IVACAFTOR NEW PATENT WO 2015128882 MSN LABORATORIES PRIVATE LIMITED PRIVATE LIMITED

WO2015128882
CRYSTALLINE FORMS OF N-(2,4-DI-TERT-BUTYL-5-HYDROXYPHENYL)-1,4-DIHYDRO-4-OXOQUINOLINE-3-CARBOXAMIDE AND PROCESS FOR THE PREPARATION THEREOF
MSN LABORATORIES PRIVATE LIMITED


The present invention relates to crystalline forms ofN-(2,4-di-tert-butyl-5- hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 and also process for the preparation of said compound of formula- 1 which is represented by the following structural formula:

Brief description of the invention:
The first aspect of the present invention is to provide a crystalline form of yV-(2,4-di-tert-butyl-5-hydroxy phenyl)- l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 (hereinafter designated as crystalline form-M).
The second aspect of the present invention is to provide a process for the preparation of crystalline form-M of N-(2,4-di-tert-butyl-5-hydroxy phenyl)- 1 ,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1.
The third aspect of the present invention is to provide a crystalline form of N-(2,4-di-tert-butyl-5-hydroxy phenyl)- l ,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 (hereinafter designated as crystalline form-S).
The fourth aspect of the present invention is to provide a process for the preparation of crystalline form-S of N-(2,4-di-tert-butyl-5-hydroxy phenyl)- 1 ,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1.
The fifth aspect of the present invention is to provide a crystalline form of JV-(2,4-di-tert-butyl-5-hydroxy phenyl)- l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 (hereinafter designated as crystalline form-N).
The sixth aspect of the present invention is to provide a process for the preparation of crystalline form-N of 7V-(2,4-di-tert-butyl-5-hydroxy phenyl)- 1 ,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1.
The seventh aspect of the present invention is to provide an improved process for the preparation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)- l ,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1.
The eighth aspect of the present invention is to provide a process for the preparation of crystalline form-B of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula-1.
Examples:
Example-1: Preparation of N-(2,4-di-tert-butyI-5-hydroxyphenyl)-l,4-dihydro-4-oxo quinoline-3-carboxamide (formula-1)
A mixture of 4-oxo-l,4-dihydroquinoline-3-carboxylic acid (5 gm), N,N-dimethylformamide (50 ml), 1-Hydroxybenzotriazole (HOBT) (3.40 gm), l-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC.HC1) (5.57 gm), 5-amino-2,4-di-tert-butylphenol (7.36 gm) and triethylamine (6 ml) was stirred for 52 hrs at 25-35° C. Distilled off the solvent completely under reduced pressure. Methanol (75 ml) was added to the obtained compound at 25-35° C and stirred for 45 min at the same temperature.
The reaction mixture was cooled to 0° C to 5° C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the ■ title compound.
Yield: 5 gm; Purity by HPLC: 99.5%.
The PXRD and DSC of the obtained compound are illustrated in figure- 1 and figure-5 respectively.

Claim:
1. A process for the preparation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4- oxoquinoline-3 -carboxamide compound of formula-1 , comprising of reacting 4-oxo- l ,4-dihydroquinoline-3-carboxylic acid

with 5-Amino-2,4-di-tert-butylphenol

in presence of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl), hydroxybenzotriazole (HOBt) and a suitable base in a suitable solvent provides N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-l ,4-dihydroquinoline-3- carboxamide compound of formula-1 , optionally purifying the obtained compound from a suitable solvent provides pure compound of formula-1
Use of crystalline Form-M or Form-S or Form-N of N-(2,4-di-tert-butyl-5- hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide according to the preceding claims for the preparation of pharmaceutical composition.
..........SEE MORE.......https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015128882&recNum=1&tab=PCTClaims&maxRec=&office=&prevFilter=&sortOption=&queryString=

Dr MSN Reddy, Chairman and Managing Director, MSN Laboratories





MSN Laboratories Pvt.Ltd.
MSN House
Plot No: C-24
Industrial Estate, Sanathnagar
Hyderabad - 18 Telangana, INDIA
Phone : +91 40 30438600
Fax : +91 40 30438638

 /////// IVACAFTOR,  NEW PATENT,  WO 2015128882,  MSN LABORATORIES PRIVATE LIMITED,

NEW PATENT, WO 2015128718, HIKAL LIMITED NOVEL ECONOMIC PROCESS FOR VILDAGLIPTIN

WO2015128718, NOVEL ECONOMIC PROCESS FOR VILDAGLIPTIN
HIKAL LIMITED [IN/IN]; 3A, International Biotech Park Hinjewadi 411057 Pune (IN)
The present invention relates to a commercially viable novel process for manufacturing Vildagliptin in high yield with high chemical and chiral purity.



Vildagliptin is chemically known as l-[{(3-hydroxy-l-adamantyl)amino}acetyl]-2-cyano(s)-pyrrolidine, which is a dipeptidylpeptidase IV (DPP-IV) inhibitor and found usefulness in the treatment of diabetes mellitus. Vilda liptin is represented below:

(Formula I)
Vildagliptin (I) and the process for its preparation was first disclosed in US Patent US 6,166,063. The said process is described in scheme (1) and involves purification by flash chromatography and therefore it can not be manufactured industrially.
Scheme 1:

Formula (1 )
A similar synthesis is subsequently reported in J Med. Chem. 2003, 46, 2774-2789. An improved process is described in PCT Patent Publication WO 2004/092127A1 , which is an improvement over the process in scheme (1) that involves the use of N-chloroacetyl
proline amide (III) in situ, use of Vilsmeier reagent for dehydration of amide to nitrile and replacement of column chromatography with crystallization making the process scalable. Another very similar synthesis of Vildagliptin is described in US Patent Publication US 2008/0167479A1 that involves the modification of dehydration of N-chloroacetyl proline amide (III) in scheme (1) to corresponding nitrile (IV) by using cheaper reagent cyanuric chloride. The related key intermediates 1 -(haloacetyl)-2-cyano pyrroloine are described in several patents although not targeting the synthesis of Vildagliptin. In International PCT Patent Publication WO 98/19998A2 proline amide is treated with bromoacetyl bromide followed by dehydration with TFAA. In another PCT Patent Publication WO 01/96295A2 the method described involve chloroacetylation in THF followed by dehydration with TFAA. In PCT Patent Publication WO 2006/10.0181, a process for the synthesis of l-(haloacetyl)-2-cyano pyrroloine is described wherein the proline amide was coupled with chloroacetyl chloride followed by dehydration of amide using Vilsmeier reagent and its variants e.g., POCl₃-DMF, SOCl₂-DMF, cyanuric chloride-DMF etc).
According to PCT Patent Publication WO 2004/092127A1 the process described involve coupling of (I) with chloroacetyl chloride in DMF-isopropylacetate followed by dehydration with Vilsmeier reagent to obtain (IV) that was converted to Vildagliptin by reaction with (V) in 2-butanone in presence of KI. Although the chiral purity of the final compound is very good (>99.99%) however there is no indication about yield and chemical purity.
Scheme 2

Formula (1)
The method disclosed in PCT Patent Publication WO 2008/084383A2 is described in scheme (3) that involves in situ preparation of compound (IV) in 66% yield by reaction of- (I) with (II) in DMF-isopropyl acetate followed by the addition of cyanuric chloride and final coupling was carried out in THF to minimize the formation of dialkyl product (VI).

Although the chiral purity is very good the chemical yield is moderate that too after repeated crystallizations thus making the process not feasible commercially. According to PCT Patent Publication WO2010/022690A2 the reaction of chloroacetyl chloride with prolinamide in ether type (THF) solvent resulting triethylamine hydrochloride contaminated amide (III) followed by dehydration with TFAA gave (IV) in 77% yield. The final step to Vildagliptin is carried out in a mixture of DMF, isopropyl acetate and ethyl methyl ketone and the product with 99.9% purity is obtained through a number of crystallization step of different fractions using methyl ethyl ketone. The yield is not reported for final step. It does not appear to be attractive for commercial purpose.
Scheme 4

Formula (1)
An altogether different method for the process of Vildagliptin is described in PCT Patent Publication WO201 1/101861 Al and summarized in scheme (4). The method involves preparation of acid (XI) by two different approaches consisting of coupling bromoacetyl ester (VII) with (V) followed by hydrolysis or formation of imine (X) by the reaction of (V) with 2-oxo acetic acid followed by reduction using NaBH₄. All these steps are high yielding. Subsequently Vildagliptin is prepared by coupling of acid (XI) with (XII) using DCC-DMAP. The major drawback of the synthesis appears to be the significantly lower yield of final product after purification moreover the chiral integrity is not disclosed.
Another new approach (scheme 5) is described in PCT Patent Publication WO2012/00421 OA 1 that involves n-formyl protected acid (XIII) formed by the reaction of 3-hydroxy adamentyl amine with 50% aq. glyoxalic acid followed by the coupling of prolinamide with T3P or CDI followed by dehydration using TFAA. The hydrolysis of formyl group with acidic or basic condition produced Vildagliptin. Poor yield in the first step that involved costly 3-hydroxy adamantyl amine might be disadvantageous. Moreover the Yield of Vilgagliptin after final purification is very low and the chemical as well as chiral purity is not disclosed. Therefore this process does not look scalable.
Scheme 5

In yet another PCT Patent Publication WO 2013/083326A1 describes a process that involves the salt formation of prolinamide with chloro or bromo acetic acid followed by coupling with DCC to produce haloacetyl prolinamide which in situ reacted with 2.2 equivalent of 3-hydroxy adamentyl amine to compound (XXI) in 76.5% yield. The Vildagliptin is prepared by dehydration of compound (XXI) by POCI3 or isocyanuric acid in around 75% yields without any mention of chemical or chiral purity. The process does not offer any superiority over prior art except the use of inexpensive dehydrating agent. The use of high excess of 3-hydroxy adamantly amine however makes the process less attractive.

XXI
Accordingly therefore, based on the drawbacks mentioned in all the prior arts, there is an urgent need for economically viable synthesis of highly pure (both chemical and chiral) Vildagliptin to address mainly the drawbacks associated with the prior arts that can be defined as a process that involve use of less hazardous less costly and environment friendly reagents that will give highly pure material with fewer number of steps and finally cost effective.

Summary of the Invention
Accordingly, the present invention provides an improved process for the preparation of Vildagliptin of formula (I),

(Formula I)
which comprises the steps of:
(a) obtaining compound of formula (4) by reacting compound of formula (2) with compound of formula (3) under alkaline condition with or without a catalyst using a suitable solvent;
(b) obtaining a compound of formula (5) by hydrolyzing compound of formula (4) in acidic or basic condition with or without solvent;
(c) obtaining compound of formula (9) by reacting compound of formula (5) with (S)- pyrrolidine-2-carboxylic acid methyl ester and its salts of formula (6) in presence of a suitable acid-amine coupling agents in a suitable solvent or a combination of solvents;
(d) obtaining compound of formula (10) by reacting compound of formula (9) wherein R₂ is H with compound of formula (7) in alkaline condition in a suitable solvent or a combination of solvents thereof;
(e) obtaining compound of formula (1 1) by reacting compound of formula (9) with ammonia optionally in a suitable organic solvent;
(f) optionally obtaining compound of formula (1 1) by reacting compound of formula (5) with L-prolinamide of formula (8) in presence of a suitable acid-amine coupling agents in a suitable solvent or a combination of solvents;
(g) obtaining compound of formula (12) by reacting compound of formula (10) with ammonia optionally in a suitable organic solvent;
(h) obtaining compound of formula (13) by dehydrating compound of formula (1 1) using a dehydrating agent in a suitable solvent;
(i) obtaining compound of formula (14) by dehydrating compound of formula (12) by a compatible dehydrating agent in a suitable solvent;
(j) obtaining Vildagliptin of formula (1) by dehydrating compound of formula (11),
The above process is illustrated in the followin general synthetic scheme 6):

(3)

Example 16.1: (S)-l-[2-(3-hydroxy-adamantan-l-ylamino)-acetyl]-pyrrolidine-2-carbonitrile (Vildagliptin)
Dissolved (S)- 1 -[2 -(3 -hydroxy-adamantan- 1 -ylamino)-acetyl] -pyrrolidine-2-carboxylic acid amide (50 g, 1 eq.) by adding 2-Me-THF (250 mL, 10V) under stirring in a clean and dry 1 L 4 neck RBF equipped with magnetic stirrer, thermometer pocket, reflux condenser and an addition funnel. Meanwhile a mixture of trifluoroacetic acid (23.8 mL, 2 eq.) and trifluoroacetic anhydride (43.90 mL, 2.0 eq.) was prepared and added slowly under stirring to the reaction mass over 5-6 h. The stirring continued at 20-25°C for 1 h. The reaction mixture was cooled to 5-10 °C and a solution of K₂C0₃ (214.1 g, 10 eq.) in water (300 mL, 6V) was added slowly over 30 min and stirred for 5-6 h. After complete conversion checked by HPLC, water (200 mL, 2 V) was added and stirred for 10 min. separated organic and aqueous layers. The aqueous layer was extracted using DCM (1 ^χ 200 mL) (DCM-1). The 2-Me-THF layer was concentrated to isolate crude product. Added aqueous citric acid solution (citric acid - 98 g, 3.0 eq; water - 6V) to crude product and washed the combined aqueous layer with DCM extract obtained above (DCM-1) and then followed by DCM (3 ^χ 100 mL). Adjusted pH of aqueous layer to 9-10 after DCM wash using aq. ammonia and extracted aqueous layer using DCM (4 x 100 mL). Washed combined DCM layer with water (50 mL, IV). Concentrate DCM layer followed by stripping of ethyl acetate to isolate crude product; yield range: 75-85%. HPLC purity: > 99%. The crude was further purified by crystallization by dissolving under reflux with ethyl acetate (255 mL, 6V w.r.t to crude wt.) and IPA (85 mL, 2V) and crude compound (42.4 g) under stirring It was allowed to cool to 20-25°C and then to 0-5°C and stirred for 1 h at 0-5°C. Filtered the solid formed and washed with chilled ethyl acetate (42.5 mL, 1 V). Suck dried the solid for 3-4 h to get pure Vildagliptin 34.50 g (60-75 %); Ή NMR (CDC1₃, 400 MHz) δ: 1.52-1.69 (m, 12H); 1.78 (brs, 2H); 2.04-2.38 (m, 6H); 3.37-3.69 (m, 4H); 4.76-4.78 (m, 0.8H); 4.85-4.87 (m, 0.2H).

claim:
(1) An improved process for the synthesis of a compound of formula (I),

(I)
which comprises the steps of:
a) reacting a compound of formula (2) with a compound of formula (3) under alkaline condition with or without a catalyst using a suitable solvent to get a compound of formula (4);

(2) (3) (4)
wherein R₂ = H, C₂-C₆ alkyl group containing a double bond optionally substituted with halogen (such as CI, Br, I etc), S, O, Si etc. or a group containing C7-C₁₀ alkyl aryl optionally substituted by atoms selected from N, O, S, halogen Si etc. or the hetero atom can be a part of the chain.
b) hydrolyzing a compound of formula (4) in acidic or basic condition with or without solvent to get a compound of formula (5);

(5)
Wherein R₂ = H.
c) reacting a compound of formula (5) with L-proline alkyl ester and its salts of formula (6) in presence of a suitable acid-amine coupling agents in a suitable solvent or a combination of solvents to get a compound of formula (9);

(9) (6)
Wherein R_\ = C₁-C₃ linear, cyclic or branched chain or C7-C₁₀ alkyl aryl group and R₂ = H, C₂-C₆ alkyl group containing a double bond optionally substituted with halogen (such as CI, Br, I etc), S, O, Si etc. or a group containing C₇-C₁₀ alkyl aryl optionally substituted by atoms selected from N, O, S, halogen Si etc. or the hetero atom can be a part of the chain.
d) reacting a compound of formula (9) with a compound of formula (7) in alkaline condition in a suitable solvent or a combination of solvents thereof to get a compound of formula (10);

(10) (7)
Wherein R_P = R₃O-CO- or R₄SO₂- and Ri = Q-C₃ linear, cyclic or branched chain or C₇-C[₀ alkyl aryl group.
e) obtaining compound of formula (1 1) by reacting compound of formula (9) with ammonia optionally in a suitable or anic solvent;

(")
Wherein R₂ = H, C₂-C₆ alkyl group containing a double bond optionally substituted with halogen (such as CI, Br, I etc), S, O, Si etc. or a group containing C₇-C₁₀ alkyl aryl optionally substituted by atoms selected from N, O, S, halogen Si etc. or the hetero atom can be a part of the chain.
f) optionally obtaining a compound of formula (1 1) by reacting a compound of formula (5) with L-prolinamide of formula (8) in presence of a suitable acid-amine coupling agents in a suitable solvent or a combination of solvents;

(8)
g) reacting a compound of formula (10) with ammonia optionally in a suitable organic solvent to get compound of formula (12);

(12)
Wherein R_P = R3O-CO- or R4SO2- h) obtaining a compound of formula (13) by dehydrating a compound of formula ( 1 1) by using a dehydrating agent in a suitable solvent;

(13)
Wherein R₂ = H, C₂-C₆ alkyl group containing a double bond optionally substituted with halogen (such as CI, Br, I etc), S, O, Si etc. or a group containing C₇-Ci₀ alkyl aryl optionally substituted by atoms selected from N, O, S, halogen Si etc. or the hetero atom can be a part of the chain
i) obtaining a compound of formula ( 14) by dehydrating compound of formula (12) by a dehydrating agent in a suitable solvent;

(14)
Wherein R_P = R₃O-CO- or R₄S0₂-j) dehydrating compound of formula (1 1) using a suitable dehydrating agent in a suitable solvent to get Vildagliptin of formula (I); CLIPPED HERE        SEE MORE IN PATENT

.
..................ceremony by Mr. Jai Hiremath, Vice-Chairman and Managing Director, Hikal and his wife

(From Left)
Dr. Peter Pollak, Kannan Unni, Prakash Mehta, Sugandha Hiremath, Baba Kalyani, Jai Hiremath, Shivkumar Kheny,Sameer Hiremath.

Jai Hiremath, Chairman and Managing Director Jai Hiremath is the Chairman and Managing Director of Hikal Ltd. A Chartered Accountant from England and Wales, he has completed the Advanced Management Program for professionals and entrepreneurs from Harvard University, USA in 2004. He has more than 35 years of experience in the chemical and pharmaceutical industry. Mr. Hiremath established the company in 1988 and under his leadership; Hikal has grown to become one of leading life sciences companies globally. Mr. Hiremath is the Past President of the Indian Chemical Council (ICC) and the former Chairman of the Chemical Committee of the Federation of Indian Chamber of Commerce and Industry (FICCI). Mr. Hiremath is also a board member of Novartis (India) Ltd and National Safety Council (NSC) of India. Most recently he has been elected to serve as a board member of DCAT (Drug, Chemical and Associated Technology Association) headquartered in New Jersey, U.S.A.

Sameer Hiremath, President and Joint Managing Director Sameer Hiremath is the President & Joint Managing Director of Hikal Ltd. His responsibilities include overseeing the day to day operations of the company. Mr. Hiremath did his Chemical Engineering from MIT (Maharashtra Institute of Technology), Pune and an MBA cum M.S. degree in Information Technology from Boston University, USA. Over the years, he has held various positions at Hikal including that of Executive Director. He has over 16 years of experience in plant operations and manufacturing at Hikal.

Hikal is headquartered in Mumbai, India.
Hikal Ltd.
Great Eastern Chambers
Sector 11, CBD-Belapur
Navi Mumbai
India - 400 614
Tel: +91-22-3097 3100
Fax: +91-22-2757 4277
//////WO2015128718, HIKAL LIMITED,  NOVEL ECONOMIC PROCESS FOR VILDAGLIPTIN

MEGAFINE PHARMA (P) LTD, NEW PATENT, WO2015128875 A PROCESS FOR PREPARATION OF DABIGATRAN ETEXILATE MESYLATE AND INTERMEDIATES THEREOF

WO2015128875
A PROCESS FOR PREPARATION OF DABIGATRAN ETEXILATE MESYLATE AND INTERMEDIATES THEREOF
MEGAFINE PHARMA (P) LTD. [IN/IN]; Sethna, 4th Floor 55, Maharishi Karve Road, Marine Lines Mumbai 400002 (IN)

MEGAFINE
The present invention relates to an improved process for the preparation of Dabigatran etexilate and its acid addition salts thereof, wherein the said process substantially eliminates the potential impurities. The present invention also relates to an intermediate of Dabigatran etexilate and process for preparation thereof.

Dabigatran etexilate mesylate is an oral anticoagulant from the class of the direct thrombin inhibitors. Direct thrombin inhibitors (DTIs) are a class of medication that act as anticoagulants (delaying blood clotting) by directly inhibiting the enzyme thrombin. It is used to help prevent strokes or serious blood clots in people who have atrial fibrillation (a condition in which the heart beats irregularly, increasing the chance of clots forming in the body and possibly causing strokes) without heart valve disease. Dabigatran etexilate mesylate is approved in both US and Europe and commercially available under the brand name of Pradaxa.
Dabigatran etexilate mesylate is a double prodrug of the active substance, Dabigatran of formula (II). It is the pharmacologically active molecule formed through hydrolysis c

Dabigatran and process for its preparation was first disclosed in WO9837075 (henceforth Ό75) disclosed process involves the reaction of l-methyl-2-[N-[4amidinophenyl] aminomethyl]benzimidazol-5 -yl-carboxylicacid-N-(2-pyridyl)- N-(2-ethoxycarbonylethyl)amide hydrochloride of formula (VI) with hexylchloroformate in presence of potassium carbonate in tetrahydrofuran/water to provide l-methyl-2-[N -[4-(N -n-hexyloxycarbonylamidino) phenyl Jaminomethyl Jbenzimidazol- 5-yl-carboxylicacid- N-(2-pyridyl)- N-(2-ethoxy carbonylethyl)amide (herein after referred as dabigatran etexilate) of compound of formula (I). But WO'075 does not discuss or exemplify process for preparation of Dabigatran etexilate mesylate salt.
The key step of the disclosed process is the conversion of the nitrile of the Formula (V) into the amidine hydrochloride of formula (VI) by pinner reaction. The low yields of the pinner reaction can be derived from the water sensibility of the reaction on the one hand while the realization of the reaction is rendered more difficult on the other by the fact that the ester as well as amide, function of the molecule is susceptible to hydrolysis. According to Example 58b of said patent in an analogous manner to Example 25d 1.2 g of l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-5-benzimidazole-carboxylic acid-N-(2-pyridyl)-N-[2-(ethoxycarbonylethyl]-amide (V) is reacted with ethanol saturated with hydrochloric acid in large dilution. The evaporated crude product is then converted to hydrochloric acid salt of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-5- benzimidazole-carboxylic acid-N-(2-pyridyl)-N-[2-(ethoxycarbonyl)-ethyl]- amide compound of formula(VI) using ethanol and ammonium carbonate. The disclosed process was not suitable for large scale production because of tedious workup procedures, less yield, low purity, separation by column chromatography, which in turn results in excessive production time and costlier process and less eco-friendly. The purification step performed by using large dilutions and column chromatography makes scale up and
commercialization of the process strongly limited. Hence, this process commercially viable.

Formula (VI)
SCHEME - I
Example 1 13 of WO'075 reveals the total yield of the final compound (I) is 22%.
J.Med.Chem. 2002, 45, 1757-1766 describes a process for preparation of compound of formula (III) as depicted in scheme -II.

SCHEME - II
The process for preparation of mesylate salt of dabigatran etexilate and its polymorphic forms was disclosed in US2005/234104. The disclosed process involves the reaction of Dabigatran etexilate with methane sulfonic acid in acetone to provide Dabigatran etexilate mesylate.
According to WO 2012/153158 (henceforth W0' 158) dabigatran etexilate base compound of formula (I) is characterized by mass spectrum, 1H NMR and melting point (128-129°C).WO 2008/059029 reports the melting point of 128 ±3°C for the anhydrous form-Ill. Further W0' 158 discloses that according to WO2006/000353 dabigatran etexilate of formula (I) is prepared as described in Examples 5A and 5B by reacting the tosylate salt of (6) and hexylchloroformate in an acetone-aqueous medium, obtained product is dried at 45°C and is not characterized by analytical data. On the basis of the calculations the product is presumed to be anhydrous. Thus according to WO 2006/000353 dabigatran etexilate is prepared by crystallization from an acetone/water system (Example 5A) and in said process no drying agent or other dehydrating agent is used.
Further W0' 158 reveals that on following the example 5A of WO 2006/000353 authors failed to obtain anhydrous dabigatran etexilate but rather modification thereof containing four moles of water was observed in dabigatran etexilate.
Further W0' 158 discloses that two anhydrous and tetrahydro form of dabigatran etexilate are described in WO 2006/131491. In this international patent application no process is disclosed for preparation of dabigatran etexilate but reference is made rather to basic patent and hence the said new forms are obtained by recrystallization from ethyl acetate (anhydrous form-I and anhydrous II Examples 1 and 2) and a mixture of acetone and water (tetrahydrate form, example 3).
According to disclosure of W0' 158, WO 2007/007142 three further variants are disclosed for the preparation of dabigatran etexilate (1) starting from the tosylate salt of the amidine (6); said procedures differ from each other in the reaction conditions and the work-up method. Thus Example 6A is identical with Example 5A of WO 2006/000353, however in the working up method of new variants 6B and 6C an azeotropic distillation is employed using butyl acetate for dehydration. Accordingly in these cases actually the anhydrate of dabigatran etexilate (1) is formed and consequently the yield is lower (yield of 1 using ditosylate of 6).
As per W0' 158, an article published in 2009 (UP .^'Com. Journal 2009, 9, 20) reports a detailed process for the realization of the Pinner-reaction mentioned in the basic patent, wherein the hydrolysis of the nitrile derivative of formula (V) is carried out at room temperature with the aid of an approximately 100 molar amount of hydrochloric acid. The process involves five re-crystallization steps to obtain pure di-hydrochloride (characterized by XRD). The disadvantages of the disclosed process are high dilution ratio, low yield, process is restricted to smaller batch size at commercial scale, process results in formation of impurities and is not cost effective at commercial scale, and involve 5 purification steps thereby making the said process unsuitable at industrial scale.
WO 2010/045900 discloses the preparation of free base of dabigatran etexilate of formula (I), from oxalate salt of nitrile compound of formula (V) via monohydrochloride and dihydrochloride of the amidine of formula (VI). These salts are found to degrade and lead to the formation of impurities and thereby yield dabigatran etexilate with low purity. Thus making the process less favorable at industrial scale.
Like any synthetic compound, Dabigatran etexilate mesylate contain extraneous compounds or impurities that can come from many sources. They may be un-reacted starting materials, by-products of reaction, products ,of side reaction, and/or degradation products. To meet the regulatory quality norms, identification, isolation, synthesis and characterization of the impurities followed by their control to the ICH levels in the final drug compound is a must. Potential impurities of Dabigatran etexilate mesylate are disclosed in EP2522662 and it also addresses the stability issues associated with dabigatran etexilate mesylate. Additionally W0' 158 discloses the additional set of impurities which are formed due to the use of poor quality of hexyl chloroformate. Hence, there is a need of simple, efficient and production friendly process for the preparation of dabigatran etexilate mesylate with high purity, yield and higher throughput.

The present invention relates to an improved process for preparation of l-methyl-2- [N-[4-(N-nhexyloxycarbonylamidino)phenyl]aminomethyl]benz imidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula (I) also known as dabigatran etexilate and its methane sulfonate salt compound of formula (la), represented by the following structural formulae:

Dabigatran Etexilate Dabigatran Etexilate Mesylate
The process of the present invention is an improved, commercially viable and industrially advantageous process for the preparation of Dabigatran etexilate mesylate wherein, the said process substantially eliminates the impurities formed during the preparation of Dabigatran etexilate mesylate.
Further, the present invention also provides novel acid additions salts of ethyl N-[(2- { [(4-cyanophenyl)amino]methyl} - 1 -methyl- 1 -H-benzimidazol-5-yl0carbonyl]-N- pyridin-2-yl-beta-alaninate (DEM-III), preferably p-toluene sulfonic acid salt, represented by structural formula (V), an useful intermediate in the synthesis of highly pure compound (la).

.p-toluene sulfonic acid addition sail
Formula (V)
............................

Formula (la)

Formula (la)



n)Dabigatran etexilate mesylate:
52.6 gm ' of ethyl 3-[(2{[4(hexyloxycarbonylaminoiminomethyl)phenylamino] methyl} - 1 -methyl- 1 H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate dihydrate was added to 293 gm of acetone. The obtained mixture was heated to 40-46° C. with stirring. After a clear solution has formed, the contents of the apparatus was filtered and the filtrate was cooled to 30° C. to 36° C. 42 gm of acetone was precooled to 0° C. to 5° C and to it was added 7.5gm of 99.5% methanesulfonic acid. The obtained methanesulfonic acid solution was added in to the solution of ethyl 3-[(2- { [4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl } - 1 -methyl- 1 H-benzimi-dazole-5-carbonyl)pyridin-2-ylamino]propionate base at 26° C. to 36° C. within 15 to 40 minutes. Then the mixture was stirred for 40 to 60 minutes at 26° C. to 33° C. It was then cooled to 17° C. to 23° C. and stirred for a further 40 to 80 minutes. The crystal suspension was filtered and washed 270 ml of acetone. The product was dried under vacuum at 45-50° C. for at least 4 hours.
Yield: 53g (91.93%); Purity by HPLC: 99.81%.
CLAIM
Claim:
1. A process for the preparation of dabigatran etexilate of formula (I) or its acid addition salts thereof, comprising;
a. reacting hexyl-4-riitrophenyl carbonate compound of formula (XII) with 1- methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide (VI) or its acid addition salt in presence of a base and in a suitable organic solvent to provide dabigatran etexilate (I);

CLIPPED 2-43
44. The process as claimed in claim 18, wherein the form-I of dabigatran etexilate mesylate has purity greater than 99%; preferably 99.5%; more preferably 99.81% when determined by HPLC.
45. The process of any of the preceding claims, dabigatran etexilate of formula (I) or its acid addition salt of formula (la) has less than about 0.2% of DBIMP-1 impurity, has less than about 0.2% of DBIMP-2 impurity, has less than about 0.2% of DBIMP-3 impurity, has less than about 0.2% of DBIMP-4 impurity, has less than about 0.2% of DBIMP-5 impurity, has less than about 0.2% of DBIMP-6 impurity, has less than about 0.2% of DBIMP-7 impurity, has less than about 0.2% of DBIMP-8 impurity, has less than about 0.2% of DBIMP-9 impurity, has less than about 0.2% of DBIMP-10 impurity, has less than about 0.2% of DBIMP-11 impurity, has less than about 0.2% of DBIMP-12 impurity.

DBIMP-8

DBIMP- 1 DBIMP-12

ABOUT MEGAFINE

PROFILE

The company's R&D strengths are in creating intellectual property assets by developing non-infringing, novel, cost effective and environmentally friendly processes for APIs and finding easier solutions to complex chemistry challenges. We are specialized in constructing chiral molecules with strong expertise and experience in the resolution processes. Our R&D team consists of more than 60 qualified scientists with extensive expertise and experience in Process Research and Development activities for APIs and their critical intermediates. Our main philosophy is backward integration of APIs synthesis starting from basic raw material, thereby being self-dependent for critical intermediates to control cost and quality. Solid state studies, particularly polymorphism and particle size are proving to be bottle neck in marketing newer APIs. At Megafine, scientists are skilled in providing solutions to the problems associated with them. We have two research centres, one at Nashik, Maharashtra, India and another at Vapi, Gujarat, India. R&D centre at Vapi is mainly focused to provide critical intermediates with high purity and low cost through intensive research to our main R&D centre at Nashik and as well as to API manufacturers around the globe. A well - equipped R&D centre is supported by kilo lab having reactors from 5 lit to 250 lit, SSR/GLR vessels to solve scale-up issues at production. We are very specific in creating online documentations for various phases of process development including the scale-up, safety, and engineering reports which help production to have a safe and robust process and also to support regulatory filings.

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Megafine, established in 1995, is a privately owned and professionally managed enterprise with it's corporate office in Mumbai and two multipurpose manufacturing sites at Vapi & Nashik in India, both successfully inspected by US-FDA & the Nashik facility is also approved by EMEA, PMDA & KFDA. Both the plants are also certified by WHO GMP, ISO 9001:2008, 14001:2004 & OHSAS 18001:2007 and have been audited by several Innovators and leading Generic companies from time to time.
Megafine provides innovative & integrated API solutions with it's decades of experience and skill in the development of novel chemical processes catering to the global drug discovery and generic companies. Our continuous investment in research and development generates a steady flow of APIs enabling timely introduction of new products in the market. Megafine is committed to respecting third party intellectual property rights, manufacture products which are commercially competitive and meet the most stringent quality standards. Besides manufacturing its own Active Pharmaceutical Ingredients (APIs) & Advanced Intermediates, we also contract manufacture for global drug discovery and generic companies.
Our focus is on niche products; with a presence in more than 40 countries. Our partners are essentially drug discovery and generic drug companies across the globe for whom we develop a range of new niche products in select therapeutic categories like Anthelmintic, Cardiology, Urinary Incontinence, CNS (Central Nervous System), & a few others. We supply a wide range of high quality generic and custom manufactured APIs in volumes that range from a few grams to tons.
Megafine has special expertise in Polymorphs and Chiral products.
A perfect blend of Human talent, R&D Labs, Pilot Plant & cGMP manufacturing facilities backed by our Quality Assurance, Regulatory Affairs and Intellectual Property cell gives Megafine an edge.
Our regulatory team is well trained & experienced to comply with US-FDA, EDQM, Japanese PMDA & other regulatory authority requirements. The company has over 150 regulatory filings across the globe for its APIs to its credit with an impressive pipeline.

/////////MEGAFINE PHARMA (P) LTD, NEW PATENT, WO 2015128875  A PROCESS FOR PREPARATION OF DABIGATRAN ETEXILATE MESYLATE AND INTERMEDIATES THEREOF

Cefdinir is a third-generation oral cephalosporin antibiotic sold under the brand names Cefzon and Omnicef

As of 2008, cefdinir, as Omnicef, was the highest-selling cephalosporin antibiotic in the United States, with more than US$585 million in retail sales of its generic versions alone.^[1]

It was discovered by Fujisawa Pharmaceutical Co., Ltd. (now Astellas) and introduced in 1991 under the brand name Cefzon.^[2][3]Warner-Lambert licensed this cephalosporin for marketing in US from Fujisawa.^[4] Abbott obtained U.S. marketing rights to Omnicef (cefdinir) in December 1998 through an agreement with Warner-Lambert Company.^[5] It was approved by FDA on Dec 4, 1997.^[6] It is available in US as Omnicef by Abbott Laboratories and in India as Cednir by Abbott, Kefnir by Glenmark and Cefdiel by Ranbaxy.

The ongoing patent battle relating to Cefdinir polymorphism and crystalline forms is described from a scientific point of view. This case study illustrates some of the strategies adopted by generic bulk manufacturers to challenge originator's patents on polymorphic forms. 

The filing of patents claiming new crystalline forms, usually 4−6 years after the original product patent, is a typical strategy applied by such companies to extend patent protection. This patent protection approach by big pharma forces generic bulk producers to discover and file patents on new polymorphs if they want to market the drug after expiry of the product patents. 

Polymorphism is of paramount importance due to its effect on some physical characteristics of powders such as melting point, flowability, vapour pressure, bulk density, chemical reactivity, apparent solubility and dissolution rate, and optical and electrical properties. In other words, polymorphism can affect drug stability, manipulation, and bioavailability

The patent strategy adopted by Fujisawa to protect the life cycle of Cefdinir (1) was based on the filing of a second patent, several years after the product patent, covering the commercialised anhydrous crystalline form of the drug. As a consequence, to overcome the Cefdinir (1) patent protection of the U.S. and Japanese markets, generic bulk producers had to discover a new crystalline form, with the same bioavailability as the marketed one. 

The situation, with competition among several companies, resulted in the generation of a patent “tangle”. In addition to overcoming the Fujisawa patent, the principal aim of generic bulk producers was to generate a competitive market advantage by protecting their new crystal form.

This patent extended the protection of Cefdinir (1) marketed in the United States up to December 2011, 9 years after the expiration of the patent covering the structure........Abbott US2005/0059818

An invention must:

A. be novel.

B. not be obvious for a person skilled in the art

C. be useful.

D. contain sufficient details to allow others to reproduce the invention.

Crystalline form patents represent a small but very important segment of product patents because of the possibility to extend the medicine market protection, thus delaying competition from generic firms. We think that for these specific types of patent applications, the following basic rules should be applied:

1. The crystalline form cannot be characterised by a single technique.

2. When a pharmaceutical application or advantage is claimed to justify the usefulness of the patent application, volatile impurities must comply with ICH guidelines,23 and the new crystalline form must be sufficiently stable to be used as a medicine.

3. A new polymorph must have an advantage over the one previously described. All the patent applications described in this paper do not show a clear advantage of the claimed polymorph with respect to Fujisawa's anhydrous form. The claiming of a crystalline form or solvate without a clear understanding of the usefulness is common to several patent case studies. From our direct experience, an interesting example is Cabergoline (Parkinson's disease):  the originator and generic companies claimed up to 14 crystalline forms and solvates.24 What is the meaning of all these patent applications? Where is the advantage with respect to the previously reported crystalline forms or solvates?

Figure The priority filing dates of all the patents claiming Cefdnir crystalline forms are reported.

Astellas Pharma Inc. (アステラス製薬株式会社 Asuterasu Seiyaku Kabushiki-gaisha^?) is a Japanese pharmaceutical company, formed on 1 April 2005 from the merger of Yamanouchi Pharmaceutical Co., Ltd. (山之内製薬株式会社 Yamanouchi Seiyaku Kabushiki-gaisha^?) and Fujisawa Pharmaceutical Co., Ltd. (藤沢薬品工業株式会社 Fujisawa Yakuhin Kōgyō Kabushiki-gaisha^?).

Polymorphisms and Patent, Market, and Legal Battles:  Cefdinir Case Study

Walter Cabri ,*^† Paolo Ghetti , Giovanni Pozzi , and Marco Alpegiani

Antibioticos S.p.A., Research & Development, Strada Rivoltana km 6/7, 20089 Rodano, Milano, Italy

Org. Process Res. Dev., 2007, 11 (1), pp 64–72

DOI: 10.1021/op0601060

 http://pubs.acs.org/doi/abs/10.1021/op0601060

References

1.  "2008 Top 200 generic drugs by retail dollars"  PDF (399.4 KB). Drug Topics (May 26, 2009). Retrieved on July 24, 2009.
2.  http://www.astellas.com/en/corporate/news/detail/astellas-filed-lawsuit-against.html
3.  http://wenku.baidu.com/view/a2ef6330b90d6c85ec3ac6fa.html
4.  http://www.elsevierbi.com/publications/the-pink-sheet/52/005/comprecin-has-excellent-chance-to-reach-us-market-this-year-dupont-prophenytoin-crosslicense-deal?p=1
5.  http://www.globenewswire.com/newsarchive/mrx/pages/news_releases.html?d=94045
6. http://www.drugs.com/mtm/cefdinir.html
7.  http://www.toku-e.com/Assets/MIC/Cefdinir.pdf
8.  "Omnicef capsules Patient Information" (PDF). Abbott Laboratories. February 2004. Archived from the original (PDF) on 2006-11-18. Retrieved 2006-11-24.

External links

• Medline Plus: Cefdinir

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