=655

ASTRAZENECA 

SYNTHESIS

WO 2002050051, WO 1996016051

PATENT

WO 2003051821

WO 2003020710

TW I291951

WO 2013063512

WO 2013063526

US 20140323412

EP 3012252

PATENT

WO 2003020710

https://patents.google.com/patent/WO2003020710A1/und

PATENT

WO 2014174066 

WO 02/50051 discloses the compound 1 ,1 -dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(/V-{(R)-1 ‘-phenyl-1 ‘- [/V-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1 ,5-benzothiazepine (elobixibat; lUPAC name: /V-{(2R)-2-[({[3,3-dibutyl-7-(methylthio)-1 ,1 -dioxido-5-phenyl-2,3,4,5-tetrahydro-1 ,5-benzothiazepin-8-yl]oxy}acetyl)amino]-2-phenyl-ethanolyl}glycine). This compound is an ileal bile acid transporter (I BAT) inhibitor, which can be used in the treatment or prevention of diseases such as dyslipidemia, constipation, diabetes and liver diseases. According to the experimental section of WO 02/50051 , the last synthetic step in the preparation of elobixibat consists of the hydrolysis of a ie f-butoxyl ester under acidic conditions. The crude compound was obtained by evaporation of the reaction mixture under reduced pressure and purification of the residue by preparative HPLC using acetonitrile/ammonium acetate buffer (50:50) as eluent (Example 43). After freeze drying the product, no crystalline material was identified.

Example 1

Preparation of crystal modification I

Toluene (1 1 .78 L) was charged to a 20 L round-bottom flask with stirring and 1 ,1 -dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(/V-{(R)-1 ‘-phenyl-1 ‘-[/\/’-(i-butoxycarbonylmethyl)carbamoyl]-methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1 ,5-benzothiazepine (2.94 kg) was added. Formic acid (4.42 L) was added to the reaction mass at 25-30 °C. The temperature was raised to 1 15-120 °C and stirred for 6 hours. The reaction was monitored by HPLC to assure that not more than 1 % of the starting material remained in the reaction mass. The reaction mass was cooled to 40-43 °C. Purified water (1 1 .78 L) was added while stirring. The reaction mass was further cooled to 25-30 °C and stirred for 15 min.

The layers were separated and the organic layer was filtered through a celite bed (0.5 kg in 3 L of toluene) and the filtrate was collected. The celite bed was washed with toluene (5.9 L), the filtrates were combined and concentrated at 38-40 °C under vacuum. The reaction mass was then cooled to 25-30 °C to obtain a solid.

Ethanol (3.7 L) was charged to a clean round-bottom flask with stirring, and the solid obtained in the previous step was added. The reaction mass was heated to 40-43 °C and stirred at this temperature for 30 min. The reaction mass was then cooled to 25-30 °C over a period of 30 min., and then further cooled to 3-5 °C over a period of 2 h, followed by stirring at this temperature for 14 h. Ethanol (3.7 L) was charged to the reaction mass with stirring, while maintaining the temperature at 0-5 °C, and the reaction mass was then stirred at this temperature for 1 h. The material was then filtered and washed with ethanol (1 .47 L), and vacuum dried for 30 min. The material was dried in a vacuum tray dryer at 37-40 °C for 24 h under nitrogen atmosphere. The material was put in clean double LDPE bags under nitrogen atmosphere and stored in a clean HDPE drum. Yield 1 .56 kg.

Crystal modification I has an XRPD pattern, obtained with CuKal -radiation, with

characteristic peaks at °2Θ positions: 3,1 ± 0.2, 4,4 ± 0.2, 4,9 ± 0.2, 5,2 ± 0.2, 6,0 ± 0.2, 7,4 ± 0.2, 7,6 ± 0.2, 7,8 ± 0.2, 8,2 ± 0.2, 10,0 ± 0.2, 10,5 ± 0.2, 1 1 ,3 ± 0.2, 12,4 ± 0.2, 13,3 ± 0.2, 13,5 ± 0.2, 14,6 ± 0.2, 14,9 ± 0.2, 16,0 ± 0.2, 16,6 ± 0.2, 16,9 ± 0.2, 17,2 ± 0.2, 17,7 ± 0.2, 18,0 ± 0.2, 18,3 ± 0.2, 18,8 ± 0.2, 19,2 ± 0.2, 19,4 ± 0.2, 20,1 ± 0.2, 20,4 ± 0.2, 20,7 ± 0.2, 20,9 ± 0.2, 21 ,1 ± 0.2, 21 ,4 ± 0.2, 21 ,8 ± 0.2, 22,0 ± 0.2, 22,3 ± 0.2, 22,9 ± 0.2, 23,4 ± 0.2, 24,0 ± 0.2, 24,5 ± 0.2, 24,8 ± 0.2, 26,4 ± 0.2,^‘27,1 ± 0.2 and 27,8 ± 0.2. The X-ray powder diffractogram is shown in FIG. 4.

PATENT

WO 2014174066

エロビキシバット水和物 Elobixibat Hydrate C36H45N3O7S2▪H2O : 713.9 [1633824-78-8]

References

Elobixibat

Clinical data
Routes of administration	Oral
ATC code	None
Legal status
Legal status	Investigational
Identifiers
IUPAC name[show]
CAS Number	439087-18-0
PubChem CID	9939892
ChemSpider	8115513
UNII	865UEK4EJC
KEGG	D10796
ChEMBL	CHEMBL3039515
Chemical and physical data
Formula	C36H45N3O7S2
Molar mass	695.89 g/mol
3D model (JSmol)	Interactive image

//////////Elobixibat hydrate, japan 2018, A-3309, AJG-533, Goofice, A 3309, AJG 533, AZD 7806

CCCCC1(CN(C2=CC(=C(C=C2S(=O)(=O)C1)OCC(=O)NC(C3=CC=CC=C3)C(=O)NCC(=O)O)SC)C4=CC=CC=C4)CCCC

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Forodesine

• Molecular FormulaC₁₁H₁₄N₄O₄
• Average mass266.253 Da

CAS No. : 284490-13-7

Forodesine (INN; also known as Immucillin H; trade names Mundesine and Fodosine) is a transition-state analog inhibitor of purine nucleoside phosphorylase^[1] studied for the treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) and for treatment of B-cell acute lymphocytic leukemia (B-ALL).

Forodesine was originally discovered by Vern Schramm‘s laboratory at the Albert Einstein College of Medicine in New York and Industrial Research Limited in New Zealand.

Forodesine is being developed by BioCryst Pharmaceuticals. As of 2008, it is currently in phase II clinical trials.^[2].

In 2006, BioCryst entered into a licensing agreement with Mundipharma International Holdings Limited to develop and commercialize forodesine in markets across Europe, Asia, and Australasia for use in oncology.^[3]

In April 2017, forodesine was approved in Japan for the treatment of relapsed/refractory peripheral T-cell lymphoma.^[4]

ema

On 20 September 2010, orphan designation (EU/3/10/780) was granted by the European Commission to Mundipharma Research Limited, United Kingdom, for forodesine for the treatment of chronic lymphocytic leukaemia

EU/3/10/780: Public summary of opinion on orphan designation: Forodesine for the treatment of chronic lymphocytic leukaemia

P/69/2010: European Medicines Agency decision on the granting of a product specific waiver for forodesine hydrochloride (EMEA-000785-PIP01-09)

On 20 September 2010, orphan designation (EU/3/10/780) was granted by the European Commission to Mundipharma Research Limited, United Kingdom, for forodesine for the treatment of chronic lymphocytic leukaemia.

What is chronic lymphocytic leukaemia?

Chronic lymphocytic leukaemia (CLL) is cancer of a type of white blood cell called B lymphocytes. In this disease, the lymphocytes multiply too quickly and live for too long, so that there are too many of them circulating in the blood. The cancerous lymphocytes look normal, but they are not fully developed and do not work properly. Over a period of time, the abnormal cells replace the normal white blood cells, red blood cells and platelets (components that help the blood to clot) in the bone marrow (the spongy tissue inside the large bones in the body). CLL is the most common type of leukaemia and mainly affects older people. It is rare in people under the age of 40 years. CLL is a long-term debilitating and life-threatening disease because some patients develop severe infections. What is the estimated number of patients affected by the condition? At the time of designation, CLL affected approximately 3 in 10,000 people in the European Union (EU)*. This is equivalent to a total of around 152,000 people, and is below the threshold for orphan designation, which is 5 people in 10,000. This is based on the information provided by the sponsor and the knowledge of the Committee for Orphan Medicinal Products (COMP).

What treatments are available? Treatment for CLL is complex and depends on a number of factors, including the extent of the disease, whether it has been treated before, and the patient’s age, symptoms and general state of health. Patients whose CLL is not causing any symptoms or is only getting worse very slowly may not need

Forodesine Hydrochloride was originally developed by BioCryst Pharmaceuticals and then licensed to Mundipharma and in particular is marketed in Japan under the trade name Mundesine®. Forodesine Hydrochloride is a transitional analogue inhibitor of purine nucleoside phosphorylase (PNP). Mundesine® is approved for the treatment of peripheral T-cell lymphoma (PTCL).

Mundesine® is a capsule that contains 100mg of free Forodesine per capsule. The recommended dose is 300mg orally, twice daily.

In 2004, the compound was eligible for orphan drug treatment for non-Hodgkin’s lymphoma (NHL), chronic myelogenous leukemia (CLL) and hairy cell leukemia, respectively. In 2007, the compound was eligible for the EU orphan drug for the treatment of acute lymphoblastic leukemia (ALL) and cutaneous T-cell lymphoma (CTCL). In 2010, the compound was eligible for EU orphan drug for treatment of CLL. In 2006, the compound obtained Japanese orphan drug eligibility for CTCL treatment.

Forodesine, or 7-[(2S,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-2-pyrrolidinyl]-l,5-dihydropyrrolo[2,3-e]pyrimidin-4-one, is an inhibitor of purine nucleoside phosphorylase. It is currently in development as a treatment for peripheral T-Cell Lymphoma .

W099/19338 describes a compound genus as a new class of inhibitors of nucleoside metabolism, including Forodesine. The compounds effect as inhibitors of purine nucleoside phosphorylase is taught as efficacious to suppress T-cell function and to treat infections caused by protozoan parasites.

WO00/61783 describes a number of processes for preparing molecules described in W099/19338. Reaction scheme 3 on page 23 of the published application describes a synthesis of Forodesine, characterised by the removal of two acid labile protecting groups in the final step to yield the hydrochloride salt.

Forodesine is a particularly difficult molecule to make on a commercial scale. The current process for manufacture requires a coupling reaction under cryogenic temperature conditions of -55C. Subsequent steps involve the use of a high pressure hydrogenation reaction. Such extreme reaction conditions provide for safety concerns, particularly when conducted on a bulk scale. Further the products of the reaction were extremely challenging to purify. The effect of all this is to require more sophisticated and expensive equipment at the manufacturing plant; all of which add up to an increased cost of goods for patients. Accordingly a new manufacturing process was sought.

Surprisingly a new route has been invented which is shorter, cheaper, less dangerous and provides an increased overall yield whilst still conforming to the required purity profile.

The current manufacturing process is described in Fig 1.

5C

, MeOH, reflux xchange

tallisation

Fig l

Within the diagram, the following acronyms are used, wherein NCS is N-Chlorosuccinimide, OTBDMS is t-butyldimethylsiloxy protecting group, MtBE is methyl t-butyl ether, (BOC)₂0 is di-t-butyldicarbonate and BOC is t-butyloxycarbonyl protecting group,

Particularly problematic in this process is the requirement to conduct the coupling of process step (iii) at exceptionally low temperature. Further challenges are provided by process step (v) the hydrogenation reaction to remove the benxylyoxymethyl (BOM) protecting group, before removing the other acid labile protecting groups.

Conducting hydrogenation reactions with their need for a high pressure environment requires specialist equipment. Such apparatus is expensive, adding to the cost of the materials produced. Despite the use of specialist equipment, safety concerns can never be eradicated. Whilst BOM can, in certain circumstances, be acid labile, treatment of analogues of the molecules described in Fig 1 with acid has always resulted in incomplete removal of the protecting group, leading to a large number of partially deprotected impurities. This makes purification exceptionally difficult as well as reducing the overall yield for the step.

A new improved process has been developed as described in Fig 2:

Toluene

Fig 2

The new route has a number of clear advantages. The coupling reaction (ix) is conducted at a warmer -15°C, rather than the challenging cryogenic conditions of -55°C required previously. It eradicates the hydrogenation step, avoiding the need for dangerous high pressure conditions. It also makes the overall process much quicker and cheaper; not only are the conditions challenging, but the reagents used in large quantities such as palladium are expensive and environmentally challenging.

The classical method to remove a BOM protecting group is by catalytic hydrogenation. It is however known to be unstable in acid conditions. For this reasons there have been previous attempts to remove BOM at the same time as the three acid labile protecting groups. This has always been unsuccessful as treatment with acid typically resulted in incomplete deprotection, leading to a mixture of products. This made for a tricky purification and a reduced yield. Surprisingly under the particular conditions described herein it has been possible to effect the transformation in greater yield and without a difficult purification. The final product is obtained in equal or greater purity than material obtained from the previous route.

PATENT

WO2013158746A1 *

Scheme 13

HO _OH 1 . HCI/Acetone, MeOH OCH,

2. PPh₃, imidazole I

HO (EtO)₂POCH₂CN

OH O O

Ribose Λ 13a

References for preparation of compound 13a:

1. Mishra, Girija Prasad; Rao, Batchu Venkateswara; Tetrahedron: Asymmetry (2011), 22(7), 812-817.

2. Brock, E. Anne; Davies, Stephen G.; Lee, James A.; Roberts, Paul M.; Thomson,

James E; Organic Letters (2011), 13(7), 1594-1597.

3. WO 2010/085377 A2 (incorporated by reference).

4. Yadav, J. S.; Reddy, P. Narayana; Reddy, B. V. Subba; Synlett (2010), (3), 457- 461.

5. Song, Kai; Zheng, Guo-jun; Huaxue Shiji (2010), 32(2), 171-172.

6. Prabhakar, Peddikotla; Rajaram, Singanaboina; Reddy, Dorigondla Kumar;

Shekar, Vanam; Venkateswarlu, Yenamandra; Tetrahedron: Asymmetry (2010), 21(2), 216-221.

7. CN 101182342 A.

8. Baird, Lynton J.; Timmer, Mattie S. M.; Teesdale-Spittle, Paul H.; Harvey, Joanne

E; Journal of Organic Chemistry (2009), 74(6), 2271-2277.

9. Wang, Xiang-cheng; Wang, Gang; Qu, Gang-lian; Huaxue Shijie (2008), 49(4), 226-228.

10. Ivanova, N. A.; Valiullina, Z. R.; Shitikova, O. V.; Miftakhov, M. S; Russian

Journal of Organic Chemistry (2007), 43(5), 742-746.

11. Braga, Fernanda Gambogi; Coimbra, Elaine Soares; Matos, Magnum de Oliveira;

Lino Carmo, Arturene Maria; Cancio, Marisa Damato; da Silva, Adilson David; European Journal of Medicinal Chemistry (2007), 42(4), 530-537.

12. Wender, Paul A.; Bi, F. Christopher; Buschmann, Nicole; Gosselin, Francis; Kan, Cindy; Kee, Jung-Min; Ohmura, Hirofumi; Organic Letters (2006), 8(23), 5373- 5376.

13. Fei, Xiangshu; Wang, Ji-Quan; Miller, Kathy D.; Sledge, George W.; Hutchins, Gary D.; Zheng, Qi-Huang; Nuclear Medicine and Biology (2004), 31(8), 1033- 1041.

14. Abdel-Rahman, Adel A.-H.; Abdel-Megied, Ahmed E.-S.; Goda, Adel E.-S.; Zeid,

Ibrahim F.; El Ashry, El Sayed H; Nucleosides, Nucleotides & Nucleic Acids (2003), 22(11), 2027-2038.

15. Palmer, Andreas M.; Jager, Volker; European Journal of Organic Chemistry

(2001), (7), 1293-1308.

16. Paquette, Leo A.; Bailey, Simon; Journal of Organic Chemistry (1995), 60(24),

7849-56.

17. Classon, Bjoern; Liu, Zhengchun; Samuelsson, Bertil; Journal of Organic

Chemistry (1988), 53(26), 6126-30.

18. Kissman, Henry M.; Baker, B. R; Journal of the American Chemical Society

(1957), 79 5534-40.

References for cyclizations related to preparation of compounds of type 13d:

1. Davies, Stephen G.; Durbin, Matthew J.; Goddard, Euan C; Kelly, Peter M.;

Kurosawa, Wataru; Lee, James A.; Nicholson, Rebecca L.; Price, Paul D.;

Roberts, Paul M.; Russell, Angela J.; Scott, Philip M.; Smith, Andrew D; Organic & Biomolecular Chemistry (2009), 7(4), 761-776.

2. Davies, Stephen G.; Nicholson, Rebecca L.; Price, Paul D.; Roberts, Paul M.;

Russell, Angela J.; Savory, Edward D.; Smith, Andrew D.; Thomson, James E; Tetrahedron: Asymmetry (2009), 20(6-8), 758-772.

3. Davies, Stephen G.; Nicholson, Rebecca L.; Price, Paul D.; Roberts, Paul. M.;

Smith, Andrew D; Synlett (2004), (5), 901-903.

4. Brock, E. Anne; Davies, Stephen G.; Lee, James A.; Roberts, Paul M.; Thomson, James E; Organic Letters (2011), 13(7), 1594-1597.

5. Gary B. Evans, Richard H. Furneaux, Andrzej Lewandowicz, Vern L. Schramm, and Peter C. Tyler, Journal of Medicinal Chemistry (2003), 46, 3412-3423.

PATENT

WO 2016110527

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016110527

The invention also provides for the synthesis of a compound of formula (II)

By reacting a compound of Formula (VII)

With di-t-butyldicarbonate.

Preferably the reaction is conducted at -10 to -20°C, in methyl t-butyl ether & heptane

The invention also provides for the synthesis of a compound of formula (VII)

By reacting a compound of Formula (IV)

With a suitable base to form

Before reacting with a compound of Formula (III)

Example 1

Stage 1 Manufacture of (III)

Compound of formula (III) (approx. 130g) in toluene solution is added to a suspension of N-Chlorosuccinimide in toluene at 20°C over a period of 90min. The reaction mixture is stirred at 20°C for 1 hour then chilled to 0°C and stirred for a further hour. The precipitated succinimide by-product is removed by filtration and the filtered solution charged directly to a 45% potassium hydroxide solution (aq) containing

tetrabutylammonium bromide. The reaction mixture is stirred at 0°C and completion of reaction is confirmed by GC analysis. Water is then added to the two-phase mixture to dissolve inorganic precipitates and the toluene product solution is washed with a 28% ammonium hydroxide/acetic acid buffer mixture with sodium chloride added. After phase separation the organic phase solution is stabilised with triethylamine. Magnesium sulfate is added to dry the solution. After filtration, the yield of (III) is determined by R.O.E. and GC purity.

Stage 2 Manufacture of (II)

Stage 2a Lithiation

A suspension of compound of formula (IV) (approx. 200g) in MtBE is chilled to -15°C and treated with /7-Hexyl lithium (2.5M in hexanes) added over 2h, maintaining the reaction mixture at -15°C. The mixture is then stirred for 3h at -15°C.

Stage 2b Coupling with (IV)

After lithiation is complete, a compound formula (III) in toluene solution is added to the reaction mixture maintaining the contents at -15°C. The reaction mixture is then stirred at this temperature for 1.5h.

Stage 2c Boc anhydride quench

A solution of di-t-butyldicarbonate in MtBE is added to the above reaction mixture at -15°C. The solution is stirred for a further 30min.

Workup and Purification

The reaction mixture is quenched by addition of RO water, then filtered. The aqueous layer is separated and run to waste. The organic layer is again washed with water. The organic layer is concentrated to a low volume and solvent replaced by heptane. The mix is stirred for 16h and filtered again.

The solution is passed through a silica gel column and eluted with heptane. The resulting solution is treated with charcoal – stirred for 3h, then filtered. The product (II) is progressed as a solution in heptane to the next stage.

Stage 3 Manufacture of Crude Forodesine (la)

Stage 3 Deprotection with cone. HCI

Concentrated hydrochloric acid is added to (II) in heptane and the mixture stirred. The acid phase is separated off and stirred for 16h at ambient temperature. The solution is then heated to 40°C for 6h. The water is then distilled off under reduced pressure to a minimum volume.

Ethanol is then added to precipitate the crude Forodesine (la) which is isolated by filtration after cooling 0-5°C. It is washed with ethanol and dried in a vacuum oven at 75°C to a constant weight.

Stage 4a Decolourization of crude Forodesine (la) using Ion-Exchange Column

Crude Forodesine (la) is dissolved in water and loaded onto a freshly prepared ion-exchange column containing Dowex 50WX4 resin in the Na⁺ form activated with 30% sodium hydroxide solution. The ion-exchange column is eluted with 4 x lOOmL water followed by 4 x lOOmL 2M HCI. The HCI fractions are collected separately as they contain the desired product. The 2M HCI fractions are combined and concentrated under vacuum with minimum RO water added to dissolve the residue. 1,4-Dioxane is added to the aqueous solution to precipitate the product. The mixture is stirred at 20°C for 1.5h. The product is filtered, washed with 1,4-dioxane and dried in a vacuum oven at 35°C to a constant weight to give decolourised BCX1777.

Stage 4b Recrystallization of Forodesine

Decolourised Forodesine is added to in 0.6M dilute hydrochloric acid and heated to 45°C to dissolve. The resulting solution is hot filtered and washed through with some RO Water. The solution is cooled to 20°C and ethanol added over at least lh. The mixture is then seeded with Forodesine HCI. The resulting slurry is stirred for 8h at 20°C, then cooled to 2°C for a further 1.5h. The product is isolated by filtration, washed twice with cold ethanol then dried in a vacuum oven at 75°C to a constant weight to give a white crystalline Forodesine HCI (approx. 50g).

While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one of skill in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof. Moreover, all embodiments described herein are considered to be broadly applicable and combinable with any and all other consistent embodiments, as appropriate.

PAPER

 Journal of Medicinal Chemistry (2009), 52(4), 1126-1143.

Third-Generation Immucillins: Syntheses and Bioactivities of Acyclic Immucillin Inhibitors of Human Purine Nucleoside Phosphorylase

References

External links

• “From cell biology to therapy: forodesine”. Hematology Meeting Reports. 2 (5): 106–111. 2008.
• Gore, L; Stelljes, M; Quinones, R (2007). “Forodesine treatment and post-transplant graft-versus-host disease in two patients with acute leukemia: Facilitation of graft-versus-leukemia effect?”. Seminars in Oncology. 34 (6 Suppl 5): S35–9. doi:10.1053/j.seminoncol.2007.11.005. PMID 18086346.
• 18 December 2006 Fodosine orphan designation by the European Commission for acute lymphoblastic leukaemia.
• BioCryst Pharmaceuticals, Inc. have entered into an exclusive license agreement with Mundipharma for develop and commercialize BioCryst’s lead compound, Forodesine.
• Birmingham, Alabama – February 2, 2006 Mundipharma will obtain rights in markets across Europe, Asia and Australasia to Forodesine™ in the field of oncology in exchange for a $10 million up-front payment. Furthermore, Mundipharma will commit up to an additional $15 million to assist in the evaluation of Forodesine’s™ therapeutic safety and efficacy profile. BioCryst may also receive future event payments totalling $155 million in addition to royalties on product sales of Forodesine™ by Mundipharma.
• News BioCryst provides Fodosine update March 27, 2007. “Voluntarily Placed on Hold by BioCryst (…) we don’t think the final response rate will be as high as 18%”.
• The European Commission granted a marketing authorisation valid throughout the European Union for Atriance on 22 August 2007 for acute lymphoblastic leukaemia. What benefit has Atriance shown during the studies? Atriance was shown to be effective in a proportion of the patients in both studies. In the first study, among the 39 children and young adults who se cancer had not responded to two or more previous treatments, five (13%) had a complete response to treatment after a month, with no evidence of disease and normal blood counts. In the second study, among the 28 adults and adolescents with cancer that had not responded to two or more previous tre atments, five (18%) had a complete response to treatment. In both studies, more patients had a partial response to Atriance treatment, with blood counts returning towards normal levels.
• Lino Berton collects all the information on Forodesine in www.linoberton.com site, putting them in a row. In 2014 he published the book Qualcosa che non muore where he tells his incredible experience in the closed trial early in 2007.
• Il Giornale.it (in Italian). “Come si boicotta un farmaco che funziona”. Dated 08-01-2016.

Forodesine

Clinical data
Trade names	Mundesine and Fodosine
Routes of administration	oral
Identifiers
IUPAC name[show]
CAS Number	209799-67-7
PubChem CID	444499
ChemSpider	392417
UNII	426X066ELK
KEGG	D06596
ChEMBL	CHEMBL218291
Chemical and physical data
Formula	C11H14N4O4
Molar mass	266.26 g·mol−1
3D model (JSmol)	Interactive image

/////////Forodesine Hydrochloride, Forodesine, BCX 1777, Immucillin-H, FOSODINE, JAPAN 2017

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PADELIPORFIN

759457-82-4; 457P824,

RN: 759457-82-4
UNII: EEO29FZT86

3-[(2S,3S,12R,13R)-8-acetyl-13-ethyl-20-(2-methoxy-2-oxoethyl)-3,7,12,17-tetramethyl-18-(2-sulfoethylcarbamoyl)-2,3,12,13-tetrahydroporphyrin-22,24-diid-2-yl]propanoic acid;palladium(2+)

 (SP-4-2)-[(7S,8S,17R,18R)-13-acetyl-18-ethyl-5-(2-methoxy-2-oxoethyl)-2,8,12,17-tetramethyl-3-[[(2-sulfoethyl)amino]carbonyl]-21H,23H-porphine-7-propanoato (4-)-kN21,kN22,kN23,kN24] palladate(2-)

Chemical Formula: C37H41K2N5O9PdS
Molecular Weight: 916.43

cas 698393-30-5

WST11; WST-11; WST 11; Stakel; padeliporfin; palladiumbacteriopheophorbide monolysine taurine.

Palladate(2-​)​, [(7S,​8S,​17R,​18R)​-​13-​acetyl-​18-​ethyl-​7,​8-​dihydro-​5-​(2-​methoxy-​2-​oxoethyl)​-​2,​8,​12,​17-​tetramethyl-​3-​[[(2-​sulfoethyl)​amino]​carbonyl]​-​21H,​23H-​porphine-​7-​propanoato(4-​)​-​κN²¹,​κN²²,​κN²³,​κN²⁴]​-​, potassium (1:2)​, (SP-​4-​2)​-

Tookad : EPAR -Product Information

Product details

Pharmacotherapeutic group

Antineoplastic agents

Therapeutic indication

Tookad is indicated as monotherapy for adult patients with previously untreated, unilateral, low risk, adenocarcinoma of the prostate with a life expectancy ≥ 10 years and:

• Clinical stage T1c or T2a;
• Gleason Score ≤ 6, based on high-resolution biopsy strategies;
• PSA ≤ 10 ng/mL;
• 3 positive cancer cores with a maximum cancer core length of 5 mm in any one core or 1-2 positive cancer cores with ≥ 50 % cancer involvement in any one core or a PSA density ≥ 0.15 ng/mL/cm³.

Photodynamic therapy (PDT) is a non-surgical treatment of tumors in which non-toxic drugs and non-hazardous photosensitizing irradiation are combined to generate cytotoxic reactive oxygen species in situ. This technique is more selective than the commonly used tumor chemotherapy and radiotherapy. To date, porphyrins have been employed as the primary photosensitizing agents in clinics. However, current sensitizers suffer from several deficiencies that limit their application, including mainly: (1) relatively weak absorption in the visible spectral range which limits the treatment to shallow tumors; (2) accumulation and long retention of the sensitizer in the patient skin, leading to prolonged (days to months) skin phototoxicity; and (3) small or even no differentiation between the PDT effect on illuminated tumor and non-tumor tissues. The drawbacks of current drugs inspired an extensive search for long wavelength absorbing second-generation sensitizers that exhibit better differentiation between their retention in tumor cells and skin or other normal tissues.

In order to optimize the performance of the porphyrin drugs in therapeutics and diagnostics, several porphyrin derivatives have been proposed in which, for example, there is a central metal atom (other than Mg) complexed to the four pyrrole rings, and/or the peripheral substituents of the pyrrole rings are modified and/or the macrocycle is dihydrogenated to chlorophyll derivatives (chlorins) or tetrahydrogenated to bacteriochlorophyll derivatives (bacteriochlorins).

Due to their intense absorption in favorable spectral regions (650-850 nm) and their ready degradation after treatment, chlorophyll and bacteriochlorophyll derivatives have been identified as excellent sensitizers for PDT of tumors and to have superior properties in comparison to porphyrins, but they are less readily available and more difficult to handle.

Bacteriochlorophylls are of potential advantage compared to the chlorophylls because they show intense near-infrared bands, i.e. at considerably longer wavelengths than chlorophyll derivatives.

The spectra, photophysics, and photochemistry of native bacteriochlorophylls (Bchls) have made them optimal light-harvesting molecules with clear advantages over other sensitizers presently used in PDT. In particular, these molecules have a very high extinction coefficient at long wavelengths (λ_max=760-780 nm, ε=(4-10)xl0⁴ M^-1cm^-1), where light penetrates deeply into tissues. They also generate reactive oxygen species (ROS) at a high quantum yield (depending on the central metal).

Under normal delivery conditions, i.e. in the presence of oxygen at room temperature and under normal light conditions, the BChl moieties are labile and have somewhat lower quantum yields for triplet state formation, when compared with, e.g., hematoporphyrin derivative (HPD). However, their possible initiation of biological redox reactions, favorable spectral characteristics and their ready degradation in vivo result in the potential superiority of bacteriochlorophylls over other compounds, e.g. porphyrins and chlorophylls, for PDT therapy and diagnostics and for killing of cells, viruses and bacteria in samples and in living tissue. Chemical modification of bacteriochlorophylls is expected to further improve their properties, but this has been very limited due to lack of suitable methods for the preparation of such modified bacteriochlorophylls .

The biological uptake and PDT efficacy of metal-free derivatives of Bchl have been studied with the objective to manipulate the affinity of the sensitizers to the tumor cellular compartment. Cardinal to this approach is the use of highly lipophilic drugs that may increase the accumulation of the drug in the tumor cells, but also renders its delivery difficult. In addition, the reported biodistribution shows significant phototoxic drug levels in non-tumor tissues over prolonged periods (at least days) after administering the drug.

In applicant’s previous Israel Patent No. 102645 and corresponding EP 0584552, US 5,726,169, US 5,726,169, US 5,955,585 and US 6,147,195, a different approach was taken by the inventors. Highly efficient anti- vascular sensitizers that do not extravasate from the circulation after administration and have short lifetime in the blood were studied. It was expected that the inherent difference between vessels of normal and abnormal tissues such as tumors or other tissues that rely on neovessels, would enable relatively selective destruction of the abnormal tissue. Hence, it was aimed to synthesize Bchl derivatives that are more polar and, hence, have better chance to stay in the vascular compartment, where they convey the primary photodynamic effect. To this end, the geranylgeranyl residue at the C-17 position of Bchl a (Compound 1, depicted in Scheme 1 herein) has been replaced by various residues such as amino acids, peptides, or proteins, which enhance the sensitizer hydrophilicity. One particular derivative, Bchl-Ser (Scheme 1, Compound 1, wherein R is seryl), was found to be water-soluble and highly phototoxic in cell cultures. Following infraperitoneal injection, the Bchl-Ser cleared from the mouse blood and tissues bi-exponentially in a relatively short time (t_1/2~2 and 16 h, respectively). Clearance from the circulation was even faster following intravenous injection. Under the selected treatment protocol (light application within minutes after drug injection), phototoxicity was predominantly conferred to the tumor vasculature (Rosenbach-

Belkin et al., 1996; Zilberstein et al., 2001 and 1997). However, unfortunately, like native Bchl, the Bchl-Ser derivative undergoes rapid photo-oxidation, forming the corresponding 2-desvinyl-2-acetyl-chlorophyllide ester and other products.

To increase the stability of the Bchl derivatives, the central Mg atom was replaced by Pd in the later applicant’s PCT Publication WO 00/33833 and US 6,569,846. This heavy atom was previously shown to markedly increase the oxidation potential of the Bchl macrocycle and, at the same time, to greatly enhance the intersystem-crossing (ISC) rate of the molecule to its triplet state. The metal replacement was performed by direct incorporation of Pd²⁺ ion into a Bpheid molecule, as described in WO 00/33833. Based on the pigment biodistribution and pharmacokinetics, it was assumed that the derivative Pd-Bpheid remained in the circulation for a very short time with practically no extravasation to other tissues, and is therefore a good candidate for vascular-targeting PDT that avoids skin phototoxicity. The treatment effect on the blood vessels was demonstrated by intravital microscopy of treated blood vessels and staining with Evans-Blue. Using a treatment protocol with a minimal drug-to-light interval, Pd-Bpheid (also designated Tookad) was found to be effective in the eradication of different tumors in mice, rats and other animal models and is presently entering Phase I/II clinical trials in patients with prostate cancer that failed radiation therapy (Chen et al, 2002; Schreiber et al., 2002; Koudinova et al., 2003).

Because of its low solubility in aqueous solutions, the clinical use of Pd-Bpheid requires the use of solubilizing agents such as Cremophor that may cause side effects at high doses. It would be highly desirable to render the Pd-Bpheid water-soluble while retaining its physico-chemical properties. Alternatively, it would be desirable to prepare Bchl derivatives that are cytophototoxic and, at the same time, more water-soluble than Pd-Bpheid itself. Such water solubility is expected to further enhance the drug retention in the circulation and, thereby, the aforementioned selectivity. In addition, having no need to use carriers such as detergents or lyposomes, may prevent side effects.

SYNTHESIS

START FROM CAS 17499-98-8, Phorbine, magnesium deriv., Bacteriochlorophyll a_P

PADELIPORFIN

Paper

Novel water-soluble bacteriochlorophyll derivatives for vascular-targeted photodynamic therapy: Synthesis, solubility, phototoxicity and the effect of serum proteins
Photochemistry and Photobiology (2005), 81, (July/Aug.), 983-993

PAPER

Journal of Medicinal Chemistry (2014), 57(1), 223-237

With the knowledge that the dominant photodynamic therapy (PDT) mechanism of 1a (WST09) switched from type 2 to type 1 for 1b (WST11) upon taurine-driven E-ring opening, we hypothesized that taurine-driven E-ring opening of bacteriochlorophyll derivatives and net-charge variations would modulate reactive oxygen species (ROS) photogeneration. Eight bacteriochlorophyll a derivatives were synthesized with varying charges that either contained the E ring (2a–5a) or were synthesized by taurine-driven E-ring opening (2b–5b). Time-dependent density functional theory (TDDFT) modeling showed that all derivatives would be type 2 PDT-active, and ROS-activated fluorescent probes were used to investigate the photogeneration of a combination of type 1 and type 2 PDT ROS in organic- and aqueous-based solutions. These investigations validated our predictive modeling calculations and showed that taurine-driven E-ring opening and increasing negative charge generally enhanced ROS photogeneration in aqueous solutions. We propose that these structure–activity relationships may provide simple strategies for designing bacteriochlorins that efficiently generate ROS upon photoirradiation.

Modulation of Reactive Oxygen Species Photogeneration of Bacteriopheophorbide a Derivatives by Exocyclic E-Ring Opening and Charge Modifications

REFERENCES

1: Kessel D, Price M. Evaluation of DADB as a Probe for Singlet Oxygen Formation during Photodynamic Therapy. Photochem Photobiol. 2012 Feb 2. doi: 10.1111/j.1751-1097.2012.01106.x. [Epub ahead of print] PubMed PMID: 22296586.

2: Betrouni N, Lopes R, Puech P, Colin P, Mordon S. A model to estimate the outcome of prostate cancer photodynamic therapy with TOOKAD Soluble WST11. Phys Med Biol. 2011 Aug 7;56(15):4771-83. Epub 2011 Jul 13. PubMed PMID: 21753234.

3: Chevalier S, Anidjar M, Scarlata E, Hamel L, Scherz A, Ficheux H, Borenstein N, Fiette L, Elhilali M. Preclinical study of the novel vascular occluding agent, WST11, for photodynamic therapy of the canine prostate. J Urol. 2011 Jul;186(1):302-9. Epub 2011 May 20. PubMed PMID: 21600602.

4: Dandler J, Wilhelm B, Scheer H. Photochemistry of bacteriochlorophylls in human blood plasma: 1. Pigment stability and light-induced modifications of lipoproteins. Photochem Photobiol. 2010 Mar-Apr;86(2):331-41. Epub 2009 Nov 23. PubMed PMID: 19947966.

5: Dandler J, Scheer H. Inhibition of aggregation of [Pd]-bacteriochlorophyllides in mesoporous silica. Langmuir. 2009 Oct 20;25(20):11988-92. PubMed PMID: 19772311.

6: Ashur I, Goldschmidt R, Pinkas I, Salomon Y, Szewczyk G, Sarna T, Scherz A. Photocatalytic generation of oxygen radicals by the water-soluble bacteriochlorophyll derivative WST11, noncovalently bound to serum albumin. J Phys Chem A. 2009 Jul 16;113(28):8027-37. PubMed PMID: 19545111.

7: Moore CM, Pendse D, Emberton M. Photodynamic therapy for prostate cancer–a review of current status and future promise. Nat Clin Pract Urol. 2009 Jan;6(1):18-30. Review. PubMed PMID: 19132003.

8: Preise D, Oren R, Glinert I, Kalchenko V, Jung S, Scherz A, Salomon Y. Systemic antitumor protection by vascular-targeted photodynamic therapy involves cellular and humoral immunity. Cancer Immunol Immunother. 2009 Jan;58(1):71-84. Epub 2008 May 17. PubMed PMID: 18488222.

9: Fleshker S, Preise D, Kalchenko V, Scherz A, Salomon Y. Prompt assessment of WST11-VTP outcome using luciferase transfected tumors enables second treatment and increase in overall therapeutic rate. Photochem Photobiol. 2008 Sep-Oct;84(5):1231-7. Epub 2008 Apr 8. PubMed PMID: 18399928.

10: Berdugo M, Bejjani RA, Valamanesh F, Savoldelli M, Jeanny JC, Blanc D, Ficheux H, Scherz A, Salomon Y, BenEzra D, Behar-Cohen F. Evaluation of the new photosensitizer Stakel (WST-11) for photodynamic choroidal vessel occlusion in rabbit and rat eyes. Invest Ophthalmol Vis Sci. 2008 Apr;49(4):1633-44. PubMed PMID: 18385085.

11: Fabre MA, Fuseau E, Ficheux H. Selection of dosing regimen with WST11 by Monte Carlo simulations, using PK data collected after single IV administration in healthy subjects and population PK modeling. J Pharm Sci. 2007 Dec;96(12):3444-56. PubMed PMID: 17854075.

12: Brandis A, Mazor O, Neumark E, Rosenbach-Belkin V, Salomon Y, Scherz A. Novel water-soluble bacteriochlorophyll derivatives for vascular-targeted photodynamic therapy: synthesis, solubility, phototoxicity and the effect of serum proteins. Photochem Photobiol. 2005 Jul-Aug;81(4):983-93. PubMed PMID: 15839743.

13: Mazor O, Brandis A, Plaks V, Neumark E, Rosenbach-Belkin V, Salomon Y, Scherz A. WST11, a novel water-soluble bacteriochlorophyll derivative; cellular uptake, pharmacokinetics, biodistribution and vascular-targeted photodynamic activity using melanoma tumors as a model. Photochem Photobiol. 2005 Mar-Apr;81(2):342-51. PubMed PMID: 15623318.

14: Plaks V, Posen Y, Mazor O, Brandis A, Scherz A, Salomon Y. Homologous adaptation to oxidative stress induced by the photosensitized Pd-bacteriochlorophyll derivative (WST11) in cultured endothelial cells. J Biol Chem. 2004 Oct 29;279(44):45713-20. Epub 2004 Aug 31. PubMed PMID: 15339936.

////////PADELIPORFIN,  WST11, WST-11, WST 11, Stakel, padeliporfin, palladiumbacteriopheophorbide monolysine taurine, EU 2017, EMA 2017

CCC1C(C2=NC1=CC3=C(C(=C([N-]3)C(=C4C(C(C(=N4)C=C5C(=C(C(=C2)[N-]5)C(=O)C)C)C)CCC(=O)O)CC(=O)OC)C(=O)NCCS(=O)(=O)O)C)C.[Pd+2]

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DAROLUTAMIDE, WO 2018036558, 苏州科睿思制药有限公司 , New patent

CRYSTAL FORM OF ANDROGEN RECEPTOR ANTAGONIST MEDICATION, PREPARATION METHOD THEREFOR, AND USE

一种式(I)所示ODM-201的晶型B，其特征在于，其X射线粉末衍射在衍射角2θ为16.2°±0.2°、9.0°±0.2°、22.5°±0.2°处有特征峰。

Novel crystalline forms of an androgen receptor antagonist medication, particularly ODM-201 (also known as darolutamide; designated as Forms B and C), processes for their preparation and compositions comprising them are claimed. Represents a first filing from Crystal Pharmaceutical Co Ltd and the inventors on this API.

Orion and licensee Bayer are codeveloping darolutamide, an androgen receptor antagonist, for treating castration-resistant prostate cancer and metastatic hormone-sensitive prostate cancer.

专利CN102596910B公开了ODM-201的制备方法，但并未公开任何的晶型信息。专利WO2016120530A1公开了式(I)(CAS号：1297538-32-9)所示的晶型I，式(Ia)(CAS号：1976022-48-6)所示的晶型I’和式(Ib)(CAS号：1976022-49-7)所示的晶型I”。文献Expert Rev.Anticancer Ther.15(9),(2015)已报道：ODM-201是由1:1比例的(Ia)和(Ib)两种非对应异构体组成，即为式(I)所示结构。因此，现有关于ODM-201的晶型只有晶型I报道。

Prostate cancer has become an important disease threatening the health of men. Its incidence is higher in western countries and shows a year-by-year upward trend. In the past, Asian countries with a lower incidence of the disease have also seen an increase in the number of patients in recent years. Clinical treatment of prostate cancer commonly used methods are surgical resection, radiation therapy and blocking androgen endocrine therapy. Androgen is closely related to the growth of prostate and the occurrence of prostate cancer. Therefore, endocrine therapy has become an effective way to treat prostate cancer. The method includes orchidectomy, estrogen therapy, gonadotropin-releasing hormone analog therapy, gonadotropin-releasing hormone antagonist therapy, androgen antagonistic therapy, etc., wherein androgen antagonist therapy can be both early treatment of prostate cancer can also be combined Surgery for adjuvant therapy is currently one of the main clinical treatment of prostate cancer. Androgen receptor as a biological target of androgen play an important role in the field of biomedical research.

Clinical trials have shown that exogenous androgen administration to patients with prostate cancer can lead to an exacerbation of the patient’s condition; conversely, if the testicles are removed and the level of androgens in the patient is reduced, the condition is relieved, indicating that androgens contribute to the development of prostate cancer Significant influence. According to receptor theory, androgen must bind with androgen receptor (AR) to cause subsequent physiological and pathological effects, which is the basis for the application of androgen receptor (AR) antagonist in the treatment of prostate cancer. In vitro experiments have shown that AR antagonists can inhibit prostate cell proliferation and promote apoptosis. Depending on the chemical structure of AR antagonists, they can be divided into steroidal AR antagonists and non-steroidal AR antagonists. Non-steroidal anti-androgen activity is better, there is no steroid-like hormone-like side effects, it is more suitable for the treatment of prostate cancer.

ODM-201 (BAY-1841788) is a non-steroidal oral androgen receptor (AR) antagonist used clinically to treat prostate cancer. The binding affinity of ODM-201 to AR was high, with Ki = 11nM and IC50 = 26nM. Ki was the dissociation constant between ODM-201 and AR complex. The smaller the value, the stronger the affinity. half maximal inhibitory concentration “refers to the half-inhibitory concentration measured, indicating that a certain drug or substance (inhibitor) inhibits half the amount of certain biological processes. The lower the value, the stronger the drug’s inhibitory ability. In addition, ODM-201 does not cross the blood-brain barrier and can reduce neurological related side effects such as epilepsy. Bayer Corporation has demonstrated in clinical trials the effectiveness and safety of ODM-201, demonstrating its potential for treating prostate cancer.

The chemical name of ODM-201 is: N – ((S) -l- (3- (3- chloro-4-cyanophenyl) -lH-pyrazol-l-yl) -propan- The chemical name contains the tautomer N – ((S) -1- (3- (3- 4-cyanophenyl) -1H-pyrazol- 1 -yl) -propan-2-yl) -5- (1 -hydroxyethyl) 1297538-32-9, the structural formula is shown in formula (I) :

The different crystalline forms of solid chemical drugs can lead to differences in their solubility, stability, fluidity and compressibility, thereby affecting the safety and efficacy of pharmaceutical products containing the compounds (see K. Knapman, Modern Drug Discovery, 3, 53 -54,57,2000.), Resulting in differences in clinical efficacy. It has been found that new crystalline forms (including anhydrates, hydrates, solvates, etc.) of the active ingredients of the medicinal product may give rise to more processing advantages or provide substances with better physical and chemical properties such as better bioavailability, storage stability, ease Processed, purified or used as an intermediate to promote conversion to other crystalline forms. The new crystalline form of the pharmaceutical compound can help improve the performance of the drug and broaden the choice of starting material for the formulation.

Patent CN102596910B discloses the preparation of ODM-201, but does not disclose any crystal form information. Patent WO2016120530A1 discloses a crystalline form I represented by the formula (I) (CAS number: 1297538-32-9), a crystalline form I ‘represented by the formula (Ia) (CAS number: 1976022-48-6) and a compound represented by the formula (CAS No. 1976022-49-7). Document Expert Rev. Anticancer Ther. 15 (9), (2015) It has been reported that ODM-201 is composed of a 1: 1 ratio of (Ia) And (Ib), which is the structure shown in Formula (I), so the only existing crystal form I for ODM-201 is reported.

However, the lower solubility of Form I and the high hygroscopicity, and the preparation of Form I requires the use of highly toxic acetonitrile solvents, which are carcinogenic in animals and are the second class of solvents that should be controlled during the process development stage. Form I preparation method is more complex, long preparation cycle, the process needs heating, increasing the cost of industrial preparation, is not conducive to industrial production. In order to overcome the above drawbacks, there is still a need in the art for a systematic and comprehensive development of other polymorphs of ODM-201 of formula (I), simplifying the preparation thereof, enabling its pharmacological development and releasing its potential, Preparation of a better formulation of the drug ingredients.

The inventors found through experiments that Form B and Form C of the present invention, and found that Form B and Form C of the present invention have more excellent properties than the prior art. Dissolution is a prerequisite for drug absorption, and increased solubility will help to increase the bioavailability of the drug and thereby improve the drug’s druggability. Compared with the prior art, the crystalline forms B and C of the invention have higher solubility and provide favorable conditions for drug development. Compared with the prior art, the crystalline forms B and C of the invention also have lower hygroscopicity. Hydroscopic drug crystal form due to adsorption of more water lead to weight changes, so that the raw material crystal component content is not easy to determine. In addition, the crystalline form of the drug substance absorbs water and lumps due to high hygroscopicity, which affects the particle size distribution of the sample in the formulation process and the homogeneity of the drug substance in the preparation, thereby affecting the dissolution and bioavailability of the sample. The crystal form B and the crystal form C have the same moisture content under different humidity conditions, and overcome the disadvantages caused by high hygroscopicity, which is more conducive to the long-term storage of the medicine, reduces the material storage and the quality control cost.

In addition, the present invention provides Form B and Form C of ODM-201 represented by formula (I), which have good stability, excellent flowability, suitable particle size and uniform distribution. The solvent used in the preparation method of crystal form B and crystal form C of the invention has lower toxicity, is conducive to the green industrial production, avoids the pharmaceutical risk brought by the residue of the toxic solvent, and is more conducive to the preparation of the pharmaceutical preparation. The novel crystal type provided by the invention has the advantages of simple operation, no need of heating, short preparation period and cost control in industrialized production. Form B and Form C of the present invention provide new and better choices for the preparation of pharmaceutical formulations containing ODM-201, which are of great significance for drug development.

The problem to be solved by the invention

The main object of the present invention is to provide a crystal form of ODM-201 and a preparation method and use thereof.

//////////DAROLUTAMIDE, WO 2018036558, 苏州科睿思制药有限公司 , New patent, CRYSTAL

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SOFOSBUVIR, NEW PATENT, WO 2018032356, Pharmaresources (Shanghai) Co Ltd

WO-2018032356, Pharmaresources (Shanghai) Co Ltd

CHEN, Ping; (CN).
PENG, Shaoping; (CN).
LI, Yinqiang; (CN).
LI, Dafeng; (CN).
DONG, Xuejun; (CN)

Process for the preparation of lactone derivatives and their intermediates are important precursors for the synthesis of anti-hepatitis C virus agents, including sofosbuvir . Represents a first filing from Pharmaresources (Shanghai) Co Ltd and the inventors on this API. Gilead Sciences , following its acquisition of Pharmasset , has developed and launched sofosbuvir, a pure chiral isomer of PSI-7851, a next-generation HCV uracil nucleotide analog polymerase inhibitor prodrug for once-daily oral use.

Scheme 1

In a similar process reported in CN105418547A (Scheme 2) , the Witting product was epoxidized followed by ring-opening fluorolation by HF-Et₃N or other fluoro-containing reagents, significant amount of regioisomer was observed which was difficult to remove from the oily mixture.

Scheme 4

Examples

Example 1： preparation of 2-fluoropropanoyl chloride (3)

 

 

Chlorosulfonic acid (660 mL, 10 mol, 20 eq) was added to a solution of phthaloyl dichloride (1.4 L, 10 mol, 20 eq) and ethyl-2-fluoropropanoate (600 g, 5 mol) at room temperature. The solution was heated at 120 ℃ for 4 hs. 2- (R) -fluoropropanoyl chloride was distilled from the reaction mixture under reduced pressure and recovered as a colourless oil (320 g, 58.2％) . ¹H-NMR (CDCl₃， 400 MHz) ： δ 5.08 (dq, J ＝ 48.8, 6.8 Hz, 1 H) , 1.63 (dd, J ＝22.8, 6.8 Hz, 3 H) .

Example 2： preparation of (4R) -3- (2-fluoropropanoyl) -4-isopropyloxazolidin-2-one (4)

 

 

n-Butyl lithium (2.5 M in hexane, 30 mL, 75 mmol, 1.1 eq) was added to a solution of 4-(R) -4-isopropyl-2-oxazolidinone (8.8 g, 68.2 mmol, 1 eq) in dry THF (80 mL) at -50 ℃ under N₂ atomosphere. After 30 min, 2-fuoropropanoyl chloride (6.8 mL, 0.9 eq) was added, and the solution was stirred for 4 hs at -50 ℃. The reaction was then quenched with a saturated solution of NH₄Cl (50 mL) , extracted with MTBE (80 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure. The product was purified over silica (Hexane/EtOAc＝ 10/1) and recovered as a brown oil (9 g, 74.8％) . ¹H-NMR (CDCl₃, 400 MHz) : δ 6.00 (dm, J ＝ 49.2Hz, 1 H) , 4.27 -4.53 (m, 3 H) , 2.43 (dm, J ＝ 52.6 Hz, 1 H) , 1.63 (td, J ＝ 23.2Hz, 3 H) , 0.92 (dq, J ＝ 17.8 Hz, 6 H) .

[0206]

Example 3： preparation of (4S) -3- (2-fluoropropanoyl) -4-isopropyloxazolidin-2-one (5)

[0207]

 

n-Butyl lithium (2.5 M in hexane, 75 mL, 187 mmol, 1.1eq) was added to a solution of 4- (S) -4-isopropyl-2-oxazolidinone (22 g, 170 mmol, 1 eq) in dry THF (200 mL) at -50 ℃ under N₂ atomosphere. After 30 min 2-fuoropropanoyl chloride (17 mL, 153 mmol, 0.9 eq) was added, and the solution was stirred for 1 h at -50 ℃. After the starting material was completely consumed, the reaction was then quenched with a saturated solution of NH₄Cl (125 mL) , extracted with MTBE (200 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure. The product was purified over silica (hexane/EtOAc＝ 10/1) and recovered as a brown oil (34 g, 83.3％) . ¹H-NMR (CDCl₃, 400 MHz) : δ 5.93 (dm， J ＝ 48.8 Hz, 1 H) , 4.19 -4.17 (m, 3H) , 2.35 (dm, J ＝ 52.8 Hz , 1 H) , 1.55 (td, J ＝ 23.6 Hz, 3 H) , 0.85 (dq, J ＝ 18 Hz, 6 H) .

 

Example 4： preparation of (4R) -3- (2-fluoropropanoyl) -4-phenyloxazolidin-2-one (6)

 

 

n-Butyl lithium (2.5 M in hexane, 13.5 mL, 33.74 mmol, 1.1 eq) was added to a solution of (R) -4-phenyloxazolidin-2-one (5 g, 30.67 mmol, 1 eq) in dry THF (75 mL) at -50 ℃ under N₂ atomosphere. After 30 minutes, 2-fuoropropanoyl chloride (3.75 g, 33.74 mmol) was added, and the solution was stirred for 1 h at -50 ℃ to -60 ℃. The reaction was then quenched with a saturated solution of NH₄Cl, extracted with EtOAc, washed with NaHCO₃(sat) , brine and dried over MgSO₄. Solvents were removed under reduced pressure. The product was purified over silica (hexane /EtOAc) and recovered as a brown oil (4 g, 55％) . ¹H-NMR (CDCl₃, 400 MHz) : δ 7.35-7.21 (m, 5 H) , 5.99-5.84 (md, 1 H) , 5.42-5.33 (dd, 1 H) , 4.72 (dd, 1 H) , 4.31 (m, 1 H) , 1.50 (m, 3 H) .

 

Example 5： preparation of (4s) -3- (2-fluoropropanoyl) -4-phenyloxazolidin-2-one (7)

 

 

n-Butyl lithium (2.5 M in hexane, 67.5 mL, 169 mmol, 1.1 eq) was added to a solution of (s) -4-phenyloxazolidin-2-one (25 g, 153 mmol, 1 eq) in dry THF (375 mL) at -60 ℃ under N₂ atomosphere. After 30 min, 2-fuoropropanoyl chloride (18.7 g, 169 mmol) was added, and the solution was stirred for 1h at -50 ℃ to -60 ℃. The reaction was then quenched with a saturated solution of NH₄Cl, extracted with EtOAc, washed with NaHCO₃ (sat) , brine and dried over MgSO₄. Solvents were removed under reduced pressure. The product was purified over silica (hexane /EtOAc) and recovered as a brown oil (16.5 g, 45.4％) . ¹H-NMR (CDCl₃, 400 MHz) : δ 7.36-7.20 (m, 5 H) , 5.95-5.80 (md, 1 H) , 5.42-5.30 (dd, 1 H) , 4.71 (dd, 1 H) , 4.30 (m, 1 H) , 1.51 (m, 3 H) .

 

Example 6： preparation of (4S) -4-benzyl-3- (2-fluoropropanoyl) oxazolidin-2-one (8)

 

 

n-Butyl lithium (2.5 M in hexane, 54.7 mL, 137 mmol, 1.1eq) was added to a solution of (S) -4-benzyloxazolidin-2-one (22 g, 124 mmol, 1eq) in dry THF (220 mL) at -60 ℃ under N₂ atomosphere. After stirring 30 min at -60 ℃, 2-fuoropropanoyl chloride (15.2 g, 137 mmol) was added dropwisely below -50 ℃ , after adding the solution was stirred for 1h at -50 ℃ to -60 ℃. The reaction was then quenched with a saturated solution of NH₄Cl, extracted with EtOAc, washed with NaHCO₃ (sat) , brine and dried over MgSO₄. Solvents were removed under reduced pressure. The product was purified over silica (hexane/EtOAc) and recovered as a brown oil (25.8 g, 82.7％) . ¹H-NMR(400 MHz, CDCl₃ ) ： δ 7.29-7.13 (m, 5 H) , 6.01-5.81 (qd, 1 H) , 4.71-4.58 (md, 1 H) , 4.29-4.04 (m, 2 H) , 3.32-3.16 (dd, 1 H) , 2.79-2.74 (m, 1 H) , 1.51 (m, 3 H) .

 

Example 7： preparation of (4R) -4-benzyl-3- (2-fluoropropanoyl) oxazolidin-2-one (9)

 

 

Use the procedure described in Example 6, (R) -4-benzyloxazolidin-2-one as the start material to give the desired compound (4R) -4-benzyl-3- (2-fluoropropanoyl) oxazolidin-2-one (yield: 85％) . ¹H-NMR (400 MHz, CDCl₃ ) ： δ 7.27 -7.12 (m, 5 H) , 6.00-5.83 (qd, 1 H) , 4.72-4.55 (md, 1 H) , 4.27-4.03 (m, 2 H) , 3.32 -3.16 (dd, 1 H) , 2.79 -2.72 (m, 1 H) , 1.53 (m, 3 H) .

[0221]

Example 8： preparation of (4R) -3- (2-fluoropropanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (10)

[0222]

[0223]

n-Butyl lithium (2.5 M in hexane, 48 mL) was added to a solution of (R) -4-isopropyl-5,5-diphenyloxazolidin-2-one (28.1 g) in dry THF (150 mL) at -65 ℃ under N₂ atomosphere. After stirring 30 min at -60 ℃, 2-fuoropropanoyl chloride (16.4 g, 1.5 eq) was added dropwisely below -60 ℃. After adding the solution was stirred for 2 h at -60 ℃. The reaction was then quenched with a saturated solution of NH₄Cl, extracted with EtOAc, washed with NaHCO₃ (sat) , brine and dried over MgSO₄. Solvents were removed under reduced pressure. The crude product was recrystalized in (DCM/PE) to give (4R) -3- (2-fluoropropanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (30 g, 85％) . ¹H-NMR (CDCl₃, 400 MHz) : δ 7.50 -7.26 (m, 10 H) , 5.89 (ddq, J ＝ 64.4, 49.3, 6.6 Hz, 1 H) , 5.37 (dd, J ＝ 70.8, 3.4 Hz, 1 H) , 2.00 (dd, J ＝ 7.3, 3.3 Hz, 1 H) , 1.70 (dd, J ＝ 23.4, 6.7 Hz, 1.5 H) , 1.12 (dd, J ＝ 23.8, 6.6 Hz, 1.5 H) , 0.83 (ddd, J ＝ 28.0, 16.7, 6.9 Hz, 6 H) .

[0224]

Example 9： preparation of (4S) -3- (2-fluoropropanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11)

[0225]

[0226]

Use the procedure described in Example 8 and (S) -4-isopropyl-5, 5-diphenyloxazolidin-2-one as the start material to give the desired compound (4S) -3- (2-fluoropropanoyl) -4-isopropyl- 5,5-diphenyl oxazolidin-2-one (yield: 82％) . ¹H-NMR (CDCl₃, 400 MHz) : δ 7.51 -7.27 (m, 10 H) , 5.90 (ddq, J ＝ 64.4, 49.3, 6.6 Hz, 1 H) , 5.38 (dd, J ＝ 70.8, 3.4 Hz, 1H) , 2.01 (dd, J ＝ 7.3, 3.3 Hz, 1 H) , 1.71 (dd, J ＝ 23.4, 6.7 Hz, 1.5 H) , 1.13 (dd, J ＝ 23.8, 6.6 Hz, 1.5 H) , 0.84 (ddd, J ＝ 28.0, 16.7, 6.9 Hz, 6 H) .

[0227]

Example 10： preparation of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12)

[0228]

[0229]

Method A: TiCl₄ (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4R) -3- (2-fluoropropanoy l ) -4-isopropyloxazolidin-2-one (4) (10 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N₂ atomosphere. After 10 min, diisopropylethyl amine (10.3 mL, 1.26 eq) was added and the solution was stirred for 2 hs at-78 ℃, then the second batch of TiCl₄ (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added. After 10 min, acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (10.2 g, yield: 80％, purity: 97.2％) . ¹H-NMR (400 MHz, CDCl₃) ： δ 5.89 (dddd, J ＝ 17.1, 10.5, 6.5, 0.8 Hz, 1 H) , 5.42 (d, J ＝17.2 Hz, 1 H) , 5.30 (d, J ＝ 10.1 Hz, 1 H) , 4.68 (dd, J ＝ 14.8, 6.5 Hz, 1 H) , 4.44 (d, J ＝ 4.0 Hz, 1 H) , 4.32 (t, J ＝ 8.5 Hz, 1 H) , 4.24 (dd, J ＝ 9.1, 3.4 Hz, 1 H) , 3.61 (d, J ＝ 6.5 Hz, 1 H) , 2.37 (dd, J ＝ 7.0, 4.1 Hz, 1 H) , 1.73 (s, 1.5 H) , 1.67 (s, 1.5 H) , 0.92 (ddd, J ＝ 7.8, 5.6, 2.4 Hz, 6 H) ； ¹⁹F-NMR (400 MHz, CDCl₃) : -158.3 ppm.

[0230]

Method B: TiCl₄ (1 M in DCM, 50 mL, 50mmol, 1.1 eq) was added to a solution of (4R) -3- (2-fluoropropanoy l ) -4-isopropyloxazolidin-2-one (10 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N₂ atomosphere. After 10 min, (-) -spartein (14.5 g, 1.26 eq) was added and the solution was stirred for 2 hs at-78 ℃, then the second batch of TiCl₄ (1 M in DCM, 50 mL, 50 mmol, 1.1eq) was added. After 10 min, acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with NH₄Cl (sat 50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (9.4 g, yield: 75％, purity: 96.5％) .

[0231]

Example 11： preparation of (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (13)

[0232]

[0233]

TiCl₄ (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoropropanoy l ) -4-isopropyloxazolidin-2-one (4) (10 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N₂ atomosphere. After 10 min, diisopropylethyl amine (15.9 g, 2.5 eq) was added and the solution was stirred for 2 hs at-78 ℃. Then acrylaldehyde (7 mL, 2eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (10.4 g, yield: 83％, purity: 92.8％) . ¹H-NMR (400 MHz, CDCl₃) ： δ 5.92 (d， J ＝ 1.1 Hz， 1 H) ， 5.44 (d, J ＝ 17.2 Hz, 1 H) , 5.34 -5.28 (m, 1 H) , 4.73 (dd, J ＝ 13.9, 6.2 Hz, 1 H) , 4.43 (m, 1 H) , 4.37 -4.30 (m, 1H) , 4.27 -4.21 (m, 1 H) , 2.43 -2.31 (m, 1H) , 1.77 (s, 1.5 H) , 1.71 (s, 1.5 H) , 0.91 (dd, J ＝ 12.1, 7.0 Hz, 6 H) ； ¹⁹F-NMR (400 MHz, CDCl₃) ： δ -159.1ppm.

[0234]

Example 12： preparation of (S) -4-benzyl-3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) oxazolidin-2-one

[0235]

[0236]

TiCl₄ (1 M in DCM, 50 mL, 50mmol, 1.1 eq) was added to a solution of (4S) -4-benzyl-3-(2-fluoro propanoyl) oxazolidin-2-one (8) (12.3 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N₂ atomosphere. After 10 min, TMEDA (15.9 g, 2.5 eq) was added and the solution was stirred for 2 hs at -78 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (50 mL) . The products were extracted into DCM (20 mL*2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (13 g, yield: 86％, purity: 91.5％) . ¹H-NMR (400 MHz, CDCl₃) ： δ 7.38 -7.27 (m, 3 H) , 7.22 (d, J ＝ 6.8 Hz, 2 H) , 5.96 (dddd, J ＝ 17.0, 10.5, 6.2, 1.2 Hz, 1 H) , 5.47 (d, J ＝ 17.2 Hz, 1 H) , 5.35 (d, J ＝ 10.5 Hz, 1 H) , 4.75 (dd, J ＝ 13.9, 6.2 Hz, 1 H) , 4.66 (td, J ＝ 7.1, 3.6 Hz, 1 H) , 4.23 (dd, J ＝ 16.3, 5.0 Hz, 2 H) , 3.33 (dd, J ＝ 13.3, 3.3 Hz, 1 H) , 2.76 (dd, J ＝13.3, 10.0 Hz, 1 H) , 1.81 (s, 1.5 H) , 1.76 (s, 1.5 H) ； ¹⁹F-NMR (400 MHz, CDCl₃) ： δ -158.47 ppm.

[0237]

Example 13： preparation of (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-phenyloxazolidin-2-one

[0238]

[0239]

TiCl₄ (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoropropanoyl) -4-phenyloxazolidin-2-one (7) (11.6 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N₂ atomosphere. After 10 min, Et₃N (12.5 g, 2.5 eq) was added and the solution was stirred for 2 hs at-78 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (12 g, yield: 83％, purity: 90.5％) . ¹H-NMR (400 MHz, CDCl₃) : δ 7.43 -7.30 (m, 5 H) , 5.81 (dddd, J ＝ 17.0, 10.5, 6.3, 1.1 Hz, 1 H) , 5.46 (dd, J ＝ 8.4, 5.1 Hz, 1 H) , 5.37 (dt, J ＝ 17.2, 1.2 Hz, 1 H) , 5.23 (d, J ＝ 10.4 Hz, 1 H) , 4.74 (t, J ＝ 8.7 Hz, 1 H) , 4.64 (dd, J ＝ 13.5, 6.3 Hz, 1 H) , 4.31 (dd, J ＝ 8.9, 5.2 Hz, 1 H) , 1.60 (s, 1.5H) , 1.55 (s, 1.5 H) ； ¹⁹F-NMR (400 MHz, CDCl₃) ： δ -158.47 ppm.

[0240]

Example 14： preparation of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-phenyloxazolidin-2-one

[0241]

[0242]

TiCl₄ (1 M in DCM, 50 mL, 50mmol, 1.1 eq) was added to a solution of (4R) -3- (2-fluoro propan oyl) -4-phenyloxazolidin-2-one (6) (11.6 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N₂ atomosphere. After 10 min, DIPEA (15.9 g, 2.5 eq) was added and the solution was stirred for 2 hs at-78 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78℃. Then the reaction was quenched with a saturated solution of NH₄Cl (50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (11.1 g, yield: 77％, purity: 91.5％) . ¹H-NMR (400 MHz, CDCl₃) : δ 7.44 -7.29 (m, 5 H) , 5.74 -5.63 (m, 1 H) , 5.48 (dd, J ＝ 8.4, 5.3 Hz, 1 H) , 5.35 -5.26 (m, 1 H) , 5.15 (d, J ＝ 10.5 Hz, 1 H) , 4.73 (t, 1 H) , 4.52 (dd, J ＝ 14.8, 6.2 Hz, 1 H) , 4.28 (dd, J ＝ 8.9, 5.3 Hz, 1 H) , 1.68 (s, 1.5 H) , 1.63 (s, 1.5 H) ； ¹⁹F-NMR (400 MHz, CDCl₃) ： δ -161.93 ppm.

[0243]

Example 15： preparation of (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one

[0244]

[0245]

Method 1: LiHMDS (1 M in THF, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoro propanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11) (17.4 g, 49.2 mmol, 1 eq) in dry THF (100 mL) at -20 ℃ under N₂ atomosphere. After 1.5 hs, acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -20 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (50 mL) . The products were extracted into EA (50 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the crude product was used directly in the next step. m/z (ES+) : 412 [M+H] +.

[0246]

Method 2: (n-Bu) ₂BOTf (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoro propanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11) (17.4 g, 49.2 mmol, 1 eq) in dry DCM (100 mL) at 0 ℃ under N₂ atomosphere. After 15 min, 2, 6-lutidine (10.5g, 2eq) was added and the solution was stirred for 2 hs at 0 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at 0 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (100 mL) . The products were extracted into DCM (40 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the crude product was used directly in the next step (17.82 g, yield: 88％ (Internal standard yield) .

[0247]

Method 3: (n-Bu) ₂BOTf (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoro propanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11) (17.4 g, 49.2 mmol, 1 eq) in dry DCM (100 mL) at 0 ℃ under N₂ atomosphere. After 15 min, DIPEA (13 g, 2 eq) was added and the solution was stirred for 2 hs at 0 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at 0 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (100 mL) . The products were extracted into EA (50 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the crude product was used directly in the next step (16.2 g, yield: 80％ (Internal standard yield ) .

[0248]

Method 4: (C₆H₁₂) ₂BOTf (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoro propanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11) (17.4 g, 49.2 mmol, 1 eq) in dry DCM (100 mL) at 0 ℃ under N₂ atomosphere. After 15 min, 2, 6-lutidine (10.5 g, 2 eq) was added and the solution was stirred for 2 hs at 0 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at 0 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (100 mL) . The products were extracted into DCM (50 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the crude product was used directly in the next step (14.6 g, yield: 80％ (Internal standard yield ) .

[0249]

Example 16： preparation of (3R, 4R, 5R) -3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyl dihydro furan-2 (3H) -one

[0250]

Method 1:

[0251]

[0252]

N-Bromosuccinimide (19.6 g, 1.1 eq) was added portionwisely to a solution of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12) (25.9 g, 100 mmol, 1 eq) in DME/H₂O (4: 1, 130ml) at -5 ℃, and stirred for 2 hs . After the reaction was complete, NaHCO₃ (sat, 20 mL) was added and stirred for 0.5 h at rt. The mixture were extracted by DCM (50 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed, the residue dissolved by MTBE (1V) , the solid was filtered off to recover the auxiliary, the filtrate was concentrated to dryness to obtained the (3R, 4R, 5R) -5- (bromomethyl) -3-fluoro-4-hydroxy-3-methyldihydrofuran-2 (3H) -one (18a) . ¹H-NMR (400 MHz, CDCl₃) : δ 4.62 -4.53 (m, 1 H) , 4.37 (dd, J ＝ 3.0, 1.9 Hz, 1 H) , 3.73 (dd, J ＝ 10.1, 8.7 Hz, 1 H) , 3.60 (ddd, J ＝ 10.1, 5.8, 1.9 Hz, 1 H) , 2.59 (dd, J ＝ 2.5, 1.7 Hz, 1 H) , 1.67 (d, J ＝ 22.7 Hz, 3 H) ； ¹⁹F-NMR (400 MHz, CDCl₃) ： δ -172.248 ppm.

[0253]

Alternative Method 1a: Br₂ (17.6 g, 1.1 eq) was added portionwisely to a solution of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12) (25.9 g, 100 mmol, 1 eq) in MeCN/H₂O (4: 1, 130 mL) between -5 ℃ to -10 ℃ and stirred for 2 hs . After the reaction was complete, Na₂S₂O₃ (10％, 20 ml) was added and stirred for 0.5 h at rt then separated . The water phase was re-extracted by DCM (50 mL *2) , the combine organic phase was concentrated, dissolved by MTBE (1V) , the solid was filtered off to recover the auxiliary, the filtrate was concentrated to dryness to used in the next step.

[0254]

Alternative Method 1b: N-chlorosuccinimide (13.3 g, 1.1 eq) was added portionwisely to a solution of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12) (25.9 g, 100 mmol, 1 eq) in 100ml CH3CN at -5 ℃, and stirred for 2 hs . After the reaction was complete, NaHCO₃ (sat, 20 mL) was added and stirred for 0.5 h at rt. The mixture were extracted by DCM (50 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed, the residue dissolved by MTBE (1V) , the solid was filtered off to recover the auxiliary, the filtrate was concentrated to dryness to obtained the (3R, 4R, 5R) -5- (chloromethyl) -3-fluoro-4-hydroxy-3-methyldihydrofuran-2 (3H) -one (18b) , m/z (ES+) : 183 [M+H] +.

[0255]

The related lactone 18a or 18b (0.14eq) was dissolved in EtOH (104 mL) , then KOH (30％in H₂O, 50 mL) was added into, the result mixture was reflux for 4 hs. Then HCl (16.7 mL, 12 M) was added into the mixture and reflux for another 2 hs. The solvent was removed and the residue was recrystalized in toluene to give the desired compound as a white solid (yield: 80～85％) . m/z (ES+) : 165 [M+H] +. ¹H-NMR (400 MHz, MeOD) : δ 4.34 (ddd， J ＝ 8.0， 4.2， 2.3 Hz， 1 H) , 4.02 (ddd, J ＝ 17.6, 15.2, 5.1 Hz, 2 H) , 3.74 (dd, J ＝ 13.0, 4.2 Hz, 1 H) , 1.60 (s, 1.5 H) , 1.54 (s, 1.5 H) ； ¹⁹F-NMR (400 MHz, MeOD) : -172.47 ppm.

[0256]

Method 2:

[0257]

[0258]

Osmium tetroxide (OsO4) (0.1 equiv) was added in one portion to a stirring solution of the (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12) (25.9 g, 100 mmol, 1 eq) in acetone/water (8: 1 ratio) under nitrogen. After 5 min, NMO (N-methylmorpholine N-oxide, 60％by weight in water, 1.1 equiv) was added in one portion and stirred for 24 h. The resulting reaction mixture was concentrated under reduced pressure and immediately purified via column chromatography to obtain the desired lactone (3R, 4R, 5S) -3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyldihydrofuran-2 (3H) -one (21) , yield: 87％, m/z (ES+) : 165 [M+H] +.

[0259]

15.1 g (92.3 mmol) (3R, 4R, 5S) -3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyl dihydrofuran-2 (3H) -one (21) was dissolved in 25 mL pyridine and 11.1 g (96.9 mmol) methanesulfonyl chloride was slowly added dropwise at -25 degC. It was stirred for a day at -25 deg and a day at -10 deg. After adding 20 mL of ethyl acetate and 20 mL water, the solvent was removed on a rotary evaporator. After neutralization with dilute sodium hydrogen carbonate solution, the solvent was removed in vacuo again, the residue was digested with ethyl acetate, the eluate was dried with magnesium sulfate and concentrated in vacuo to dryness. Recrystallization from ethyl acetate/diethyl ether gave a colorless crystalline product ( (2S, 3R, 4R) -4-fluoro-3-hydroxy-4-methyl-5-oxotetrahydrofuran-2-yl) methyl methanesulfonate (18c) . Yield: 31 ％.

[0260]

33.8g of ( (2S, 3R, 4R) -4-fluoro-3-hydroxy-4-methyl-5-oxotetrahydrofuran-2-yl) methyl methanesulfonate was disslolved in EtOH (104 mL) , then KOH (16.8 g , 3 eq) in H₂O (52 mL) was added into, the result mixture was reflux for 4 hs. Then HCl (16.7 mL, 12 M) was added into, the mixture was reflux for another 2 hs. The solvent was removed and the residue was recrystalized in toluene to give the desired compound as a white solid (10.5 g, yield: 45％) .

[0261]

Alternative reagents and reactions to those disclosed above can also be employed. For example, 4-methylbenzene-1-sulfonyl chloride can be used instead of methanesulfonyl chloride. Moreover, primary alcohol can be converted to chloro or bromo by using Ph₃P/CCl4, PPh₃P/CBr₄, PPh₃/NCS, PPh₃/NBS, or PPh₃/C₂Cl₆ as a halogenation reagent. The desired product can be obtained in good yields using these reagents and reactions.

[0262]

Method 3: Using a method analogous to that described as hereinabove and (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methyl pent-4-enoyl) -4-isopropyloxazolidin-2-one (13) as starting material provides the desired compound 19 (yield: 63.2％)

[0263]

Method 4： Using a method analogous to that described as hereinabove and (S) -4-benzyl-3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) oxazolidin-2-one (14) as starting material provides the desired compound 19 (yield: 71.8％)

[0264]

Method 5： Using a method analogous to that described as hereinabove and (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-phenyloxazolidin-2-one (15) as the start material gives the desired compound 19 (yield: 65.7％)

[0265]

Method 6： Using a method analogous to that described as hereinabove and (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-phenyloxazolidin-2-oneas (16) starting material provides the desired compound 19 (yield: 59.5％)

[0266]

Method 7： Using a method analogous to that described as hereinabove and (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (17) as starting material gives the desired compound 19 (yield: 66.7％)

[0267]

Example 17: preparation of ( (3R, 4R) -3- (benzoyloxy) -4-fluoro-4-methyl-5-oxotetra hydro fur an-2-yl) methyl benzoate

[0268]

[0269]

(3R, 4R) -3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyldihydrofuran-2 (3H) -one (19) (25.4 g, 0.154 mol) obtained from example 3 was dissolved in 200 ml of THF. 4- (Dimethylamino) -pyridine (8.2 g, 0.066 mol) and triethylamine (35 g, 0.35 mol) were added and the reaction mixture was cooled to 0 ℃. Benzoyl chloride (46.0 g, 0.33 mol) was added, and the mixture was warmed to 35-40 ℃ in the course of 2 hs. Upon completion of the reaction, water (100 mL) was charged and the mixture was stirred for 30 min. Phases were separated and to the aqueous phase methyl-tert-butyl ether (100 mL) was added and the mixture was stirred for 30 min. Phases were separated and the organic phase was washed with saturated NaCl solution (100 mL) . The combined organic phases were dried over Na₂SO₄ (20 g) filtered and the filtrate was evaporated to dryness. The residue was taken up in iso-propanol (250 mL) and the mixture was warmed to 50 ℃ and stirred for 60 min, then cooled down to 0 ℃ and further stirred for 60 min. The solid was filtered and the wet cake was washed with i-propanol (50 mL) and then dried under vacuum. The title compound ( (3R, 4R) -3- (benzoyloxy) -4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl) methyl benzoate (47.5 g, 82.6 ％yield) was obtained. ‘H-NMR (CDCl₃, 400 MHz) : 8.10 (d, 7＝7.6 Hz, 2H) , 8.00 (d, 7＝7.6 Hz, 2H) , 7.66 (t, 7＝7.6 Hz, IH) , 7.59 (t, 7＝7.6 Hz, IH) , 7.50 (m, 2H) , 7.43 (m, 2H) , 5.53 (dd, 7＝17.6, 5.6 Hz, IH) , 5.02 (m, IH) , 4.77 (dd, 7＝12.8, 3.6 Hz, IH) , 4.62 (dd, 7＝12.8, 5.2 Hz, IH) , 1.77 (d, 7＝23.2 Hz, 3H) .

///////////////////

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HEAR GREAT DR VIJAY KIRPALANI AT, SEE BELOW

Flow Chemistry Society – India, welcome you to a “free-to-attend” Conference on ” Advances in Chemical Process Technology 2018″ which is being held on: Thursday 26th April 2018 along with ChemSpec India 2018 in Hall 1, NSE, Goregaon, Mumbai, India

Chemspec India 2018, the country’s leading exhibition dedicated to Fine and Speciality Chemicals, takes place for the fourteenth time from 25-26 April 2018

To attend the conferences or know more please contact:
Mr. Kiran Iyer,
M: 91-98201-71374
E: kiran@chemicalweekly.com

//////////////////////#mumbai #conferences #flowchemistry #chemicalprocessing #howto #nse #VIJAYKIRPALANI

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Pic…. Shobha crasto, Lionel and Aishal collecting my award named The Golden Globe Tigers Awards 2018, for Excellence in Pharma, at kuala lumpur, Malaysia, 23 april 2018 at Pullman city centre hotel, Kuala lumpur, Malaysia. Dr Anthony could not travel as he is wheelchair bound and 90 percent paralysed

DR ANTHONY M CRASTO

The Golden Globe Tigers Award 2018 is the highest recognition amongst individual and organizations who have achieved the highest levels of standards and benchmark in numerous areas such as CSR, Pharma, Social Media & Digital Marketing, Education Leadership Award and so on. The award ceremony took place in Pullman Kuala Lumpur City Centre Hotel & Residences on the 23rd of April, where a number of respectable attendees were present not only from Malaysia but from many different parts of the world such as Iceland, Saudi Arabia, India, China, South Africa and such!

The Golden Globe Tigers Award not only aims to increase awareness on CSR practices but also continuously innovate practices towards sustainable development. It is organized by the founder of the World CSR Day, World Sustainability Congress and World Women Leadership Congress.

Dr. Anthony  Melvin Crasto, graduated from Mumbai  University, Completed his Ph.D from ICT, 1991, Mumbai, India, in the field of Organic Chemistry, Currently he is working with GLENMARK PHARMACEUTICALS LTD,  Research Centre as a Principal Scientist, in Process Research at Mahape, Navi Mumbai, India, for the last 10 years,  His total  Industry experience is  30 +yrs with major Multinationals companies.

Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now  RPG lifesciences, etc. He has worked with notable Scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri , Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did Custom Synthesis for various multinationals in his career like BASF, Novartis, Sanofi, Pfizer etc., He has worked in Drug Discovery, Natural products, Bulk Drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP,  Scaleups, Pharma Plant, API plant etc, he is now helping millions, His friends call him worlddrugtracker.

His New Drug Approvals,  All about drugs,  Eurekamoments, Organic spectroscopy international, etc in Organic/ Medchem  are some most read blogs. He has hands on experience in initiation and developing Novel routes for Drug molecules and implementing them on commercial scale over a 30  year tenure till date Feb’  2018,  Around 30 plus commercial products in his career. He has good knowledge of IPM, GMP, QbD, Regulatory aspects, Technology transfer,  Manufacturing,  Formulations, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc. He has several  International  patents published worldwide.

He suffered a one in a million disease in the form of a paralytic stroke/ Acute Transverse Mylitis in Dec’ 2007 and is 90 % paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, he has several million hits on Google,  60 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto

He is a prolific presenter and is invited to major conferences in Mumbai, where he can travel easily. He speaks at universities on topics of  Drug discovery, Patents, Qbd, GMP, Tech transfer, polymorphism, Literature search tools, Computer programs and Topics of  interest to Pharma Students.

His extraordinary skill on the Computers give him the edge to write/present his thoughts. He demonstrates them to students and professionals alike.

Notably he has 20 lakh plus views on New Drug Approvals Blog in 216 countries, This blog has 3.5 lakh viewers in USA alone.

AWARDS

“100 Most Impactful Health care Leaders Global listing”, conferred at Taj lands end, Mumbai, India on 14 Feb 2014 by World Health Wellness congress and awards

“Best Worlddrugtracker “ Award for lifetime acheivement in Pharma… 7 th July 2017 , The venue…Taj land ends, Bandra, Mumbai India

“Lifetime achievement award” WORLD HEALTH CONGRESS 2017 in Hyderabad, 22 aug 2017 at JNTUH KUKATPALLY. HYDERABAD, TELANGANA, INDIA,

” Lifetime Achievement Award”, at the The Middle East Healthcare Leadership Awards – 12th October, 2017 -The Address, Dubai Mall, Dubai…UAE……….Mohammed Bin Rashid Boulevard, Downtown Dubai – Dubai – United Arab Emirates

International award for Outstanding contribution in Pharma  at World Health and wellness Congress award, 14th Feb, 2018, at Taj Lands ends, Bandra, Mumbai, India

Conferred very prestigious IDMA award for contribution to society in Pharma at INDIAN DRUGS ANNUAL DAY 2018 VMCC IITBombay Powai, Mumbai India 22 Feb 2018,I was Guest of honor at and was felicitated by president,Indian Drug manufacturers association (IDMA)

The Golden Globe Tigers Awards 2018, for Excellence in Pharma, at kuala lumpur, Malaysia, 23 april 2018 at Pullman hotel.

Biography

READ MY BIOGRAPHY……….http://scijourno.com/2017/01/09/dr-anthony-crasto/  Written by Mr. Amrit B. Karmarkar
Director, InClinition

///////////////

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+91- 999-997-2051

info@synthesiswithcatalysts.com

bpk@synthesiswithcatalysts.com

Axay Parmar

Founder at Synthesis with Catalysts Pvt. Ltd, axayrp@gmail.com

Basu Agarwal and Dr Razi Abdi

shr@synthesiswithcatalysts.com, ba@synthesiswithcatalysts.com

Synthesis with Catalysts Pvt Ltd was founded with an aim to help aromatic chemical, essential oil, pharmaceutical, API manufacturers to develop new products, increase productivity and improve production methodologies.

We have an advanced research and development centre where we innovate new chemical processes and improve the existing ones and help our customers implement the same. We support our research with pilot production of the products.

We are also developing precious metal complexes, Catalysts, Legends etc.

We are continuously working to reset standards of purity with our products.

The team at Synthesis with Catalysts Pvt Ltd has an vast experience and well renowned scientists of India have found it suitable to continue their Research in our facilities. The team with Synthesis with Catalysts Pvt Ltd has presented countless number of research papers all across the world.

We have a world class lab with all advance analytical testing machines.

RESEARCH & DEVELOPMENT

Synthesis with Catalysts Pvt Ltd.’s strength lies in its state-of- the-art infrastructure and R&D capabilities. Innovative process development is the foundation of SWC’s success. Our team of highly qualified R&D experts in process of research and technology development work 24 hours for inventing new processes and Optimizing product development capabilities. Our main focus is developing innovative processes, which could help our partners in reducing their costs and production time. Our Scientists constantly work for cost-effective ways of developing products, ensuring better service for our clients.

////////////1,2 Diaminocyclohexane, Synthesis with Catalysts Pvt Ltd

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A cartoon representing how, in history, we are continuously faced with new scientific advancements that make us question what the future holds and whether what we currently have is still useful or should be replaced.

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Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite

https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.8b00565

The research interests of his group lie in issues related to application of oriented organic synthesis, in particular total synthesis of biologically active natural products, medicinal chemistry and crop protection. This team has been credited with having accomplished total synthesis of more than 25 natural products with impressive biological activities. “Some of our recent achievements include identification of potential leads, like antibiotic compound based on hunanamycin natural product for treating food infections, anti-diabetic molecule in collaboration with an industry partner and  anti-TB compound using a strategy called ‘re-purposing of a drug scaffold’,” said Reddy.

A total of two awardees out of four were from CSIR institutes. In addition to Reddy, Rajan Shankarnarayanan, CSIR – CCMB, Hyderabad (basic sciences), also was conferred with the award. Vikram Mathews, CMC, Vellore (medical research) and Prof Ashish Suri, AIIMS, New Delhi (clinical research), were the others to receive the awards.

With more than 80 scientific publications and 35 patents, Reddy is one of the most prominent scientists in the city and has already been honoured with the Shanti Swarup Bhatnagar prize in chemical sciences. Reddy is also a nominated member of the scientific body of Indian Pharmacopoeia, government of India and was  elected as a fellow of the Telangana and Maharashtra Academies of Sciences in addition to the National Academy of Sciences, India (NASI).

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ABSTRACT All-trans-retinal, a retinoid metabolite naturally produced upon photoreceptor light activation, is cytotoxic when present at elevated levels in the retina. To lower its toxicity, two experimentally validated methods have been developed involving inhibition of the retinoid cycle and sequestration of excess of all-trans-retinal by drugs containing a primary amine group. We identified the first-in-class drug candidates that transiently sequester this metabolite or slow down its production by inhibiting regeneration of the visual chromophore, 11-cis-retinal. Two enzymes are critical for retinoid recycling in the eye. Lecithin:retinol acyltransferase (LRAT) is the enzyme that traps vitamin A (all-trans-retinol) from the circulation and photoreceptor cells to produce the esterified substrate for retinoid isomerase (RPE65), which converts all-trans-retinyl ester into 11-cis-retinol. Here we investigated retinylamine and its derivatives to assess their inhibitor/substrate specificities for RPE65 and LRAT, mechanisms of action, potency, retention in the eye, and protection against acute light-induced retinal degeneration in mice. We correlated levels of visual cycle inhibition with retinal protective effects and outlined chemical boundaries for LRAT substrates and RPE65 inhibitors to obtain critical insights into therapeutic properties needed for retinal preservation.

http://molpharm.aspetjournals.org/content/early/2014/12/23/mol.114.096560

Expansion of First-in-class Drug Candidates that Sequester Toxic All-trans-retinal and Prevent Light-induced Retinal Degeneration

Sreeni Labs Private Limited, Hyderabad, India is ready to take up challenging synthesis projects from your preclinical and clinical development and supply from few grams to multi-kilo quantities. Sreeni Labs has proven route scouting ability  to  design and develop innovative, cost effective, scalable routes by using readily available and inexpensive starting materials. The selected route will be further developed into a robust process and demonstrate on kilo gram scale and produce 100’s of kilos of in a relatively short time.

Accelerate your early development at competitive price by taking your route selection, process development and material supply challenges (gram scale to kilogram scale) to Sreeni Labs…………

INTRODUCTION

Sreeni Labs based in Hyderabad, India is working with various global customers and solving variety of challenging synthesis problems. Their customer base ranges from USA, Canada, India and Europe. Sreeni labs Managing Director, Dr. Sreenivasa Reddy Mundla has worked at Procter & Gamble Pharmaceuticals and Eli Lilly based in USA.

The main strength of Sreeni Labs is in the design, development of innovative and highly economical synthetic routes and development of a selected route into a robust process followed by production of quality product from 100 grams to 100s of kg scale. Sreeni Labs main motto is adding value in everything they do.

They have helped number of customers from virtual biotech, big pharma, specialty chemicals, catalog companies, and academic researchers and drug developers, solar energy researchers at universities and institutions by successfully developing highly economical and simple chemistry routes to number of products that were made either by very lengthy synthetic routes or  by using highly dangerous reagents and Suzuki coupling steps. They are able to supply materials from gram scale to multi kilo scale in a relatively short time by developing very short and efficient synthetic routes to a number of advanced intermediates, specialty chemicals, APIs and reference compounds. They also helped customers by drastically reducing number of steps, telescoping few steps into a single pot. For some projects, Sreeni Labs was able to develop simple chemistry and avoided use of palladium & expensive ligands. They always begin the project with end in the mind and design simple chemistry and also use readily available or easy to prepare starting materials in their design of synthetic routes

Over the years, Sreeni labs has successfully made a variety of products ranging from few mg to several kilogram scale. Sreeni labs has plenty of experience in making small select libraries of compounds, carbocyclic compounds like complex terpenoids, retinal derivatives, alkaloids, and heterocyclic compounds like multi substituted beta carbolines, pyridines, quinolines, quinolones, imidazoles, aminoimidazoles, quinoxalines, indoles, benzimidazoles, thiazoles, oxazoles, isoxazoles, carbazoles, benzothiazoles, azapines, benzazpines, natural and unnatural aminoacids, tetrapeptides, substituted oligomers of thiophenes and fused thiophenes, RAFT reagents, isocyanates, variety of ligands,  heteroaryl, biaryl, triaryl compounds, process impurities and metabolites.

Sreeni Labs is Looking for any potential opportunities where people need development of cost effective scalable routes followed by quick scale up to produce quality products in the pharmaceutical & specialty chemicals area. They can also take up custom synthesis and scale up of medchem analogues and building blocks.  They have flexible business model that will be in sink with customers. One can test their abilities & capabilities by giving couple of PO based (fee for service) projects.

Some of the compounds prepared by Sreeni labs;

See presentation below

LINK ON SLIDESHARE

Managing Director at Sreeni Labs Private Limited

Few Case Studies : Source SEEENI LABS

QUOTE………….

One virtual biotech company customer from USA, through a common friend approached Sreeni Labs and told that they are buying a tetrapeptide from Bachem on mg scale at a very high price and requested us to see if we can make 5g. We accepted the challenge and developed solution phase chemistry and delivered 6g and also the process procedures in 10 weeks time. The customer told that they are using same procedures with very minor modifications and produced the tetrapeptide ip to 100kg scale as the molecule is in Phase III.

One East coast customer in our first meeting told that they are working with 4 CROs of which two are in India and two are in China and politely asked why they should work with Sreeni Labs. We told that give us a project where your CROs failed to deliver and we will give a quote and work on it. You pay us only if we deliver and you satisfy with the data. They immediately gave us a project to make 1.5g and we delivered 2g product in 9 weeks. After receiving product and the data, the customer was extremely happy as their previous CRO couldn’t deliver even a milligram in four months with 3 FTEs.

One Midwest biotech company was struggling to remove palladium from final API as they were doing a Suzuki coupling with a very expensive aryl pinacol borane and bromo pyridine derivative with an expensive ligand and relatively large amount of palldium acetate. The cost of final step catalyst, ligand and the palladium scavenging resin were making the project not viable even though the product is generating excellent data in the clinic. At this point we signed an FTE agreement with them and in four months time, we were able to design and develop a non suzuki route based on acid base chemistry and made 15g of API and compared the analytical data and purity with the Suzuki route API. This solved all three problems and the customer was very pleased with the outcome.

One big pharma customer from east coast, wrote a structure of chemical intermediate on a paper napkin in our first meeting and asked us to see if we can make it. We told that we can make it and in less than 3 weeks time we made a gram sample and shared the analytical data. The customer was very pleased and asked us to make 500g. We delivered in 4 weeks and in the next three months we supplied 25kg of the same product.

Through a common friend reference, a European customer from a an academic institute, sent us an email requesting us to quote for 20mg of a compound with compound number mentioned in J. med. chem. paper. It is a polycyclic compound with four contiguous stereogenic centers.  We gave a quote and delivered 35 mg of product with full analytical data which was more pure than the published in literature. Later on we made 8g and 6g of the same product.

One West coast customer approached us through a common friend’s reference and told that they need to improve the chemistry of an advanced intermediate for their next campaign. At that time they are planning to make 15kg of that intermediate and purchased 50kg of starting raw material for $250,000. They also put five FTEs at a CRO  for 5 months to optimize the remaining 5 steps wherein they are using LAH, Sodium azide,  palladium catalyst and a column chromatography. We requested the customer not to purchase the 50kg raw material, and offered that we will make the 15kg for the price of raw material through a new route  in less than three months time. You pay us only after we deliver 15 kg material. The customer didn’t want to take a chance with their timeline as they didn’t work with us before but requested us to develop the chemistry. In 7 weeks time, we developed a very simple four step route for their advanced intermediate and made 50g. We used very inexpensive and readily available starting material. Our route gave three solid intermediates and completely eliminated chromatographic purifications.

One of my former colleague introduced an academic group in midwest and brought us a medchem project requiring synthesis of 65 challenging polyene compounds on 100mg scale. We designed synthetic routes and successfully prepared 60 compounds in a 15 month time.  

UNQUOTE…………

The man behind Seeni labs is Dr.Sreenivasa  Reddy Mundla

Dr. Sreenivasa Reddy Mundla

Managing Director at Sreeni Labs Private Limited

Sreeni Labs Private Limited

Road No:12, Plot No:24,25,26

Links

LINKEDIN https://in.linkedin.com/in/sreenivasa-reddy-10b5876

FACEBOOK https://www.facebook.com/sreenivasa.mundla

RESEARCHGATE https://www.researchgate.net/profile/Sreenivasa_Mundla/info

EMAIL mundlasr@hotmail.com,  Info@sreenilabs.com, Sreeni@sreenilabs.com

Dr. Sreenivasa Mundla Reddy

Dr. M. Sreenivasa Reddy obtained Ph.D from University of Hyderabad under the direction Prof Professor Goverdhan Mehta in 1992. From 1992-1994, he was a post doctoral fellow at University of Wisconsin in Professor Jame Cook’s lab. From 1994 to 2000,  worked at Chemical process R&D at Procter & Gamble Pharmaceuticals (P&G). From 2001 to 2007 worked at Global Chemical Process R&D at Eli Lilly and Company in Indianapolis. 

In 2007  resigned to his  job and founded Sreeni Labs based in Hyderabad, Telangana, India  and started working with various global customers and solving various challenging synthesis problems. 
The main strength of Sreeni Labs is in the design, development of a novel chemical route and its development into a robust process followed by production of quality product from 100 grams to 100’s of kg scale. 

Experience

Education

PUBLICATIONS

Article: Expansion of First-in-Class Drug Candidates That Sequester Toxic All-Trans-Retinal and Prevent Light-Induced Retinal Degeneration

Jianye Zhang · Zhiqian Dong · Sreenivasa Reddy Mundla · X Eric Hu · William Seibel ·Ruben Papoian · Krzysztof Palczewski · Marcin Golczak

Article: ChemInform Abstract: Regioselective Synthesis of 4Halo ortho-Dinitrobenzene Derivative

Sreenivasa Mundla

Aug 2010 · ChemInform

Article: Optimization of a Dihydropyrrolopyrazole Series of Transforming Growth Factor-β Type I Receptor Kinase Domain Inhibitors: Discovery of an Orally Bioavailable Transforming Growth Factor-β Receptor Type I Inhibitor as Antitumor Agent

Hong-yu Li · William T. McMillen · Charles R. Heap · Denis J. McCann · Lei Yan · Robert M. Campbell · Sreenivasa R. Mundla · Chi-Hsin R. King · Elizabeth A. Dierks · Bryan D. Anderson · Karen S. Britt · Karen L. Huss

Apr 2008 · Journal of Medicinal Chemistry

Article: ChemInform Abstract: A Concise Synthesis of Quinazolinone TGF-β RI Inhibitor Through One-Pot Three-Component Suzuki—Miyaura/Etherification and Imidate—Amide Rearrangement Reactions

Hong-yu Li · Yan Wang · William T. McMillen · Arindam Chatterjee · John E. Toth ·Sreenivasa R. Mundla · Matthew Voss · Robert D. Boyer · J. Scott Sawyer

Feb 2008 · ChemInform

Article: ChemInform Abstract: A Concise Synthesis of Quinazolinone TGF-β RI Inhibitor Through One-Pot Three-Component Suzuki—Miyaura/Etherification and Imidate—Amide Rearrangement Reactions

Hong-yu Li · Yan Wang · William T. McMillen · Arindam Chatterjee · John E. Toth ·Sreenivasa R. Mundla · Matthew Voss · Robert D. Boyer · J. Scott Sawyer

Nov 2007 · Tetrahedron

Article: Dihydropyrrolopyrazole Transforming Growth Factor-β Type I Receptor Kinase Domain Inhibitors: A Novel Benzimidazole Series with Selectivity versus Transforming Growth Factor-β Type II Receptor Kinase and Mixed Lineage Kinase-7

Hong-yu Li · Yan Wang · Charles R Heap · Chi-Hsin R King · Sreenivasa R Mundla · Matthew Voss · David K Clawson · Lei Yan · Robert M Campbell · Bryan D Anderson · Jill R Wagner ·Karen Britt · Ku X Lu · William T McMillen · Jonathan M Yingling

Apr 2006 · Journal of Medicinal Chemistry

Read full-text, Source

Article: Studies on the Rh and Ir mediated tandem Pauson–Khand reaction. A new entry into the dicyclopenta[ a, d]cyclooctene ring system

Hui Cao · Sreenivasa R. Mundla · James M. Cook

Aug 2003 · Tetrahedron Letters

Article: ChemInform Abstract: A New Method for the Synthesis of 2,6-Dinitro and 2Halo6-nitrostyrenes

Sreenivasa R. Mundla

Nov 2000 · ChemInform

Article: ChemInform Abstract: A Novel Method for the Efficient Synthesis of 2-Arylamino-2-imidazolines

• Sreenivasa R. Mundla · Larry J. Wilson · Sean R. Klopfenstein · William L. Seibel · Nick N. Nikolaides

  Nov 2000 · ChemInform
  Article: A new method for the synthesis of 2,6-dinitro and 2-halo-6-nitrostyrenes

  Sreenivasa R Mundla

   Aug 2000 · Tetrahedron Letters

  Read full-text, Source
  Article: A Novel Method for the Efficient Synthesis of 2-Arylamino-2-imidazolines

  Sreenivasa R Mundla · Larry J Wilson · Sean R Klopfenstein · William L. Seibel · Nick N Nikolaides

  Aug 2000 · Tetrahedron Letters

  Download 

  Read full-text, Source
   Article: Regioselective Synthesis of 4-Halo ortho-Dinitrobenzene Derivatives

  Sreenivasa R Mundla

  Jun 2000 · Tetrahedron Letters

  Download Follow

  Article: Synthesis and Evaluation of Analogues of the Partial Agonist 6-(Propyloxy)-4-(methoxymethyl)-β-carboline-3-carboxylic Acid Ethyl Ester (6-PBC) and the Full Agonist 6-(Benzyloxy)-4-(methoxymethyl)-β- carboline-3-carboxylic Acid Ethyl Ester (Zk 93423) at Wild Type and Recombinant GABA A Receptors

  Eric D. Cox · Hernando Diaz-Arauzo · Qi Huang · Mundla S. Reddy · Chunrong Ma · Brad Harris · Ruth McKernan · Phil Skolnick · James M. Cook

  Aug 1998 · Journal of Medicinal Chemistry

Sreenivasa Reddy Mundla

The present invention provides 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl) -5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole monohydrate, i.e., Formula I.

EXAMPLE 1 Preparation of 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl-5,6-dihydro-4H -pyrrolo[1,2-b]pyrazole monohydrate

Galunisertib

¹H NMR (CDCl₃): δ=9.0 ppm (d, 4.4 Hz, 1H); 8.23-8.19 ppm (m, 2H); 8.315 ppm (dd, 1.9 Hz, 8.9 Hz, 1H); 7.455 ppm (d, 4.4 Hz, 1H); 7.364 ppm (t, 7.7 Hz, 1H); 7.086 ppm (d, 8.0 Hz, 1H); 6.969 ppm (d, 7.7 Hz, 1H); 6.022 ppm (m, 1H); 5.497 ppm (m, 1H); 4.419 ppm (t, 7.3 Hz, 2H); 2.999 ppm (m, 2H); 2.770 ppm (p, 7.2 Hz, 7.4 Hz, 2H); 2.306 ppm (s, 3H); 1.817 ppm (m, 2H). MS ES+: 370.2; Exact: 369.16

ABOVE MOLECULE IS

https://newdrugapprovals.org/2016/05/04/galunisertib/

Accelerating Generic Approvals by Dr Anthony Crasto

KEYWORDS   Sreenivasa Mundla Reddy, Managing Director, Sreeni Labs Private Limited, Hyderabad, Telangana, India,  new, economical, scalable routes, early clinical drug development stages, Custom synthesis, custom manufacturing, drug discovery, PHASE 1, PHASE 2, PHASE 3,  API, drugs, medicines

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4-(2-fluoro-4-nitrophenyl)morpholine

1H NMR (400MHz, CDCl3)  8.03 (ddd J=1.0, 2.6 and 9.0Hz, 1H, ArH), 7.94 (dd J=2.6 and 13.1Hz, 1H, ArH), 6.94 (t J=8.7Hz, 1H, ArH), 3.90 (t J=4.7Hz, 4H, 2xCH2O), 3.31 (m, 4H, 2xCH2N).

13C NMR (100MHz, CDCl3)  153.3 (d J=249.5), 145.6 (d J=7.8Hz), 121.1 (d J=3.0Hz), 117.0 (d J=3.9Hz), 112.7 (d J=6.4Hz), 66.7, 50.0 (d J=4.9Hz).

HRMS [M] Calcd for C10H11FN2O3 226.0748, Found 226.0749.

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Palladium-catalyzed acetoxylation of the primary γ-C(sp³)–H bonds in the amino acids Val, Thr, and Ile was achieved using a newly discovered 5-methylisoxazole-3-carboxamide directing group. The γ-acetoxylated α-amino acid derivatives could be easily converted to γ-mercapto amino acids, which are useful for native chemical ligation (NCL). The first application of NCL at isoleucine in the semisynthesis of a Xenopus histone H3 protein was also demonstrated.

5-Methylisoxazole-3-carboxamide-Directed Palladium-Catalyzed γ-C(sp³)–H Acetoxylation and Application to the Synthesis of γ-Mercapto Amino Acids for Native Chemical Ligation

link

https://pubs.acs.org/doi/abs/10.1021/acs.orglett.6b01160

hps://pubs.acs.org/doi/suppl/10.1021/acs.orgletttt.6b01160/suppl_file/ol6b01160_si_001.pdf

Kalyan Kumar Pasunooti,

kalyan kumar <kalyandrf@gmail.com>

Dr. Kalyan Kumar Pasunooti pursued his PhD degree from Nanyang Technological University (NTU) (www.ntu.edu.sg), Singapore (2007 – 2011) in the field of Medicinal, Peptide & Protein chemistry. His graduate research work is focused on “Synthesis of bioactive amino acid building blocks and their applications towards the peptides and glycopeptides.” His have total 16 years of academic and industry experience with major multinationals companies & academic institutions and have worked with many collaborative professors around the globe. He authored with more than 28 international peer-reviewed high impact publications such as PNAS, Wily (Angew Chemie), RSC (Chem Comm and Org Biomol Chem), most of American Chemical Society journals (Journal of American Chemical Society, Org. Lett., ACS Chem Bio, J Comb Chem and Bioconugate Chem) and Elsevier (Tetrahedron Letters) journals which are featured many times in Chem. Eng. News and other journals. He holds American patent while work with Johns Hopkins-School of Medicine, USA and this molecule in phase II clinical trials for treating cancer.

Prior to his graduate studies, he spent 5 years as a research scientist in reputable research organizations namely GVK Bio, India (www.gvkbio.com) (2006-2007) and Dr. Reddy’s Laboratories Ltd (www.drreddys.com) (2003-2006) in India. After his PhD graduation, he worked for world leading research institutes such as Johns Hopkins-School of Medicine, USA (www.hopkinsmedicne.org) (2012-2013), Nanyang Technological University-NTU, Singapore) (www.ntu.edu.sg) (2013 – 2017) and Singapore MIT Alliance for research & Technology-SMART (www.smart.mit.edu) (2017–2018). His research interests focused on development of next generation biologically relevant peptide & protein therapeutics using their newly discovered methodologies for biomedical applications.

He has excellent skills in designing synthesis, purification and characterization of complex peptide and small molecules for medicinal chemistry applications. He gained extensive experience in Medicinal, Carbohydrate, Peptide & Protein and nucleotide & nucleoside Chemistry and familiar with modern methods and experienced in designing & executing synthesis for various bioactive peptide and small molecule inhibitors. He well versed in synthesis and characterization of complex organic molecules and with the analytical data interpretation.

 

Dr. Kalyan Kumar Pasunooti

Research Scientist at Singapore-MIT Alliance for Research & Technology Centre

Singapore’

Accomplished Peptide, Protein and Medicinal chemist with 16 years of academic and industrialexperience in the field of drug discovery and development. Specializations: Peptide & Protein Chemistry,Medicinal Chemistry (Drug Discovery and Development) and Chemical Biology.

Experience

Research Scientist

Company NameSingapore-MIT Alliance for Research & Technology Centre

Dates EmployedJul 2017 – Present

Employment Duration1 yr 4 mos

LocationSingapore

Medicinal Chemistry and Drug Discovery

Research Fellow

Company NameNanyang Technological University, Singapore

Dates EmployedOct 2013 – Jun 2017

Employment Duration3 yrs 9 mos

LocationSingapore

Peptide & Protein Chemistry and Medicinal Chemistry

Postdoctoral Fellow

Company NameJohns Hopkins Medicine

Dates EmployedMay 2012 – Sep 2013

Employment Duration1 yr 5 mos

LocationBaltimore, Maryland Area

Medicinal chemistry, Drug Discovery, Pharmacology and Chemical Biology

Postdoctoral Associate

Company NameNanyang Technological University

Dates EmployedJul 2011 – Mar 2012

Employment Duration9 mos

LocationSingapore

Organic synthesis, Peptide & Carbohydrate chemistry and Medicinal chemistry.

Senior Research Associate in Medicinal Chemistry

Company NameGVK Biosciences

Dates EmployedJan 2007 – Jul 2007

Employment Duration7 mos

LocationHyderabad Area, India

Synthesis of bioactive molecules for medicinal chemistry applications.

Junior Scientist in Medicinal Chemistry (Anti-Infective group)

Company NameDr. Reddy’s Laboratories

Dates EmployedAug 2003 – Dec 2006

Employment Duration3 yrs 5 mos

LocationHyderabad Area, India

Medicinal chemistry (Anti-Infective group): My work entails design and synthesis of newoxazolidinone derivatives and new chemical entities as novel antibacterial agents. As a researchscientist my job demanded me to carry out extensive literature survey to design possible syntheticroutes for a proposed molecule and to carry out the total synthetic part in the laborator… See more

Education

• Nanyang Technological University

  Degree NamePhD

  Field Of StudyOrganic and Bioorganic chemistry

  Dates attended or expected graduation2007 – 2011

• Osmania University

  Degree NameM. Sc

  Field Of StudyPhysical Organic Chemistry

  Dates attended or expected graduation2000 – 2002

• Kakatiya University

  Degree NameB. Sc,

  Field Of StudyMathematics Physics Chemistry

  Dates attended or expected graduation1996 – 1999

 Research Scientist at Singapore-MIT Alliance for Research and Technology

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ANTHONY MELVIN CRASTO

https://newdrugapprovals.org/

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

Join me on Linkedin

Join me on Facebook FACEBOOK

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Anthony Melvin Crasto Dr. | ResearchGate

 amcrasto@gmail.com

CALL +919323115463  INDIA

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Hello All

I have an exciting news which I want to share today.

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For free registration, please visit https://www.carbanio.com/register

In case if you still want to know more, you can get in touch with them via businesssupport@carbanio.com

Ayesha MD

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It’s a receptor that binds glucose strongly and with the highest selectivity yet. Could help with #diabetes treatment: http://ow.ly/EPzn30mDYjf 

Read all at

https://cen.acs.org/biological-chemistry/Latest-artificial-glucose-binding-receptor/96/i46?platform=hootsuite

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Established in 1996, Orochem Technologies Inc. started as a Biotech and Chromatography company to manufacture unique Sample Prep Technology “Products” for the Bioanalysis, Drug Discovery, and the Genomics and Proteomics markets.

Established in 1996, Orochem Technologies Inc. started as a Biotech and Chromatography company to manufacture unique Sample Prep Technology Products for the Bioanalysis, Drug Discovery, and the Genomics and Proteomics markets. Backed with unique expertise in high throughput formats, membranes and surface chemistries, Orochem was one of the first companies to translate the concept of pre-filters from single to high throughput formats, a concept now widely implemented for sample prep plates in the biotech and analytical markets. In the year 2001 Orochem manufactured the first commercially available Protein Crash and Precipitation 96-well plate for Bioanalytical processes. By the year 2006, with the acquisition of Column Engineering Inc, Orochem evolved to become a “full-service” provider for silica manufacturing utilized for analytical and preparatory chromatography. Orochem invests heavily into R&D in-house and owns strong intellectual property in stationary phases for achiral and Chiral Chromatography.

Orochem’s is globally recognized as an organization that conceives, develops, and installs some of the most technologically viable solutions for “highest purities” for industrial or “metric ton” scale purification for API’s, nutritional supplements, fatty acids, and specialty sugars. Orochem provides Simulated Moving Bed (SMB) Chromatography technology for the laboratory scale, pilot scale and large-scale purification of commercially viable molecules for its customers around the world. Orochem’s products and services for Simulated Moving Bed Chromatography include Synthesis and manufacture of stationary phases “tailored for specific separations”, a uniquely engineered SMB system and the installation and commissioning of the SMB systems at customer sites with well-trained Orochem technical service engineers.

Orochem owns several manufacturing facilities around the world. The  Naperville, Illinois, USA site has about 84,000 square feet of manufacturing area where most of the Membrane Filter Plates, Silica manufacturing, Silica bonding, Solid Phase Extraction products and HPLC Columns are manufactured. Orochem India, Mumbai has 20,000 square feet facility and manufactures Sample prep products for the Discovery & Clinical Research organizations in Asia. Simulated Moving Bed chromatography systems are designed, built and assembled completely at our US locations in Naperville in Illinois.

USA (HQ)

Orochem Technologies Inc.
   630 210 8300
   630 210 8315
   info@orochem.com
   340 Shuman Blvd., Naperville, 60563, IL.

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Itraconazole has been found to possess potent antiangiogenic activity, exhibiting promising antitumor activity in several human clinical studies. The wider use of itraconazole in the treatment of cancer, however, has been limited by its potent inhibition of the drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4). In an effort to eliminate the CYP3A4 inhibition while retaining its antiangiogenic activity, we designed and synthesized a series of derivatives in which the 1,2,4-triazole ring is replaced with various azoles and nonazoles. Among these analogues, 15n with tetrazole in place of 1,2,4-triazole exhibited optimal inhibition of human umbilical vein endothelial cell proliferation with an IC₅₀ of 73 nM without a significant effect on CYP3A4 (EC₅₀ > 20 μM). Similar to itraconazole, 15n induced Niemann-Pick C phenotype (NPC phenotype) and blocked AMPK/mechanistic target of rapamycin signaling. These results suggest that 15n is a promising angiogenesis inhibitor that can be used in combination with most other known anticancer drugs.

Novel Tetrazole-Containing Analogues of Itraconazole as Potent Antiangiogenic Agents with Reduced Cytochrome P450 3A4 Inhibition

Yingjun Li^†§, Kalyan Kumar Pasunooti^†§, Ruo-Jing Li^†, Wukun Liu^†, Sarah A. Head^†, Wei Q. Shi^† , and Jun O. Liu*^†‡ 

^†Department of Pharmacology and Molecular Sciences and ^‡Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States

J. Med. Chem., 2018, 61 (24), pp 11158–11168

DOI: 10.1021/acs.jmedchem.8b01252

Publication Date (Web): November 27, 2018

Copyright © 2018 American Chemical Society

*E-mail: joliu@jhu.edu. Phone 410-955-4619. Fax 410-955-4520.

https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01252

■ ASSOCIATED CONTENT *S Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.8b01252. Molecular formula strings (CSV) Detail of synthesis procedures; kinetic curve of CYP3A4 enzyme activities; philipin staining of compound 15c, 15g; competition assay of itraconazole photoaffinity probe; and NMR and HPLC chart of representative compounds (PDF)

■ AUTHOR INFORMATION Corresponding Author *E-mail: joliu@jhu.edu. Phone 410-955-4619. Fax 410-955- 4520. ORCID Wei Q. Shi: 0000-0001-5453-1753 Jun O. Liu: 0000-0003-3842-9841 Author Contributions § Y.L. and K.K.P. contributed equally to this work. Notes The authors declare no competing financial interest.

■ ACKNOWLEDGMENTS This work was supported by the National Cancer Institutes (grant R01CA184103) and the Flight Attendant Medical Research Institute

4-(4-(4-(4-(((2S,4R)-2-((1H-Tetrazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)- 1-sec-butyl-1H-1,2,4-triazol-5(4H)-one (15n).

1 H NMR (500 MHz, CDCl3, δH): 8.46 (s, 1H), 7.61 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.43 (d, J = 9 Hz, 2H), 7.24 (dd, J = 8.5, 2.0 Hz, 1H), 7.03 (d, J = 9.0 Hz, 2H), 6.81 (d, J = 9.0 Hz, 2H), 5.36 (d, J = 14.0 Hz, 1H), 5.27 (d, J = 14.0 Hz, 1H), 4.38 (t, J = 5.0 Hz, 1H), 4.31−4.27 (m, 1H), 3.95 (dd, J = 8.5, 6.5 Hz, 1H), 3.88−3.83 (m, 2H), 3.53 (dd, J = 9.5, 6.5 Hz, 1H), 3.38 (br s, 4H), 3.26 (br s, 4H), 1.89−1.83 (m, 1H), 1.74−1.69 (m, 1H), 1.39 (d, J = 7.0 Hz, 3H), 0.90 (t, J = 7.5 Hz, 3H).

13C NMR (125 MHz, CDCl3, δC): 162.5, 152.8, 152.7, 152.0, 136.3, 133.9, 133.3, 131.5, 130.1, 129.6, 127.2, 123.6, 116.8, 115.4, 107.4, 74.8, 67.9, 67.6, 56.6, 52.7, 36.5, 31.0, 28.5, 19.2, 10.8.

HRMS (ESI) calcd for C34H37Cl2N9O4, 706.2424; found, 706.2425.

HPLC purity: 95.9%, tR = 10.5 min

Kalyan Kumar Pasunooti,

kalyan kumar <kalyandrf@gmail.com>

Dr. Kalyan Kumar Pasunooti pursued his PhD degree from Nanyang Technological University (NTU) (www.ntu.edu.sg), Singapore (2007 – 2011) in the field of Medicinal, Peptide & Protein chemistry. His graduate research work is focused on “Synthesis of bioactive amino acid building blocks and their applications towards the peptides and glycopeptides.” His have total 16 years of academic and industry experience with major multinationals companies & academic institutions and have worked with many collaborative professors around the globe. He authored with more than 28 international peer-reviewed high impact publications such as PNAS, Wily (Angew Chemie), RSC (Chem Comm and Org Biomol Chem), most of American Chemical Society journals (Journal of American Chemical Society, Org. Lett., ACS Chem Bio, J Comb Chem and Bioconugate Chem) and Elsevier (Tetrahedron Letters) journals which are featured many times in Chem. Eng. News and other journals. He holds American patent while work with Johns Hopkins-School of Medicine, USA and this molecule in phase II clinical trials for treating cancer.

Prior to his graduate studies, he spent 5 years as a research scientist in reputable research organizations namely GVK Bio, India (www.gvkbio.com) (2006-2007) and Dr. Reddy’s Laboratories Ltd (www.drreddys.com) (2003-2006) in India. After his PhD graduation, he worked for world leading research institutes such as Johns Hopkins-School of Medicine, USA (www.hopkinsmedicne.org) (2012-2013), Nanyang Technological University-NTU, Singapore) (www.ntu.edu.sg) (2013 – 2017) and Singapore MIT Alliance for research & Technology-SMART (www.smart.mit.edu) (2017–2018). His research interests focused on development of next generation biologically relevant peptide & protein therapeutics using their newly discovered methodologies for biomedical applications.

He has excellent skills in designing synthesis, purification and characterization of complex peptide and small molecules for medicinal chemistry applications. He gained extensive experience in Medicinal, Carbohydrate, Peptide & Protein and nucleotide & nucleoside Chemistry and familiar with modern methods and experienced in designing & executing synthesis for various bioactive peptide and small molecule inhibitors. He well versed in synthesis and characterization of complex organic molecules and with the analytical data interpretation.

 

Dr. Kalyan Kumar Pasunooti

Research Scientist at Singapore-MIT Alliance for Research & Technology Centre

Singapore’

Accomplished Peptide, Protein and Medicinal chemist with 16 years of academic and industrialexperience in the field of drug discovery and development. Specializations: Peptide & Protein Chemistry,Medicinal Chemistry (Drug Discovery and Development) and Chemical Biology.

Experience

Research Scientist

Company NameSingapore-MIT Alliance for Research & Technology Centre

Dates EmployedJul 2017 – Present

Employment Duration1 yr 4 mos

LocationSingapore

Medicinal Chemistry and Drug Discovery

Research Fellow

Company NameNanyang Technological University, Singapore

Dates EmployedOct 2013 – Jun 2017

Employment Duration3 yrs 9 mos

LocationSingapore

Peptide & Protein Chemistry and Medicinal Chemistry

Postdoctoral Fellow

Company NameJohns Hopkins Medicine

Dates EmployedMay 2012 – Sep 2013

Employment Duration1 yr 5 mos

LocationBaltimore, Maryland Area

Medicinal chemistry, Drug Discovery, Pharmacology and Chemical Biology

Postdoctoral Associate

Company NameNanyang Technological University

Dates EmployedJul 2011 – Mar 2012

Employment Duration9 mos

LocationSingapore

Organic synthesis, Peptide & Carbohydrate chemistry and Medicinal chemistry.

Senior Research Associate in Medicinal Chemistry

Company NameGVK Biosciences

Dates EmployedJan 2007 – Jul 2007

Employment Duration7 mos

LocationHyderabad Area, India

Synthesis of bioactive molecules for medicinal chemistry applications.

Junior Scientist in Medicinal Chemistry (Anti-Infective group)

Company NameDr. Reddy’s Laboratories

Dates EmployedAug 2003 – Dec 2006

Employment Duration3 yrs 5 mos

LocationHyderabad Area, India

Medicinal chemistry (Anti-Infective group): My work entails design and synthesis of newoxazolidinone derivatives and new chemical entities as novel antibacterial agents. As a researchscientist my job demanded me to carry out extensive literature survey to design possible syntheticroutes for a proposed molecule and to carry out the total synthetic part in the laborator… See more

Education

• Nanyang Technological University

  Degree NamePhD

  Field Of StudyOrganic and Bioorganic chemistry

  Dates attended or expected graduation2007 – 2011

• Osmania University

  Degree NameM. Sc

  Field Of StudyPhysical Organic Chemistry

  Dates attended or expected graduation2000 – 2002

• Kakatiya University

  Degree NameB. Sc,

  Field Of StudyMathematics Physics Chemistry

  Dates attended or expected graduation1996 – 1999

 Research Scientist at Singapore-MIT Alliance for Research and Technology

READ

ANTHONY MELVIN CRASTO

https://newdrugapprovals.org/

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

Join me on Linkedin

Join me on Facebook FACEBOOK

Join me on twitter

Join me on google plus Googleplus

Anthony Melvin Crasto Dr. | ResearchGate

 amcrasto@gmail.com

CALL +919323115463  INDIA

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