CN1120337A - Process for production of an imidazole derivative - Google Patents

Process for production of an imidazole derivative Download PDF

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CN1120337A
CN1120337A CN94191674A CN94191674A CN1120337A CN 1120337 A CN1120337 A CN 1120337A CN 94191674 A CN94191674 A CN 94191674A CN 94191674 A CN94191674 A CN 94191674A CN 1120337 A CN1120337 A CN 1120337A
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base
alkyl group
low alkyl
hydrogen atom
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山田弘美
宗贞清贵
洪桂子
谷口干雄
藤田芳司
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Pharmacia and Upjohn Co
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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

The production method of imdazole derivatives
The present invention relates to a kind of method of producing imdazole derivatives.More particularly, the present invention relates to a kind of production and can be used for preventing and treating the imdazole derivatives of hypertension, congestive heart failure, renal failure, glaucoma, hyperuricemia etc. and the method for intermediate thereof.
The inventor finds that the Angiotensin II antagonist can be used as the medicament that prevents or treat hypertension, congestive heart failure, renal failure, glaucoma, hyperuricemia etc., and furtherd investigate this class medicine, have an effect rapidly after long, active higher, the intravenous injection of their shelf-life, oral back by body absorb well, toxicity is lower and acting duration is long.Found that the novel imidazole derivatives shown in the following formula with hydrazine crosslinking structure:
Figure A9419167400071
And submitted the application (JP-A3-277537, JP-A3-323474, JP-A4-095191, JP-A4-216809 and disclosed PCT application WO93/08193) of claimed this derivative to.
In the method for producing above-mentioned imidazolium compounds; when the two keys of C ring through the compound that narrow Er Si-the Alder reaction generates are reduced (reacting flow chart of face as follows); particularly when R is protecting group such as benzyl etc.; usually in methyl alcohol; under hydrogen environment; use the palladium hydroxide catalyzer to carry out reduction reaction, go to keep reaction as slough benzyl etc. and might carry out simultaneously.Yet, in this reduction reaction, particularly for wherein-the C ring shown in the P-forms the compound (I) of dicyclo, also generates the by product (3) of 10-60% ring scission except last compound (2), this depends on R 13Group and R 17The kind of group and size and reaction conditions.Therefore, be necessary with the column chromatography purifying.Such reduction reaction all can not be satisfactory on productive rate and aspect economies of mass production.
In addition, should be taken into account the possibility that exists generation π-allyl group-palladium complex to participate in this side reaction.But, when using platinum oxide to replace palladium hydroxide, also observe similar side reaction with palladium-carbon.Therefore, detailed mechanism is unknown.Find that also this side reaction is rare under the situation of using the Lindlar catalyzer.But when using this catalyzer, required reaction can not be carried out in some cases, may be owing to contain impurity in the raw material when mass production, and have the problem of reproducibility.
Figure A9419167400091
The route of synthesis formerly of the compound of producing with method of the present invention is described among the WO93/08193.
Even the C that the objective of the invention is to improve above-mentioned imdazole derivatives encircles two key reductive selectivity so that also can reach high yield and the necessity of the purification step that eliminating is complicated in mass production.
In order to address the above problem, the inventor has carried out deep research, found that the two keys of C ring can be reduced by selectivity and C ring scission reaction do not take place.
That is to say, the invention provides the imdazole derivatives shown in a kind of production formula (II):
Figure A9419167400092
R wherein, R 1, R 2, R 3, R 4, R 5, R 13, R 14, R 15, R 16, R 17And R 18The following definition, or the method for acceptable ester or salt on its pharmacology, this method comprises makes compound shown in the formula (I) and imide (HN=NH) reaction: R wherein 1Be hydrogen atom, low alkyl group, lower alkoxy, lower alkylthio, lower alkyl amino, low-grade alkenyl ,-CF 3Base, aryl or aralkyl;
R is hydrogen atom or is selected from following group
Figure A9419167400102
Wherein x is-CH 2-,-NR '-, Sauerstoffatom or-S (O) n-, wherein R ' is hydrogen atom or low alkyl group, wherein n is 0,1 or 2;
X wherein 1, X 2And X 3Respectively do for oneself hydrogen atom, halogen atom, low alkyl group, lower alkoxy, nitro, cyano group, 1H-tetrazolium-5-base or its an alkali metal salt ,-CO 2R 7Base ,-CONR ' R " base ,-CONHSO 2R 8Basic, amino ,-NHSO 2CF 3The base or-SO 3The H base, or be selected from following group
Figure A9419167400111
Y be 1H-tetrazolium-5-base or its an alkali metal salt (can optionally be replaced) by cyano group, benzyl, tosyl group, methoxyl methyl, ethoxymethyl, methoxy (ethoxy) methyl or trimethyl silyl ethoxymethyl ,-CO 2R 7Base ,-CONR ' R " base ,-CONHSO 2R 8Basic, amino ,-NHSO 2CF 3The base or-SO 3The H base;
R 2, R 3, R 4And R 5Hydrogen atom or low alkyl group or R respectively do for oneself 2And R 3, or R 4And R 5Formation=O key together;
R 6Be hydrogen atom, halogen atom, low alkyl group ,-CF 3The base or-CF 2CF 3Base;
R 7Be hydrogen atom, alkali metal atom or low alkyl group;
R ' and R " respectively do for oneself hydrogen atom or low alkyl group, or R ' and R " form alicyclic structure together;
R 8Be low alkyl group, cycloalkyl or aryl;
R 9Be low alkyl group, lower alkoxy, cycloalkyl, cycloalkyloxy, aryl or aryloxy;
R 10, R 11And R 12Respectively do for oneself hydrogen atom, halogen atom, low alkyl group, lower alkoxy, nitro, cyano group ,-CO 2R 7The base or-CONR ' R " base;
R 13, R 14, R 15, R 16, R 17And R 18Respectively do for oneself hydrogen atom, low alkyl group, rudimentary fluoroalkyl ,-C (R ') (R ")-OR 19Base ,-(CH 2) j-CO 2R 7Base ,-(CH 2) j-CN base ,-(CH 2) j-C (=O) R ' base ,-(CH 2) j-CONR ' R " base or-(CH 2) j-aryl, wherein j is 0,1 or 2, wherein R 16And R 18Can form together-(CH 2) i-Ji, wherein i is 1,2 or 3, wherein aryl is phenyl, pyridyl, pyrimidyl, piperazinyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, oxadiazole base Huo isoxazolyl (can optionally be replaced by halogen atom, low alkyl group, hydroxyl, lower alkoxy, nitro or cyano group);
R 19Be hydrogen atom or the low alkyl group that replaced by hydroxyl or ether selectivity.
At first, the variable substituting group that is used for the The compounds of this invention general formula is explained.
With R 1The low alkyl group of expression has C 1-C 8Alkyl, for example, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl etc.With R 1The lower alkoxy of expression has methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, positive hexyloxy, positive heptan oxygen base, n-octyloxy etc.With R 1The lower alkylthio of expression has methylthio group, ethylmercapto group, positive rosickyite base, iprotiazem base, positive butylthio, positive penta sulfenyl, just own sulfenyl, positive heptan sulfenyl, positive hot sulfenyl etc.With R 1The lower alkyl amino of expression have methylamino-, dimethylamino, ethylamino, diethylin, n-propylamine base, two n-propylamine bases, isopropylamino, n-butyl amine base, pentylamine base, tetramethyleneimine also, piperidino-(1-position only), piperazine also, morpholino etc.With R 1The low-grade alkenyl of expression has vinyl alkene, 1-propenyl, 2-propenyl, 2-methyl isophthalic acid-propenyl, 1-butylene base, crotyl, 1-pentenyl, pentenyl, 1-hexenyl, 1-heptenyl, 1-octenyl etc.With R 1The low-grade alkynyl of expression has ethynyl, 1-propenyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 1-pentynyl, valerylene base, 1-hexin base, 1-heptyne base, 1-octyne base etc.With R 1The aryl or aralkyl of expression has C 6-C 10Aryl or aralkyl, for example, phenyl, naphthyl, benzyl, styroyl, 3-phenyl propyl, 4-phenyl butyl etc.These aryl and aralkyl can be substituted base as above-mentioned low alkyl group or lower alkoxy, halogen atom, nitro, cyano group etc. and optionally replace.
When R be replace or during unsubstituted phenmethyl, with X 1, X 2And X 3The halogen atom that limits has fluorine atom, chlorine atom, bromine atoms and iodine atom.Low alkyl group and lower alkoxy have low alkyl group defined above and lower alkoxy.Work as X 1, X 2And X 3When being 1H-tetrazolium-5-base, its an alkali metal salt has sodium salt, sylvite etc.Work as X 1, X 2And X 3Be-CO 2R 7During base, R in this group 7Example hydrogen atom, alkali metal atom such as lithium, sodium, potassium etc., the alcohol ester of low alkyl group defined above are arranged.Work as X 1, X 2And X 3Be-CONR ' R the example in " time, in this group-NR ' R " have amino, methylamino-, dimethylamino, ethylamino, diethylin, n-propylamine base, two n-propylamine bases, diisopropylaminoethyl, dibutylamino, pyrrolidyl, piperazine also, morpholino etc. ,-CONHSO 2R 8R in the base 8Example methyl, trifluoromethyl, ethyl, n-propyl, normal-butyl, isobutyl-, the tertiary butyl, cyclopentyl, cyclohexyl, amyl group etc. are arranged.Work as X 1, X 2And X 3Be when being selected from following group: , Y and R 7Identical with above-mentioned definition.With R 9The low alkyl group of expression and lower alkoxy are as defined above.Work as R 9When being cycloalkyl or cycloalkyloxy, the example is 5-7 unit ring compound such as cyclopentyl, cyclohexyl, suberyl etc.With R 9The aryl of expression or the example of aryloxy have phenyl replacement or unsubstituted such as phenyl, p-hydroxybenzene, to carboxyl phenyl, ortho-nitrophenyl base etc.With R 10, R 11Or R 12The low alkyl group, lower alkoxy of expression ,-CO 2R 7" example of base as defined above for base or CONR ' R.When R was the diphenyl methyl that replaces, the example of 1H-tetrazolium-substituent an alkali metal salt of 5-base had sodium salt, sylvite etc.When Y is CO 2R 7Base ,-CONR ' R " or-CONHSO 2R 8During base, R in these groups 7,-NR ' R " and R 8Example as defined above.When R represents with following formula: , with R 6The halogen of expression and the example of low alkyl group, the example of an alkali metal salt of 1H-tetrazolium-5-base of representing with Y and with Y represent-CO 2R 7The base ,-CONR ' R " base or-CONHSO 2R 8R in the base 7, NR ' R " and R 8Example as defined above.
Work as R 2, R 3, R 4And R 5When being low alkyl group, the example is C 1-C 8Alkyl, for example, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl etc.
Work as R 13, R 14, R 15, R 16, R 17And R 18When being low alkyl group, the example is C 1-C 8Alkyl, for example, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl etc.Work as R 13, R 14, R 15, R 16, R 17And R 18When being rudimentary fluoroalkyl, the example has trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl group etc.Work as R 13, R 14, R 15, R 16, R 17And R 18Be-(CH 2) j-CO 2R 7,-(CH 2) j-C (=O) R ' ,-C (R ') (R ")-OR 19, or-(CH 2) j-CONR ' R " time, R 7, R ' and R " example as defined above.
The used imide generation that can in all sorts of ways in the inventive method for example by the oxidation of hydrazine, is decomposed azo-2-carboxylic acid's di-potassium with acid, decompose the arylsulfonyl hydrazine with alkali, azanol-acetin method etc. (Organic Reactions, 40,91-155 (1991)).Wherein, see that from angle simple to operate and safe decomposing p-toluene sulfonyl hydrazide with sodium acetate is suitable for.
Reaction between imide and general formula (I) compound can be carried out under room temperature to 120 ℃ effectively.Be reflected in the solvent and carry out, solvent has alcoholic solvent such as methyl alcohol, ethanol, propyl alcohol etc., ether solvents such as tetrahydrofuran (THF), glycol dimethyl ether etc.When using p-toluene sulfonyl hydrazide to generate imide, be expected in the backflow glycol dimethyl ether, to make in the generation imide compound reaction of imide and formula (I).
According to former method, the 10-60% open-loop products generates as by product.But above-mentioned reaction can quantitatively produce product with the two keys of C ring that are reduced and no coupling product.
In addition, when R is protecting group such as benzyl etc., after according to the two keys of present method reduction C ring; the product that is reduced is in methyl alcohol; in the presence of the 20% palladium hydroxide-carbon of catalytic amount, under 1-3 atmospheric hydrogen pressure, react so that slough protecting group as sloughing benzyl etc. with conventional method.Therefore, method of the present invention also can be used for preparing synthetic intermediate (4) (seeing top reacting flow chart).Moreover, according to JP-A3-277537, JP-A3-323474, method described in JP-A4-095191 and JP-A4-216809 and the WO93/08193 combines imdazole derivatives (5) crystallization that can get to the end by making phenylbenzene tetrazolium part with this intermediate, does not almost have by product (seeing top reacting flow chart).
If desired, available ordinary method will be converted into its ester or salt with the compound that the inventive method is produced.Ester or salt are ester or salt acceptable, nontoxic on the pharmacology.Suitable ester comprises the ester of straight or branched lower alcohol such as the ester of methyl alcohol, ethanol etc.Suitable salt comprises an alkali metal salt such as sodium salt, sylvite etc., with alkaline earth salt such as halogenation hydrogen salt such as hydrogen fluoride, hydrogenchloride etc., inorganic acid salt such as nitrate, vitriol etc., low-grade alkane sulfonate such as mesylate etc., organic acid salt such as maleate, fumarate etc., and amino acid salts such as aspartate etc.
The following example further describes the present invention.
Embodiment 1
1-benzyl-2-normal-butyl-5 shown in the following formula, 8-dimethyl-5,8-ethano--5,6,7,8-tetrahydrochysene-1H-1,3,4a, 8a-four azepines-ring penta naphthalene-4,9-diketone synthetic:
With 1-benzyl-2-normal-butyl-5,8-dimethyl-5,8-ethano--5,8-dihydro-1H-1,3,4a, 8a-four azepines-ring penta naphthalene-4,9-diketone (58g, 0.14mol) and p-toluene sulfonyl hydrazide (187g 1.0mol) is dissolved in glycol dimethyl ether (400ml), reflux mixture.In 4 hours, in this solution, drip sodium acetate (165g, aqueous solution 2.0mol) (400ml).Mixture is cooled to room temperature, and then is cooled to 0 ℃, leach sedimentary crystallization.Crystallization is dissolved in methylene dichloride, and anhydrous sodium sulfate drying is used in water and salt water washing, and underpressure distillation removes and desolvates.With this resistates and the resistates (1-benzyl-2-normal-butyl-5,8-dimethyl-5, the 8-ethano--5 that obtain with similarity method, 8-dihydro-1H-1,3,4a, 8a-four azepines-ring penta naphthalene 4, the 8-diketone, 56.5g) merge, with silica gel column chromatography (acetone: ethane: methylene dichloride=5: 1: 40) carry out purifying, so that remove the impurity that produces by reagent, obtain title compound colorless solid (105g, 91%).In the reduction of this imide, title compound is unique product, does not find the by product that is generated in the reduction with palladium hydroxide.Title compound has following NMR spectrum.
1H-NMR(CDCl 3)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)
Embodiment 2
2-normal-butyl-5 shown in the following formula, 8-dimethyl-5,8-ethano--5,6,7,8-tetrahydrochysene-1H-1,3,4a, 8a-four azepines-ring penta naphthalene-4,9-diketone synthetic:
With 1-benzyl-2-normal-butyl-5,8-dimethyl-5,8-ethano--5,6,7,8-tetrahydrochysene-1H-1,3,4a, 8a-four azepines-ring penta naphthalene-4, (53g 0.13mol) is dissolved in the mixed solvent of methyl alcohol (300ml) and methylene dichloride (80ml) the 9-diketone.Adding 20% palladium hydroxide in this solution (contains 50% water, 10g), under nitrogen atmosphere, stirred the mixture 4 hours under 3 normal atmosphere and room temperature.Filtration catalizer, and underpressure distillation is except that desolvating.The gained resistates is dissolved in the mixed solvent of ethanol and toluene, and underpressure distillation is except that desolvating.Repeat these processes three times, obtain title compound colorless solid (41.1g, 100%).Title compound has following NMR spectrum.
1H-NMR(CDCl 3+CD 3OD)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)
According to the present invention, the method for the two keys of C ring of the imdazole derivatives that a kind of selective reduction has the hydrazine crosslinking structure is provided, thereby might even when mass production, also can has produced useful imdazole derivatives and not have the purification step of complexity with high yield.

Claims (3)

1. produce the imdazole derivatives shown in the following formula for one kind:
Figure A9419167400021
R wherein, R 1, R 2, R 3, R 4, R 5, R 13, R 14, R 15, R 16, R 17And R 18The following definition, or the method for acceptable ester or salt on its pharmacology, this method comprises makes compound shown in the formula (I) and imide (HN=NH) reaction:
Figure A9419167400022
R wherein 1Be hydrogen atom, low alkyl group, lower alkoxy, lower alkylthio, lower alkyl amino, low-grade alkenyl ,-CF 3Base, aryl or aralkyl;
R is hydrogen atom or is selected from following group
Wherein x is-CH 2-,-NR '-, Sauerstoffatom or-S (O) n-, wherein R ' is hydrogen atom or low alkyl group, wherein n is 0,1 or 2;
X wherein 1, X 2And X 3Respectively do for oneself hydrogen atom, halogen atom, low alkyl group, lower alkoxy, nitro, cyano group, 1H-tetrazolium-5-base or its an alkali metal salt ,-CO 2R 7Base ,-CONR ' R " base ,-CONHSO 2R 8Base, amino-NHSO 2CF 3The base or-SO 3The H base, or be selected from following group
Y be 1H-tetrazolium-5-base or its an alkali metal salt (can optionally be replaced) by cyano group, benzyl, tosyl group, methoxyl methyl, ethoxymethyl, methoxy (ethoxy) methyl or trimethyl silyl ethoxymethyl ,-CO 2R 7Base ,-CONR ' R " base ,-CONHSO 2R 8Basic, amino ,-NHSO 2CF 3The base or-SO 3The H base;
R 2, R 3, R 4And R 5Hydrogen atom or low alkyl group or R respectively do for oneself 2And R 3, or R 4And R 5Formation=O key together;
R 6Be hydrogen atom, halogen atom, low alkyl group ,-CF 3The base or-CF 2CF 3Base,
R 7Be hydrogen atom, alkali metal atom or low alkyl group;
R ' and R " respectively do for oneself hydrogen atom or low alkyl group, or R ' and R " form alicyclic structure together;
R 8Be low alkyl group, cycloalkyl or aryl;
R 9Be low alkyl group, lower alkoxy, cycloalkyl, cycloalkyloxy, aryl or aryloxy;
R 10, R 11And R 12Respectively do for oneself hydrogen atom, halogen atom, low alkyl group, lower alkoxy, nitro, cyano group ,-CO 2R 7The base or-CONR ' R " base;
R 13, R 14, R 15, R 16, R 17And R 18Respectively do for oneself hydrogen atom, low alkyl group, rudimentary fluoroalkyl ,-C (R ') (R ")-OR 19,-(CH 2) j-CO 2R 7Base ,-(CH 2) j-CN base ,-(CH 2) j-(C=O) R ' base ,-(CH 2) j-CONR ' R " base or-(CH 2) j-aryl, wherein j is 0,1 or 2, wherein R 16And R 18Can form together-(CH 2) i-Ji, wherein i is 1,2 or 3, wherein aryl is phenyl, pyridyl, pyrimidyl, piperazinyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, oxadiazole base Huo isoxazolyl (can optionally be replaced by halogen atom, low alkyl group, hydroxyl, lower alkoxy, nitro or cyano group);
R 19Be hydrogen atom or the low alkyl group that replaced by hydroxyl or ether selectivity.
2. produce the imdazole derivatives shown in the following formula for one kind:
Figure A9419167400051
R 1, R 2, R 3, R 4, R 5, R 13And R 17As defined above, or the method for acceptable ester or salt on its pharmacology, this method comprises makes the compound shown in the following formula:
Figure A9419167400052
R wherein 1, R 2, R 3, R 4, R 5, R 13And R 17As defined above, with imide (HN=NH) reaction, then product is carried out hydrogenolysis.
3. produce the imdazole derivatives shown in the following formula for one kind: R wherein 1, R 2, R 3, R 4, R 5, R 13, R 17With Y as defined above, or the method for acceptable ester or salt on its pharmacology, this method comprises makes the compound shown in the following formula:
Figure A9419167400062
R wherein 1, R 2, R 3, R 4, R 5, R 13, R 17, Y reacts with imide (HN=NH) as defined above.
CN94191674A 1993-03-19 1994-03-04 Process for production of an imidazole derivative Pending CN1120337A (en)

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JP5060067A JPH06271576A (en) 1993-03-19 1993-03-19 Manufacturing of imidazole derivative

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AU644539B2 (en) * 1991-09-10 1993-12-09 Tanabe Seiyaku Co., Ltd. Imidazoindolizine derivatives and process for preparation thereof
JPH06107661A (en) * 1991-10-24 1994-04-19 Upjohn Co:The Imidazole derivative and medicinal composition having same as effective component

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Publication number Publication date
JPH08508468A (en) 1996-09-10
WO1994021641A1 (en) 1994-09-29
AU6351994A (en) 1994-10-11
CA2155573A1 (en) 1994-09-29
JPH06271576A (en) 1994-09-27
EP0689544A1 (en) 1996-01-03
NZ263008A (en) 1996-12-20

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