JP2002088058A - Method for (2s,4s)-n,n-dimethyl-1-allyloxycarbonil-4- benzoylthio-2-pyrrolidinecarboxamide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing (2S,4S)-N,N-dimethyl-1- allyloxycarbonyl-4-benzoyl-2-pyrrolidinecarboxamide having an excellent quality in an excellent yield. SOLUTION: This method for producing the (2S,4S)-N,N-dimethyl-1- allyloxycarbonyl-4-benzoyl-2-pyrrolidinecarboxamide, characterized by reacting an N,N-dimethyl-1-allyloxycarbonyl-4-X-2-pyrrolidinecarboxamide (X is a releasing group derived from a hydroxyl group) with the alkali metal salt of thiobenzoic acid in the presence of water.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to the following general formula (1):

Embedded image (Wherein, X represents a leaving group derived from a hydroxyl group) N, N-dimethyl-1-allyloxycarbonyl-4-substituted-2-pyrrolidinecarboxamide [hereinafter, referred to as compound (1) Is reacted with an alkali metal salt of thiobenzoic acid to obtain the following formula (2)

Embedded image And a method for producing (2S, 4S) -N, N-dimethyl-1-allyloxycarbonyl-4-benzoylthio-2-pyrrolidinecarboxamide [hereinafter sometimes referred to as compound (2)]. Compound (2) is used as an important intermediate when constructing the side chain portion at the 2-position of penem compounds and carbapenem compounds having excellent antibacterial activity (for example, JP-A-4-217661).

[0002]

2. Description of the Related Art Conventionally, as a method for producing compound (2), (2S, 4R) -N, N-dimethyl-1-allyloxycarbonyl-4-methanesulfonyloxy-2-pyrrolidinecarboxamide [compound (1) Wherein the leaving group X is a methanesulfonyloxy group] is reacted with potassium thiobenzoate in toluene or a mixed solvent of toluene and dimethylformamide (JP-A-4-217661).

[0003]

However, in this method, the yield and quality of compound (2) are not sufficient. An object of the present invention is to provide a method for producing compound (2) which is excellent in yield and quality.

[0004]

Means for Solving the Problems As a result of intensive studies, the present inventors have conducted a reaction between compound (1) and an alkali metal salt of thiobenzoic acid in the presence of water to obtain the following formula (3)

Embedded image (2S, 4S) -N, N-dimethyl-1-allyloxycarbonyl-4-thiobenzoylthio-2-
The production of by-products such as pyrrolidinecarboxamide [hereinafter sometimes referred to as dithio-form (3)] was suppressed, and it was found that the above object could be achieved, and the present invention was completed. That is, the present invention relates to a method for producing a compound (2) in which the compound (1) is reacted with an alkali metal salt of thiobenzoic acid in the presence of water.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
In the compound (1) used as a raw material in the present invention, the leaving group (X) derived from a hydroxyl group is preferably a substituted sulfonyloxy group, and examples of the substituted sulfonyloxy group include a methanesulfonyloxy group and an ethanesulfonyl group. Aliphatic sulfonyloxy groups such as oxy groups,
An aromatic sulfonyloxy group such as a benzenesulfonyloxy group and a p-toluenesulfonyloxy group is exemplified.

Compound (1) is reacted with a suitable acid halide or acid anhydride using trans-1-allyloxycarbonyl-4-hydroxy-L-proline as a raw material,
It can be prepared by deriving a hydroxyl group into a group having an elimination ability. For example, compound (1) in which the leaving group (X) is a substituted sulfonyloxy group is trans-1-allyloxycarbonyl-4-hydroxy-
It can be prepared by reacting L-proline with sulfonic chloride or sulfonic anhydride (for example, JP-A-4-217661).

The alkali metal salts of thiobenzoic acid used in the present invention include lithium salts, sodium salts and potassium salts, and if necessary, two or more of them can be used. Among them, potassium salts are preferred. The amount of the alkali metal salt of thiobenzoic acid to be used is generally 1 to 1.5 mol, preferably 1.3 to 1 mol, per 1 mol of compound (1).
1.5 mol.

An alkali metal salt of thiobenzoic acid can be prepared by neutralizing thiobenzoic acid with an alkali metal hydroxide or carbonate. The alkali metal salt of thiobenzoic acid is usually prepared as an aqueous solution, and is used after being dehydrated by azeotropic distillation or the like before the reaction.

In the present invention, the reaction of the compound (1) with the alkali metal salt of thiobenzoic acid is carried out in the presence of water to suppress the formation of by-products such as the dithio form (3). Can be. The amount of water to be present is generally 0.1 to 1 mol, preferably 0.2 to 0.5 mol, per 1 mol of compound (1). The dithio form (3)
Is an alkali metal salt of dithiobenzoic acid formed by disproportionation of an alkali metal salt of thiobenzoic acid.
It is thought to be produced by reacting with

The reaction solvent includes, for example, aromatic hydrocarbons such as benzene, toluene, chlorobenzene and o-dichlorobenzene; aprotic polar solvents such as acetonitrile, dimethylformamide, sulfolane and dimethylacetamide. And a mixed solvent thereof can be used if necessary. Among them, toluene,
Dimethylformamide and a mixed solvent of toluene and dimethylformamide are preferred. The amount of the solvent used is the same as the compound (1)
100 to 100 parts by weight, usually 200 to 3000 parts by weight,
Preferably it is in the range of 400 to 1000 parts by weight.

[0011] The reaction temperature is usually in the range of 50 to 150 ° C, preferably 50 to 100 ° C, more preferably 50 to 80 ° C.

The post-treatment method after the reaction can be appropriately selected. The reaction solution is mixed with toluene and water, the compound (2) is extracted to the oil layer side, and then the compound (2) is crystallized. It is preferable to remove it. As the crystallization method, it is preferable to concentrate the oil layer containing the compound (2) as necessary, add hexane, and cool as necessary to precipitate crystals of the compound (2). The precipitated crystals are preferably separated by filtration, washed with a mixed solvent of toluene and hexane, usually two to three times the amount of the crystals, and further washed with hexane, usually two to three times the amount of the crystals. By the operation, the content of low-polar impurities [for example, a compound having a structure in which thiobenzoic acid is added to an allyl group of compound (2)] in the crystal can be reduced.

[0013]

EXAMPLES Examples of the present invention will be shown below, but the present invention is not limited to these examples. Example 1 To a solution of 140 g (purity 98.5%, 1.00 mol) of thiobenzoic acid in 200 g of toluene was added 50 g of water, and the mixture was cooled to 10 ° C. 122 g (1.07 mol) of a 49% aqueous potassium hydroxide solution was dropped therein at 10 to 15 ° C (pH 9.5 to 10), and the mixture was kept at 10 to 15 ° C for 1 hour. Was separated. Water layer in toluene 1
After washing with 00 g to remove neutral components, 304 g of an aqueous potassium thiobenzoate solution (concentration 57%: yield 99%) was obtained.

To 59.0 g (0.191 mol) of the obtained 57% aqueous potassium thiobenzoate solution, 99 g of toluene was added, and after azeotropic dehydration at normal pressure, 47 g of dimethylformamide was added to form a homogeneous solution. 0.792 g of water (0.0
The mixture was heated to 65 to 70 ° C. with stirring, and then heated to (2S, 4R) -N, N-dimethyl-1-allyloxycarbonyl-4-methanesulfonyloxy-2-
143 g of a toluene solution of pyrrolidinecarboxamide [the compound (1) in which the leaving group X is a methanesulfonyloxy group] (concentration: 32.8%, 0.147 mol)
Was added dropwise over 30 minutes and then kept at 68-70 ° C. for 14 hours.

The obtained reaction solution was cooled to room temperature, 203 g of toluene and 143 g of water were added and stirred, and then separated into an oil layer and an aqueous layer. The oil layer was washed with a 10% aqueous sodium chloride solution three times (95 g / time), and then concentrated at 50 ° C. or lower to about 1/3 volume. 33 g of hexane was added to the obtained concentrate.
And cooled to 35 ° C., and 10 mg of a seed crystal was added thereto to add 1
After stirring for an hour, the mixture was cooled to 0 ° C. and stirred for 30 minutes.
The obtained slurry was filtered, and the residue was filtered twice with a mixed solvent of toluene / hexane = 2/1 (volume ratio) (14.6 g / vol.).
After washing twice, further washing twice with hexane (50 g / times), and drying, 37.6 g of compound (2) crystals were obtained (purity 99%, yield 70%). The content of the dithio form (3) in the crystal is 0.2% or less, and the content of the low polarity component is 0.1%.
It was less than 1%.

Example 2 The same operation as in Example 1 was performed except that the residue after filtration was not further washed twice with hexane (50 g / times) in the latter stage of Example 1. As a result, the compound (2) crystal was 38.
6 g (purity 98%, yield 72%) was obtained. The content of the dithio form (3) in the crystal was 0.2% or less, and the content of the low-polar component was about 1%.

Comparative Example 1 In the middle stage of Example 1, the same operation as in Example 1 was performed except that 0.792 g of water was not added during the reaction. As a result, 38.4 g of compound (2) crystals (purity of 98) were obtained.
%: 70% yield). Dithio form in the crystal (3)
Was 1.3%.

[0018]

According to the method of the present invention, high purity (2
(S, 4S) -N, N-dimethyl-1-allyloxycarbonyl-4-benzoylthio-2-pyrrolidinecarboxamide can be produced in good yield.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Katsuhisa Masumoto 2-10-1, Tsukahara, Takatsuki-shi, Osaka Sumitomo Kagaku Kogyo Co., Ltd. F-term (reference) 4C069 AA18 BD06 CC20

Claims (2)

[Claims] (1) The following general formula (1): (In the formula, X represents a leaving group derived from a hydroxyl group), N-N-dimethyl-1-allyloxycarbonyl-4-substituted-2-pyrrolidinecarboxamide is reacted with thiobenzoic acid in the presence of water. The following formula (2) characterized by reacting with an alkali metal salt: (2S, 4S) -N, N-dimethyl-1-allyloxycarbonyl-4-benzoylthio-2-pyrrolidinecarboxamide represented by the formula: 2. The method according to claim 1, wherein the amount of water present is N, N-dimethyl-1.
The method according to claim 1, wherein the amount is 0.2 to 1 mol per 1 mol of -allyloxycarbonyl-4-substituted-2-pyrrolidinecarboxamide.