Sunday 26 July 2015

WO 2015104605.new patent on Rivaroxaban, Wockhardt Ltd



Process for preparing rivaroxaban - comprising the reaction of a thioester compound and its salts with 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one.

WO-2015104605
SHUKLA, Jagdish Dattopant; (IN).
YADAV, Ramprasad; (IN).
MERWADE, Arvind Yekanathsa; (IN).
DEO, Keshav; (IN)



Wockhardt Ltd
The synthesis of (II) via intermediate (I) is described (example 7, page 15)
4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one (formula III) is (I) and rivaroxaban is (II) (claim 1, page 16).

The present invention relates to a process for the preparation of Rivaroxaban and its novel intermediates, or pharmaceutically acceptable salts thereof. The present invention provides novel intermediates, which may be useful for the preparation of Rivaroxaban or its pharmaceutically acceptable salts thereof. The process of preparation by using novel intermediate is very simple cost effective and may be employed at commercial scale. The product obtained by using novel intermediate yield the Rivaroxaban of purity 99% or more, when measured by HPLC. The present invention especially relates to a process for the preparation of Rivaroxaban from thioester of formula II, or a pharmaceutically acceptable salt thereof, wherein R is leaving group.

front page image





A PROCESS FOR PREPARING RIVAROXABAN OR A
PHARMACEUTICALLY ACCEPTABLE SALT THEREOF

Field of Invention

The present invention relates to a process for the preparation of Rivaroxaban and its novel intermediates, or pharmaceutically acceptable salts thereof. The present invention provides novel intermediates, which may be useful for the preparation of Rivaroxaban or its pharmaceutically acceptable salts thereof. The process of preparation by using novel intermediate is very simple cost effective and may be employed at commercial scale. The product obtained by using novel intermediate yield the Rivaroxaban of purity 99% or more, when measured by HPLC. The novel thioester intermediate represented by formula II


Formula II
or a pharmaceutically acceptable salt thereof, wherein R is leaving group.

Background of the invention

The drug compound having the adopted name "Rivaroxaban" has chemical name, 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5- yljmethyl)-2-thiophenecarboxamide; and has the structural formula I,


Formula I
The commercial pharmaceutical product XARELTO® tablets, contains rivaroxaban as active ingredient. Rivaroxaban is a factor Xa inhibitor useful as oral anticoagulant. Rivaroxaban can be used for the prevention and treatment of various thromboembolic diseases, in particular of deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infract, angina pectoris and restenoses after angioplasty or aortocoronary bypass, cerebral stroke, transitory ischemic attacks, and peripheral arterial occlusive diseases.

U.S. Patent No. 7, 157,456 describes Rivaroxaban and process for the preparation thereof. The process of US '456 for rivaroxaban involves reaction of 2-[(2S)-2-oxiranylmethyl]-lH-isoindole-l,3(2H)-dione with 4-(4-aminophenyl)-3-morpholinone to provide 2-((2R)-2-hydroxy-3- { [4-(3-oxo-4-morpholiny)phenyl]amino Jpropyl)- lH-isoindole- 1 ,3(2H)-dione, which on cyclization using Ν,Ν-carbonyl diimidazole to afford 2-({5S)-2-Oxo-3-[4-(3-oxo-4-morpholiny)phenyl]-l,3-oxazolidin-5-yl}methyl)-lH-isoindole-l,3(2H)-dione, which on reacted with methylamine followed by reaction with 5-chlorothiophene-2-carbonyl chloride to provide Rivaroxaban.


Various processes for the preparation of rivaroxaban, its intermediates, and related compounds are disclosed in U.S. Patent Nos. 7,585,860; 7,351,823, 7,816,355, and 8,101,609; patent application Nos. WO 2011/012321, WO 2012/156983, WO 2012/153155, WO 2013/053739, WO 2013/098833, WO 2013/156936, WO 2013/152168, WO 2013/120464, WO 2013/164833, US 2012/0283434 and US 2013/184457; and J. Med. Chem. 2005, 48, 5900-5908.

The reported processes suffers one or the other problems like lower yield, use of carcinogenic reagents like hydrobromic acid at elevated temperature, longer reaction time, and the like.

Therefore, there is a need to develop a simple and industrially feasible process for Rivaroxaban and its intermediates or a pharmaceutically acceptable salt thereof.

Wockhardt Ltd chairman Habil Khorakiwala




process includes the step of , reacting thioester of formula IIA or pharmaceutically acceptable salt thereof
Formula IIA
with 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholine-3-one of formula III,
Formula III



Formula I


EXAMPLE 7: One pot process for Rivaroxaban
The triphenylphosphine (11.5g) and mercaptobenzothiazole disulphide (15.31g) were taken in methylene chloride and reaction mixture was stirred at 28°C -30°C for 1 hr. The 5-chlorothiophene-2-carboxylic acid (7.2g) and triethylamine (3.8 g) were added to the above reaction mixture. The reaction mixture is stirred at 0°C -25 °C for 1 hr. after 1 hr 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholine-3-one (lOg) and triethylamine (3.8g) were added. The resulting reaction mixture further stirred for 2 hrs. After completion of the reaction, water was added and stirred for 10 min. aqueous layer was separated and washed with methylene chloride. The organic layer was acidified to pH 6-7 with 2N hydrochloric acid and finally the organic layer was concentrated to get desired product. The product was purified and dried to yield Rivaroxaban.
Yield: 10.0 gm
Purity: 99.3 %
EXAMPLE 8: One pot process for Rivaroxaban
Exemplified procedure in example 7 with the replacement of solvent ethyl acetate and base potassium hydroxide were used to get the rivaroxaban.
EXAMPLE 9: One pot process for Rivaroxaban
Exemplified procedure in example 7 with the replacement of solvent acetonitile and base potassium carbonate were used, methylene chloride was added in the reaction mixture to extract the Rivaroxaban.





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Wednesday 22 July 2015

Selin Sinem Erciyas

 
Selin Sinem Erciyas

Selin is a partner specializing in Patent, Life Sciences and Trademark Law. She has been involved in a number of advisory and litigation IP matters and has handled hundreds of contentious and non-contentious oppositions and court actions involving patents and trademarks. Selin has led on a number of patent infringements, declaration of non-infringement and nullity actions. 
She is a graduate of Ankara University and holds an LL.M. degree in European and International Commercial Law from the Ludwig-Maximilians University of Munich. 
She worked at the European Patent Office as a trainee lawyer in International and Legal PCT Affairs Department. She is a member of Ankara Bar Association.
 

 





SELIN SINEM ERCIYAS

Tel:
Work +90 312 213 86 37
Email:

WORK DEPARTMENT

Intellectual Property, Life Sciences, Commercial Litigation.

POSITION

Selin Sinem Erciyas is partner in Intellectual Property Department, specializing in Patent Law and Life Sciences issues. Selin has been involved in a number of advisory and litigation matters on all fields of IP and handled hundreds of both contentious and non-contentious administrative oppositions and court actions involving patents and trademarks. Selin took responsibility in a number of patent infringement actions, declaration of non-infringement actions and nullity actions. She represents number of multinational pharmaceutical companies before the Ministry of Health in relation with regulatory issues and assists these pharmaceutical companies in regulatory examinations before the MOH. Selin is a counsel to the Association of Research-Based Pharmaceutical Companies (AIFD). She represented the AIFD at the commission meetings of the Turkish Parliament on the draft Patent Law in Turkey. Selin represented AIFD and EFPIA before the Turkish Government and EU Delegation to Turkey in relation with patent and regulatory matters.

CAREER

Gün+Partners 2006 - to date Trainee Lawyer – European Patent Office- International and Legal PCT Affairs Department- 2006.

LANGUAGES

Turkish, German, English.

MEMBER

Ankara Bar Association, AIPPI, FICPI, GRUR, MARQUES.

EDUCATION

Ludwig Maximilians University of Munich (LL.M Eur.- European and International Commercial Law 2005) Ankara University (Faculty of Law- LL.B- 2002) Arı College -1998.

Selin Sinem Yalıncaklı ERCİYAS

KORESEHITLERI CAD 17ZINCIRLIKUYU34394 ISTANBULTURKEY


Aysel Korkmaz

 
Aysel Korkmaz

Aysel is a managing associate specializing in the Patent and Dispute Resolution. She is currently working on patent litigation ranging from infringement to negative clearance actions, data protection and exclusivity particularly in the pharmaceuticals and machinery sectors. 

She also advises on insurance and reinsurance litigation and disputes, particularly high level construction and fire claims. She represents London Reinsurers in relation to the fire at the Cargo Building at the Istanbul airport. 
She is a graduate of Yeditepe University in Istanbul and holds an LL.M. in International Commercial and Business Law from University of East Anglia in the UK and she has been a member of the Istanbul Bar Association since 2005.
 
 









East Anglia Üniversitesi, Norwich, İngiltere (Yüksek Lisans, Uluslar arası Ticaret Hukuku, 2007)
Yeditepe Üniversitesi, Hukuk Fakültesi, İstanbul (Lisans, 2004)
Akyurt Sağlık Meslek Lisesi, Ankara (1999)

Experience


Managing Associate

Gün + Partners
 – Present (7 years 4 months)

Education


University of East Anglia

Master of Laws (LL.M.)

Yeditepe University

Bachelor of Laws (LL.B.)
.........

Monday 13 July 2015

Zydus Cadila Healthcare Ltd, WO 2015102017, New patent lorcaserin

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Lorcaserin.svg
Processes for the preparation of lorcaserin
Zydus Cadila Healthcare Ltd
WO 2015102017, 09 July2015 
Applicants: CADILA HEALTHCARE LIMITED [IN/IN]; Zydus Tower, Satellite Cross Roads Ahmedabad – 380 015 Gujarat (IN)
Inventors: DWIVEDI, Shriprakash Dhar; (IN).
SHAH, Alpeshkumar Pravinchandra; (IN).
GAJJAR, Samir Rameshbhai; (IN).
KHERA, Brij; (IN)



On 10 May 2012, after a new round of studies submitted by Arena, an FDA panel voted to recommend lorcaserin with certain restrictions and patient monitoring. The restrictions include patients with a BMI of over 30, or with a BMI over 27 and a comorbidity such as high blood pressure or type 2 diabetes.
On 27 June 2012, the FDA officially approved lorcaserin for use in the treatment of obesity for adults with a BMI equal to or greater than 30 or adults with a BMI of 27 or greater who “have at least one weight-related health condition, such as high blood pressure, type 2 diabetes, or high cholesterol
Useful for treating obesity.
The present invention relates to stable crystalline Form I of Iorcaserin hydrochloride of Formula (IA) and processes for its preparation. The invention also relates to processes for the preparation of lorcaserin and pharmaceutically acceptable salts, solvates and hydrates thereof.

front page image
Stable crystalline form I of lorcaserin hydrochloride and its process of preparation are claimed.  Represents the first patenting from Cadila on lorcaserin, which was developed and launched by Arena Pharma and Eisai.
In July 2015, Newport Premium™ reported that Cadila is potentially interested in lorcaserin.

Lorcaserin hydrochloride is an agonist of the 5-HT2c receptor and shows effectiveness at reducing obesity in animal models and humans developed by Arena Pharmaceuticals. It is chemically represented as (R)-8-chloro-l -methyl -2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride having Formula (I) as depicted herein below.

(IA)
U.S. Patent No. 6,953,787 B2 discloses compound of Formula (I) and pharmaceutically acceptable salt, solvates or hydrates thereof and process for preparation thereof.
U.S. Patent No. 8,168,624 B2 discloses (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride hemihydrate and process for its preparation. The patent also discloses crystalline Form I, Form II and Form III of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride. The crystalline Form
I and Form II are reported as anhydrous, non-solvated crystal forms. The crystalline Form III displays a dehydration feature calculated as a 3.7% weight loss which is consistent with the theoretical weight loss of 3.7% for a hemihydrate.
The patent discloses that anhydrous Form I and Form II readily converts to a hemihydrate, upon exposure to moisture. The dynamic vapor sorption (DVS) data for each of the three crystal forms reveals the hygroscopic nature of both Forms I and II, which readily adsorb moisture at relative humidity (RH) greater than about 40-60%. In addition, both Forms I and II were calculated to adsorb about 3.8% moisture between about 40 and about 80% RH which is consistent with conversion to the hemihydrate (Form III). X-ray powder diffraction (XRPD) carried out on both Forms I and II after the DVS cycle confirmed this conversion. In contrast, the DVS data in connection with Form III shows that it is substantially non-hygroscopic, adsorbing less than 0.5% water at 90% RH and the XRPD pattern showed no change in crystalline form after the DVS cycle.
International (PCT) Publication Nos. WO 2003/086306 Al, WO 2005/019179 Al, WO 2006/069363 Al, WO 2007/120517 Al, WO 2008/07011 1 Al and WO 2009/1 1 1004 Al disclose various synthetic approaches for the preparation of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine, its related salts, enantiomers, crystalline forms and intermediates.
International (PCT) Publication No. WO 2006/071740 Al discloses combination of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine with other agents. International (PCT) Publication No. WO 2012/030938 Al discloses various salts of lorcaserin with optically active acids.
U.S. PG-Pub No. US 2014/0187538 Al discloses amorphous lorcaserin hydrochloride and amorphous solid dispersion comprising lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers and processes for their preparation.
International (PCT) Publication No. WO 2014/135545 Al discloses solid dispersion comprising amorphous lorcaserin hydrochloride and one or more pharmaceutically acceptable water soluble polymers.
see…..https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015102017&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription


Example-7: Preparation of crystalline Form I of lorcaserin hydrochloride. In a round bottom flask, 560g of methyl ethyl ketone and 40 ml water were taken and 100 g of 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine was added and stirred for 10 minutes. The reaction mass heated to 55 to 60°C and 19.3 g of. L-(+)-tartaric acid was added slowly and stirred for one to two hours. The reaction mass was further stirred at 10-15°C for an hour and the product was filtered and washed with a mixture of methyl ethyl ketone and water. The wet cake and 150 ml methyl ethyl ketone were taken in another flask and heated to 75-80°C. 20-25 ml water was, added and stirred for an hour. Further, the reaction mass was stirred for an hour at 0-5°C. The product was filtered and washed with methyl ethyl ketone.
100 g tartrate salt of 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine and 300 mL water were taken in another round bottom flask. 200 mL methylene dichloride was added and the reaction mass was cooled to 10-20°C. 17.2 g sodium hydroxide dissolved in 89 ml water was added into the reaction mass at 10-20°C. The reaction mass was stirred for an hour at 25-30°C and the layers were separated. The solvent was removed from the organic layer under vacuum and then 100 mL ethyl acetate was added into that and distilled out. Further, 100 mL ethyl acetate was added and stirred for 15 minutes. The reaction mass was filtered through a hyflow bed and the filtrate was treated with dry HC1 gas till a pH of 1.5 to 2.5 was obtained at 0-10°C and it was stirred for about 30 minutes to an hour. The product was then filtered and washed with ethyl acetate and then dried in a vacuum oven at 50°C to 55°C for 2 hours. The product was further dried at 90°C to 110°C for 20 hours to obtain crystalline Form I of lorcaserin hydrochloride. Yield: 87.5-98.6 %.
Example-8: Preparation of crystalline Form I of lorcaserin hydrochloride

In a round bottom flask, 2.20 g lorcaserin, 30 mL methylene chloride, 17.4 mL of 1M HCI in ether were added and the mixture was stirred for 5-15 minutes at room temperature. The solvent was removed under reduced pressure to give a white solid. This solid was again dissolved in 30 ml methylene chloride, 17.4 mL of 1M HCI solution and stirred for 5-15 minutes at room temperature. The solvent was removed under reduced pressure to give lorcaserin hydrochloride. The product was dried in a vacuum oven at 50°C to 55°C for 2 hours. The product was further dried at 90°C to 110°C for 20 hours to obtain crystalline Form I of lorcaserin hydrochloride.
Example-9: Preparation of crystalline Form I lorcaserin hydrochloride
50 g of lorcaserin hydrochloride hemihydrate and 50 g of hydroxypropylmethyl cellulose (HPMC) 3CPC were mixed in a blender at 25°C to 35°C. The mixture was mixed for 30 minutes and unloaded. The solid thus obtained was dried in a vacuum oven at 50°C to 55°C for 2 hours. The product was further dried at 90°C to 110°C for 20 hours to obtain crystalline Form I of lorcaserin hydrochloride.

Pankaj R. Patel (right), Chairman and Managing Director,

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Thursday 9 July 2015

Sofosbuvir new patent...WO 2015097605, Mylan


Sofosbuvir.svg
 WO 2015097605

 Mylan Laboratories Ltd.
 Process for the preparation of sofosbuvir

 02 July 2015

The present disclosure relates to processes for the preparation of sofosbuvir or of its pharmaceutically acceptable salts. The present disclosure also provides intermediates useful in the synthesis of sofosbuvir.

Kaushik, Vipin Kumar; Vakiti, Srinivas; Ravi, Vijaya Krishna; Tirumalaraju, Bhavanisankar

Nucleoside phosphoramidates are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.
 Sofosbuvir (PSI-7977) is a nucleotide analog inhibitor of HCV NS5B polymerase, which is developed by Pharmasset and used for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen. SOVALDI® tablets contain sofosbuvir, which is chemically named as (S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2yl)methoxy)-(phenoxy)phosphorylamino) propanoate and is represented by the following chemical structure:



 

 Formula-1 Sofosbuvir and a process for the preparation are disclosed in U.S. Patent No. 7,964,580 B2 and PCT Publication No. WO 2008/121634 A2, which are hereby incorporated by reference. The present disclosure provides a novel process for the preparation of sofosbuvir or its pharmaceutically acceptable salts that employs novel intermediates.


 SUMMARY OF THE DISCLOSURE
A first aspect of the present disclosure is to provide a process for the preparation of sofosbuvir or its pharmaceutically acceptable salts. In one embodiment, the present disclosure provides a process for the preparation of sofosbuvir or its pharmaceutically acceptable salts that includes the steps of: a) reacting the compound of formula 4 with a compound of formula 5 to get a compound of formula 3;

 

4 b) hydrolyzing the compound of formula 3 to get a compound of formula 2; and



 

 3 2 c) optionally deprotecting the compound of formula 2 to get sofosbuvir of formula 1 or its pharmaceutically acceptable salts.




 



1 2 wherein R is hydrogen or any hydroxy protecting group and X is a leaving group such as tosylate, camphorsulfonate, mesylate, trifluoroacetate, trifluorosulfonate, an aryloxide, heteroaryl oxide or an aryloxide or heteroaryl oxide substituted with at least one electron-withdrawing group. In another embodiment, the present disclosure provides a novel intermediate of formula 3a.



In an additional embodiment, the present disclosure provides a crystalline compound of formula 3a, which is characterized by a powdered X-ray diffraction pattern as shown in Figure 1. In September 2014, Gilead entered into non-exclusive licensing agreements with various generic companies (including Mylan) to manufacture and supply generic sofosbuvir. In April 2015, Mylan launched its generic version of the drug as MyHep, in India


 scheme-II.

 Sofosbuvir Scheme-II In another embodiment the present disclosure provides a process for the preparation of sofosbuvir as shown in below


scheme-Ill.

 Example 3: Preparation of sofosbuvir (formula 1). N-Benzoyl Sofosbuvir (6 g) was added to 70% w/w aqueous acetic acid (90 mL) and the contents were stirred at 90-95 °C. After completion of the reaction, which was monitored by qualitative HPLC, the reaction mass was cooled to ambient temperature, diluted with water and filtered through a Hyflo filter.

Thereafter, obtained filtrate was extracted with ethyl acetate which was further washed with ~4%w/w aqueous hydrochloric acid followed by ~9%w/w aqueous sodium carbonate solution. Finally, the ethyl acetate layer was washed with water and dried.

The dried layer was concentrated under reduced pressure at 60-65 °C. Thereafter, the concentrated mass was dissolved in a mixture of 5% isopropanol in methylene dichloride and isopropyl ether was added to precipitate the product. After stirring at 0-5 °C for 2 hours, the product was filtered, washed with methylene dichloride/isopropyl ether mixture, which was recrystallized with methylene dichloride/isopropyl ether mixture to yield sofosbuvir as white crystals (3 g)......https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015097605&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription



Mylan launches Sovaldi tablets in India

Sovaldi is indicated for the treatment of chronic hepatitis-C infection as a component of a combination antiviral treatment




Pharma giant Mylan NV today said its subsidiary Mylan Pharmaceuticals has launched Gilead Sciences' Sovaldi (sofosbuvir 400mg tablets) in the country.

Sovaldi is indicated for the treatment of chronic hepatitis-C infection as a component of a combination antiviral treatment.

It is estimated that around 12 million people are chronically infected with hepatitis-C in India, Mylan said in a release.

In February this year, Gilead appointed Mylan as its exclusive distributor of Sovaldi in India.

Mylan president Rajiv Malik said they have a history of partnering with Gilead to tackle key public health issues in India and around the world, beginning with expanding access to high quality and affordable HIV/AIDS antiretrovirals.

"We are proud to continue our work together with the launch of Sovaldi as it supports our joint commitment to meeting the unmet medical needs of patients in India," Malik said.

Gregg Alton, Executive Vice-President, Corporate and Medical Affairs, Gilead Sciences said it makes an important milestone in the company's ongoing effort to make its hepatitis-C medicines accessible to as many patients, in as many places, as quickly as possible.Sovaldi is sold by Mylan's dedicated sales force as part of its Hepato Care segment.

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