JPS60178860A - Preparation of 3-mercaptopyrrolidine or salt thereof - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an intermediate for penem, carbapenem derivatives (antimicrobial agents), etc. easily in very high yield with retained optical activity of raw materials, by reacting 3-mercaptopyrrolidine having an amino protecting group into contact with an acid. CONSTITUTION:A compound expressed by the formula (R is a protecting group of amino group) is brought into contact with an acid, e.g. a hydrogen halide such as hydrogen chloride, hydrogen bromide or hydrogen fluoride, an organic sulfonic acid such as methanesulfonic, ethanesulfonic, phenylsulfonic acid or toluenesulfonic acid, an organic acid such as mono- - trichloroacetic acid or trifluoroacetic acid or a mineral acid such as sulfuric, nitric or perchlonic acid usually at 0-40 deg.C, preferably 10 deg.C- about room temperature usually for 0.5- 5hr to give advantageously 3-mercaptopyrrolidine or a salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for producing 3-mercaptopyrrolidine and its salts.

As a result of intensive research into the method for producing 3-mercaptopyrrolidine, the present inventors discovered a new method for producing 3-mercaptopyrrolidine and completed the present invention.

3-Mercaptopyrrolidine is useful as a raw material for the synthesis of various compounds, such as penem, which has excellent antibacterial activity.
It is used for the 1'dJ isomer among carbapenem derivatives. By using the method VC of the present invention, 3-mercaptopyrrolidine can be obtained easily and in an extremely high yield, and moreover, the optically active isomer can be obtained as it is. Therefore, the method of the present invention is also useful as an OSE synthesis method in the chemical and pharmaceutical industries that use 3-mercaptopyrrolidine as an intermediate raw material.

The method of the present invention comprises a method for obtaining 3-mercaptopyrrolidine or a salt thereof by contacting a compound having the general formula (wherein R represents a protecting group for an amino group) with an acid.

In the general formula (I), R is a 4H group of an amine group, which is eliminated in the presence of an acid, and is not particularly limited. Examples of such protecting groups include an optionally substituted aralkyloxycarbonylalkenyloxycarbonyl group, an optionally substituted alkoxycarbonyl group, a 1-methylcyclobutyloxycarbonyl group, and a 4-methylcyclobutyloxycarbonyl group. A (1,4-dimethyl)piperidinooxycarbonyl group, a 4-pyridylmethyloxycarbonyl group, an aralkyl group, etc. can be provided.

When R is an acylkylox7carbonyl group, examples thereof include benzyloxycarbonyl, phenethyloxycarbonyl, α-methylbenzyloxycarbonyl, and the like. Substituents for the aralkyloxycarbonyl group include, for example, alkyl such as methyl, ethyl, Ω-propyl, n-butyl, and n-pentyl; alkoxy such as methoxy, ethoxy, rhoproloxy, n-butyloxy, and rhopentyloxy; chlorine; Examples include bromine, fluorine, a large number of halogens; trifluoromethyl; nitro; and the like. There is no limit to the number of these basket replacements.

When R is an alkenyl group, examples include vinyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, and the like. As a substituent for the alkenyl group, phenyl can be used.

When R is an alkoxycarbonyl group, examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, Ω-butyloxycarbonyl, 1-butyloxycarbonyl, t-butyloxycarbonyl, n-pentyloxycarbonyl, etc. can. Substituents for alkoxycarbonyl groups include chlorine, bromine,
Fluorine, iodine, halogen or trimethylsilyl can be removed. There is no limit to the number of these substitutions.

When R is an aralkyl group, examples include diphenylmethyl, triphenylmethyl, and the like.

The reaction takes place in the presence of an acid. Examples of acids that can be used include hydrogen halides such as hydrogen chloride, hydrogen bromide, and hydrogen fluoride; methanesulfonic acid, ethanesulfonic acid, phenyldisulfonic acid, toluenesulfonic acid, t and m sulfonic acids; chloroacetic acid. , dichloroacetic acid, trichloroacetic acid,
Examples include organic acids such as trifluoroacetic acid; mineral acids such as sulfuric acid, nitric acid, and perchloric acid. The amount of acid to be used is preferably from equimolar to a small excess of equimolar.

The reaction is carried out in the presence of a trace bath. The omega agents used include, for example, ethers such as ether, dioxane, and tetrahydrofuran; alcohols such as methanol and ethanol; amides such as dimethylformamide and dimethylacetamide; aromatic hydrocarbons such as benzene and toluene; Nitriles; organic acids such as acetic acid; halogenated hydrocarbons such as dichloromethane and dichloroethane; water; nitromethane; and dimethyl sulfoxide. It is preferable to use these solvents depending on the frequency of coughing.

For example, when using hydrogen halide, 15 to 30%
It is preferable to add Ariso bath agent Δ to the vinegar bath liquid as needed. There is no particular limit to the reaction temperature V'c, but
In order to suppress side reactions, it is desirable to conduct the reaction at a relatively low temperature, usually from 0°C to 40°C, preferably from 10°C to around room temperature.

The reaction time varies depending on the reaction temperature, #*fA, etc., and is 0.5 to 5 hours.

After completion of the reaction, the target compound, 3-mercaptopyrrolidine, is collected from the reaction mixture according to a conventional method. For example, it can be obtained by removing the cine bath from the reaction mixture, adding a solvent to the +1A solution obtained, and collecting the precipitated crystals. The obtained target compound can be further purified, if necessary, by conventional methods such as recrystallization, reprecipitation, or chromatography.

Incidentally, the compound of the present invention having the above general formula (1) is described in JP-A-59-13757.

Next, the present invention will be explained in more detail with reference to Examples.

Example 1゜3(S)-Mercapto-1-p-nitropenzyloxycarbonylpyrrolidine 56.5 gf: 30% HBr-
0) When dissolved in i3000H125- and continued stirring at room temperature for 4 hours, p-nitrobenzyl bromide precipitated without foaming. Remove the precipitated p-nitrobenzyl bromide and add 1.5 g of ethyl ether to 1 g to form an oil! , 15! ! 1′! It was precipitated. The supernatant was removed by filtration, and the residue was dissolved in 100% methanol.
Then, when 250 ml of ethyl acetate was added, crystals were precipitated.

The precipitated crystals were collected by IP, washed with ethyl acetate, and dried to obtain 294 g of the desired product.

Grass harvest 80.0 cm, 189-193°C [α) D-153,3 (0 = 2.054, H2O)
Rp I/cm-' (Nu, 1ot); 2γ
00, 2530, 2400.

1565, 1035, 88O NMR, δppm (a6-DMso); 1.70
~2.48 (2H.

m), 3.15-4.21 (6H, m) Example 2゜3 When treated in the same manner as in Example 1 using (R)-mercapto-1-p-nitropenzyloxycarbonylpyrrolidine, the target product 31 .3 i b'-obtained.

Yield: 85 inches, 191-193°C [α), +154.0 (Ij=1.975, )L
20) Engineering R2νcm-'(Nujot); 270
5, 2540, 2400.

1570, 1038, 88O NMR, δppm ((16-DMSO); IJ5
~2.40 (2H.

m), 3.12-4.01 (6H, m),
! 1.42 (IH, B) Example 3 Using 23.7 g of 3-mercapto-1-benzyloxycarbonylpyrrolidine, the following treatment was carried out in the same manner as in Example 1 to obtain the desired product mis, p.

Yield 82% mp, 172-174°C Engineering R2cm-'(Nujot); 2703,
2540, 2400.

1568. 1036. 88O NMR, δ 1)l)01 (a6-niaso);
1.72-2.47 (2H.

m), 3.12 to 4.11 (6) L, m) Special Feature 1 - Applicant Sankyo Co., Ltd. Agent Shoji Kashide, Attorney

Claims (1)

[Scope of Claims] A method for producing 3-mercaptopyrrolidine or a salt thereof, which comprises contacting a compound having the general formula (wherein R represents a protecting group for an amine group) with an acid.