Regorafenib, SHILPA MEDICARE LIMITED, New patent, WO 2016005874

WO2016005874, 

PROCESS FOR THE PREPARATION OF REGORAFENIB AND ITS CRYSTALLINE FORMS

SHILPA MEDICARE LIMITED [IN/IN]; 10/80,Second Floor,Rajendra Gunj, Raichur, ರಾಯಚೂರು , karnataka 584102 (IN)

RAMPALLI, Sriram; (IN).
UPALLA, Lav Kumar; (IN).
RAMACHANDRULA, Krishna Kumar; (IN).
PUROHIT, Prashant; (IN).
AKSHAY KANT, Chaturvedi; (IN)

The present invention relates to a process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2- carboxamide or Regorafenib (I): Formula (I). The present invention further relates to a process for the purification of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2- carboxamide or Regorafenib (I) to provide highly pure material. The present invention further relates to a process for the preparation stable crystalline material of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]- N-methyl pyridine-2-carboxamide or Regorafenib (I) useful in the preparation of pharmaceutical compositions for the treatment of cancer.

4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide or Regorafenib is low molecular weight, orally available, inhibitor of multiple protein kinases, including kinases involved in tumour angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF, BRAFV600E), and the tumour microenvironment (PDGFR, FGFR). In preclinical studies regorafenib has demonstrated antitumour activity in a broad spectrum of tumour models including colorectal tumour models which is mediated both by its antiangiogenic and antiproliferative effects. Major human metabolites (M-2 and M-5) exhibited similar efficacies compared to Regorafenib both in vitro and in vivo models.

Regorafenib was approved by USFDA in 2012 and is marketed under the brand name Stivarga®, is an important chemotherapeutic agent useful for the treatment of adult patients with metastatic colorectal cancer (CRC) who have been previously treated with, or are not considered candidates for, available therapies. These include fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy.

Regorafenib is chemically known as 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I). Regorafenib is a white to slightly pink or slightly brownish solid substance with the empirical formula C2iHi5ClF4N403 and a molecular weight of 482.82. Regorafenib is practically insoluble in water, dilute alkaline solution, dilute acid solution, n-heptane, glycerine and toluene. It is slightly soluble in acetonitrile, dichloromethane, propylene glycol, methanol, 2-propanol, ethanol and ethyl acetate. It is sparingly soluble in acetone and soluble in PEG 400 (macrogol). Regorafenib is not hygroscopic.

Regorafenib is generically disclosed in US 7351834, and specifically disclosed in US 8637553. US ‘553 disclose a process for the preparation of Regorafenib starting from 3-fluoro-4-nitrophenol. The process is as demonstrated below:

The present inventors has repeated the above process and found the following disadvantages:

Unwanted reactions are observed during the formation of Regorafenib, due to the involvement of prolonged time in process.

> Incomplete reactions were observed with excessive impurity formations due to incomplete conversion.

Removal of impurities from final product

US 2010173953 disclose Regorafenib monohydrate and crystalline Form I of Regorafenib. This patent application further discloses that crystalline Form I of Regorafenib stated in this application is obtained as per the process disclosed in WO 2005009961 A2 (Equivalent to US ‘553). The compound obtained was having a melting point of 186-206° C.

This patent publication discloses a process for the preparation of Regorafenib monohydrate comprises dissolving Regorafenib Form I obtained as per WO ‘961 in acetone

and the solution is filtered, followed by addition of water until precipitation, which was filtered and dried at room temperature

US 2010/0113533 discloses crystalline Form II of Regorafenib, comprises dissolving Regorafenib Form I obtained as per WO ‘961 in ethyl acetate, the suspension was heated to 40-45°C, addition of isocyanate solution (isocyanate in ethyl acetate) and is cooled to room temperature to yield the crystals, which was filtered, washed with ethyl acetate and dried at room temperature.

US 2010/0063112 discloses Form III of Regorafenib, process comprises of heating

Regorafenib monohydrate at 100°C or 60 min, and further 15 min at 110°C, followed by cooling to room temperature.

As polymorphism has been given importance in the recent literatures owing to its relevance to the drugs having oral dosage forms due to its apparent relation to dose preparation/suitability in composition steps/ bioavailability and other pharmaceutical profiles, stable polymorphic form of a drug has often remained the clear choice in compositions due to various reasons of handling, mixing and further processing including bioavailability and stability.

Exploring new process for these stable polymorphic forms which are amenable to scale up for pharmaceutically active / useful compounds such as 4-[4-({[4-chloro-3-(trifluoro methyl)phenyl]carbamoyl } amino)-3 -fluorophenoxy] -N-methylpyridine-2 -carboxamide or Regorafenib may thus provide an opportunity to improve the drug performance characteristics of such products.

Hence, inventors of the present application report a process for the preparation of a stable and usable form of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluoi phenoxy]-N-methylpyridine-2-carboxamide or Regorafenib, which may be industrially amenable and usable for preparing the corresponding pharmaceutical compositions. The present invention provides an improved process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fiuorophenoxy]-N-methylpyridine-2-carboxamide or Regorafenib crystalline forms specifically for crystalline polymorphic forms Form I and Form III. Crystalline polymorphic forms of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl } amino)-3 -fluorophenoxy] -N-methylpyridine-2 -carboxamide or Regorafenib obtained by the process of the present invention is non-hygroscopic and chemically stable and has good dissolution properties.

The process related impurities that appear in the impurity profile of the Regorafenib may be substantially removed by the process of the present invention resulting in the formation of highly pure material. The process of the present invention is as summarized below:

Example 1

Preparation of 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methyl amide

4-Amino-3-fiuorophenol (l lg, 0.08 moles) and of 4-Chloro-N-methyl-2-pyridinecarboxamide (8.85 g, 0.05 moles) was added to a reaction flask containing N, N-dimethylacetamide (55 ml) at 25-30°C and stirred for 15 minutes. The reaction mixture was heated to 110-115°C and then potassium tert-butoxide in tetrahydrofuran (60 ml, 0.06 moles) was added slowly over a period of 3 to 4hours. Distill off solvent at same temperature, cooled the reaction mass to 25-30°Cand water(110 ml) was added slowly over a period of 15min. and cooled the reaction mass to 0-5°C . Adjust the pH of the reaction mass in between 7 and 7.5 by using 10% aqueous hydrochloric acid (~7 ml). Stir the reaction mass for 30min at the same temperature. Filter the product, washed with water (22 mL) and Dried at 50-55 °C for 12hrs. The obtained crude material was added to the flask containing Ethyl acetate (55 mL).The reaction mass was heated to reflux to get a clear solution and stirred for 15min at reflux. Cooled to 0-5°C, stir for 2hrs at the same temperature. Filter the product, washed with Toluene (9 mL) and dried at 50-55°C for 3-5hrs.

Above recrystallized material was added to the reaction flask containing methylene dichloride (270 mL) at 25-30°C and stirred for 10-15 min. Activated carbon (1 g) and silica gel (4.4 g) was added to the reaction mass and stir for lh at the same temperature. Filter the reaction mass through hyflow bed and wash with methylene dichloride (18 mL).Distill off solvent still~l-2 volumes of methylene dichloride remains in the flask and then cooled to 25-30°C. Toluene (20 mL) was added and stirred for 30min at the same temperature. Filtered the product, washed with Toluene (9 mL) and dried at 50-55°C for 12h.

Yield: 9 gm

Chromatographic Purity (By HPLC): 98%

Example 2

Preparation of Regorafenib

4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methyl amide (4g, 0.01 moles) was added in to a reaction flask containing acetone (20 ml) at 25-30°C and stirred for 15 minutes. 4-chloro-3-trifluoromethylisocyanate (6.1g, 0.02 moles) was added slowly over a period of 5 to 10 minutes and stirred the reaction mixture 3 to 4 hours. Toluene (20 n L) was added to the reaction mass and stirred for 30 min at 25-30°C.The obtained reaction mass was filtered and washed with toluene (8 mL). Dried the material still constant weight appears to yield title product a crystalline material.

Yield: 5.5 gm

Chromatographic Purity (By HPLC): 97%

Example 3

Purification of Regorafenib using acetone and toluene mixture

4- [4-( { [4-chloro-3 -(trifluoromethyl)phenyl] carbamoyl } amino)-3 -fluorophenoxy] -N-methylpyridine-2-carboxamide (I) or Regorafenib (1 g) was added slowly in to the reaction flask containing acetone (2 mL) and toluene (3 mL) at 25-30°C and stirred for 15 minutes.

The reaction mixture was heated to 50-55°C and stirred the reaction mixture for 30 minutes.

Cooled the reaction mass to 25-30°C and stirred for 1 hour. Filter the material, washed with toluene (2 mL) and suck dried for 15 min, followed by drying at 50-55°C for 10-12h to yield

Pure 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methyl pyridine-2-carboxamide (I) or Regorafenib.

Yield: 0.88gm

Chromatographic Purity (By HPLC): 99.3 %

Example 4

Purification of Regorafenib using acetone

4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3 -fluorophenoxy] -N-methylpyridine-2-carboxamide (I) or Regorafenib (1 g) was added slowly in to the reaction flask containing acetone (5 mL) at 25-30°C and stirred for 15 minutes. The reaction mixture was heated to 50-55°C and stirred the reaction mixture for 30 minutes. Cooled the reaction mass to 0-5°C and stirred for 1 hour. Filter the material, washed with acetone (1 mL) and suck dried for 15 min. The obtained wet cake was added in to the reaction flask containing acetone (5 mL) at 25-30°C and stirred for 15 minutes. The reaction mixture was heated to 50- 55°C and stirred the reaction mixture for 30 minutes. Cooled the reaction mass to 0-5°C and stirred for 1 hour. Filter the material, washed with acetone (1 mL) and dried at 60-65°C for 12 h to yield Pure 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methyl pyridine -2-carboxamide (I) or Regorafenib.

Yield: 0.7 gm

Chromatographic Purity (By HPLC): 99.77%

Example 5

Double – Purification of Regorafenib using acetone and toluene mixture

4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] Carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I) or Regorafenib (1 g) was added slowly in to the reaction flask containing acetone (2 mL) and toluene (3 mL) at 25-30°C and stirred for 15 minutes. The reaction mixture was heated to 50-55°C and stirred the reaction mixture for 30 minutes. Cooled the reaction mass to 25-30°C and stirred for 1 hour. Filter the material, washed with toluene (2 mL) and suck dried for 15 min. The obtained wet cake was added in to the reaction flask containing acetone (2 mL) and toluene (3 mL) mixture at 25-30°C and stirred for 15 minutes. The reaction mixture was heated to 50-55°C and stirred the reaction mixture for 30 minutes. Cooled the reaction mass to 25-30°C and stirred for 1 hour. Filter the material, washed with toluene (2 mL) and dry at 60-65°C for 12h.

Yield: 0.80gm

Chromatographic Purity (By HPLC): 99.79 %

Moisture content: 0.09%

Impurity-A: 0.03%

Impurity-B: Not detected

Impurity-C: 0.02%

Example 6

Preparation of Regorafenib Form I

4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methyl amide (1.3 g, 0.004 moles) was added in to a reaction flask containing acetone (13 mL) at 25-30°C and stirred for 15 minutes.4-chloro-3-trifluoromethylisocyanate (6.6 g, 0.006 moles) wasadded slowly over a period of 15 to 20 minutes and stirred the reaction mixture 3 to 4 hours. The obtained reaction mass was filtered and washed with acetone. Dried the material still constant weight appears to yield title product a crystalline material.

Yield: 1.9 g

Chromatographic Purity (By HPLC): 98.4 %

XRPD was found to resemble similar to Fig-1.

Omprakash Inani – Chairman, Vishnukant C Bhutada – Managing Director, Namrata Bhutada – Non Executive Director, Ajeet Singh Karan – Independent Director, Carlton Felix Pereira – Independent Director, Pramod Kasat – Independent Director, Rajender Sunki Reddy – Independent Director, N P S Shinh – Independent Director,

Mr. Omprakash Inani		Mr. Omprakash Inani – CHAIRMAN Mr. Omprakash Inani has more than 30 years of Business experience. He monitors business and functional aspects of the Company along with the operations of all the plants. Additionally, he is member of Audit and Remuneration committee of Shilpa Medicare Group of Companies. Currently he is also a council Member in “Academy of Medical Education, Dental College & V.L. College of Pharmacy”, “Taranath Shikshana Samsthe, Raichur” and a trustee in “Akhil Bhartiya Maheshwari Education Trust, Pune”. Mr. Omprakash Inani is also Managing Committee Member of “Karnataka State Cotton Assn., Hubli”.
Mr. Vishnukant C. Bhutada		Mr. Vishnukant C. Bhutada – MANAGING DIRECTOR Mr. Vishnukant has vast and diverse Business experience of API and Intermediates and presently leads the core Business and functional teams which accelerate growth and performance by Innovating for Affordable solutions at Shilpa Medicare Group of Companies. He is the key decision maker with the teams for Shilpa Group for successful API and Generics formulation strategies. His untiring efforts have led the company to a leadership position in the Indian pharmaceutical domain and helped create a prominent presence for Oncology APIs globally. For his efforts on APIs Business, Mr. Vishnukant was awarded “Best Entrepreneur Award” by Late Dr Shankar Dayal Sharma – President of India in 1995. Subsequently, various state honours were conferred upon him -like -“Best Entrepreneur” from Karnataka State Govt. in 1996; “Excellence in Exports” from Vishweshwarayya Industrial Trade Centre, Bangalore 1996; and Export Excellence Award-2006” by FKCCI, Bangalore. Success has never stopped coming his way- as he was awarded “First runner up” at the Emerging India Awards London 2008 by CNBC TV18. Recently, his efforts in the Shilpa Group for environment sustainability, has led to “Best National Energy Conservation Award in Drugs & Pharmaceutical Sector for the year 2012” by Hon’ble President of India, Dr. Pranab Mukherjee.
Dr. Vimal Kumar Shrawat		Dr. Vimal Kumar Shrawat – CHIEF OPERATING OFFICER Dr. Shrawat by qualification holds degrees of M.Sc (Organic Chemistry), Ph.D. (from Delhi University) and joined Shilpa Medicare in 2009. He has vast experience of more than 25 years of working in large pharma industries like Ranbaxy/ Dabur Pharma- presently known as Fresenius Kabi Oncology Ltd., spanning across activities of R&D, Pilot and Plant Productions, QA/QC, Administration, CRAMS, Project management etc. Presently, Dr. Shrawat is spearheading the entire Operations/ Control of Shilpa Medicare. His vision of team work and time bound approach always guides and motivates teams at all operational sites. His keen interest and consistent efforts for R&D has led him to become one of key contributor in large number of Patent/applications of Shilpa Medicare.
Dr. Pramod Kumar		Dr. Pramod Kumar – MANAGING DIRECTOR(LOBA FEINCHEMIE GMBH AUSTRIA), SENIOR VICE-PRESIDENT (SHILPA MEDICARE LTD) Dr. Pramod Kumar, who by qualification holds degrees of M.Pharm, Ph.D (Pharmaceutical chemistry) and a PGDBA, joined Shilpa Medicare in 1989. Since 2009 he is Managing Director of Loba FeinchemieGmBH, Austria and driving all R&D driven commercial processes. Dr. Pramod Kumar has more than 25 years of experience in Pharmaceutical industry, spanning across activities of production, QA/QC, administration, import/export, CRAMS etc. His efforts in CRAMS have led to the formation of Joint venture company RAICHEM MEDICARE Pvt LTD with Italian companies ICE SPA / P.C.A SPA.
Mr. Prashant Purohit		Mr. Prashant Purohit – VICE-PRESIDENT-CRD Mr. Prashant Purohit by qualification holds degrees of, M.Sc.(Organic Chemistry) and Diploma in Business Management and joined Shilpa Medicare in 1996. He is presently heading Chemical R&D wings of Shilpa Medicare Group. He has vast experience of handling CRAMS and Generics APIs R&D. His vast experience of nearly 35 years in R & D and production in Pharmaceutical Industry has consistently enriched the portfolio of Shilpa Medicare Group of Companies. He is one of key contributor in large number of Patent/applications of Shilpa Medicare.
Dr. Akshay Kant Chaturvedi		Dr. Akshay Kant Chaturvedi – HEAD- CORPORATE IPM & LEGAL AFFAIRS Dr. Akshay Kant by qualification holds degrees of M.Sc, Organic Chemistry (Univ. Gold Medalist), Ph.D. (Medicinal Chem), LL.B., M.B.A. and joined Shilpa Medicare in Jun 2012. Besides above qualifications, he is a Registered Patent Agent (IN-PA-1641) at Indian patent Office. He has various certificates of Advanced Courses of IP from WIPO-Geneva, which include Patent Searching/ Drafting of Patents/ Arbitration and Mediation through WIPO/ Copyrights in Publishing Industries/ Patent Management/ Biotech IP etc. He has vast experience of about 21 years of working in large pharma industries like Jubilant Organosys Ltd./Dabur Pharma Ltd.- presently known as Fresenius Kabi Oncology Ltd./ DrReddys Labs, spanning across activities of R&D and IP-Patenting etc. Presently, Dr. Akshay is spearheading the entire IP portfolio management/ Legal Affairs of Contractual Business of Shilpa Medicare Group. His vision of innovative and creative thinking, team work and time bound approach always guide and motivate teams at all locations.His keen interest and consistent efforts for R&D has led him to become one of key contributor in large number of Patent/applications of Shilpa Medicare.
Dr. Seshachalam U.		Dr. Seshachalam U. -ASSOCIATE VICEPRESIDENT- QUALITY AND RA Dr. Seshachalam by qualification holds M.Sc (Chemistry) and Ph.D. (Chemistry) and joined Shilpa Medicare in 2008. He is presently heading Regulatory Affairs wings of Shilpa Medicare Group of Companies. He has vast experience of handling regulatory affairs related to Generics APIs. Being instrumental in Shilpa Medicare’s efforts to achieve recognition of different authorities, his key contribution in successful inspection and audit by various regulatory authorities is one of the core strength to the organization’s aims and objectives.
Mr. Sharath Reddy		Mr. Sharath Reddy – VICE-PRESIDENT PROJECTS & OPERATIONS Mr. Sharath Reddy by qualification holds M.Pharm from BITS Pilani and has overall experience of about 22 years predominately in the field of pharmaceuticals new projects and operations. His expertise of Oncology specialized equipment and Utilities designing has boosted organizations confidence to takeover new endeavors of upcoming projects with faster pace of time. His efforts have led to successfully executing Energy Saving projects of Shilpa Medicare Group of Companies and registration of the project under Clean Development Mechanism with UNFCC (Under Kyoto Protocol).
Mr. R K Somani		Mr. R K Somani – VICE-PRESIDENT FORMULATION -BUSINESS DEVELOPMENT Mr. R. K. Somani is a professional Chartered Accountant and holds a Diploma in Central Excise.He has overall business experience of more than 21 years predominately in the field of pharmaceuticals. Mr. Somani is one of the key drivers of Formulation business besides handling various key Contract Businesses of advanced oncology/ Non-Oncology APIs. He is known for successfully building formulations portfolio and spearheading the Generic sales operation.

Shilpa Medicare Limited
1st Floor, 10/80,
Rajendra Gunj,
RAICHUR ರಾಯಚೂರು – 584 102.
Karnataka, India.
Telephone: +91-8532-236494
Fax: +91-8532-235876
Email: info@vbshilpa.com

RAICHUR ರಾಯಚೂರು, Karnataka, India

Raichur

City in India

Raichur is a city municipality in the district of Raichur in the south indian state of Karnataka. Raichur, located between Krishna and Tungabhadra rivers, is the headquarters of Raichur district. Wikipedia

Historical Stone Elephants in Malayabad, Raichur Taluk ...

View of Raichur city and lake Aam Talab

///Regorafenib, SHILPA MEDICARE LIMITED, new patent, WO 2016005874, raichur, karnataka, india

WO 2015186065 NEW PATENT RELATED TO AFATINIB FROM SUN PHARMACEUTICALS, INDIA

Afatinib

439081-18-2

850140-73-7 dimaleate

Tovok, BIBW2992, Tomtovok

Boehringer Ingelheim Int,

An irreversible EGFR/HER2 inhibitor

Molecular Weight:	485.94
Molecular Formula:	C24H25ClFN5O3

N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide

4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4 - (N, N-dimethylamino)-1-oxo-2-buten-1-yl] - amino} -7 - ((S )-tetrahydrofuran-3-yloxy)-quinazoline

(E)-4-Dimethylamino-but-2-enoic acid {4-(3-chloro-4-fluoro- phenylanimo)-7-[(S)-(tetrahydro-furan-3-yl) oxy]-quinazolin-6-yl} -amide

 4 - [(3_ chloro-4 - fluorophenyl) amino] -6 - {[4_ (N, N-dimethylamino)-buten-1-oxo-_2_ - yl] amino}-7 - ((S) - tetrahydrofuran-3 - yloxy) - quinazoline

EMA:Link, US FDA:link

See photos

Sun Pharmaceutical Industries Ltd.  
Website
Directions
Pharmaceutical Company
Address: Sun House, CTS No. 201 B/1, Western Express Highway, Goregaon East, Mumbai, Maharashtra 400063

PATENT

WO2015186065

 PROCESS FOR THE PREPARATION OF 4-DIMETHYLAMINOCROTONIC ACID

SUN PHARMACEUTICAL INDUSTRIES LIMITED [IN/IN]; Sun House, Plot No. 201 B/1 Western Express Highway Goregaon (E) Mumbai, Maharashtra 400 063 (IN)

VERMA, Shyam Sunder; (IN).
SINGH, Shravan Kumar; (IN).
SINGH, Kaptan; (IN).
PRASAD, Mohan; (IN)

Afatinib is a tyrosine kinase inhibitor disclosed in U.S. Patent Nos. RE43,431 and

6,251,912. Afatinib is depicted by Formula la:

Formula la

Afatinib is presented as the dimaleate salt and is chemically designated as 2-butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(35)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2£)-,(2Z)-2-butenedioate (1 :2) having the structure depicted by Formula I:

Formula I

Processes for the preparation of 4-dimethylaminocrotonic acid or its salts are disclosed in U.S. Patent No. 7,126,025 and U.S. Publication No. 2012/0046494.

U.S. Patent No. 7,126,025 discloses a process for the preparation of 4-dimethylaminocrotonic acid or its salts by reacting but-2-enoic acid with

chlorotrimethylsilane in pyridine to obtain trimethylsilylcrotonate, which is brominated with a brominating agent under free radical conditions and in the presence of methylene chloride, acetonitrile, 1,2-dichloroethane, carbon tetrachloride, or ethyl acetate to give trimethylsilyl-4-bromocrotonate. The bromocrotonate compound is treated with dimethylamine in tetrahydrofuran to provide the 4-dimethylaminocrotonic acid.

U.S. Patent No. 7,126,025 also discloses a process for the preparation of 4-dimethylaminocrotonic acid by treating methyl or ethyl 4-bromocrotonate with dimethylamine to provide methyl or ethyl 4-dimethylaminocrotonate, which is hydrolyzed to provide the 4-dimethylaminocrotonic acid.

U.S. Publication No. 2012/0046494 discloses a process for the preparation of 4-dimethylaminocrotonic acid or its salts by converting alkyl 4-chloro-3 -hydroxy butyrate to alkyl 4-hydroxy crotonate, which is brominated to obtain alkyl 4-bromo crotonate. The alkyl 4-bromo crotonate is treated with dimethyl amine to provide alkyl 4-dimethylaminocrotonate, which is hydrolyzed to get the 4-dimethylaminocrotonic acid.

The use of pyridine or carbon tetrachloride is toxic to humans and therefore their use for the manufacture of a drug substance is not advisable. The bromocrotonate compounds, being lachrymatory in nature, are difficult to handle on an industrial scale.

The present invention provides a faster, more efficient, and industrially feasible process for the preparation of 4-dimethylaminocrotonic acid of Formula II, which is used as an intermediate for the preparation of afatinib or its salts.

A first aspect of the present invention provides a process for the preparation of 4-dimethylaminocrotonic acid of Formula II or its salts,

Formula II

comprising the steps of:

i) converting 2,2-diethoxy-N,N-dimethylethanamine of Formula III

Formula III

to ethyl-4-(dimethylamino)crotonate of Formula IV; and

Formula IV

ii) hydrolyzing the ethyl-4-(dimethylamino)crotonate of Formula IV.

A second aspect of the present invention provides a process for the preparation of afatinib of Formula la or its salts,

Formula la

comprising the steps of:

i) converting 2,2-diethoxy-N,N-dimethylethanamine of Formula III

Formula III

to ethyl-4-(dimethylamino)crotonate of Formula IV;

Formula IV

ii) hydrolyzing the ethyl -4-(dimethylamino)crotonate of Formula IV to obtain 4- dimethylaminocrotonic acid of Formula II or its salts; and

Formula II

iii) converting the 4-dimethylaminocrotonic acid of Formula II or its salts to afatinib of Formula la or its salts.

EXAMPLES

Example 1 : Preparation of ethyl-4-(dimethylamino)crotonate (Formula IV)

In a round bottom flask, 2,2-diethoxy-N,N-dimethylethanamine (Formula III, 200 g) and deionized water (100 mL) were added at about 20°C to about 25°C. To the solution, concentrated hydrochloric acid (240 mL) was added at about 25°C to about 50°C. The temperature of the reaction mixture was raised to about 70°C. The reaction mixture was stirred at about 60°C to about 70°C for about 12 hours. The reaction mixture was cooled to about 0°C. To the reaction mixture, about 200 mL of aqueous potassium hydroxide (240 g in 250 mL water) was added at about 0°C to about 10°C to attain a pH of 9.0. To the reaction mixture, ethyl(diethoxyphosphoryl) acetate (200 g) and 2-methyltetrahydrofuran (600 mL) were added at about 0°C to about 5°C. Further, 50 mL of aqueous potassium hydroxide was added to the reaction mixture at about -5°C to about 0°C to attain a pH of about 13.5. The reaction mixture was stirred at about -5°C to about 0°C for about 1 hour. The reaction mixture was filtered, and then the filtrate was recovered under vacuum at about 45°C to about 50°C to obtain ethyl-4-(dimethylamino)crotonate as an oily mass.

Yield: 89%

Example 2: Preparation of 4-dimethylaminocrotonic acid hydrochloride (Formula ID

In a round bottom flask, ethyl -4-(dimethylamino)crotonate (Formula IV, 120 g) and ethanol (480 mL) were added at about 25°C to about 35°C. To the solution, aqueous sodium hydroxide (30.5 g in 60 mL water) was added at about 10°C to about 20°C. The temperature of the reaction mixture was raised to about 50°C. The reaction mixture was stirred at about 50°C to about 55°C for about 1 hour. The reaction mixture was cooled to about 5°C. To the reaction mixture, concentrated hydrochloric acid (120 mL) was added to attain a pH of 1.5. The reaction mixture was filtered on Celite^® and washed with ethanol (50 mL). The filtrate was recovered under vacuum at about 55°C to about 60°C to obtain a crude mass. Ethanol (240 mL) was added to the crude mass, and then the reaction mixture was stirred at about 55°C to about 60°C for about 15 minutes to obtain a solution. In the solution, sodium chloride was obtained as a byproduct. The solution was filtered to discard sodium chloride. The filtrate was recovered under vacuum at about 55°C to about 60°C to obtain a residue. To the residue, isopropanol (400 mL) was added, and then the reaction mixture was stirred at about 55°C to about 60°C to obtain a clear solution. The solution was gradually cooled to about 25°C to about 30°C. The solution was further stirred at the same temperature for about 2 hours. The solid obtained was filtered, and then washed with isopropanol (50 mL). The solid was dried under vacuum at about 55°C to about 60°C to provide 4-dimethylaminocrotonic acid hydrochloride.

Yield: 63%

Sun Pharma managing director Dilip Shanghvi.


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New patent, WO 2015155704, An improved process for the preparation of pramipexole dihydrochloride monohydrate

WO 2015155704, An improved process for the preparation of pramipexole dihydrochloride monohydrate

PIRAMAL ENTERPRISES LIMITED [IN/IN]; Piramal Tower, Ganpatrao Kadam Marg Lower Parel Mumbai 400013 (IN) Inventors: PATIL, Pravin; (IN). PANSARE, Prakash; (IN). JAGTAP, Ashutosh; (IN). KRISHNAMURTHY, Dhileepkumar; (IN)

Pramipexole, (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole, represented by the following formula I (the compound of formula I), is a dopamine D2/D3 agonist used for treatment of Schizophrenia, and particularly for the treatment of Parkinson's disease. Pramipexole is marketed in the form of dihydrochloride monohydrate salt under the brand name Mirapex.

Formula I

The compound of formula I is disclosed in US Patent no. 4,886,812 (US '812 Patent). The US' 812 Patent also describes a process for the preparation of the compound of formula I and its dihydrochloride monohydrate salt involving the propylation reaction of the compound of formula II with n-propylbromide as a propylating agent in the presence of potassium carbonate by using methanol as a solvent to provide the reaction mixture. The resulting reaction mixture is then refluxed for 3 hours. After completion of the reaction, water is added to the reaction mixture. The reaction mixture is then extracted with ethyl acetate and concentrated to obtain the residue. The obtained residue is purified by silica gel chromatography and the corresponding fraction is concentrated under reduced pressure to obtain the compound of formula I which is then converted into its dihydrochloride monohydrate salt. Although, US '812 Patent describes the process for the preparation of the compound of formula I from the compound of formula II, it does not teach the process for converting the compound of formula I into its dihydrochloride monohydrate salt. Also, the process described in US '812 Patent involves propylation of the compound of formula II using 4 molar equivalents of n-propylbromide as the propylating agent. N-propylbromide is known to be carcinogenic compound and its average threshold limit value for 8 hours exposure is 10 parts per million. Therefore, on commercial scale, excess use of such a hazardous reagent is not desirable. Further, propylation of the compound of formula II using the process described in US '812 Patent generates one major impurity namely (6S)-2,6-benzothiazolediamine,4,5,6,7-tetrahydro-N²,N⁶-dipropyl. The US '812 Patent does not teach any purification method for removal of this impurity.

Indian Patent Application no. 694/MUM/2006 describes a process for the preparation of the dihydrochloride monohydrate salt of the compound of formula I involving treating the alcoholic solution of the compound of formula I with hydrochloric acid and precipitating the dihydrochloride monohydrate salt of the compound of formula I by addition of water. The process disclosed in this patent application does not involve any purification step for the purification of the compound of formula I or its dihydrochloride monohydrate salt and thus, the final active pharmaceutical ingredient (API), the dihydrochloride monohydrate salt of the compound of formula I prepared by this process does not have the desired pharmaceutically acceptable purity.

Indian patent application no. 605/MUM/2008 describes a process for the preparation of the dihydrochloride salt of the compound of formula I. The process for the preparation of the dihydrochloride salt of the compound of formula I involves the propylation reaction of the compound of formula II with n-propanal as a propylating agent by using a mixture of methanol and water as the solvent. To the resulting reaction mixture, glacial acetic acid and sodium borohydride are charged and the reaction mixture is stirred for 30-40 minutes at a temperature of 15 to 20°C. The reaction mixture is then cooled to -5 to 0°C and to the reaction mixture; second lot of n-propanal with methanol and sodium borohydride is added. The resulting reaction mixture is stirred for 30-40 minutes and quenched with brine solution. The reaction mixture is distilled under vacuum to obtain a residue. To the obtained residue, ethyl acetate and water are added. Two layers formed are separated and ethyl acetate layer is concentrated under vacuum to obtain the crude compound of formula I. The resulting crude compound of formula I is then recrystallised by using acetonitrile to yield the pure compound of formula I. To the pure compound of formula I; ethanolic hydrochloric acid solution is added. The reaction mixture is stirred for 1 hour to precipitate the solid. The precipitated solid is filtered and suspended in ethanol. The reaction mixture is then stirred at reflux temperature for 30 minutes and at room temperature for 1 hour to precipitate the dihydrochloride salt of the compound of formula I. The precipitated dihydrochloride salt of the compound of formula I is dissolved in a mixture of ethanol and water; and filtered through hyflo. The filtrate is then distilled under vacuum and recrystallised by using ethanol to obtain the pure dihydrochloride salt of the compound of formula I. The process disclosed in said patent involves the use of 3 molar equivalents of sodium borohydride and n-propanal which renders the process costlier and hence, this process is not viable for scale up.

The general process for producing the dihydrochloride monohydrate salt of the compound of formula I is depicted in the following Scheme I:

(S)-2-amino-6-propinamido-4, 5,6,7- tetrahydrobenzothiazole

sodium borohydride

o e compoun o ormu a

Scheme I

Scheme-II.

methanol-water purification

Scheme-II

Examples

Example 1:

Step A: Synthesis of compound of formula I:

To the reaction flask dichloromethane (1500 ml), methanol (1500 ml) and the compound of formula II (100 gm) were charged at a temperature of 25-30° C. The reaction mixture was cooled to a temperature of 3-8 °C and to the reaction mixture, sulphuric acid (8.69 gm); n-propanal (13.98 ml) and sodium borohydride (2.46 g) were charged. The reaction mixture was stirred for 20-30 minutes at a temperature of 3-8°C. To the reaction mixture, n-propanal (41.94g) followed by sodium borohydride (7.38g) were added in three different lots at a temperature of 3-8°C. After completion of the reaction, the reaction mixture was quenched with brine solution. The quenched reaction mixture was further concentrated up to 15-16 volumes at 50-55°C under vacuum. The reaction mixture was cooled to 15-20°C. To the reaction mixture potassium carbonate (150 g), ethyl acetate (900 ml) and methanol (100 ml) were charged. The two layers formed were separated. The organic layer was then concentrated up to 7 to 8 volumes. To the organic layer ethyl acetate (500 ml) and brine solution (240 g) were added. The two layers formed were separated. The organic layer was treated with activated charcoal and filtered through hyflo. The organic layer was then concentrated under vacuum to obtain residue. To the obtained residue diisopropyl ether (200 ml) was added and reaction mixture was stirred for 20-30 minutes at 45-50°C. The reaction mixture was then cooled at 25-30°C to precipitate solid. The precipitated solid was then filtered and washed with diisopropyl ether (200ml) to obtain the compound of formula I.

Step B: Synthesis of monohydrochlonde salt of the compound of formula I:

To the reaction flask, the compound of formula I (as obtained in the step A) and isopropyl alcohol (900 ml) were charged and the reaction mixture was stirred at a temperature of 25-35°C for 1 hour. The reaction mixture was then filtered through hyflo and washed with isopropyl alcohol (100 ml). To the filtrate cone, hydrochloric acid (42.20 ml) was added to obtain a solid. The obtained solid was then filtered and washed with isopropyl alcohol (200 ml) to yield the monohydrochloride salt of the compound of formula I.

Step C: Purification of the monohydrochloride salt of the compound of formula I:

To the reaction flask, the monohydrochloride salt of the compound of formula I (as obtained in the step B) and the mixture of methanol (300 ml) and water (5.01 ml) were charged and the reaction mixture was stirred at a temperature of 55-60°C for 2 hours. The resulting reaction mixture was then cooled to a temperature of 20-25°C to precipitate solid. The precipitated solid was then filtered and washed with isopropyl alcohol (200 ml) to obtain the pure monohydrochloride salt of the compound of formula I.

Step D: Synthesis of the dihydrochloride monohydrate salt of the compound of formula I:

To the reaction flask, the pure monohydrochloride salt of the compound of formula I (as obtained in the step C), methanol (600 ml) and cone, hydrochloric acid (33.67 ml) were charged and the reaction mass was stirred at a temperature of 3-8°C for 2 hours. To the reaction mass, activated charcoal (4g) was charged and the reaction mass was stirred for 30-45 minutes at temperature of 40-50°C. The activated charcoal was filtered through hyflo and filtrate was concentrated under vacuum to obtain residue. To the residue, isopropyl alcohol (700 ml) was charged and the reaction mass was maintained for 2-3 hours at 15-20°C to precipitate solid. The precipitated solid was then filtered and washed with isopropyl alcohol (100 ml). The solid was then dried under vacuum to yield dihydrochloride monohydrate salt of the compound of formula I. Yield 36%, purity 99.77%.

Details for HPLC analysis:

Column: Inertsil ODS-3, 125 X 4.0 mm, 5μιη

Part No: C/N 5020

Mobile phase

Mobile phase A: Buffer solution

Mobile phase B: Acetonitrile: Buffer (500:500 v/v)

Flow rate: 1.5 ml/min

Injection volume: 5 μΐ

Run time: 25 minutes

Detector: 264 nm.

Column temperature: 40°C

Diluent: Acetonitrile: Buffer (200:800 v/v)

Procedure:

For system suitability inject (5μί) of the system suitability solution. The resolution between Pramipexole (the compound of formula I) related compound and Pramipexole should not be less than 6.0. The tailing factor for Pramipexole should not be more than 2.0. Inject Standard solution in six replicates into the chromatograph. For the Pramipexole peak, the relative standard deviation should not be more than 5.0%.

Inject (5μί) of blank preparation and test solution into the chromatograph, measure the responses of all the peaks and calculate all known impurities and unknown impurities by the formula given below. In the sample chromatogram disregard any peak due to the blank. Retention time and relative retention times are given in the table below.

Calculation :- SPL (Area) Cone STD

% impurities = X X 100

STD (Area) Cone SPL

Where:

SPL (Area) - is area of peak due to impurities in sample preparation.

STD (Area) - is mean area of peak of Pramipexole in reference solution (a) for injections.

Cone SPL - concentration of Pramipexole in test solution in mg/mL

Cone STD - concentration of Pramipexole in test solution in mg/mL

Chairman of Piramal Enterprises Ltd. Ajay Piramal

Swati Piramal