WO2003091209A1 - Process for producing 1-(lower alkyl)-3-hydroxypyrrolidine compound - Google Patents

Abstract

A process by which a 1-(lower alkyl)-3-hydroxypyrrolidine useful as an intermediate for fine chemicals such as medicines and agricultural chemicals is easily produced at low cost with satisfactory selectivity. Either a 1-benzyl-3-hydroxypyrrolidine compound or a 3-hydroxypyrrolidine compound is catalytically reduced with an aldehyde or ketone in the presence of a metal catalyst. Thus, the 1-(lower alkyl)-3-hydroxypyrrolidine compound is produced.

Description

 Specification

Method for producing 1-lower alkyl-3-hydroxypyrrolidines

 The present invention is useful as an intermediate for synthesizing fine chemicals such as pharmaceuticals and agricultural chemicals.

Wherein X represents a hydroxyl group or a protected hydroxyl group, and R ¹ and R ² each independently represent a hydrogen atom or a lower alkyl group. The present invention relates to a method for producing a salt.

 More specifically, as a raw material,

General formula (2)

 (Wherein X represents a hydroxyl group or a protected hydroxyl group) 1-benzyl-3-hydroxypyrrolidines or a salt thereof,

Or also as raw material

General formula (3)

(Wherein, X represents a hydroxyl group or a protected hydroxyl group) represented by the formula:

一般式 （4 )

General formula (4)

(Wherein, R ′ and R ² each independently represent a hydrogen atom or a lower alkyl group) by reacting the aldehyde or ketone represented by the above formula with the above-mentioned 1-lower alkyl-13-hydroxypyrrolidine And a method for producing a salt thereof. Background art

 As a method for producing the 1-lower alkyl-13-hydroxypyrrolidines represented by the general formula (1), a method of reacting a 3-hydroxypyrrolidine with a lower alkyl halide is well known. . However, this method inevitably generates a quaternary ammonium salt obtained by reacting two moles of the halogenated lower alkyl, which causes a problem of lowering the yield of the desired product and increasing the amount of impurities.

In recent years, the secondary amino group of 3-hydroxypyrrolidine has been once acylated and then reduced with lithium aluminum hydride (LAH) or the like. (Journal of Organic Chemistry, Vol. 63, No. 23, pp. 82666, 1989). However, in this method, there were problems with the industrial production method, such as the fact that the reaction involved multiple steps and the use of LAH, which was expensive and had safety problems.

 When 1-benzyl-3-hydroxypyrrolidine, which is easy to prepare, is used as a raw material, debenzylation is once carried out by catalytic reduction in the presence of a metal catalyst to isolate 3-hydroxypyrrolidine. The method of using a lower alkyl halide of the above or a method of performing a reduction reaction after acylation results in carrying out the alkylation reaction, and further involves many reaction steps, is inefficient, and has a problem.

 On the other hand, as an example of using a catalytic reduction reaction to alkylate a compound similar to 3-hydroxypyrrolidine,

 3-hydroxypyrrolidine is reacted with benzaldehyde in the presence of a metal catalyst in a catalytic reduction reaction to produce 1-benzyl-3-hydroxypyrrolidine (Japanese Patent Application Laid-Open No. H11-212,469).

 Method of methylation by reacting formaldehyde with 2-hydroxymethylpiperidine in the presence of PdZC catalyst (Journal of Organic Chemistry, Vol. 29, 288, pp. 19664) It has been known.

 However, there is no known example of lower alkylation of 3-hydroxypyrrolidine using a catalytic reduction reaction, and debenzylation using 1-benzyl-3-hydroxypyrrolidine as a raw material. There are no known examples of lower alkylation performed consecutively or simultaneously without isolating 3-hydroxypyrrolidin. Disclosure of the invention

 In view of the above, the present invention is based on 1-benzyl-3-hydroxypyrrolidines or 3-hydroxypyrrolidines as a raw material, in an inexpensive and simple manner, with good selectivity (less by-products of quaternary ammonium salts). It is an object of the present invention to provide a method for producing a lower alkyl-3-hydroxypyrrolidine.

As a result of diligent studies to solve the above-mentioned problems, the general formula (3) An aldehyde or ketone represented by the general formula (4) is reacted with a hydroxypyrrolidine or a salt thereof using a catalytic reduction reaction in the presence of a metal catalyst to obtain an inexpensive, simple and highly selective compound. It has been found that lower alkyl-1-hydroxypyrrolidines or salts thereof can be obtained.

 In addition, the catalytic reduction reaction is used to convert a 1-benzyl-3-hydroxypyrrolidine represented by the general formula (2) or a salt thereof to a 3-hydroxypyrrolidine represented by the general formula (3) or a salt thereof. The conversion of 3-hydroxypyrrolidines or a salt thereof to a 1-lower alkyl-3-hydroxypyrrolidine represented by the general formula (1) or a salt thereof is carried out by a 3-hydroxypyrrolidine (3) or They have found that they can be performed continuously or simultaneously without isolating the salt, and have completed the present invention.

 That is, the present invention relates to the general formula (1)

Wherein X represents a hydroxyl group or a protected hydroxyl group, and R ¹ and R ² each independently represent a hydrogen atom or a lower alkyl group. Or a method for producing a salt thereof,

 (a) — General formula (2)

(Wherein X represents a hydroxyl group or a protected hydroxyl group) 1-Benzyl · 3-hydroxypyrrolidine or a salt thereof is debenzylated to give a general formula (3)

(Wherein, X represents a hydroxyl group or a protected hydroxyl group), a step of converting into 3-hydroxypyrrolidines or a salt thereof, and

 (b) the compound (3) or a salt thereof,

General formula (4)

(Wherein R ¹ and R ² are the same as defined above) to give a 1-lower alkyl-3-hydroxypyrrolidine or a salt thereof represented by the general formula (1). Manufacturing process.

Is carried out continuously or simultaneously in the presence of a metal catalyst by utilizing a catalytic reduction reaction.

In addition, the present invention provides a method of reacting a 3-hydroxypyrrolidine represented by the general formula (3) or a salt thereof with an aldehyde or ketone represented by the general formula (4) to thereby represent the compound represented by the general formula (1). A method for producing a lower alkyl-13-hydroxypyrrolidine or a salt thereof, wherein the reaction is carried out by utilizing a catalytic reduction reaction in the presence of a metal catalyst. Hereinafter, the present invention will be described in detail.

 First, the raw materials used in the present invention will be described.

 (1) 1-benzyl-3-hydroxypyrrolidine represented by the general formula (2) and 3-hydroxypyrrolidine represented by the general formula (3)

 The 1-benzyl-3-hydroxypiperidines represented by the general formula (2) used in the present invention can be used for reducing 1-benzyl-3-pyrrolidinone described in Japanese Patent Application Laid-Open No. H10-150997 to reduce microorganisms. The 1-benzyl-3-hydroxypyrrolidine obtained by the above method can be prepared by protecting a hydroxyl group as required.

 The 3-hydroxypyrrolidine represented by the general formula (3) is obtained by converting 1-benzyl-3-hydroxypyrrolidine (2) obtained as described above to It can be prepared by a method of hydrocracking using a noble metal catalyst described in 2 etc.

 In the general formulas (2) and (3), X represents a hydroxyl group or a protected hydroxyl group.

 The protective group for the hydroxyl group is not particularly limited, and ether-based protective groups such as methoxymethyl ether, benzyl ether, tetrahydropyranyl ether, and trimethylsilyl ether, acetyl ester, benzoyl ester, methanesulfonyl ester, and methyl carbonate Examples include ester-based protecting groups such as esters.

The 1-benzyl-3-hydroxypyrrolidine represented by the general formula (2) and the 3-hydroxypyrrolidine represented by the general formula (3) may be used as a free form, or may be used as an acid. And the salt form thereof can also be suitably used in the present invention. The acid that forms the salt is not particularly limited, but mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid; carboxylic acids such as formic acid, acetic acid, oxalic acid, maleic acid, phthalic acid, and tartaric acid; Organic sulfonic acids such as methanesulfonic acid and toluenesulfonic acid; organic phosphonic acids such as methanephosphonic acid and benzoic acid; and amino acids such as glycine, alanine and aspartic acid. be able to.

 The salt of 1-benzyl-3-hydroxypyrrolidine (2) with an acid and the salt of 3-hydroxypyrrolidine (3) with an acid may be prepared in advance in the form of a salt. Before or after the start of the catalytic reduction reaction of the present invention, it may be formed in a reaction system by mixing with the above acid.

(2) Aldehyde or ketone represented by general formula (4)

 In the present invention, lower alkylation is performed using an aldehyde or ketone represented by the general formula (4).

In the general formula (4), R ¹ and R ² independently represent a hydrogen atom or a lower alkyl group.

 Here, the lower alkyl group means a linear or branched alkyl group having 1 to 4 carbon atoms. Examples of the linear alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, an n-propyl group, and an n-butyl group. Examples of the branched alkyl group having 1 to 4 carbon atoms include an isopropyl group, a sec-butyl group, and a t-butyl group.

 Specific examples of the aldehyde or ketone represented by the general formula (4) include, for example, formaldehyde, paraformaldehyde, acetaldehyde, propionylaldehyde, butyraldehyde, pentylaldehyde, acetone, 2-butanone, 2-pentanol Non-, 3-pentanone, 2-hexanone, 3-hexanone, 3-heptanone, -heptanone, methyl isopropyl ketone, X-isopropylisopropyl ketone, disopropyl ketone, methyl-t-butyl ketone, Ethyl t-butyl ketone and the like. From the viewpoint of the reactivity with 3-hydroxypyrrolidines and the usefulness of the product, preferred is formaldehyde, acetoaldehyde or acetone.

 Next, the manufacturing process will be described.

(1) Process for producing 1-lower alkyl-3-hydroxypyrrolidines (1) by debenzylation and lower alkylation using 1-benzyl-3-hydroxypyrrolidine (2) or a salt thereof as a raw material Next, using 1-benzyl-3-hydroxypyrrolidine (2) or a salt thereof as a raw material, debenzylation and lower alkylation are carried out successively or simultaneously to obtain a lower alkyl-1-hydroxypyrrolidine. (1) or a method for producing a salt thereof will be described.

 In this method, the starting material, 1-benzyl-3-hydroxypyrrolidine or a salt thereof, is debenzylated by a catalytic reduction reaction in the presence of a metal catalyst, and the aldehyde or ketone is mixed with the system, followed by contact. By performing the reduction reaction, debenzylation and lower alkylation are successively performed to produce 1-lower alkyl-3-hydroxypyrrolidine or a salt thereof. Here, the term “continuously” means that lower alkylation is continuously performed in the same reaction solution without isolating 3-hydroxypyrrolidine or a salt thereof produced by the debenzylation reaction. Therefore, the method may not include a step of isolating 3-hydroxypyrrolidine or a salt thereof.

 Alternatively, by mixing the starting material 1-benzyl-1-hydroxypyrrolidine (2) or a salt thereof with the above aldehyde or ketone, and performing a catalytic reduction reaction in the presence of a metal catalyst, debenzylation and lower alkylation are performed. To produce 1-lower alkyl-3-hydroxypyrrolidines (1) or a salt thereof. Simultaneously here means that the debenzylation reaction and the lower alkylation are performed in concert. Therefore, the method may not include a step of isolating 3-hydroxypyrrolidine or a salt thereof.

This method is usually performed using a solvent. As the solvent, those used in ordinary catalytic reduction reactions can be used.Examples include alcohols such as methanol and ethanol, carboxylic acids such as acetic acid, ethers such as dioxane and tetrahydrofuran, toluene and hexane. Hydrocarbons, amides such as dimethylformamide, and water. These solvents may be used alone or in combination of two or more. The amount of the solvent to be used is not particularly limited, and may be appropriately set in consideration of economy. Usually, the amount of the solvent is about 0.1 to 1 times the weight of the raw material 1-benzyl-3-hydroxypyrrolidine. Use 0 times the weight Good results are obtained.

 The amount of the aldehyde or ketone used is not particularly limited as long as it is 1 equivalent or more based on the starting material, 1-benzyl-13-hydroxypyrrolidine or a salt thereof, and the aldehyde or ketone is used as a reaction solvent. Can also be used.

 As the metal catalyst, those known as catalysts used in the catalytic reduction reaction can be used, and examples thereof include palladium-based catalysts, platinum-based catalysts, rhodium-based catalysts, ruthenium-based catalysts, and nickel-based catalysts. It may be supported on silica or silica. For example, a palladium catalyst (palladium carbon) supported on charcoal powder, Raney nickel catalyst and the like can be mentioned. These metal catalysts can be used alone or in combination of two or more. In particular, when debenzylation and lower alkylation are carried out at the same time, if one of the metal catalysts is a palladium-based catalyst, good results can be obtained from the viewpoint of the reaction rates of debenzylation and lower alkylation. Therefore, it is preferable to use palladium carbon or the like.

 The amount of the catalyst used is not particularly limited, but by using 0.1 to 20% by weight based on 1-benzyl-1-hydroxypyrrolidine or its salt as a raw material, the reaction can be performed with high selectivity. , And can be implemented efficiently.

 In the present method, the metal catalyst used in the debenzylation can be used as it is for the lower alkylation without any additional metal catalyst.

 The catalytic reduction reaction is preferably performed under a hydrogen atmosphere at normal pressure (about 0.1 IMPa) to 1 MPa, more preferably at normal pressure (about 0.1 MPa) to 5 MPa, preferably a reaction solution. Can be carried out at a temperature within the range from the freezing point to the boiling point, more preferably at room temperature to 100 ° C.

According to this method, 1-benzyl-3-hydroxypyrrolidine or a salt thereof can be used as a starting material without isolating the 3-hydroxypyrrolidine (3) or a salt thereof after debenzylation, to obtain a 1-lower alkyl radical. 3-hydroxypyrrolidine (1) or a salt thereof can be produced. (2) A method for producing 1-lower alkyl-13-hydroxypyrrolidines from 3-hydroxypyrrolidines (3) by catalytic reduction with an aldehyde or ketone in the presence of a metal catalyst

 In the present invention, 3-hydroxypyrrolidines (3) or salts thereof which have been previously debenzylated are catalytically reduced with the above aldehyde or ketone in the presence of a metal catalyst to obtain 1-lower alkyl-1-hydroxypyrrolidine. Production of class (1) or a salt thereof can also be suitably carried out.

 Use the same reagents (solvent, ketone or aldehyde, metal catalyst) as in the above-mentioned method using 1-benzyl-3-hydroxypyrrolidine, except that 3-hydroxypyrrolidine (3) or its salt is used as a raw material. The amount used and the reaction conditions are the same as above.

 In addition, the method of the present invention can be applied to optically active 3-hydroxypyrrolidines or salts thereof, and 1-benzyl-3-hydroxypyrrolidines or salts thereof. Optically active monoalkyl-1-hydroxypyrrolidines or salts thereof having the same configuration as the raw materials can be obtained.

 The 1-lower alkyl-13-hydroxypyrrolidines or salts thereof produced by the above method can be easily isolated by post-treatment such as filtration of the catalyst, followed by concentration, distillation and the like. . BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

 In the following examples, thin-layer chromatography, which is a means for confirming that a single product was produced, was developed using a developing solvent: ethyl ethyl acetate Z ammonium water = 10 volumes Z 10 volumes 1 volume And iodine color development.

 (Example 1)

4.34 g of (S) -3hydroxypyrrolidine are dissolved in 10.25 g of water, 8.20 g of 37% formaldehyde aqueous solution (formalin) and 0.27 g of 10% palladium carbon were added, and the mixture was subjected to a catalytic reduction reaction under stirring at a hydrogen pressure of 0.1 to 0.3 MPa at about 40 for 6 hours. I let it.

 It was confirmed by thin layer chromatography (TLC) that 3-hydroxypyrrolidine had disappeared and 1-methyl-3-hydroxypyrrolidine had been formed as a single product. "

 The palladium carbon was filtered off, and the filtrate was concentrated to obtain 5.41 g of a crude product of (S) -1-methyl-3-hydroxypyrrolidine as a pale yellow oil. This was further distilled to give 1.56 g of (S) _1-methyl-3-hydroxypyrrolidine distillate as a colorless oil.

 (Example 2)

 Dissolve 8.71 g of (S) _- 3-hydroxypyrrolidine in 10.29 g of water, add 11.30 g of acetone and 0.38 g of 10% palladium on carbon, and add water with stirring. Catalytic reduction was performed at an elementary pressure of 0.1 to 0.3 MPa and about 45 ° C for 2 days.

 TLC confirmed that 1-isopropyl-13-hydroxypyrrolidine was produced as a single product.

 The palladium carbon was removed by filtration, and the filtrate was concentrated. 2 OmL of water was added to the concentrate, and extracted 6 times with 4 OmL of ethyl acetate. The obtained ethyl acetate phase was concentrated to obtain 5.10 g of a crude product of (S) -11-isopropyl-13-hydroxypyrrolidine as a pale brown oil.

 (Example 3)

 4.46 g of (S) -1 -Penzyl 3-hydroxypyrrolidine were dissolved in 14.98 g of methanol. 2.51 g (1.0 equivalent) of concentrated hydrochloric acid was added. 0.20 g of 10% palladium carbon was suspended in 1.93 g of water, and the mixture was subjected to a catalytic reduction reaction under stirring at a hydrogen pressure of 0.1 to 0.3 MPa and 50 ° C. After 4 hours, it was confirmed that the absorption of hydrogen had stopped.

4.14 g of a 37% aqueous formaldehyde solution (formalin) was added, and the mixture was subjected to a catalytic reduction reaction under stirring at a hydrogen pressure of 0.1 to 0.3 MPa and 40. 3. 5 hours after water Elemental absorption has ceased.

 In TLC, there was no spot corresponding to (S) -1-benzyl-1-hydroxypyrrolidine and (S) -3-hydroxypyrrolidine, and (S) -1-methyl-3-hydroxypyrrolidine was a single product. Confirmed that it was generated. The palladium carbon was filtered off, and the filtrate was concentrated to obtain 4.10 g of a crude product of (S) -1-methyl-13-hydroxypyrrolidine hydrochloride as a pale yellow oil.

 (Example 4)

 (R) — 3-Hydroxypyrrolidine hydrochloride 187.lg is dissolved in 556.lg of methanol, 243.5 g of 37% aqueous formaldehyde solution (formalin) and 18.5 g of 10% palladium on carbon are added and stirred. Under a normal hydrogen pressure, a catalytic reduction reaction was performed at about 45 ° C. for 19 hours.

 TLC confirmed that (R) -1-methyl-3-hydroxypyrrolidine hydrochloride was produced as a single product.

Palladium carbon was filtered off. The filtrate was added with 1 equivalent of a 30% aqueous sodium hydroxide solution based on (R) -1-methyl-3-hydroxypyrrolidine hydrochloride, and concentrated. Toluene was added to the obtained concentrate to perform azeotropic dehydration. The precipitated sodium chloride is filtered off, concentrated and distilled to give (R) -1-methyl-3-hydroxypyrrolidine distillate 123.7 g (specific rotation: [] ₂₅ ° = -2. 0.6 °, neat) was obtained as a clear, colorless oil.

 1 H-NMR (D 20):

 1.70 (m, 1H), 2.15 (m, 1H), 2.32 (s3H), 2.43 (dd, 1H), 2.59 (m, 1H), 2.67 (m, 1H), 1..90 (dd, 1H), 4.42 (m, 1H), 4.87 (s, 1H)

 1 3 C-NMR (D 2 O):

 36.55, 43.80, .56.48, 65.56, 73.44 Industrial availability

According to the present invention, as described above, an inexpensive and simple method, with good selectivity Lower alkyl-13-hydroxypyrrolidine can be produced.

Claims

The scope of the claims  (a) General formula (2)

(Wherein X represents a hydroxyl group or a protected hydroxyl group) 1-benzyl '3-hydroxypyrrolidines or a salt thereof is debenzylated,  General formula (3)

(Wherein, X represents a hydroxyl group or a protected hydroxyl group), a step of converting to a 3-hydroxypiperidine or a salt thereof, and  (b) the above compound (3) or a salt thereof, General formula (4) (Four)

(Wherein, R ¹ and R ² each independently represent a hydrogen atom or a lower alkyl group).  Step of producing 1 lower alkyl-13-hydroxypyrrolidines represented by the general formula (1) or a salt thereof Wherein a catalytic reduction reaction is carried out in the presence of a metal catalyst.

(Wherein, R ¹ and R ² each independently represent a hydrogen atom or a lower alkyl group, and X represents a hydroxyl group or a protected hydroxyl group). A method for producing a pyrrolidine or a salt thereof.  2. A step of converting to 3-hydroxypyrrolidine represented by the general formula (3) or a salt thereof as described in claim 1, and a 1-lower group represented by the general formula (1) according to claim 1 The 1-lower alkyl 1-3 according to claim 1, wherein the step of producing the alkyl-3-hydroxypyrrolidine or a salt thereof is continuously performed using a catalytic reduction reaction in the presence of a metal catalyst. —A method for producing hydroxypyrrolidines or salts thereof. 3. A step of converting into 3-hydroxypyrrolidine represented by the general formula (3) or a salt thereof according to claim 1, and a lower one represented by the general formula (1) according to claim 1. 2. The process for producing an alkyl-3-hydroxypyrrolidine or a salt thereof, which is carried out simultaneously by utilizing a catalytic reduction reaction in the presence of a metal catalyst, according to claim 1, wherein A method for producing hydroxypyrrolidines or a salt thereof. 4. General formula (3)

(Wherein X represents a hydroxyl group or a protected hydroxyl group), or a 3-hydroxypiperidine or a salt thereof represented by the formula: General formula (4)

(Wherein, R ¹ and R ² each independently represent a hydrogen atom or a lower alkyl group) in the presence of a metal catalyst using a catalytic reduction reaction, General formula (1)

(Wherein, X, R ′ and R ² are the same as those described above). 1-Lower alkyl — 3-hydroxypyrrolidine or a salt thereof.  5. A method for producing 1-methyl-3-hydroxypyrrolidine or a salt thereof as the compound represented by the formula (1), wherein formaldehyde is used as the compound represented by the formula (4). 4. The production method according to 4.  6. An optically active form of the compound represented by the formula (1), wherein an optically active form is used as the compound represented by the formula (2) or the formula (3). 4. The production method according to 4 or 5.  7. The method according to claim 1, 2, 3, 4, 5, or 6, wherein X is an unprotected hydroxyl group.  8. The compound according to claim 1, 2, 3, 4, 5, 6, 7 or 8, wherein the compound represented by the formula (2) or the formula (3) is used as a salt with hydrochloric acid or hydrobromic acid. Production method. 9. Claims 1, 2, 3, 4, using a catalyst containing palladium as the metal catalyst  The production method according to 5, 6, 7 or 8.