JP4112651B2 - Process for producing cis-hexahydroisoindoline - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing cis-hexahydroisoindoline useful as a raw material for producing pharmaceuticals, characterized by reducing cis-hexahydrophthalimide using a borane reagent.
[0002]
More specifically, the present invention is characterized in that cis-hexahydrophthalimide is reduced using a borane reagent, for example, a benzyl succinic acid derivative useful as a therapeutic agent for diabetes (Japanese Patent Laid-Open No. 4-356458, The present invention relates to a method for producing cis-hexahydroisoindoline, which is a production raw material of JP-A-6-340623.
[0003]
[Prior art]
Until now, cis-hexahydroisoindoline has been produced by catalytic reduction of cis-1,2,3,6-tetrahydrophthalimide in the presence of palladium to obtain cis-hexahydrophthalimide, followed by hydrogenation. A method of reducing using lithium aluminum has been reported (WO94 / 03437).
[0004]
As for the method for producing hexahydroisoindoline, 1,2,3,6-tetrahydrophthalimide is reduced with lithium aluminum hydride to obtain 3a, 4,7,7a-tetrahydroisoindoline, and then oxidized. A method of catalytic reduction using platinum, a method of high-pressure catalytic reduction of tetrahydrophthalimide using a metal catalyst, etc. have been reported (J. Org. Chem., 20, 1687-1694 (1955), Japanese Patent Laid-Open 6-298727).
[0005]
[Problems to be solved by the invention]
In order to examine the production method of cis-hexahydroisoindoline, the present inventors catalytically reduced cis-1,2,3,6-tetrahydrophthalimide in the presence of palladium to obtain cis-hexahydrophthalimide. Thereafter, reduction with lithium aluminum hydride revealed that trans-hexahydroisoindoline was produced as a by-product together with cis-hexahydroisoindoline.
[0006]
Also, cis-1,2,3,6-tetrahydrophthalimide is reduced with lithium aluminum hydride to obtain cis-3a, 4,7,7a-tetrahydroisoindoline, and then catalytic reduction is performed in the presence of palladium. When cis-hexahydroisoindoline was produced, it was found that trans-hexahydroisoindoline was present as a by-product in the reaction product.
[0007]
The trans product, which is a by-product, is an oily substance similar to the cis product, and its boiling point is very close to the boiling point of the cis product. It is.
[0008]
Usually, supply of a high-quality production raw material is required for improving the quality and stable supply of the final product, but at present, an efficient method for producing a cis isomer that does not contain a trans isomer has not been established.
[0009]
Furthermore, in the above production method, lithium aluminum hydride used as a reducing agent is a reagent widely used at the laboratory level, but there is a problem such as danger because it is highly reactive for use in production on an industrial production scale. There is. Further, the above-described method using high-pressure catalytic reduction using a metal catalyst requires a special production apparatus and facility, and is not necessarily a simple method.
[0010]
As described above, it has been desired to develop a method for producing a high-quality cis-hexahydroisoindoline that can be carried out more easily without accompanying by-product of the trans form and is suitable for industrial production.
[0011]
[Means for Solving the Problems]
As a result of diligent research to solve the above-mentioned problems, the present inventors have reduced cis-hexahydrophthalimide using a borane reagent and retained the steric form without generating a trans form as a by-product. The inventors have found that indoline can be obtained and have accomplished the present invention.
[0012]
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a novel process for producing cis-hexahydroisoindoline, which can be carried out by reducing cis-hexahydrophthalimide in an inert solvent using a borane reagent.
[0013]
The borane reagent used in the production method of the present invention includes a reagent capable of generating a borane complex or diborane in the reaction system (for example, Org. Reactions, 1963, Vol. 13, pages 1 to 54). Preferred examples of the reagent include borane-tetrahydrofuran complex, sodium borohydride / boron trifluoride-diethyl ether complex, and the like.
[0014]
The inert solvent used in the production method of the present invention can be used as long as it does not inhibit this reaction, and preferably includes ether solvents such as diethyl ether, tetrahydrofuran, diethylene glycol dimethyl ether and the like. Tetrahydrofuran can be mentioned as a particularly preferred solvent.
[0015]
In the production method of the present invention, the amount of the reagent used is preferably 2.3 to 10 times the molar amount of the substrate in terms of the amount of borane, and the reaction temperature is preferably 0 ° C. to reflux temperature. The reaction time is usually 2 to 48 hours.
[0016]
The cis-hexahydroisoindoline produced in the production method of the present invention can be easily purified by vacuum distillation or steam distillation.
[0017]
As a method for carrying out the present invention more suitably, sodium borohydride / boron trifluoride-diethyl in 2.6-fold molar amount (in terms of borane) with respect to cis-hexahydrophthalimide in tetrahydrofuran with stirring under ice-cooling. A method of mixing an ether complex, adding cis-hexahydrophthalimide and heating to reflux for 22 to 24 hours can be mentioned. After cooling, the resulting reaction product was added with hydrochloric acid and heated to reflux for 2 hours. The reaction mixture is concentrated under reduced pressure, and the residue is once steam-distilled under acidic conditions, then again steam-distilled under alkaline conditions to acidify the fraction, and then concentrated under reduced pressure, and the residue is treated according to a conventional method. Can be purified.
[0018]
In the present invention, the cis-hexahydrophthalimide used as a starting material is, for example, catalytically reducing cis-tetrahydrophthalimide in the presence of a metal catalyst such as palladium, or cis-hexahydrophthalic anhydride with urea, ammonia or the like. It can be manufactured by heating.
[0019]
Thus, the method for producing cis-hexahydroisoindoline using the borane reagent of the present invention is an excellent method for producing no trans product as a by-product. Moreover, it is a very useful manufacturing method which can be carried out mildly and simply, and is suitable for industrial production.
[0020]
【Example】
The present invention will be described in more detail with reference to the following reference examples, examples and comparative examples, but the present invention is not limited to the contents thereof. In addition, the gas chromatography analysis in an Example and a comparative example was implemented on condition of the following.
Column used: GL Science Company NEUTRABOND-5 (0.25 mm id × 60 m, film thickness 1.5 μm)
Column temperature: 100 ° C. (1 min.) To 10 ° C./min. -160 ° C (8 min.)-10 ° C / min. ~ 220 ° C
Inlet temperature: 150 ° C
Carrier gas: helium flow rate: 3 ml / min.
Detector: Hydrogen flame ionization detector Split ratio: 33: 1
[0021]
Reference example 1
51.6 g of cis-hexahydrophthalimide cis-1,2,3,6-tetrahydrophthalimide was dissolved in 500 ml of methanol, 2.0 g of 10% palladium carbon was added, and the mixture was stirred in a hydrogen stream at room temperature and normal pressure for 2 days. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from methanol to obtain 47.78 g of cis-hexahydrophthalimide as colorless crystals.
[0022]
¹ H-NMR (CDCl ₃ ) δ ppm:
1.4-1.55 (m, 4H), 1.7-2.0 (m, 4H), 2.85-3.0 (m, 2H), 8.2-8.6 (br, 1H) )
[0023]
Reference example 2
Cis-hexahydrophthalimide 3.59 g of cis-hexahydrophthalic anhydride and 1.54 g of urea were mixed, heated and melted at 160 ° C., and stirred as it was for 1 hour. After allowing to cool, 4 ml of water was added to the reaction mixture, and the mixture was cooled with ice. The precipitated crystals were collected by filtration to obtain 2.80 g of colorless crystals of cis-hexahydrophthalimide. The physical property values agreed with those of the compound of Reference Example 1.
[0024]
Example 1
Reduction of cis-hexahydrophthalimide using borane-tetrahydrofuran complex 60 ml of 1.0 molar borane-tetrahydrofuran complex tetrahydrofuran solution in a 20 ml dry tetrahydrofuran solution of 3.00 g of cis-hexahydrophthalimide in an argon stream under ice-cooling and stirring. Was added dropwise and heated to reflux for 24 hours. After allowing to cool, 20 ml of concentrated hydrochloric acid was added under ice cooling, and the mixture was heated to reflux for 2 hours, and then the solvent was distilled off under reduced pressure. After 120 ml of the residue was distilled by steam distillation, the residue was made alkaline by adding sodium hydroxide under ice cooling, and steam distillation was performed again. After adding 3 ml of concentrated hydrochloric acid to about 100 ml of the distillate, the filtrate was concentrated under reduced pressure to obtain 1.51 g of cis-hexahydroisoindoline hydrochloride as colorless crystals.
[0025]
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.25-1.65 (m, 8H), 2.15-2.3 (m, 2H), 2.85-3.2 (m, 4H), 9.5-10.0 (br, 2H) )
[0026]
0.5 g of cis-hexahydroisoindoline hydrochloride was dissolved in 0.2 ml of water, and 185 mg of sodium hydroxide was added with stirring at room temperature. After adding 5 ml of methylene chloride to the reaction solution and stirring vigorously, the reaction solution was dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was distilled under reduced pressure to obtain 345 mg of a colorless oil. When the obtained oil was analyzed by gas chromatography, this oil was 100% cis-hexahydroisoindoline, and the presence of the trans isomer was not confirmed.
[0027]
¹ H-NMR (CDCl ₃ ) δ ppm:
1.2-1.7 (m, 8H), 2.0-2.5 (m, 2H), 2.33 (brs, 1H), 2.7-2.85 (m, 2H), 2. 85-3.0 (m, 2H)
[0028]
Example 2
Reduction of cis-hexahydrophthalimide with sodium borohydride / boron trifluoride-diethyl ether complex 1.68 g of sodium borohydride in 20 ml of dry tetrahydrofuran Boron trifluoride- 6.6 ml of diethyl ether complex was added. To the mixed solution was added a solution of 3.00 g of cis-hexahydrophthalimide in 40 ml of dry tetrahydrofuran, heated under reflux for 23 hours, and treated in the same manner as in Example 1 to obtain 1.73 g of colorless crystals of cis-hexahydroisoindoline hydrochloride. Got. The cis-hexahydroisoindoline hydrochloride obtained here was treated in the same manner as in Example 1 to obtain an oily substance. When the obtained oil was analyzed by gas chromatography, this oil was 100% cis-hexahydroisoindoline, and the presence of the trans isomer was not confirmed. The physical property values were the same as those of the compound of Example 1.
[0029]
Comparative Example 1
Reduction of cis-1,2,3,6-tetrahydrophthalimide with lithium aluminum hydride and catalytic reduction of the resulting product Reduction of lithium aluminum hydride (7.6 g) in a dry tetrahydrofuran (150 ml) suspension in an argon stream at 80 ° C. with stirring A solution of 15.1 g of cis-1,2,3,6-tetrahydrophthalimide in 100 ml of dry tetrahydrofuran was added dropwise. After heating to reflux overnight, the reaction mixture was ice-cooled and 10 ml of water was added little by little. The precipitate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was distilled under reduced pressure (96 to 103 ° C./20 mmHg) to obtain 6.6 g of colorless oily 3a, 4,7,7a-tetrahydroisoindoline.
[0030]
To a solution of 3a, 4,7,7a-tetrahydroisoindoline (2.00 g) in ethanol (3 ml) was added 10% palladium carbon (0.1 g), and the mixture was stirred overnight at room temperature and normal pressure in a hydrogen stream. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was distilled under reduced pressure (88-92 ° C./20 mmHg) to obtain 1.42 g of a colorless oil. When the obtained oil was analyzed by gas chromatography, this oil was a mixture of cis-hexahydroisoindoline and trans-hexahydroisoindoline, and the abundance ratio was 94.46: 5.54. .
[0031]
Comparative Example 2
Reduction of cis-hexahydrophthalimide with lithium aluminum hydride 1.52 g of lithium aluminum hydride suspension in 20 ml of dry tetrahydrofuran In a stream of argon, a solution of 3.06 g of cis-hexahydrophthalimide in 15 ml of dry tetrahydrofuran was added dropwise. Refluxed overnight. After allowing to cool, water was added to the reaction solution, the insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was distilled under reduced pressure (92-99 ° C / 20 mmHg) to obtain 1.40 g of a colorless oil. It was. When the obtained oil was analyzed by gas chromatography, this oil was a mixture of cis-hexahydroisoindoline and trans-hexahydroisoindoline, and the abundance ratio was 98.87: 1.13. .

Claims (2)

A method for producing cis-hexahydroisoindoline, comprising reducing cis-hexahydrophthalimide using a borane reagent. The method for producing cis-hexahydroisoindoline according to claim 1, wherein the borane reagent is borane-tetrahydrofuran complex or sodium borohydride / boron trifluoride-diethyl ether complex.