奧美沙坦合成方法

1、(19 E P 2 298 763A 1&(11EP 2 298 763A1(12EUROPEAN PATENT APPLICATIONpublished in accordance wi th Art. 153(4 EP C(43Date of publication:(51Int Cl.:C07D 405/14(2006.01A61K 31/4178(2006.01C07C 67/313(2006.01C07C 69/716(2006.01C07D 233/90(2006.01C07D 403/10(2006.01(86International application number:PC

2、T/JP2009/060419(87International publication number:(84Designated Contracting States:AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK TRChuo-kuTokyo 103-8426 (JP(72Inventors:SATO, KojiTokyo 134-8630 (JPYAGI, TsutomuTokyo 134-8630 (JPSAKURATANI, Ken

3、ji Tokyo 134-8630 (JPTANI, YuichiroTokyo 134-8630 (JP(74Representative: Nieuwenhuys, William Francis etalMarks & Clerk LLP 90 Long Acre LondonWC2E 9RA (GB(54METHOD FOR P RODUCING 1-BIPHENYLMETHYLIMIDAZOLE C OMPOUND(57The present invention provides a method for producing a 1-biphenylmethylimidazole c

4、ompound having superiorangiotensin II receptor antagonistic activity, or an intermediate thereof.The present invention provides a method for producing a compound having the formula (5 (R 1, R a : H, an alkyl group by oxidizing a compound having the formula (1 (R a : H, an alkyl group using an oxidiz

5、ing agent in the presence of a radical initiation reagent, and then reacting with an ammonia-generating reagent and a compound having the formula R 1CHO (R 1: H, an alkyl group or a compound having the formula R 1C(OR b 3 (R 1: H, an alkyl group; R b : an alkyl group.5 10 15 20 25 30 35 40 45 50 55D

6、escriptionField of the art0001The present invention relates to a novel method for producing a 1-biphenylmethylimidazole compound pref-erably the following Compound (13a having a superior angiotensin II receptor antagonistic activity, or an intermediate thereof.Background of the art0002Method V (see

7、Non-patent reference 1 or Method W (see Example 79 of Patent reference 1 is known as a method for producing a 1-biphenylmethylimidazole compound having an angiotensin II receptor antagonistic activity. 55 55 55 101520253035404550550003Method X is known as a method for producing an imidazole compound

8、 using tartaric acid diester (see Patentreference 2.5 10 15 2025 30 35 40 45 50 550004Method Y is known as a method for producing a 1-(tetrazolylbiphenylmethylimidazole compound from a 1-(cy-anobiphenylmethylimidazole compound (see Patent reference 3.0005Method Z is known as a method for producing a

9、 1-biphenylmethyl-4-(1-hydroxy-1-methylethylimidazole com- pound from a 1-biphenylmethyl-4-methoxycarbonylimidazole compound (see Patent reference 4.5 10 1520 25 30 35 40 45 50 550006From an industrial viewpoint, a production method is desired which is superior in that the reaction proceeds efficien

10、tly in an industrial reaction vessel such as a reactor; that it has high total yield; that it has high reaction selectivity; that it provides the desired compound with high purity; that it has a small number of reaction steps; that the reaction is safe; and the like.Prior art referencesPatent refere

11、nces0007Patent reference 1: JP (Toku-Kou-Hei 7-121918 (the corresponding US Patent: US 5616599Patent reference 2: JP (Toku-Kai 2004-217542Patent reference 3: JP 3521304Patent reference 4: International patent publication pamphlet WO 2007/047838Non-patent reference0008Non-patent reference 1: Annual R

12、eport of Sankyo Research Laboratories, 2003, vol. 55, p. 1-91Disclosure of the inventionObject of the invention0009As a result of conducting extensive studies on a method for producing a 1-biphenylmethylimidazole compound preferably the following Compound (13a or an intermediate thereof, the invento

13、rs of the present invention found that the novel production method of the present invention is superior to known production methods from an industrial viewpoint. The present invention was completed on the basis of the above findings.Means for achieving the object0010The present invention provides a

14、novel method for producing a 1-biphenylmethylimidazole compound prefer-ably the following Compound (13a having a superior angiotensin II receptor antagonistic activity, or an intermediate thereof. The production method of the present invention is indicated by the following Method A Method A(1 and Me

15、thod A(2 or Method B. 55 555 10 15 20 25 30 35 4045 50 550011In the present invention, R1 represents a C1-C4 alkyl group, R a represents a C1-C4 alkyl group, R b represents a C1-C6 alkyl group, X represents a chloro group, a bromo group or an iodo group, and Tr represents a triphenylmethyl group.001

16、2In one aspect thereof, the present invention provides the inventions of 1 to 33 described below: 1 A method for producing a compound having the following formula (5:5 1015 20 25 30 35 40 45 50 55(wherein R1 represents a hydrogen atom or a C1-C4 alkyl group, and R a represents a hydrogen atom or a C

17、1-C4 alkyl groupby oxidizing a compound having the following formula (1:(wherein R a represents a hydrogen atom or a C1-C4 alkyl group using an oxidizing agent in the presence of a radical initiation reagent,and then reacting the resulting compound with an ammonia-generating reagent and a compound h

18、aving the formula R1CHO (wherein R1 represents a hydrogen atom or a C1-C4 alkyl group or a compound having the formula R1C (OR b3 (wherein R1 represents a hydrogen atom or a C1-C4 alkyl group, and R b represents a C1-C6 alkyl group;2 The production method according to 1, wherein R1 is a 1-propyl gro

19、up and the compound having the formula R1CHO is used;3 The production method according to 1 or 2, wherein R a is an ethyl group;4 The production method according to any one of 1 to 3, wherein the radical initiation reagent is an azobis compound;5 The production method according to any one of 1 to 3,

20、 wherein the radical initiation reagent is 2,2-azobis(4-methoxy-2,4-dimethylvaleronitrile;6 The production method according to any one of 1 to 5, wherein the oxidizing agent is a halogenosuccinimide compound or a dihalogenohydantoin compound;7 The production method according to any one of 1 to 5, wh

21、erein the oxidizing agent is 1,3-dibromo-5,5-dimeth-ylhydantoin;8 The production method according to any one of 1 to 7, wherein the ammonia-generating reagent is an am-monium salt;9 The production method according to any one of 1 to 7, wherein the ammonia-generating reagent is ammonium acetate;10 Th

22、e production method according to any one of 1 to 9, wherein the reaction is carried out under light-shielding conditions;11 The production method according to 1, wherein R1 is a 1-propyl group, R a is an ethyl group, the radical initiation reagent is an azobis compound, the oxidizing agent is a halo

23、genosuccinimide compound or a dihalogenohydantoin compound, the ammonia-generating reagent is an ammonium salt, and the compound having the formula R1CHO is used;12 The production method according to 1, wherein R1 is a 1-propyl group, R a is an ethyl group, the radical initiation reagent is 2,2-azob

24、is(4-methoxy-2,4-dimethylvaleronitrile, the oxidizing agent is 1,3-dibromo-5,5-dimethylhydan-toin, the ammonia-generating reagent is ammonium acetate, the compound having the formula R1CHO is used, and the reaction is carried out under light-shielding conditions; 13 A method for producing a compound

25、 having the formula (2:5 1015 20 25 30 35 40 45 50 55(wherein R a represents a hydrogen atom or a C1-C4 alkyl groupby oxidizing a compound having the formula (1:(wherein R a represents a hydrogen atom or a C1-C4 alkyl group using an oxidizing agent in the presence of a radical initiation reagent;14

26、The production method according to 13, wherein R a is an ethyl group, the radical initiation reagent is an azobis compound, and the oxidizing agent is a halogenosuccinimide compound or a dihalogenohydantoin compound; 15 The production method according to 13, wherein R a is an ethyl group, the radica

27、l initiation reagent is 2,2-azobis(4-methoxy-2,4-dimethylvaleronitrile, the oxidizing agent is 1,3-dibromo-5,5-dimethylhydantoin, and the re-action is carried out under light-shielding conditions;16 A method for producing a compound having the formula (10a: by reacting a compound having the formula

28、(9b:5 10 1520 25 30 35 40 45 50 55(wherein R a represents a hydrogen atom or a C1-C4 alkyl group with an inorganic azide salt having the formula M (N3n (wherein M represents an alkali metal or an alkaline earth metal, and n represents 1 or 2 in an aromatic hydrocarbon in the presence of a cyclic ami

29、ne salt,and hydrolyzing the resulting compound;17 The production method according to 16, wherein R a is an ethyl group;18 The production method according to 16 or 17, wherein the inorganic azide salt is sodium azide;19 The production method according to any one of 16 to 18, wherein the cyclic amine

30、salt is a hydrochloride ora hydrobromide of N-methylpyrrolidine, N-methylpiperidine, N,N-dimethylpiperazine, N-methylmorpholine, N-meth-ylthiomorpholine, N-methylhomopiperidine or N,N-dimethylhomopiperazine;20 The production method according to any one of 16 to 18, wherein the cyclic amine salt is a

31、 hydrochloride ora hydrobromide of N-methylpiperidine, N,N-dimethylpiperazine, N-methylmorpholine or N-methylthiomorpholine;21 The production method according to any one of 16 to 18, wherein the cyclic amine salt is N-methylpiperidine hydrochloride, N,N-dimethylpiperazine dihydrochloride or N-methyl

32、morpholine hydrochloride;22 The production method according to 16, wherein R a is an ethyl group, the inorganic azide salt is sodium azide, and the cyclic amine salt is a hydrochloride or a hydrobromide of N-methylpyrrolidine, N-methylpiperidine, N,N-dimethylpiperazine, N-methylmorpholine, N-methylt

33、hiomorpholine, N-methylhomopiperidine or N,N-dimethylhomo-piperazine;23 The production method according to 16, wherein R a is an ethyl group, the inorganic azide salt is sodium azide, and the cyclic amine salt is N-methylpiperidine hydrochloride, N,N-dimethylpiperazine dihydrochloride or N-meth-ylmo

34、rpholine hydrochloride;24 A method for producing a compound having the formula (9:(wherein R1 represents a hydrogen atom or a C1-C4 alkyl group, and R a represents a hydrogen atom or a C1-C4 alkyl group by reacting a compound having the formula (14:5 10 1520 25 30 35 40 45 50 55(wherein R1 represent

35、s a hydrogen atom or a C1-C4 alkyl group, and R a represents a hydrogen atom or a C1-C4 alkyl group with a compound having the formula MeMgX (wherein X represents a chloro group, a bromo group or an iodo group;25 The production method according to 24, wherein R1 is a 1-propyl group, and R a is an et

36、hyl group;26 The production method according to 24 or 25, wherein X is a chloro group;27 The production method according to 24, wherein R1 is a 1-propyl group, R a is an ethyl group and X is a chloro group;28 A method for producing a compound having the formula (13a:a part of the reaction steps of w

37、hich comprises the production method according to any one of 1 to 12; 29 A method for producing a compound having the formula (13a:5 10 1520 25 30 35 40 45 50 55a part of the reaction steps of which comprises the production method according to any one of 13 to 15;30 A method for producing a compound

38、 having the formula (13a:a part of the reaction steps of which comprises the production method according to any one of 16 to 23; 31 A production method of a compound having the formula (13a:5 10 15 20 25 30 35 40 45 50 55a part of the reaction steps of which comprises the production method according

39、 to any one of 24 to 27;32 A compound having the formula (14a:(wherein, R a represents a hydrogen atom or a C1-C4 alkyl group, which is a synthetic intermediate for producing the compound having the formula (13a:33 The compound having the formula (14a according to 32, wherein R a is an ethyl group.0

40、013In the present invention, each of the substituents has the meanings indicated below.0014C1-C4 alkyl in the case of R1 represents a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms, and may be for example methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl or 2-methyl-2-prop

41、yl, preferably 1-propyl or 1-butyl, and most preferably 1-propyl.0015C1-C4 alkyl in the case of R a represents a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms, and may be for example methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl or 2-methyl-2-propyl, preferably methyl

42、 or ethyl, and most preferably ethyl.0016R a is preferably a C1-C4 alkyl group.0017C1-C6 alkyl group in the case of R b represents a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms, and may be for example methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 1-pen

43、tyl or 1-hexyl, preferably methyl or ethyl, and most preferably methyl.0018Alkali metal in the case of M is preferably lithium, sodium or potassium, and most preferably sodium. Alkaline earth metal in the case of M is preferably magnesium or calcium.0019X is preferably a chloro group or a bromo grou

44、p, and most preferably a chloro group.0020Compounds related to the present invention can form hydrates or solvates by placing in air or mixing with water or an organic solvent. These hydrates or solvates are included in compounds related to the present invention. 0021 In the present invention, the c

45、hemical purity of a compound or the percentage content of a compound as an5 10 15 20 25 30 35 40 45 50 55impurity can be determined in accordance with known methods in the field of organic chemistry, and can be determined according to, for example, the peak area ratio as determined by high-performan

46、ce liquid chromatography (hereinafter also referred to as HPLC or weight %, and preferably according to the peak area ratio as determined by HPLC. The measurement conditions of HPLC can be suitably selected.0022In the present invention, 4-(1-hydroxy-1-methylethyl-2-propyl-1-2-(1H-tetrazol-5-ylbiphen

47、yl-4-ylmethyl-1H-imidazole-5-carboxylic acid indicates compound (10a:and (5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl 4-(1-hydroxy-1-methylethyl-2-propyl-1-2-(1H-tetrazol-5-ylbiphenyl-4-ylmethyl-1H-imidazole-5-carboxylate indicates compound (13a:0023The production method of the present invention can be c

48、arried out in accordance with the following Method A or Method B. 55 555 10 15 20 25 30 35 4045 50 550024In Method A or Method B, R1, R a, R b, M, X and Tr have the same meanings as defined above. In the present invention, a compound having the formula (1 is also referred to as Compound (1. This app

49、lies similarly to other numbered compounds.0025There are no limitations on the solvent used in the reactions of each of the steps of Method A or Method B provided it does not inhibit the reaction and dissolves the starting materials to a certain degree, and the solvent is selected, for example, from

50、 the following solvent group. The solvent group consists of aliphatic hydrocarbons such as hexane, pentane, petroleum ether or cyclohexane; aromatic hydrocarbons such as benzene, toluene or xylene; isoparaffin hydrocarbons such as Isopar E (Shell, Isopar G (Shell, Isopar H (Shell, Isopar L (Shell, I

51、sopar M (Shell, IP Clean LX (Idemitsu, IP Clean HX (Idemitsu, IP Solvent 1620 (Idemitsu, IP Solvent 2028 (Idemitsu, Marcasol R (Maruzen, Marcasol 8 (Maruzen, Isosol 300 (Nippon Petrochemical, Shellsol TG (Shell, Shellsol TK (Shell or Shellsol TM (Shell; halogenated hydrocarbons such as methylene chl

52、oride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, cyclopentyl methyl ether, tet-rahydrofuran, 3-methyltetrahydrofuran, dioxane, dimethoxyethane (such as 1,2-dimethoxyethane or diethylene g

53、lycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone; esters such as ethyl acetate, propyl acetate or butyl acetate; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile;5 10 15 20 25 30 35 40 45 50 55carboxylic acids

54、such as acetic acid or propionic acid; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol or 2-methyl-2-propanol; amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphoramide; sulfoxides s

55、uch as dimethyl sulfoxide; sulfolanes such as sulfolane; water; and mixtures thereof.0026In the reactions of each of the steps of Method A or Method B, the reaction temperature differs depending on the solvent, the starting material(s, the reagent(s and the like, and is suitably selected in accordan

56、ce therewith. In addition, the reaction time also differs depending on the solvent, the starting material(s, the reagent(s, the reaction temperature and the like, and is suitably selected in accordance therewith.0027In the reactions of each of the steps of Method A or Method B, the desired compound

57、of each step can be isolated from the reaction mixture in accordance with a known method after the completion of the reaction. The desired compound can be obtained by, for example, (i filtering off an insoluble material such as a catalyst as necessary, (ii adding water and a solvent immiscible with

58、water (such as ethyl acetate to the reaction mixture followed by extracting the desired compound, (iii washing the organic layer with water as necessary and drying using a desiccant (such as anhydrous magnesium sulfate, and (iv evaporating the solvent. In addition, the desired compound can also be obtained by adding a