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WO1996025396A1 - Procede de preparation de composes indoline et intermediaires de cette preparation - Google Patents

Procede de preparation de composes indoline et intermediaires de cette preparation Download PDF

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Publication number
WO1996025396A1
WO1996025396A1 PCT/JP1996/000344 JP9600344W WO9625396A1 WO 1996025396 A1 WO1996025396 A1 WO 1996025396A1 JP 9600344 W JP9600344 W JP 9600344W WO 9625396 A1 WO9625396 A1 WO 9625396A1
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group
compound
acid
optically active
hetero
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PCT/JP1996/000344
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English (en)
Japanese (ja)
Inventor
Nobuyuki Yasuda
Shin-Ichi Kunii
Kouichi Kazama
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Tokyo Tanabe Company Limited
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Application filed by Tokyo Tanabe Company Limited filed Critical Tokyo Tanabe Company Limited
Priority to US08/894,855 priority Critical patent/US5936098A/en
Priority to AU46759/96A priority patent/AU718434B2/en
Priority to EP96902458A priority patent/EP0810214A4/fr
Publication of WO1996025396A1 publication Critical patent/WO1996025396A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring

Definitions

  • the present invention is useful in the production of a 5_HTo receptor antagonist 1-acyl-3- (hetero) aryl-indolin compound (hereinafter, simply referred to as “1-acyl-3-aryl-indrin compound”).
  • Method for producing 3- (hetero) arylindolin compound hereinafter, simply referred to as “3-arylindolin compound”
  • 3- (hetero) arylindolin compound” and its production intermediate 1—unru 3- (hetero) arylindole compound hereinafter, referred to as “3-arylheteroindole compound”
  • simply referred to as “1-acyl-3-arylindole compound” Simply referred to as “1-acyl-3-arylindole compound”
  • a process for producing an optically active 1-acyl-3-arylindolin compound simply referred to as “1-acyl-3-arylindolin compound”.
  • R 1 represents a phenyl group or an aromatic heterocyclic group which may have a substituent
  • R 2 represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a carbamoyl group Represents a group or a lower alkoxycarbonyl group
  • R 3 represents a group Represents
  • the method for producing the 3-arylindrin compound (2) includes the general formula (4)
  • a method for reducing a 3-arylindole compound under strongly acidic conditions namely, hydrochloric acid, hydrofluoric hydrobromide acid, or orthorin
  • Strong electrophiles such as mineral acids such as acids or lyes such as boron trifluoride, aluminum trichloride, zinc chloride in the presence of organic acids (preferably glacial acetic acid, propionic acid, trifluoroacetic acid, formic acid).
  • the method for producing the optically active substance of the 1-aryl-3-indylene compound (1) includes the optically active form of the 3-arylindrin compound (2) and the optically active form of the carboxylic acid compound (3).
  • a method for condensing an active form, a column chromatography of an epimer mixture obtained by condensing a carboxylic acid compound (3) with a 3-arylindrin compound (2), one of which is optically active and the other is a racemic form.
  • the diastereomer mixture obtained by condensing the 3-arylindolin compound (2) and the carboxylic acid compound (3), both of which are racemic, is separated by column chromatography and then separated Production methods include optical resolution using crystals, etc., but a method with a shorter number of steps, excellent operability, and a high yield is required.
  • the present invention 5-Eta T 3 receptor antagonists 1 Ashiru 3 - relates to a manufacturing method of ⁇ Li Rui down drill down Compound (1), is made in view of the above problems. That is, an object of the present invention is to provide a novel method for producing a 3-arylindrin compound (2) used in the production of a 1-aryl-3-indolin compound (1). Another object of the present invention is to provide a novel preparation of an optically active form of a 3-arylindrin compound (2) used for producing an optically active 1-acyl-3-arylindrin compound (1). It is an object of the present invention to provide a production method and a production intermediate thereof. Still another object of the present invention is to provide a method for producing an optically active substance of 1-acyl_3- 3-arylindrin compound (1).
  • the 3-arylindole compound can be removed by acylating the 1-position of the 3-arylindole compound with an organic acid such as carboxylic acid or sulfonic acid.
  • an organic acid such as carboxylic acid or sulfonic acid.
  • 1-Acyl-3- 3-arylindole compounds obtained by bonding an electron-withdrawing group are easily catalytically reduced under neutral or weakly acidic conditions and 1-acyl-3-aryl-indole compounds
  • the optically active 1-unruyl 3-arylindole compound obtained by antenylation with an organic acid such as an optically active carboxylic acid or sulfonic acid is converted into an optically active 1-acyl- with high selectivity by a catalytic reduction reaction. He learned to provide a 3-arylindrin compound, and completed the present invention.
  • 5 - HT 3 receptor antagonists 1 Ashiru 3 - Ariru Lee down drill down Compound (1) 3 used in the manufacture of - Arirui down drill down Compound (2) A method of manufacturing is provided You.
  • R 4 represents a linear, branched or cyclic alkyl group, aryl group or aromatic or saturated heterocyclic group which may have a substituent).
  • a general formula (6) which can be produced by condensing an organic acid such as sulfonic acid or a reactive derivative thereof.
  • R 1 is an aromatic heterocyclic group
  • examples include thiophene, oxazole, thiazol, furan, pyran, pyrrole, imidazole, pyrazole, isothiazole, isooxazole, pyridine, virazine.
  • substituent for R 1 include lower alkyl groups such as methyl, ethyl, propyl, and isopropyl; hydroxy groups; lower alkoxy groups such as methoxy, ethoxy, propoxy, and isopropyloxy; fluorine, chlorine, and bromine.
  • Lower alkylamino groups such as amino group, amino group, methylamino and dimethylamino group, lower alkoxycarbonyl group such as alkyl group such as rubamoyl group, rubamoyl group, sulfamoyl group and methoxycarbonyl group; And an acylamino group such as a toro group, an acetylamino and a propionylamino.
  • R 2 represents a hydrogen atom, a halogen atom such as fluorine, chlorine, or bromine; a lower alkyl group such as methyl, ethyl, propyl, or isopropyl; a low alkyl group such as a hydroxy group, methoxy, ethoxy, propoxy, or isopropyloxy. Lower alkoxy, carbamoyl or methoxycarbonyl ⁇ Coxycarbonyl group and the like.
  • R 4 represents a linear alkyl group such as methyl, ethyl and propyl; a branched alkyl group such as isopropyl and isobutyl; a cyclic alkyl group such as cyclohexyl; phenyl; Mouthphenyl, 4-methylphenyl, 2-methoxyphenyl, 4-hydroxyrubumoylphenyl, 3-methoxycarbonylcarbonyl, naphthyl, and other aryl groups, thiophene, oxazole, thiazole, furan, pyra Aromatic complexes such as pyrrole, pyrrole, imidazole, virazole, isotiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, quinoline, and isoquinoline Monovalent groups formed from rings, tetrahydrohydran, tetrahydropyran, pyr
  • substituents that these groups may have include a nitrogen atom such as fluorine, chlorine, and bromine, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, and ⁇ -cyclopentene.
  • Dinolequine carbonyl, p—Ditroben zirokine carbonyl, 3,5—Dimethoquine benzyloxy carbonyl, tert-butyloxycarbonyl, tertiary-amioxycarbonyl, p-biphenylysopropoxy ⁇ -type protecting groups such as carbonyl, diisopropylpropylmethyloxycarbonyl or furfuryloxycarbonyl, holmyl, trifluoroacetinole, tosyl, and 0-nitroethyleninoresphenol.
  • Lower alkylamino groups such as amino group, methylamino, dimethylamino, alkylamine, alkylamine, sulfamoyl, sulfamoyl, methoxy Lower alkoxycarbonyl groups such as cicarbonyl, lower alkyl groups such as methyl, ethyl, propyl and isopropyl, benzyl, acetyl, trifluoroacetyl or benzyloquinol, etc.
  • Lower alkoxy groups such as toxic, ethoxy, propoxy, and isopropyloxy; acyl groups such as acetyl and propionyl; benzyl; p-mercapto group which may be protected by p-methoxybenzyl or trityl; methylthio group
  • a lower alkylthio group such as methylsulfinyl, phenylsulfinyl, etc., a sulfininole group, such as methinoresolefonyl, benzenesulfonyl, P-toluenesulfonyl, etc., phenyl, 3-phenylphenyl, 4-methylphenyl, 4-methylphenyl, etc.
  • Examples of the organic acid (5) include acetic acid, propionic acid, drank acid, mandelic acid, camphoric acid, lingoic acid, tartaric acid, cyclohexanecarboxylic acid, benzoic acid, toluic acid, fluorobenzoic acid, and chloroacetic acid.
  • Benzoic acid methoxy benzoic acid, carbamoyl benzoic acid, methoxy carbonyl benzoic acid, naphthoic acid, furan carboxylic acid, thiophene carboxylic acid, pyridin carboxylic acid and the protecting group for the above amino group
  • Amino acids such as protected alanine, parin, phenylalanine, oral isin, isoleucine, methionine, glutamine, asparagine, and proline, and p-toluenesulfonate and camphorsulfonate
  • Amino acids such as protected alanine, parin, phenylalanine, oral isin, isoleucine, methionine, glutamine, asparagine, and proline, and p-toluenesulfonate and camphorsulfonate
  • 1-Acyru-3 Arylindole Compound (6) includes 1-benzoyl-3-phenylindole, 1-acetyl-3, -phenylindole, 1-benzoyl- 3- (3-methoxyphenyl) Indore, 1-Trifluoroacetyl-3- 3-phenylindole, 1-cyclohexylcarbonyl 3- 3-phenylindole, 3- (4-fluorophenyl) — 1- (4-methylphenyl) Carbonyl) indole, 1— (1-naphthylcarbonyl) 13-phenylindole, 5—fluoro-3- (2—methoxyphenyl) —1_ (3—pyridylcarbonyl) indole, 1 Benzoyl 6—Methoxycarbonyl 2—3— (4—Methoxyphenyl) indole, 3—Phenyl_11-1 (N—Tosylprolyl) indole, 3— (3—Methoxyfen
  • 1-Acilyl-3—Arylindolin compound (7) includes: I—Benzoyl3—Phenylindrin, 1Acetyl-3, Phenylindolin, 1Benzoyl—3 — (3—Methoxyphenyl) indolin, 1-trifluoroacetyl—3—Phenylindolin, 1—Cyclohexylcarbonyl—3—Phenylindrin, 3— (4—Fluorophenyl (Nil) 1-1 (4-methylphenylcarbonyl) indone, 1-1 (1-naphthylcarbonyl) 1-3-phenylindolin, 5-fluoro-3-(2-methoxyphenyl) 1 1 1 3-pyridylcarbonyl) indolin, 1 -benzoyl 1-6-methoxycarbonyl-3-(4-methoxyphenyl) indone, 3 _ phenyl-1-1 (N-ton)Sylprolyl) indolin, 3—
  • the method for producing the 3-arylindole compound (2) of the present invention will be described in more detail.
  • the condensation reaction of the 3-arylindole compound (4) with the organic acid (5) or a reactive derivative thereof is performed.
  • 1-acyl-3-arylindole compound (6) is obtained.
  • the reaction solvent may be any solvent that does not participate in the reaction, for example, an ether such as tetrahydrofuran. System solvents and the like.
  • the reaction is performed with the organic acid as it is, the reaction is performed in the presence of a general condensing agent used for the amide bond formation reaction. Examples of the condensing agent include N, N * -dicyclohexylcarbodiimide and the like.
  • the reactive derivative of the organic acid may be one generally used in an amide bond forming reaction, and examples thereof include an acid halide and an acid anhydride.
  • the reaction is carried out in the presence or absence of a base, at room temperature or under heating or cooling, preferably at a temperature of 180 ° C to 100 ° C.
  • the 1-acyl-3-arylindole compound (6) is reduced by a conventional catalytic hydrogenation reaction to obtain a 1-acyl-3-arylindolin compound (7).
  • the reaction solvent need only be one that does not participate in the reaction, and examples thereof include ethanol and acetic acid.
  • the catalyst include a palladium catalyst.
  • the reaction is carried out at normal pressure or under pressure, at room temperature or under heating or cooling, preferably at a temperature of 0 to 100 ° C.
  • the 3-arylindolin compound (2) easily discolors and decomposes at room temperature, and it is not preferable to store it as an intermediate for the production of the 1-acyl-3-arylindolin compound (1).
  • the 1-acyl-3-arylindole compound (6) and the 1-acyl-3-arylindrin compound (7) are stable at room temperature and are suitable for storage in bulk form. Thus, it is extremely excellent as an intermediate for the production of 1-acilyl-3- 3-arylindrin compound (1).
  • a method for producing an optically active 3-aryllindolin compound represented by the formula: A production intermediate is provided. That is, in the method for producing the 3-arylindole compound (2), the 3-arylindole compound (4) and the compound represented by the general formula (9)
  • R '' represents a linear, branched or cyclic alkyl group, aryl group or aromatic or saturated heterocyclic group which may have a substituent and which is asymmetric.
  • optically active organic acids examples include optically active mandelic acid, camphoric acid, lingoic acid, tartaric acid, and alanine, parin, and phenyl which have a protected amino group, which are used in ordinary optical resolution.
  • Amino acids such as guaranine, leucine, isoleucine, glutamine, asparagine, and proline, as well as 10-camphorsulfonate, and the like are preferred.
  • D-proline derivative and L-proline derivative represented by the following formula:
  • R D may be a protecting group for an amino group used in ordinary peptide synthesis, and is preferably benzyloquincarbonyl, p-methodinebenzyloxycarbonyl, p — Black benzodinoleoxycarbonyl, ⁇ —Nitrobenzyloxycarbonyl, 3, 5 — Dimethoxybenzyloxycarbonyl, tert —Butyloxycarbonyl, tert-aminoleoxycarbonyl, p — Urethane-type protecting groups such as biphenylpyroxypropyloxycarbonyl, diisopropylpropyloxycarbonyl, and furfuryloxycarbonyl, formyl, trifluoroacetyl, tosyl, o-ditrophenylsnolephenyl, p-methoxy 0 — nitrophenylsulfenyl, benzoyl, chloroacetyl and acetoacetyl groups Le-type protecting groups
  • optically active 1-acyl-3-arylindole compound (10) is preferably represented by the general formula (13)
  • R 1 R 2 and R D are the same as defined above.
  • optically active 1-acyl-3- 3-arylindrin compound (11) is preferably represented by the general formula (14)
  • R 1 R, R ° and * are the same as described above.
  • the process for producing the optically active 3-arylindone compound (8) is carried out by a conventional method for protecting amino groups. It can be carried out by hydrolysis under conditions for removing the group.
  • R 1 , R and * are the same as above, and R ′ is a group
  • the present invention provides a method for producing an optically active 1-acyl-3- 3-arylindrin compound represented by the formula:
  • optically active 1-acyl-3-allylindole compound (10) obtained by condensing the 3-arylindole compound (4) with the optically active organic acid (9) is reduced to obtain the optically active compound.
  • a desired optically active 1-acyl-3-arylindrin compound can be obtained.
  • a recrystallization solvent a single solvent or a mixed solvent of a plurality of solvents can be used.
  • alcohols such as methanol, ethanol, isopropyl alcohol and the like, or ethyl acetate and the like are used.
  • Lower fatty acid esters are used.
  • Benzimidazole-5-carboxylic acid ethyl ester sulfate 10.0 g, 5.0 g of 5% palladium on carbon catalyst, and a mixture of 5.0 g of ethanol 100 m1 in hydrogen at 135 ° C , ⁇ 0 kg / cm 2, and the mixture was stirred for 5 hours. After cooling, the catalyst was removed, and ethanol was concentrated and removed. The residue was neutralized by adding aqueous sodium bicarbonate, and extracted with chloroform. After drying the black mouth form layer with anhydrous magnesium sulfate, the black mouth form was distilled off. As a result, 6.9 g of 5-hydroxybenzoic acid ethyl ester was obtained.
  • (+) — 4,5,6,7—Tetrahydrobenzimidazole-5-potency White powder containing 1 g of rubonic acid hydrochloride and 80 ml of thionyl chloride were mixed and heated to reflux for 2 hours. . This reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in 200 ml of black form. 7.9 g of (+)-3-phenylindrin was dissolved in 50 ml of black-mouthed form, and added to the above-mentioned medium-mouthed form under ice-cooling. The reaction solution was then added to 8.2 ml of the dissolved triethylamine was added dropwise over 2 hours.
  • Example 1 (3-methoxyethoxyunyl) indole 45.0 g instead of 3_phenylindole was subjected to the same reaction treatment to obtain 1-benzoyl-1 3 — ((3— 42.9 g (65.0%) of methoxyphenyl) indole were obtained.
  • Example 1 5—fluoro-1- (2-methoxyethoxy) indole (10.0 g) was used instead of 3—vinylindole, and nicotinol chloride was used instead of benzoyl chloride. The reaction was carried out in almost the same manner except that chlorobenzene was used to obtain 9.5 g (66.0%) of 5-fluoro-3- (2-methoxyethoxy) -1-1-nicotinylindole. .
  • Example 1 the reaction was carried out in substantially the same manner as in Example 1 except that 10.0 g of 6-methoxycarbonyl 2- (4-methoxyphenyl) indole was used in place of 3-vinylindole. As a result, 8.2 g (59. 9%) of 1-benzoyl-6-methoxypropyl 3- (4-methoxyphenyl) indole was obtained.
  • the reaction was carried out in substantially the same manner as in Example 6 except that the acetic acid was changed to ethanol and the normal pressure was changed to a pressure of 5 to 6.4 Kg / cm 2 , and 1-benzoyl-3-phenylindole was obtained. 12.0 g (19.3 g) was obtained using 12.0 g.
  • Example 9 the same reaction treatment was carried out using 1.0 g of 1-acetyl-3-3-phenylindrin obtained in Example 8 in place of 1-benzoyl_3-phenylidrin, and 0.82 g (99.8%) of 3-phenylindolin was obtained.
  • Example 6 3.0 g of 1-benzoyl-3- (3-methoxyethoxy) indole was used instead of 1-benzoyl-3-phenylindole, and the reaction was carried out in the same manner. There was obtained 2.75 g (91.1%) of benzoyl 3- (3-methoxyethoxy) indolin.
  • Example 9 1 Benzyl-3 1 Benzoyl 3- (3-methoxyphenyl) indolin 1.00 g was treated in the same manner to give 3- (3-methoxyphenyl) as an oily semi-solid. 0.66 g (96.5%) of India was obtained.
  • Example 6 is substantially the same as Example 6, except that 3.0 g of 5_fluoro-3- (2-methoxyphenyl) 1-1-nicotinylindole was used in place of 1-benzoylindole 3-phenylindole.
  • the mixture was subjected to a reaction treatment to obtain 2.7 g (89.4%) of 5-fluoro-3- (2-methoxyphenyl) 111-nicotinylindolin. Further, this compound was subjected to a reaction treatment according to the method described in Example 9 to obtain 1.2 g (63.5%) of 5-fluoro-3- (2-methoxyphenyl) indolin.
  • 3.0 g of 5_fluoro-3- (2-methoxyphenyl) 1-1-nicotinylindole was used in place of 1-benzoylindole 3-phenylindole.
  • the mixture was subjected to a reaction treatment to obtain 2.7 g (89.4%) of 5-fluoro-3- (2-methoxypheny
  • 6-Methoxycarbonyl 3- (4-Methoxyphenyl) indolin In Example 6, 1 benzoyl-6-methoxycarbonyl was used in place of 1-benzoyl-3-phenylindole. The reaction was performed in substantially the same manner as above except that 3.0 g of roux-3- (4-methoxyphenyl) indole was used. 1 Benzoyl 6-methoxycarbonyl 2- 3- (4-methoxyphenyl) Le) I got indlin.
  • N-tosyl-D-prolyl chloride was used instead of benzoyl chloride, and the reaction temperature during cooling was reduced. The reaction was performed in substantially the same manner except that the temperature was changed to ⁇ 40 ° C., and from 3.50 g of 3-phenylindole, 3-phenylene with a melting point of 1448—149 ° C 1 -(N-tosyl-D-prolyl) indole 3.88 g (48. 2%) was obtained.
  • Example 6 2.0 g of 3-phenyl-11- (N-tosil-D-prolyl) indole was used in place of 1-benzoyl-3-vinylindole. The reaction was carried out in substantially the same manner to obtain 1.81 g (90.0%) of 3-phenyl-1- (N-tosyl-D-prolyl) indolin. 4.7 ml of concentrated hydrochloric acid and 12.4 ml of acetic acid were added thereto, and the mixture was refluxed by heating for 37 hours, and then extracted with ethyl acetate as a weak alkaline solution with aqueous sodium hydroxide solution.
  • Example 1 ⁇ -trifluoroacetyl-D-prolyl chloride was used in place of benzoyl chloride, and the reaction treatment was carried out in substantially the same manner except that the reaction temperature during cooling was changed to 140 ° C. 3-Phenyl-indol 4.0 g force, etc. 3-Fe-n-1- (N-trifluoroacetyl-D-prolyl) indole 2.29 g (2 8.6%).
  • Example 6 5.0 g of 3-phenyl-11- (N-trifluoroacetyl-D-prolyl) indole was used in place of 1-benzoyl-3-phenylindole, The reaction was performed in substantially the same manner to give 3-phenyl-1- (N-trifluoroacetyl-D-prolyl) indolin 4.91 g
  • the product was purified by silica gel column chromatography to obtain an epimer mixture, 5 — [(3- (3-hydroquinphenyl) indolin-1-ylcarbonyl)]-1,4,5,6,7—tetrahydro 2.0 g (56.8) of benzimidazole was obtained.
  • Example 20 llg of 4,5,6.7-tetrahydrobenzimidazol-5-potassium hydrochloride (racemic form) was used, and (+)-3-(3- The reaction was carried out in substantially the same manner except that 2.34 g of (+) — 3— (3-methoxyphenyl) indrin was used instead of (hydroquinphenyl) indrin, and the reaction was continued.
  • the mixture 5— [3- (3—Methoxyphenyl) indolin-1—ylcarbonyl] 1.4,5,6,7—Tetrahydrid benzoimidazole 1.90 g (48.8%).
  • Optical activity 5 [3 — (3 — Hydroxyphenyl) indolin-1-ylcarbonyl] 1-4,5,6,7 —Tetrahidrobenzimidazol: Optical activity 5 described in Example 24 — [3 — (3-Methoxyphenyl) indolin-1-1-inolecarbonyl] 1-4,5,6.7 —Tetrahydrobenzimidazole 300 mg dissolved in Clomform 9 ml Then, 3.2 ml of a 1.0 M dichloromethane solution of boron tribromide was added to this solution at ⁇ 78 ° C. in an argon stream. The mixture was stirred at ⁇ 18 ° C. for 3 hours and further at room temperature for 3 hours.
  • reaction solution was poured into ice water, neutralized with an aqueous solution of sodium hydrogen carbonate, and extracted with a mixed solution of chloroform and ethanol.
  • organic layer was dried over magnesium sulfate and evaporated.
  • the residue was purified by silica gel column chromatography, and the optically active 5- [3- (3-hydroxyphenyl) indolin-1-ylcarbonyl] 1-4,5,6,7—tetrahydrobenzene was purified. 220 mg (76.1%) of midazole were obtained.
  • Example 19 except that (+)-15-fluoro-3— (2-methoxyethoxy) indolin 0.30 g was used instead of (+)-3—phenylindolin, almost all were used.
  • the reaction was carried out to obtain an epimer mixture 5- [5-Fluoro-3- (2-methoxyethoxy) indolin-1-ylcarbonyl] -4.5,6,7-Tetrahydrobenzimidazole 0.25 g (5 2.1%). Further, this compound was recrystallized from a mixed solution of ethyl acetate and hexane according to the method described in Example 22 to obtain optically active 5- [5-fluoro-3- (2-methoxyethoxy) indolinone. 1-ylcarbonyl] -1-4.5,6,7-Tetrahydrobenzimidazole 0.1 g was obtained.
  • Example 19 0.2 g of (+) — 6—methoxycarbonyl 3- (4-methoxyethoxy) indolin was used instead of (+) — 3-phenylindolin. The others were treated in substantially the same manner to give an epimer mixture, 5- [6-methoxycarbonyl-2- 3- (4-methoxyphenyl) indolin-1 1-ylcarbonyl] 1-4,5,6,7 —0.2 g (66.7%) of tetrahydrobenzimimidazole was obtained. Further, this compound was recrystallized from a mixed solution of ethyl acetate and hexane according to the method described in Example 22 to obtain an optically active 5- [6-methoxycarbonyl-2-3- (4-methoxyphenyl). ) Indolin-1-ylcarbonyl] -14,5,6.7—Tetrahydrobenzimidazole 0.07 g was obtained. Industrial applicability
  • the 5-HT 3 receptor antagonist 1 acylu-3 is obtained without decomposing the indole compound, causing no corrosion or breakage of the reaction equipment, or causing environmental pollution by the zinc compound.

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Abstract

L'invention concerne un procédé de préparation de composés 3-arylindoline représentés par la formule générale (2). Dans cette formule, R1 représente un phényle ou un hétérocycle aromatique, pouvant être substitué, et R2 représente un hydrogène, un halo, un alkyle inférieur, un hydroxy, un alcoxy inférieur, un carbamoyle ou un alcoxycarbamoyle inférieur. Ces composés sont utiles pour préparer des antagonistes des récepteurs du type 3 de la 5-HT, que sont les composés 1-acyl-3-arylindoline représentés par la formule générale (1), dans laquelle R1 et R2 sont définis ci-dessus et R3 a la formule (a) ou (b). Dans ce procédé on utilise un composé 1-acyl-3-arylindole, obtenu en fixant un groupe électronégatif éliminable en position 1 d'un composé 3-arylindole, par l'acylation de ce composé avec un acide organique tel qu'un acide carboxylique ou un acide sulfonique, puis en effectuant une réduction catalytique modérée dans des conditions neutres ou légèrement acides pour donner un composé 1-acyl-3-arylindoline. Un composé 1-acyl-3-arylindole optiquement actif est obtenu en acylant un composé 3-arylindole avec un acide organique tel qu'un acide carboxylique ou un acide sulfonique, etc., optiquement actif, pour finalement obtenir un composé 1-acyl-3-arylindoline, par une réduction catalytique à haute sélectivité.
PCT/JP1996/000344 1995-02-17 1996-02-16 Procede de preparation de composes indoline et intermediaires de cette preparation WO1996025396A1 (fr)

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Application Number Priority Date Filing Date Title
US08/894,855 US5936098A (en) 1995-02-17 1996-02-16 Process for producing indoline compounds and intermediates for the production of the same
AU46759/96A AU718434B2 (en) 1995-02-17 1996-02-16 Process for producing indoline compounds and intermediates for the production of the same
EP96902458A EP0810214A4 (fr) 1995-02-17 1996-02-16 Procede de preparation de composes indoline et intermediaires de cette preparation

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JP2976395 1995-02-17
JP7/29763 1995-02-17

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6437147B1 (en) 2000-03-17 2002-08-20 Novo Nordisk Imidazole compounds
WO2007029629A1 (fr) * 2005-09-06 2007-03-15 Shionogi & Co., Ltd. Dérivé d’acide indolécarboxylate ayant une activité à effet antagoniste du récepteur pgd2

Citations (2)

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Publication number Priority date Publication date Assignee Title
JPS5212162A (en) * 1975-06-23 1977-01-29 Delmar Chem Production of phenylindoline
WO1995009167A1 (fr) * 1993-09-30 1995-04-06 Tokyo Tanabe Company Limited Derive d'indoline et antagoniste du recepteur 5-ht3 contenant ce derive et utilise comme ingredient actif

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6437147B1 (en) 2000-03-17 2002-08-20 Novo Nordisk Imidazole compounds
US6756384B2 (en) 2000-03-17 2004-06-29 Novo Nordisk A/S Imidazole compounds
WO2007029629A1 (fr) * 2005-09-06 2007-03-15 Shionogi & Co., Ltd. Dérivé d’acide indolécarboxylate ayant une activité à effet antagoniste du récepteur pgd2
JP5147401B2 (ja) * 2005-09-06 2013-02-20 塩野義製薬株式会社 Ｐｇｄ２受容体アンタゴニスト活性を有するインドールカルボン酸誘導体

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