JP2005281168A - Method for producing 3-pyrrolidinol - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a simple method for producing a 3-pyrrolidinol useful as an intermediate for synthesizing drugs, agrochemicals and the like. <P>SOLUTION: The method for producing 3-pyrrolidinol of formula(3) or a salt thereof comprises hydrogenating a 4-azido-1-halogeno-2-butanol of formula(1)(wherein, X means a halogen atom) or a 4-azido-1-sulfonyloxy-3-butanol of formula(2)[wherein, R is a (substituted) alkyl, (substituted) aralkyl or (substituted) aryl] or a mixture thereof in the presence of a metallic catalyst to reduce the azido group as well as carry out a cyclization reaction. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a method for producing 3-pyrrolidinol or a salt thereof useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals and the like.

  Since 3-pyrrolidinol is an industrially useful compound for a long time, there are many prior arts relating to a method for producing the compound. Among them, when focusing on the production method using 2-butanol derivatives having leaving groups at the 1-position and 4-position as raw materials, (1) a method of reacting with ammonia gas (see Patent Document 1), ( 2) A method of reacting with benzylamine (see Patent Document 2) and debenzylating the resulting 1-benzyl-3-hydroxypyrrolidine by hydrogenation under a metal catalyst.

Japanese Patent Laid-Open No. 60-104061 Japanese Examined Patent Publication No. 7-76209

  However, the above method has the following problems. That is, in the method (1), since the reactivity of ammonia is low, it takes a long time of at least 2 days to complete the reaction. In addition, the method (2) is not versatile because high pressure conditions using a special pressure resistant reaction vessel are required for debenzylation.

（式中Ｘはハロゲン原子、式中Ｒは置換もしくは無置換のアルキル基、置換もしくは無置換のアラルキル基、または置換もしくは無置換のアリール基を意味する。）
で表される４−スルホニルオキシ−１−ハロゲノ−２−ブタノールにアジド塩を反応させて、下記式（１）

（式中Ｘは、前掲と同じものを意味する。）
で表される４−アジド−１−ハロゲノ−２−ブタノール、または下記式（２）

（式中Ｒは、前掲と同じものを意味する。）
で表される４−アジド−１−スルホニルオキシ−３−ブタノール、あるいはこれらの混合物に変換する工程と、ついで金属系触媒下、水素を添加してアジド基を還元するとともに環化反応させて下記式（３）

で表される３−ピロリジノールまたはその塩に変換する工程を含む、３−ピロリジノールまたはその塩の製造法に関する。 As a result of various studies to solve the above problems, the inventors of the present invention have used 3-pyrrolidinol or a suitable reaction time from a 2-butanol derivative having a leaving group at the 1- and 4-positions using a general-purpose equipment. The present inventors have found that the salt can be produced and have completed the present invention.
That is, the present invention provides the following formula (4)

(In the formula, X represents a halogen atom, and R in the formula represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group.)
The azide salt is reacted with 4-sulfonyloxy-1-halogeno-2-butanol represented by the following formula (1):

(In the formula, X means the same as described above.)
4-azido-1-halogen-2-butanol represented by the following formula (2)

(In the formula, R means the same as described above.)
The step of converting to 4-azido-1-sulfonyloxy-3-butanol represented by the following, or a mixture thereof, and then adding hydrogen under a metal catalyst to reduce the azide group and cyclize the following: Formula (3)

The manufacturing method of 3-pyrrolidinol or its salt including the process converted into 3-pyrrolidinol or its salt represented by these.

Moreover, the reaction process of this invention can be shown with the following reaction formula.

Preferred form for carrying out the present invention

Hereinafter, the method of the present invention will be described in detail for each step.
First, 4-sulfonyloxy-1-halogen-2-butanol (4) is reacted with an azide salt to give 4-azido-1-halogeno-2-butanol (1) or 4-azido-1-sulfonyloxy- The process of converting into 3-butanol (2) or a mixture thereof will be described.

  Although 4-sulfonyloxy-1-halogeno-2-propanol (4) used as a starting material may be obtained by any method, for example, it can be easily produced by the method described in Reference Example 1. Examples of the halogen atom represented by X include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, with a chlorine atom and a bromine atom being preferred. Examples of the substituent R include a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, isopropyl, trifluoromethyl, and trichloromethyl, and a substituted or unsubstituted aralkyl (aryl) such as benzyl and 2-nitrobenzyl. Alkyl) group, phenyl, 4-tert-butylphenyl, 1-naphthyl, 2-naphthyl, 4-tolyl, 4-methoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-chlorophenyl, 3 -Substituted or unsubstituted such as chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-iodophenyl, 2,4-dinitrophenyl, 2,5-dichlorophenyl, 2,4,6-trimethylphenyl And an aryl group having 6 to 9 carbon atoms.

  Usable solvents include aprotic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and hexamethylphosphoric triamide, ether solvents such as tetrahydrofuran, 1,4-dioxane, glyme, diglyme and triglyme, dichloromethane Halogen solvents such as chloroform and 1,2-dichloroethane, hydrocarbon solvents such as benzene and toluene, nitrile solvents such as acetonitrile, ketone solvents such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, ethyl acetate, butyl acetate, etc. Ester solvents, alcohol solvents such as methanol, ethanol, isopropanol, tert-butanol, and cyclohexanol, water solvents, and mixed solvents thereof. A two-layer solvent composed of water and a water-insoluble solvent is preferred, and a two-layer solvent composed of water and toluene is particularly preferred.

Examples of the azide salt that can be used include alkali metal azide salts such as lithium azide, sodium azide, and potassium azide, alkaline earth metal azide salts such as calcium azide, and organic azide salts such as trimethylsilyl azide and diphenylphosphoryl azide. Sodium azide is preferable. The amount used is 0.8 to 1.2 equivalents relative to the substrate, but if used in excess, a compound in which two azides are substituted in the molecule is produced as a by-product, and therefore preferably 0.95 to 1.05 equivalents. is there.
The reaction temperature is appropriately selected in the range from 0 ° C. to the reflux temperature of the solvent, and preferably from room temperature to the reflux temperature of the solvent. The reaction pressure is usually normal pressure, but the reaction can be carried out under pressure. The reaction time is appropriately determined depending on the relationship such as temperature and pressure.
This reaction proceeds even without catalyst, but the reaction is accelerated when a reaction accelerator is added to the reaction system. Examples of the reaction accelerator include N, N-dimethylaminopyridine, iodide such as cesium iodide, sodium iodide and potassium iodide, bromide such as cesium bromide, sodium bromide and potassium bromide, tetrabutylammonium chloride, Examples thereof include quaternary ammonium salts such as tetrabutylammonium bromide and trimethylbenzylammonium bromide, and crown ethers such as 18-crown-6.

By performing the above reaction, 4-azido-1-halogen-2-butanol (1), 4-azido-1-sulfonyloxy-3-butanol (2), or a mixture thereof is produced.
The content ratio of the compounds (1) and (2) in the product varies depending on the selection of the substituent X, R, reaction solvent, reaction temperature, etc. of the compound (4) as a raw material. May be.
After completion of the reaction, after the usual extraction operation, the solvent is distilled off under reduced pressure, and the residue is easily purified by subjecting it to purification treatment such as distillation, recrystallization, silica gel column chromatography, etc. -1-halogeno-2-butanol (1), or 4-azido-1-sulfonyloxy-3-butanol (2), or a mixture thereof is obtained. These compounds are all compounds not described in any literature.
Even if the compounds (1) and (2) are mixed, there is no problem as long as they are used in the next step. Further, the crude product can be used as it is in the next step without any particular purification.
When optically active 4-sulfonyloxy-1-halogeno-2-butanol (4) is used as a starting material, optically active 4-azido-1-halogeno-2-butanol (1) or 4-azido-1- Sulfonyloxy-3-butanol (2) or an optically active mixture thereof is obtained. In this case, no significant racemization occurs during the reaction.

Next, 4-azido-1-halogen-2-butanol (1), 4-azido-1-sulfonyloxy-3-butanol (2), or a mixture thereof obtained in the above step is reacted under a metal catalyst. The step of adding hydrogen to reduce the azide group and cyclize to convert to 3-pyrrolidinol (3) or a salt thereof will be described.
Solvents that can be used include ether solvents such as tetrahydrofuran, 1,4-dioxane, glyme, diglyme, and triglyme, halogen solvents such as dichloromethane, chloroform, and 1,2-dichloroethane, hydrocarbon solvents such as benzene and toluene, Ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone, ester solvents such as ethyl acetate and butyl acetate, alcohol solvents such as methanol, ethanol, isopropanol, tert-butanol and cyclohexanol, water solvents and mixed solvents thereof Can be mentioned.
The metal-based catalyst that can be used is not particularly limited as long as it is a catalyst used for this type of catalytic reduction reaction, but metal-based catalysts such as palladium and platinum are preferable, and palladium-based catalysts are more preferable. Further, the palladium-based catalyst is preferably about 5 to 10% by weight of palladium-carbon powder. The amount of the metal catalyst used is suitably in the range of 0.5 to 50% by weight with respect to the raw material compound.

The reaction temperature is appropriately selected in the range from 0 ° C. to the reflux temperature of the solvent, and preferably from room temperature to the reflux temperature of the solvent. The reaction pressure is usually normal pressure, but the reaction can be carried out under pressure. The reaction time is appropriately determined depending on the relationship such as temperature and pressure.
After completion of the reaction, the target compound (3) can be collected according to a conventional method. For example, when the solvent is distilled off from the reaction mixture, the halogen atom in 4-azido-1-halogeno-2-butanol (1), which is 3-pyrrolidinol, which is the target compound, or 4-azido-1-sulfonyloxy-3 -Obtained in the form of a salt with an acid derived from a sulfonyloxy group in butanol (2).
Further, the desired product can be obtained in a free form by subsequent base treatment, and this can be purified by distillation, recrystallization, chromatography or the like, if necessary. Furthermore, the free form can be re-acidified to form a salt, which can be recrystallized or purified by chromatography or the like. In addition, when a target object is a racemate, it can also carry out optical resolution by fractional crystallization by using the optically active acid suitable for this acid treatment. Further, a salt treatment can be followed to obtain a desalted optically active substance.
When optically active 4-azido-1-halogen-2-butanol (1), 4-azido-1-sulfonyloxy-3-butanol (2), or a mixture thereof is used as a raw material for this reaction, optical activity is obtained. 3-pyrrolidinol or a salt thereof is obtained. In this case, no significant racemization occurs during the reaction.

The present invention will be specifically described below with reference to examples. The present invention is not limited to these examples.
Example 1
Production of (R) -4-azido-1-chloro-2-propanol (R) -1-chloro-4- (4-toluenesulfonyloxy) -2-propanol 224 g (0.803 mol, optical purity 99% ee) To a two-layered solution consisting of 450 mL of toluene and 150 mL of water, 4.46 g (16.1 mmol) of tetrabutylammonium chloride and 52.2 g (0.803 mol) of sodium azide were added and stirred at 60 ° C. for 27 hours. Next, the reaction solution was cooled to room temperature, allowed to stand, the separated aqueous layer was removed, and the organic layer was washed twice with 150 mL of water. The organic layer was concentrated under reduced pressure to obtain 99.2 g (crude yield 82.6%) of a crude product of the title (R) -4-azido-1-chloro-2-propanol. The crude product does not contain (R) -4-azido-1- (4-toluenesulfonyloxy) -3-propanol, and (R) -4-azido-1-chloro-2-propanol is exclusively used. Obtained.
¹ H-NMR (270 MHz, CDCl ₃ ) δ 1.79 (2H, m, C H ₂ CH ₂ N ₃ ), 2.43 (1H, d, J = 4.6 Hz, O H ), 3.52 (2H, m, CH ₂ C H ₂ N ₃ ), 3.65 (2H, dd, J = 11.2, 3.6Hz, CHC H ₂ Cl), 3.96 (1H, m, C H OH)
Optical purity 99% ee (measured after induction to 3-pyrrolidinol)

Example 2
Production of (R) -3-pyrrolidinol 89.9 g (about 0.601 mol, optical purity 99% ee) of the crude product obtained in Example 1 was dissolved in 360 mL of methanol, and 8.99 g of 10% palladium-carbon ( 10% by weight) and stirred for 4 hours at room temperature under a hydrogen gas stream. The reaction solution was filtered, and 50.1 g (0.601 mol) of a 48% aqueous sodium hydroxide solution was added to the filtrate, followed by further stirring at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and 360 mL of 2-propanol was added to the residue for dispersion, and then filtered to remove salts, and the filtrate was concentrated. The crude product was purified by distillation under reduced pressure (boiling point: 109-110 ° C./8 mmHg) to obtain 39.8 g of the title (R) -3-pyrrolidinol (total yield 62.9%).
¹ H-NMR (270 MHz, D ₂ O) δ1.72 (1H, m, HNCH ₂ C H ₂ ), 1.94 (1H, m, HNCH ₂ C H ₂ ), 2.72-3.02 (4H, m, HNC H ₂ ), 4.42 (1H, m, C H OH)
Optical purity 99% ee (HPLC, column: CHIRALCELL AS 250 × 4.6 mm, mobile phase: n-hexane / 2-propanol = 1/2, wavelength: 254 nm, temperature: room temperature, flow rate: 0.5 mL / min)

Example 3
Preparation of a mixture of (R) -4-azido-1-chloro-2-propanol and (R) -4-azido-1- (4-toluenesulfonyloxy) -3-propanol (R) -1-chloro-4 In a two-layer system solution of 20 g (71.7 mmol, optical purity 99% ee) of ethyl (4-toluenesulfonyloxy) -2-propanol and 80 mL of ethyl acetate and 40 mL of water, 997 mg (3.59 mmol) of tetrabutylammonium chloride Sodium azide 4.46 g (71.7 mmol) was added and stirred at 70 ° C. for 24 hours. Next, the reaction solution was cooled to room temperature, allowed to stand, the separated aqueous layer was removed, and the organic layer was washed twice with 40 mL of water. The organic layer was concentrated under reduced pressure to give a mixture of the title (R) -4-azido-1-chloro-2-propanol and (R) -4-azido-1- (4-toluenesulfonyloxy) -3-propanol. 12.6 g of crude product was obtained.
A part of this crude product was purified by silica gel column chromatography to obtain (R) -4-azido-1-chloro-2-propanol and (R) -4-azido-1- (4-toluenesulfonyl). When oxy) -3-propanol was isolated, the molar ratio of both was 91: 9.
(R) -4-Azido-1- (4-toluenesulfonyloxy) -3-propanol
¹ H-NMR (270 MHz, CDCl ₃ ) δ1.95 (2H, m, C H ₂ CH ₂ OTs), 2.47 (3H, s, PhC H ₃ ), 3.20 (1H, ddd, J = 12.5, 7.9, 6.6 Hz, CH ₂ C H ₂ OTs), 3.39 (1H, ddd, J = 12.5, 5.6, 5.6 Hz, CH ₂ C H ₂ OTs), 3.65 (2H, dd, J = 5.3, 2.0 Hz, C H ₂ N ₃ ), 4.75 (1H, m, C H OH), 7.39 (2H, d, J = 7.9Hz, Ar), 7.84 (2H, d, J = 7.9Hz, Ar)
Optical purity 99% ee (measured after induction to 3-pyrrolidinol)

Example 4
Production of (R) -3-pyrrolidinol 12.6 g of the crude product obtained in Example 3 was dissolved in 50 mL of methanol, and 1.26 g (10% by weight) of 10% palladium-carbon was added. Stir at room temperature for 3 hours. The reaction solution was filtered, and 6.0 g (71.7 mmol) of a 48% aqueous sodium hydroxide solution was added to the filtrate, followed by further stirring at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and 50 mL of 2-propanol was added to the residue for dispersion, and then filtered to remove salts, and the filtrate was concentrated. The crude product was purified by distillation under reduced pressure (boiling point: 109-110 ° C./8 mmHg) to obtain 3.75 g (total yield 60.0%) of the title (R) -3-pyrrolidinol.
¹ H-NMR (see Example 2)
Optical purity 99% ee (see Example 2)

Reference example 1
A solution of ethyl (R) -4-chloro-3-hydroxybutanoate (50.0 g, 0.300 mol) obtained by the method described in Tetrahedron Asymmetry, 7, 3109 (1996) under a nitrogen atmosphere. The solution was added dropwise at 40 ° C. to a solution of sodium borohydride (11.4 g, 0.300 mol) in tetrahydrofuran (200 mL). The mixture was heated for 1 hour and further reacted at room temperature for 15 hours. Methanol (200 mL) was added dropwise, cooled to 0 ° C., and 4N hydrochloric acid (100 mL) was added dropwise. After stirring at the same temperature for 30 minutes, the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The concentrated solution was extracted with ethyl acetate (200 mL × 3), and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give (R) -4-chloro-1,3-butane. Diol (35.8 g, 95% yield) was obtained.
(R) -4-chloro-1,3-butanediol (35.8 g, 0.287 mol) obtained above was dissolved in 2,6-lutidine (180 mL), and p-toluenesulfonyl chloride was cooled with ice. (54.8 g, 287 mol) was added, and the mixture was warmed to room temperature and stirred for 15 hours. After completion of the reaction, 2,6-lutidine was distilled off under reduced pressure, and ethyl acetate (150 mL) and water (75 mL) were added to the residue for separation and extraction. The organic layer was washed with 2N hydrochloric acid (100 mL) and saturated brine (70 mL) and then evaporated under reduced pressure to give (R) -4-chloro-3-hydroxy-1-p-toluenesulfonyloxybutane (56.7 g, Yield 70.8%).

  3-pyrrolidinol obtained by the method of the present invention, particularly its optically active substance, is used as a synthetic intermediate for pharmaceuticals, agricultural chemicals and the like.

Claims (9)

Following formula (1)

(In the formula, X means a halogen atom.)
4-azido-1-halogen-2-butanol represented by the following formula (2)

(Wherein R represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group.)
4-azido-1-sulfonyloxy-3-butanol represented by the following formula, or a mixture thereof, under a metal catalyst, hydrogen is added to reduce the azide group and cause a cyclization reaction: 3)

The manufacturing method of 3-pyrrolidinol or its salt represented by these. Following formula (4)

(In the formula, X and R mean the same as described above.)
The azide salt is reacted with 4-sulfonyloxy-1-halogeno-2-butanol represented by the following formula (1):

(In the formula, X means the same as described above.)
4-azido-1-halogen-2-butanol represented by the following formula (2)

(In the formula, R means the same as described above.)
It is converted into 4-azido-1-sulfonyloxy-3-butanol represented by the following, or a mixture thereof, and then, under a metal catalyst, hydrogen is added to reduce the azide group and cause a cyclization reaction. The following formula (3)

The manufacturing method of 3-pyrrolidinol or its salt represented by these.   3. The reaction of 4-sulfonyloxy-1-halogeno-2-butanol and an azide salt is carried out by adding a reaction accelerator in a two-layer solvent consisting of water and a water-insoluble solvent. The manufacturing method of 3-pyrrolidinol or its salt of description.   The method for producing 3-pyrrolidinol or a salt thereof according to claim 3, wherein the water-insoluble solvent is toluene and the reaction accelerator is a quaternary ammonium salt.   The method for producing 3-pyrrolidinol or a salt thereof according to any one of claims 1 to 4, wherein the halogen atom X in the formula is a chlorine atom or a bromine atom.   4-Azido-1-halogen-2-butanol, or 4-azido-1-sulfonyloxy-3-butanol, or a mixture thereof is an optically active substance, and 3-pyrrolidinol or a salt thereof as an objective substance is an optically active substance. The method for producing 3-pyrrolidinol or a salt thereof according to claim 1.   3. 3-Pyrrolidinol or a compound thereof according to claim 2, wherein the starting material 4-sulfonyloxy-1-halogeno-2-butanol is an optically active substance, and the target substance 3-pyrrolidinol or a salt thereof is an optically active substance. Salt production method. Following formula (1)

(In the formula, X means a halogen atom.)
4-Azido-1-halogeno-2-butanol represented by: Following formula (2)

(Wherein R represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group.)
4-Azido-1-sulfonyloxy-3-butanol represented by: