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Method for Producing Olmesartan Medoxomil

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Method for Producing Olmesartan Medoxomil (19) & (11) EP 2 426 126 A1 (12) EUROPEAN PATENT APPLICATION published in accordance with Art. 153(4) EPC (43) Date of publication: (51) Int Cl.: 07.03.2012 Bulletin 2012/10 C07D 405/14 (2006.01) A61K 31/4178 (2006.01) A61P 9/12 (2006.01) A61P 43/00 (2006.01) (21) Application number: 10769711.2 (86) International application number: (22) Date of filing: 27.04.2010 PCT/JP2010/057403 (87) International publication number: WO 2010/126013 (04.11.2010 Gazette 2010/44) (84) Designated Contracting States: (72) Inventor: YANAGIHARA, Shigeo AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Tokyo 103-8426 (JP) HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR (74) Representative: Fairbairn, Angus Chisholm Marks & Clerk LLP (30) Priority: 28.04.2009 JP 2009109159 90 Long Acre London (71) Applicant: Daiichi Sankyo Company, Limited WC2E 9RA (GB) Chuo-ku Tokyo 103-8426 (JP) (54) METHOD FOR PRODUCING OLMESARTAN MEDOXOMIL (57) A method for producing high-purity olmesartan medoxomil is provided in which a solvent containing water is used in steps of tritylation and DMDO esterification of olmesartan, EP 2 426 126 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 426 126 A1 Description Field of the art 5 [0001] The present invention relates to a method for producing high-purity olmesartan medoxomil. Background of the art [0002] Olmesartan medoxomil, which is an angiotensin II receptor antagonist, is useful as an active ingredient in 10 medicaments for treatment and prophylaxis of hypertension (for example, Patent documents 1 to 5 or Non-patent doc- ument 1 and 2). Techniques for producing high-purity olmesartan medoxomil are necessary for use of olmesartan medoxomil as a medicament. [0003] Olmesartan medoxomil is produced from olmesartan by the steps described below, but there is the problem that olmesartan which is a starting material, olmesartan medoxomil dehydrate which is a by- product, or the like, is present 15 as an impurity. 20 25 30 35 40 Prior art documents 45 Patent documents [0004] 50 Patent document 1: Japanese Examined Patent Application (Kokoku) No. Hei 7-121918 (Japanese Patent No. 2082519) Patent document 2: US Patent No. 5616599 Patent document 3: International Patent Publication No. WO2006/029056 Patent document 4: International Patent Publication No. WO2006/029057 55 Patent document 5: International Patent Publication No. WO2006/073519 2 EP 2 426 126 A1 Non-patent documents [0005] 5 Non-patent document 1: J. Med. Chem., 39, 323-338 (1996) Non-patent document 2: Annu. Rep. Sankyo Res. Lab. (Sankyo Kenkyusho Nempo) 55, 1-91 (2003) Disclosure of the invention 10 Object of the invention [0006] It is an object of the present invention to provide a method for producing high-purity olmesartan medoxomil in which the contents of impurities such as olmesartan and olmesailan medoxomil dehydrate, especially the content of olmesartan medoxomil dehydrate, are reduced. 15 Means for achieving the object [0007] The present inventors have conducted intensive research on methods for producing high-purity olmesartan medoxomil in which the contents of impurities such as olmesartan, olmesartan medoxomil dehydrate and olmesartan 20 lactone are reduced, and as a result it was found, surprisingly, that it is possible to reduce the content-of olmesartan medoxomil dehydrate by employing as a reaction solvent a solvent containing water, which was thought to lower reaction efficiency in the steps of tritylation and DMDO esterification, and the invention has been completed. [0008] The invention provides a method for producing high-purity olmesartan medoxomil which comprises steps of tritylation and DMDO esterification using a solvent containing water. 25 [0009] The invention encompasses the following aspects (1) to (21). (1) A method for producing olmesartan medoxomil comprising a step in which trityl olmesartan medoxomil is produced by (i) reacting olmesartan with trityl halide and then (ii) reacting it with DMDO halide, in a solvent in the presence of a base, wherein water is present in the reaction mixture in the tritylation step (i) and the DMDO esterification step (ii). 30 (2) The production method according to (1), wherein olmesartan medoxomil is produced by removing the trityl group from trityl olmesartan medoxomil. (3) The production method according to (1) or (2), wherein the water content in the reaction mixture is 0.3 (w/w)% or more. (4) The production method according to (1) or (2), wherein the water content in the reaction mixture is from 0.3 to 35 3,0 (w/w)%. (5) The production method according to (1) or (2), wherein the water content in the reaction mixture is from 0.3 to 1.5 (w/w)%. (6) The production method according to (1) or (2), wherein the water content in the reaction mixture is from 0,4 to 1.3 (w/w)%. 40 (7) The production method according to (1) or (2), wherein 1.0 to 28 (w/w)% water to olmesartan is added to the reaction mixture. (8) The production method according to (1) or (2), wherein 1.0 to 13 (w/w)% water to olmesartan is added to the reaction mixture, (9) The production method according to (1) or (2), wherein 2.0 to 10 (w/w)% water to olmesartan is added to the 45 reaction mixture, (10) The production method according to any one of (1) to (9), wherein the reaction solvent is used in a 5 to 20 (v/w)-fold amount to olmesartan. (11) The production method according to any one of (1) to (10), wherein the reaction solvent is acetone. (12) The production method according to any one of (1) to (11), wherein the base is 1,8-diazabicyclo[5,4,0]-7- 50 undecene. (13) The production method according to any one of (1) to (12), wherein the halide portion of the trityl halide and the DMDO halide is chloride. (14) Olmesartan medoxomil obtained by the method according to any one of (1) to (13), which comprises 0.3% or less of olmesartan medoxomil dehydrate, 55 (15) Olmesartan medoxomil obtained by the method according to any one of (1) to (13), which comprises 0.25% or less of olmesartan medoxomil dehydrate. (16) Olmesartan medoxomil obtained by the method according to any one of (1) to (13), which comprises 0.2% or less of olmesartan medoxomil dehydrate. 3 EP 2 426 126 A1 (17) Olmesartan medoxomil comprising 0.3% or less of olmesartan medoxomil dehydrate, (18) Olmesartan medoxomil comprising 0.25% or less of olmesartan medoxomil dehydrate. (19) Olmesartan medoxomil comprising 0.2% or less of olmesartan medoxomil dehydrate. (20) A medicament comprising olmesartan medoxomil according to any one of (14) to (19) as an active ingredient. 5 (21) A medicament for treatment or prophylaxis of hypertension comprising olmesartan medoxomil according to any one of (14) to (19) as an active ingredient. [0010] In the present invention, olmesartan, trityl olmesartan medoxomil, olmesartan medoxomil, olmesartan medox- omil dehydrate, trityl halide and DMDO halide are compounds represented by the structural formulas described in the 10 figure above, respectively. In the structural formulas of trityl halide and DMDO halide, each X independently represents a halogen atom such as chloro, bromo or iodo. Tr represents triphenylmethyl. DMDO represents the portion in which X is eliminated in the structural formula of DMDO halide. Trityl olmesartan and trityl olmesartan medoxomil dehydrate represent compounds represented by the structural formulas described in the figure below, respectively, 15 20 25 30 [0011] The compound names of olmesartan, trityl olmesartan medoxomil, olmesartan medoxomil, olmesartan medox- omil dehydrate and DMDO chloride (DMDO-Cl) are indicated in Examples described below. 35 Effect of the invention [0012] In the present invention, it is possible to provide high-purity olmesartan medoxomil in which the contents of impurities such as olmesartan and olmesartan medoxomil dehydrate, especially the content of olmesartan medoxomil dehydrate, are reduced. 40 Mode for carrying out the invention [0013] Olmesartan as the starting material used in the production method of the present invention can be easily produced according to the method described in Japanese Examined Patent Application (Kokoku) No. Hei 7-121918 45 (Japanese Patent No. 2082519; US Patent No. 5616599) or the like. [0014] The method for producing high- purity olmesartan medoxomil by carrying out the present invention is as follows. (Tritylation step) 50 [0015] This step is a step in which trityl olmesartan is produced by reacting olmesartan with a trityl halide in a solvent in the presence of a base. [0016] Trityl chloride or trityl bromide is usually used as the trityl halide, and trityl chloride is preferable, [0017] The solvent used is not particularly restricted, and solvents which are easily miscible with water, including ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether and tetrahydrofuran and esters such as 55 methyl acetate and ethyl acetate, are preferable. Among them, ketones are preferable and acetone is most preferable. [0018] The reaction solvent is usually used in a 5 to 20 (v/w)-fold amount to olmesartan, and this is not particularly restrictive. [0019] The base used is not particularly restricted, and an amine such as triethylamine, diisopropylethylamine, pyridine 4 EP 2 426 126 A1 or 1,8-diazabicyclo[5,4,0]-7-undecene (DBU) is preferably used, and DBU is most preferable. [0020] The reaction temperature is not particularly restricted, and the reaction is usually carried out at a temperature in the range of 0°C to the boiling point of the solvent, and preferably at 20 to 60°C. [0021] Upon completion of the reaction, trityl olmesartan may be isolated by a method usually used in the field of 5 synthetic organic chemistry.
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