NZ263008A - Preparation of optionally bridged 5,6,7,8-tetrahydro-1h-1,3,4a,8a-tetraaza-cyclopentanaphthalene-4,9-dione derivatives by selective reduction of the corresponding - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £63008 New Zealand No. International No. 263008 PCTAJS94/01949 Priority Date(s):...

Complote Specification F.ic d:..

Class: (6) 2 ij DEC 19S6' Publication Date: P.O. Journal No: - - *91 ia\ m J s 1 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of Invention: Process for production of an imidazole derivative Name, address and nationality of applicant(s) as in international application form: THE UPJOHN COMPANY, of 301 Henrietta Street, Kalamazoo, Ml 49001, United States of America ■) c\ US £830 0 8 PROCESS FOR PRODUCTION OF AN IMIDAZOLE DERIVATIVE BACKGROUND OF THE INVENTION The present invention relates to a process for producing an imidazole derivative. More particularly, the present invention relates to a process for producing an imidazole derivative 5 useful for hypertension, congestive heart failure, renal failure, glaucoma, hyperuricemia and the like and an intermediate therefor.

The present inventors have aimed at angiotensin II antagonist as an agent for preventing or treating hypertension, congestive heart failure, renal failure, glaucoma, hyperuricemia and the like, and studied intensively the drugs which have longer shelf life, higher activity, rapid 10 manifestation of action upon intravenous injection, good absorbability into the body upon oral administration, lower toxicity and long-lasting action. As the result, we found the novel imidazole derivatives having the hydrazine cross-linking structure represented by the formula: and filed applications claiming the derivatives (JP-A 3-277537, JP-A 3-323474. JP-A 4-095191, 20 JP-A 4-216809 and published PCT application WO 93/08193).

In the process for producing the above imidazole compound, when the C ring double bond of a compound produced by Diels Alder reaction is reduced (see the below Reaction Scheme), in particular when R is a protecting group such as benzyl group and the like, the reducing reaction is usually carried out in methanol under hydrogen gas atmosphere using a 25 palladium hydroxide catalyst which makes possible a simultaneous deprotecting reaction such as debenzylation and the like. However, in this reducing reaction, in particular in the case of the compound (I) in which C ring represented by -P- forms bicyclo, 10 to 60% of a ring cleavaged side product (3) is produced in addition to the end compound (2) depending upon the kind and size of R13 group and R17 group as well as the reaction conditions. Therefore, the purification 30 by column chromatography is indispensable. Such a reduction reaction is not satisfactory, both in terms of the yield and of the ccomonics of mass production.

R2 R3 R ,w0 94/21641 pct/us94/01949 R2 R3 R13 r2 r3 r» r2r3 r13 R2 R3 R13 R2R3 r13 R2 R3 R13 Tet-Tr In addition, it is thought that there is the possibility that the formation of rc-allyl-25 palladium complex participates in this side reaction. However, the similar side reaction is also observed when platinum oxide and palladium carbon are used in place of palladium hydroxide. Therefore, the detailed mechanism is not known. And it was found that this side reaction rarely occurs in the case of Lindlar catalyst However, in the case of this catalyst, the desired reaction does not proceed in some cases, probably due to the impurities contained in the raw materials 30 upon mass production, and there is a problem with reproductability.

R2 r3 j*13 I * R5 pi7 pct/us94/01949 INFORMATION DISCLOSURE The prior route to the synthesis of the compounds produced by the process of this invention is described in WO 93/08193.

SUMMARY OF THE INVENTION The Problems to be Solved by the Invention The object of the present invention is to improve the selectivity on the reduction of C ring double bond of the above imidazole derivative in order to achieve the high yield even in mass pioduction and exclude the necessity of complicated purification steps.

The Means to Solve the Problems 10 In order to solve the above problems, the present inventors have studied intensively and, as a result, found that C ring double bond can be reduced selectively without the C ring cleavage reaction.

That is, the present invention provides a process for producing an imidazole derivative represented by the formula (II): wherein r, R*. R2, R3, R4, R5, R13, R14, R15, R16, R17 and R18 are as defined below, or a pharmacologically acceptable ester or salt thereof which comprises reacting a compound represented by the formula (i): R2 R3 r r4 r5 R2 r3 \ /r13 r16 r r4 r5 wherein R1 is hydrogen atom, lower alkyl group, lower alkoxy group, lower alkylthio group, lower alkylamino group, lower alkenyl group, -CF3 group, aryl group or aralkyl group; R is hydrogen atom, or a group selected from the group consisting of 4863-P 263006 X1 Y wherein X is -CH2-, -NR'-, oxygen atom or -S(0)n-, wherein R' is hydrogen atom or lower alkyl group, wherein n is 0, 1 or 2; wherein X1, X2 and X3 are independently hydrogen atom, halogen atom,-lower alkyl group, lower alkoxy group, nitro group, cyano group, lH-tetrazol-5-yl group or alkali metal salt 10 thereof, -C02R7 group, -CONR'R" group, -CONHS02R^ group, amino group, -NHS02CF3 group or -SO3H group, or a group selected from the group consisting of co2r7 co2r7 r10 NH—C (f ^ —NH—C—CH —NH —C-R6 —O-CH-^ rP II \_/ ' « » R„.

Y or the group consisting of R12 Y is lH-tetrazol-5-yl group or alkali metal salt thereof optionally substituted with cyano group, benzyl group, tosyl group, methoxymethyl group, ethoxymethy! group, methoxyethoxymethyl group or trimethylsilylethoxymethyl group, -C02R7 group, -CONR'R" group, -C0NHS02R8 group, amino group, -NHS02CF3 group or -SO3H group; R2, R3, R4 and R5 are independently hydrogen atom or lower alkyl group, or R2 and R3, or R4 and R5 are taken together to form =0 bond; R6 is hydrogen atom, halogen atom, lower alkyl group, -CF3 group or -CF2CF3 group; R7 is hydrogen atom, alkali metal atom or lower alkyl group; R' and R" are independently hydrogen atom or lower alkyl group, or R' and R" are taken together to form the alicyclic structure; Q R° is lower alkyl group, cycloalkyl group or aryl group; is lower alkyl group, lower alkoxy group, cycloalkyl group, cycloalkoxy^gi61]^"llr^ group or aryloxy group; .7 ' ~ 1119 ^ R , R and R are independently hydrogen atom, halogen atom, lower alkyl group, .. . • • r WO 94/21641 PCT/US94/01949 lower alkoxy group, nitro group, cyano group, -C02R7 group or -CONR'R" group; R13, R14, R15, R16, R17 and R18 are independently hydrogen atom, lower alkyl group, lower fluoroalkyl group, -C(R')(R")-OR19 group, -(CH2)j-C02R7 group, -(CH2)j-CN group, -(CH2)j-C(=0)R' group, -(CH2)j-CONR'R" group or -(CH2)j-Aryl group, wherein j is 0, 1 or 2, 5 wherein R1^ and R18 may be taken together to form -(CH2)j- group, wherein i is 1, 2 or 3, wherein Aryl is phenyl group, pyridyl group, pyrimidyl group, pyridazinyl group, furyl group, thenyl group, pyrazolyl group, oxazolyl group, thiazolyl group, oxadiazolyl group or isooxazolyl group optionally substituted with halogen atom, lower alkyl group, hydroxy group, lower alkoxy group, nitro group or cyano group; R19 is hydrogen atom, or lower alkyl group optionally substituted with hydroxy group or ether group, with a diimide (HN=NH).

First, variable substituents used in the general formula of the compounds herein are explained.

As the lower alkyl group represented by R1, there are the alkyls having 1 to 8 carbon 15 atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isoamyl, n-hexyl, n-heptyl, n-octyl and the like. As the lower alkoxy group represented by R1, there are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, isoamyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy and the like. As the lower alkylthio group represented by R1, there are methylthio, ethyihio, n-propylthio, isopropylthio, n-butylthio, n-20 pentylthio, n-hexylthio, n-heptylthio, n-octylthio and the like. As the lower alkylamino group represented by R1, there are methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino, di(n-propyl)amino, isopropylamino, n-butylamino, n-pentylamino, pyrrolidino, piperidino, piperazino, morpholino and the like. As the lower alkenyl group represented by R1, there are vinyl, 1-propenyl, 2-propenyl, 2-methyI-l-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 25 2-pentenyl, 1-hexenyl, l-heptenyl, 1-octenyl and the like. As the lower alkynyl group represented by R1. there are acetylene group, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 1-heptynyl, 1-octynyl and the like. As the aryl group or aralkyl group represented by R1, there are aryl or aralkyl group having 6 to 10 carbon atoms, for example, phenyl, naphthyl, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl and the like. 30 These aryl and aralkyl groups are optionally substituted with the substituent(s) such as the above described lower alkyl group, or lower alkoxy group, halogen atom, nitro group, cyano group and the like.

When R is substituted or unsubstituted phenylmethyl group, as the halogen atom defined by X1, X2 and X3, there are fluorine atom, chlorine atom, bromine atom and iodine atom. As 35 the lower alkyl group and lower alkoxy group, there are above defined lower alkyl group and alkoxy group. When X1. X2 and X3 are lH-tetrazol-5-yl group, as the alkali metal salt thereof.

WO 94/21641 PCT/US94/01949 there are sodium salt, potassium salt and the like. Wher , X2 and X3 are -C02R7 group, as the examples of R7 in the group, there are hydrogen atom, alkali metal atom such as lithium, sodium, potassium and the like, alcohol ester of the above defined lower alkyl group. When X1, X2 and X3 are -CONR'R", the examples of -NR'R" in the group, there are amino, 5 methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino, di(n-propyl)amino; diisopropylamino, dibutylamino, pyrrolidyl, piperazino, morpholino and the like. As the examples of R8 in -C0NHS02R8 group, there are methyl, trifluoromethyl, ethyl, n-propyl, n-butyl. isobutyl, t-butyl, cyclopentyl, cyclohexyl, phenyl and the like. When X1, X2 and X3 are the group selected from the following: R12 , Y and R7 arc the same as defined above. The lower alkyl group and lower alkoxy group represented by R9 arc as defined above. When R9 is cycloalkyl group or cycloalkoxy group, the examples arc 5 to 7 membered cyclic compounds such as cyclopentyl, cyclohexyl, cyclopentyl and the like. As the examples of aryl group or aryloxy group represented by R9, 25 there are substituted or unsubstituted phenyl compounds such as phenyl, p-hydroxyphenyl, p-carboxyphenyl, o-nitrophenyl and the like. The examples of lower alkyl group, lower alkoxy group, -C02R7 group or -CONR'R" group represented by R10, R11 or R12 are as defined above. When R is substituted biphenylmethyl group, as the examples of the alkali metal salt of substituent lH-tetrazol-5-yl, there are sodium salt, potassium salt and the like. When Y is -30 CO0R7 group, -CONR'R" group or -C0NHS02R8 group, the examples of R7, -NR'R" and R8 in the groups are as defined above. When R is represented by the following formula: .WO 94/21641 PCT/US94/01949 f .7. . the example of halogen and lower alkyl group represented by R6, the examples of alkali metal salts of lH-tetrazol-5-yl represented by Y, and the examples of R7, NR'R" and R8 in -C02R7 group, -CONR'R" group or -C0NHS02R8 group represented by Y are as defined above.

When R2, R3, R4 and R5 are lower alkyl group, the examples of them are the alkyl 5 groups having 1 to 8 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl; isobutyl, t-butyl, n-pentyl, isoamyl, n-hexyl, n-heptyl, n-octyl and the like.

When R13, R14, R15, R16, R17 and R18 are lower alkyl group, the example of them are the alkyls having 1 to 8 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isoamyl, n-hexyl, n-heptyl, n-octyl and the like. When R13, R14, . 10 R15, R16, R17 and R18 are lower fluoroalkyl group, the examples of them are trifluoromethyl, 2,2,2,-trifluoroethyl, pentafluoroethyl and the like. When R13, R14, R15, R16, R17 and R18 are -(CH2)j-C02R7, -(CH2)j-C(=0)R', -C(R')(R")-OR19, or -(CH2)j-CONR'R'\ the examples of R7, R' and R" are as defined above.

The diimide used in the process of the present invention can be generated by various 15 methods, for example, by oxidation of hydrazine, decomposition of the dipotassium salt of azodicarboxylic acid by an acid, the decomposition of arylsulfohydrazide by a base, the hydroxylamine-acetic acid ester method, and the like (Organic Reactions, 40, 91-155 (1991)). Among them, the use of decomposition of p-toluenesulfohydrazide by sodium acetate is suitable in view of simplicity of the operations and high safety.

The reaction between the diimide and the compound of the general formula (I) proceeds effectively at room temperature to 120 °C. The reaction is carried out in a solvent As the solvent, there are the alcoholic solvents such as methanol, ethanol, propanol and the like, and the etheric solvent such as tetrahydrofuran, dimethoxyethane and the like. When p-toluenesulfohydrazide is used to generate the diimide, it is desirable to react the diimide and the 25 compound of the fonnula (I) while generating the diimide in refluxing dimethoxyethane.

According to the previous process, 10 to 60 % of ring opened products are produced as side products. However, the above described reaction affords quantitatively a product having the reduced C ring double bond without side products.

In addition, when R is a protecting group such as benzyl group and the like, after 30 reduction of C ring double bond according to the present method, the reduced product is reacted in methanol in the presence of the catalytic amount of 20 % palladium hydroxide-carbon under 1 to 3 atmospheric pressure hydrogen by a conventional method to easily effect the deprotection such as debenzylation and the like. Therefore, a process of the present invention is also useful for preparing an intermediate (4) for synthesis (see the above Reaction Scheme). Further, the 35 end imidazole derivative (5) can be obtained as crystals almost without side products by attaching the biphenyltetrazole part to the intermediate according to the method described in JP- 486S.P 263008 A 3-277537, JP-A 3-323474, JP-A 4-095191 and JP-A 4-216809 and WO 93/08193 (see the above Reaction Scheme). Thereby, the purification by column chromatography which was indispensable to the previous process becomes unnecessary, and it was found that the present process can be applied to the mass production in the good reproductivity.

If desired, the compounds produced by the present process can be converted into the ester or salt thereof by a conventional method. The esters or salts are pharmacologically acceptable and non-toxic ones. Suitable esters include esters of lower alcohol having a straight or branched chain such as methanol, ethanol and the like. Suitable salts include -alkali metal salts such as sodium salt, potassium salt and the like, and alkaline earth metal salts, hydrogen 10 halide salts such as hydrogen fluoride, hydrogen chloride and the like, inorganic acid salts such as nitrate, sulfate and the like, lower alkylsulfonate salts such as methanesulfonate and the like, organic acid salts such as maleate, fumarate and the like, and amino acid salts such as aspartate and the like.

As used herein, the term "lower^' refers to a compound with 1 to 8 carbon atoms.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The following Examples further illustrate the present invention in detail.

EXAMPLE 1 Synthesis of l-benzyl-2-n-butyl-5,8-dimethyl-5,8-ethano-5,6,7,8-tetrahydro-lH-l,3,4a,8a-tetraaza-cyclopentanaphthalene-4,9-dione represented by the formula: o ?h3 hac 1 -Benzyl-2-n-butyl-5,8-dimethyl-5,8-ethano-5,8-dihydro- 1H-1,3,4a,8a-tetraaza-cyclopentanaphthalene-4,9-dione (58 g, 0.14 mol) and p-toluenesulfonylhydrazide (187 g, 1.0 mol) were dissolved in dimethoxyethane (400 ml), and the mixture was heated to reflux. An aqueous solution (400 ml) of sodium acetate (165 g, 2.0 mol) was added dropwise to this 30 solution over 4 hours. The mixture was cooled to room temperature, further cooled to 0 °C, and the precipitated crystals were filtered. The crystals were dissolved in methylene chloride, washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue combined with another residue (1 -hcnzyl-^-p-hutvl-5.8-dimethyl-5,8-ethano-5,8-dihydro-1H-1,3,4a,8a-tetraaza-cyclopentanaphthale^*>4,8-dibne,c6c^g) 35 obtained by the similar procedures was purified by silica gel column chromatography (aceton^ hexane: methylene chloride=5:i:40) for the purpose of removing the impiiHties dcjlvecl/froin L^e

Claims (6)

WO 94/21641 PCT/US94/01949 -9- reagents to give the titled compound (105 g, 91%) as colorless solid. In this reduction of the diimide. only the titled compound can be obtained as a sole product and no side products which were produced in the reduction by palladium hydroxide were recognized. The tided compound has the following NMR spectrum. 5 JH-NMR (CDC13) Sppra: 0.84 (3H, t, J=7.3Hz), 1.25-1.38 (2H, m), 1.63-1.80 (6H, m), 1.82 (3H, s), 1.89 (3H, s), 2.13-2.24 (4H, m), 2.65 (2H, t, J=8.0Hz), 5.69 (2H, s). 7.09-7.15 (2H. m), 7.24-7.36 (3H, m) EXAMPLE 2 Synthesis of 2-n-butyl-5,8-dimethyl-5,8-ethano-5,6,7,8-tetrahydro-lH-l,3,4a,8a-tetraaza-cyclopentanaphthalene-4,9-dione represented by the formula; O CH3 15 1 -Benzyl-2-n-butyl-5,8-dimethyl-5,8-ethano-5,6,7,8-tetrahydro-1H-1,3,4a,8a-tetraaza-cyclopentanaphthalene-4,9-dione (53 g, 0.13 mol) was dissolved in a mixed solvent of methanol (300 ml) and methylene chloride (80ml). 20% palladium hydroxide (containing 50% water, 10 g) was added to this solution, and the mixture was stirred at 3 normal atmospheres at room 20 temperature for 4 hours under hydrogen atmosphere. The catalyst was filtered off, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in a mixed solvent of ethanol and toluene, and the solvent was distilled off under reduced pressure. These procedures were repeated three times to give the titled compound (41.1 g, 100%) as colorless solid. The titled compound has the following NMR spectrum. 25 !H-NMR (CDCI3+CD3OD) 8ppm: 0.97 (3H, t, J=7.2Hz), 1.34-1.49 (2H. m), 1.80-1.94 (6H, m), 1.86 (6H, s). 2.10-2.21 (4H, ro), 3.17 (2H, t, J=7.4Hz) Effects of the Invention According to the present invention, there is provided a process for selectively reducing the C ring double bond of an imidazole derivative having the hydrazine cross-linking structure 30 and, thereby, there becomes possible the production of the useful imidazole derivative in high yield even in the mass production and without complicated purification steps. 4868.P 263008 CLAIMS

1. A process for producing an imidazole derivative represented by the formula: r2 r3 r13 r16 wherein R, R1, R2, R3, R4, R5, R13, R14, R15, R16, R17 and R18 are as defined below, or a 10 pharmacologically acceptable ester or salt thereof which comprises reacting a compound represented by the formula: R2 R3 R13 R16 wherein R1 is hydrogen atom, lower alkyl group, lower alkoxy group, lower alkylthio group, lower alky lam ino group, lower alkenyl group, -CF3 group, aryl group or aralkyl group; 20 R is hydrogen atom, or a group selected from the group consisting of x1 25 wherein X is -CH2-, -NR'-» oxygen atom or -S(0)n-, wherein R' is hydrogen atom or lower alkyl group, wherein n is 0, 1 or 2; wherein X1, X2 and X3 are independently hydrogen atom, halogen atom, lower alkyl group, lower alkoxy group, nitro group, cyano group, lH-tetrazol-5-yl group or alkali metal salt 30 thereof, -C02R7 group, -CONR'R" group, -C0NHS02R8 group, amino group, -NHS02CF3 group or -S03H group, or a group selected from the group consisting of - V10V W ' JciV 4868.P 10 263008 -11- co2r7 ,9 I ■NH—C—CH—NH —C-R ^ II M • —O-CH o o or the group consisting,of Rio R11 yC , wherein Y is I H-tetrazol-5-yl group or alkali metal salt thereof optionally substituted with cyano group, benzyl group, tosyl group, methoxymethyl group, ethoxymethyl group, methoxyethoxymethyl group or trimethylsilylethoxymethyl group, 15 -C02R7 group, -CONR'R" group, -C0NHS02R8 group, amino group, -NHS02CF3 group or -SO3H group; R2, R3, R4 and R5 arc independently hydrogen atom or lower alkyl group, or R2 and R3, or R4 and R5 are taken together to form =0 bond; R6 is hydrogen atom, halogen atom, lower alkyl group, -CF3 group or -CF2CF3 group; 20 R7 is hydrogen atom, alkali metal atom or lower alkyl group; R' and R" arc independently hydrogen atom or lower alkyl group, or R' and R" together with the N to which they are attached form an alicyclic structure; R8 is lower alkyl group, cycloalkyl group or aryl group; R9 is lower alkyl group, lower alkoxy group, cycloalkyl group, cycloalkoxy group, aryl 25 group or aryloxy group; R10, R11 and R12 arc independently hydrogen atom, halogen atom, lower alkyl group, lower alkoxy group, nitro group, cyano group, -C02R7 group or -CONR'R" group; R13, R14, R15, R16, R17 and R18 are independently hydrogen atom, lower alkyl group, lower fluoroalkyl group, -C(R')(R")-OR19 group, -(CH2)j-C02R7 group, -(CH2)j-CN group, -30 (CH2)j-C(=0)R* group, -(CH2)j-CONR'R" group or -(CH2)j-Aryl group, wherein j is 0, 1 or 2, wherein R1^ and R18 may be taken together to form -(CH2)j- group, wherein i is 1, 2 or 3, wherein Aryl is phenyl group, pyridyl group, pyrimidyl group, pyridazinyl group, fiiryl group, llienyl group, pyrazolyl group, oxazolyl group, thiazolyl group, oxadiazolyl^tQup.QMsooxazolyl group optionally substituted with halogen atom, lower alkyl group, hy^^v group, Ww&Ralkoxy 35 group, nitro group or cyano group; R19 is hydrogen atom, or lower alkyl group optionally substituted gw>up 4868.P 263008 or ether group, with a diimide (HN=NH).

2. A process for producing an imidazole derivative represented by the formula: 5 r2 r3 r13

R4 R5 R17 10 wherein R1, R2, R3, R4, R5, R13 and R17 are as defined above, or a pharmacologically acceptable ester or salt thereof which comprises reacting a compound represented by the formula: wherein R1, R2, R3, R4, R5, R13 and R17 are as defined above, with a diimide (HN=NH), then subjecting the product to hydrogenolysis. 25 3. A process for producing an imidazole derivative represented by the formula: 4868.P 263008 acceptable ester or salt thereof which comprises reacting a compound represented by the formula: wherein P.1, R2, R3, R4, R5, R13, R17 and Y are as defined above, with a diimide (HN=NH).

4. A process for producing an imidazole derivative of the first formula of claimllsubstantially as herein described with reference to the examples.

5. A process for producing an imidazole derviative of the first formula of claim 2 substantially as herein described with reference to example 2.

6. A process for producing an imidazole derivative of the first formula of claim 3 substantially as herein described with reference to the examples.