WO1994021641A1

WO1994021641A1 - Process for production of an imidazole derivative

Info

Publication number: WO1994021641A1
Application number: PCT/US1994/001949
Authority: WO
Inventors: Hiroyoshi Yamada; Kiyotaka Munesada; Keiko Koh; Mikio Taniguchi; Yoshiji Fujita
Original assignee: The Upjohn Company
Priority date: 1993-03-19
Filing date: 1994-03-04
Publication date: 1994-09-29
Also published as: JPH08508468A; JPH06271576A; AU6351994A; CA2155573A1; EP0689544A1; NZ263008A; CN1120337A

Abstract

The object of the present invention is to improve the selectivity on reduction of the C ring double bond of an imidazole derivative having the hydrazine cross-linking structure represented by formula (I). The imidazole derivative is subjected to the reaction with a diimide (HN=NH).

Description

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 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 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, 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 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 R group as well as the reaction conditions. Therefore, the purification by column chromatography is indispensable. Such a reduction reaction is not satisfactory, both in terms of the yield and of the ecomonics of mass production.

In addition, it is thought that there is the possibility that the formation of π-allyl- 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 upon mass production, and there is a problem with reproductability.

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 production and exclude the necessity of complicated purification steps. The Means to Solve the Problems 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, R¹, 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):

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

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 X , X² and X 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 thereof, -C0₂R⁷ group, -CONR'R" group, -C0NHS0₂R⁸ group, amino group, -NHS0₂CF₃ group or -S0₃H group, or a group selected from the group consisting of

^■NH —

Y is lH-tetrazol-5-yl group or alkali metal salt thereof optionally substituted with cyano group, benzyl group, tosyl group, methoxymethyl group, ethoxymethyl group, n methoxyethoxymethyl group or trimethylsilylethoxymethyl group, -C0₂R group, -CONR'R" group, -CONHS0₂R⁸ group, amino group, -NHS0₂CF₃ group or -S0₃H group;

R², R , R and R⁵ are independently hydrogen atom or lower alkyl group, or R 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;

R⁸ is lower alkyl group, cycloalkyl group or aryl group;

R⁹ is lower alkyl group, lower alkoxy group, cycloalkyl group, cycloalkoxy group, aryl group or aryloxy group;

R , R¹¹ and R are 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, - (CH₂)_j-C(=0)R' group, -(CH₂)_j-CONR'R" group or -(CH₂)j-Aryl group, wherein j is 0, 1 or 2, wherein R¹⁶ and R 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; 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 R , there 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. 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, ethylthio, n-propylthio, isopropylthio, n-butylthio, n- 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 R , there are vinyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 1-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. 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, X and X³, there are fluorine atom, chlorine atom, bromine atom and iodine atom. As 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, there are sodium salt, potassium salt and the like. When X¹, 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, methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino, di(n-propyl)amino, diisopropylamino, dibutylamino, pyrrolidyl, piperazino, morpholino and the like. As the examples of R⁸ in -CONHS0₂R 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:

, Y and R⁷ are the same as defined above. The lower alkyl group and lower alkoxy group represented by R are as defined above. When R⁹ is cycloalkyl group or cycloalkoxy group, the examples are 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, 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 - C0₂R⁷ group, -CONR'R" group or -CONHS0₂R⁸ group, the examples of R⁷, -NR'R" and R⁸ in the groups are as defined above. When R is represented by the following formula:

, 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 -CONHS0₂R⁸ group represented by Y are as defined above.

When R², R , R⁴ and R⁵ are lower alkyl group, the examples of them are the alkyl 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 R , R , R , R , R and R are lower fiuoroalkyl 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,

-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 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 compound of the formula (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 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 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- 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 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.

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-5,6J,8-tetrahydro-lH- l,3,4a,8a-tetraaza-cyclopentanaphthalene-4,9-dione represented by the formula:

1 -Benzyl-2-n-butyl-5 , 8-dimethyl-5 , 8-ethano-5 , 8-dihydro- 1 H- 1 ,3 ,4a,8 a-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 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 (l-benzyl-2-n-butyl-5,8- dimethyl-5,8-ethano-5,8-dihydro-lH-l,3,4a,8a-tetraaza-cyclopentanaphthalene-4,8-dione, 56.5 g) obtained by the similar procedures was purified by silica gel column chromatography (acetone: hexane: methylene chloride=5:l:40) for the purpose of removing the impurities derived from the 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 titled compound has the following NMR spectrum. ^XH-NMR (CDC1₃) δppm: 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-5,6J,8-tetrahydro-lH-l,3,4a,8a- tetraaza-cyclopentanaphthalene-4,9-dione represented by the formula:

1 -B enzyl-2-n-butyl-5 , 8-dimethyl-5 , 8-ethano-5 ,6,7,8-tetrahydro- 1 H- 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 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. --Η-NMR (CDC1₃+CD₃0D) δppm: 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, m), 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 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.

Claims

CLAIMS 1. A process for producing an imidazole derivative represented by the formula:

wherein R, R¹, 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:

wherein R¹ is hydrogen atom, lower alkyl group, lower alkoxy group, lower alkylthio group, lower alkylamino group, lower alkenyl group, -CF group, aryl group or aralkyl group; R is hydrogen atom, or a group selected from the group consisting of

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 X 1 , X and X -\ 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 thereof, -C0₂R⁷ group, -CONR'R" group, -CONHS0₂R⁸ group, amino group,

-NHS0₂CF₃ group or -S0₃H group, or a group selected from the group consisting of

wherein Y is lH-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, -C0₂R⁷ group, -CONR'R" group, -CONHS0₂R⁸ group, amino group, -NHS0₂CF₃ group or -S0₃H group;

R², R³, R and R⁵ are independently hydrogen atom or lower alkyl group, or R² and R , 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;

R⁸ is lower alkyl group, cycloalkyl group or aryl group;

R¹⁰, R¹¹ and R¹² are independently hydrogen atom, halogen atom, lower alkyl group, lower alkoxy group, nitro group, cyano group, -C0 R⁷ group or -CONR'R" group;

R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are independently hydrogen atom, lower alkyl group, lower fiuoroalkyl 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, wherein R¹⁶ 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;

R is hydrogen atom, or lower alkyl group optionally substituted with hydroxy group or ether group, with a diimide (HN=NH).

2. A process for producing an imidazole derivative represented by the formula:

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.

3. A process for producing an imidazole derivative represented by the formula:

wherein R , R , R , R , R , R , R ' and Y 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, R¹⁷ and Y are as defined above, with a diimide (HN=NH).