JPH08157441A - Method for producing carbamoyloxyacetic acid and intermediate useful in the method - Google Patents

Abstract

PURPOSE: To readily obtain the subject compound useful as a raw material of penem-based antibiotics from an inexpensive raw material by reacting a specific glycol acid ester with chlorosulfonyl isocyanate and hydrolyzing the resultant carbamoyl acetic acid ester. CONSTITUTION: A compound (A) expressed by the formula: HO-CH2 -COOR [R is a 1-6C alkyl, a (substituted) phenyl or a benzyl] is reacted with chlorosulfonyl isocyanate (B) to obtain a compound (C) expressed by the formula: H2 NOC-O-CH2 -COOR and the resultant compound is hydrolyzed to afford the object compound. The reaction of the component A with the component B is performed in a solvent such as hexane, dichloromethane or toluene at from -20 to 50 deg.C for from 15min to 4 hours, and the hydrolyzing of the component C is performed with dropping water in the case of performing without isolation of the component C and in an acidic condition in the case of performing after isolating the component C, and at 0-100 deg.C in each case.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a process for producing carbamoyloxyacetic acid, which is useful as a raw material for penem antibiotics, and an intermediate thereof.

[0002]

2. Description of the Related Art The following method 2 is known as a method for synthesizing carbamoyloxyacetic acid. That is, the first synthetic method is a method of synthesizing thiocarbamyl glycolic acid or its potassium salt as a raw material by reacting bromine, manganese peroxide or acetic anhydride (Alfred Ahlgvis
t, J. Prakt. Chem., 2 (99) 45 (1919)), and the second
As for the method, a method of synthesizing glycolic acid as a raw material by reacting chlorosulfonyl isocyanate (Wa
lter Cabri et al., Tetrahedron Letters, 34, 3491 (199
3), Carlo Battistini et al., Tetrahedron Letters, 27,
513 (1986)).

[0003]

However, the first method is a method of synthesizing in a laboratory and is not industrial, and the second method improved thereafter is the actual reaction conditions, treatment, isolation method. The detailed manufacturing method such as is not described,
Further, glycolic acid used as a raw material is distributed in the form of an aqueous solution, but since chlorosulfonyl isocyanate explosively reacts with water, the glycolic acid aqueous solution cannot be directly reacted with chlorosulfonyl isocyanate. For this reason, it has been necessary to use commercially expensive glycolic acid having high purity and water content, which is commercially expensive, for the production of carbamoyloxyacetic acid.

[0004]

The inventors of the present invention have studied the production method of high purity and water-free glycolic acid without using glycolic acid. A method for producing carbamoyloxyacetic acid by isolating carbamoyloxyacetic acid ester obtained by reacting with nato as an intermediate or hydrolyzing it without isolation has been found out.

That is, the present invention provides formula (1): HO-CH ₂ -COOR (1) [wherein R represents an alkyl group having 1 to 6 carbon atoms, an optionally substituted phenyl group or a benzyl group. Represented by] and a chlorosulfonyl isocyanate represented by the formula: (2): H ₂ NOC—O—CH ₂ —COOR (2) [wherein R has 1 to 6 carbon atoms] Which represents an alkyl group, an optionally substituted phenyl group or a benzyl group], and then hydrolyzes the obtained carbamoyloxyacetic acid ester, and a useful method for the method. Do the formula _{(2): H 2 NOC-} O-CH 2 -COOR (2) [ wherein, R represents an alkyl group having 1 to 6 carbon atoms, a optionally substituted phenyl or benzyl group in About carbamoyloxy acid esters.

Hereinafter, the present invention will be described in detail. Formula (1) used as a raw material in the present invention: HO—CH ₂ —COOR (1) [wherein R represents an alkyl group having 1 to 6 carbon atoms, an optionally substituted phenyl group or a benzyl group] As the glycolic acid ester represented, a lower alkyl ester having 1 to 6 carbon atoms is most preferred, and then a benzyl ester and an optionally substituted phenyl ester are preferred in that order.

In the reaction of the glycolic acid ester with the chlorosulfonyl isocyanate, the amount of chlorosulfonyl isocyanate depends on the glycolic acid ester used.
It is 0.8 to 2 molar equivalents, preferably 1.0 to 1.3 molar equivalents.

The reaction temperature of the glycolic acid ester and chlorosulfonyl isocyanate is -20 to 50 ° C, preferably
It is 0 to 25 ° C. The reaction time is 15 minutes to 4 hours,
It is preferably 30 minutes to 2 hours.

The solvent used in this reaction may be any solvent inert to chlorosulfonyl isocyanate, preferably saturated hydrocarbons such as heptane, hexane and cyclohexane, and halogenated hydrocarbons such as dichloromethane and dichloroethane. , Toluene, xylene, and other aromatic hydrocarbons.

In the present invention, during the production process of carbamoyloxyacetic acid, the formula (2): H ₂ NOC—O—CH ₂ —COOR (2) [wherein R is an alkyl group having 1 to 6 carbon atoms and is substituted] Which represents a phenyl group or a benzyl group which may be present] is produced as an intermediate, and in the present invention, the carbamoyloxyacetic acid ester can be isolated.

The carbamoyloxyacetic acid esters thus obtained are all novel compounds, and the compounds themselves are also useful as raw materials for penem antibiotics.

When the carbamoyloxyacetic acid ester is not isolated in the process for producing carbamoyloxyacetic acid, the reaction solution is added to 1 to 5 times by weight, preferably 2 to 3 times by weight, of chlorosulfonyl isocyanate used. After dropping, 0 to 100 ℃ as it is, preferably 25 to 50
The hydrolysis of the carbamoyloxyacetic acid ester proceeds by stirring under the temperature condition of ° C. The reaction time of this hydrolysis is not particularly limited, but is 1 hour to 7 days, preferably 2 to 24 hours. As the hydrolysis proceeds, the desired carbamoyloxyacetic acid will precipitate, so
By filtering this, carbamoyloxyacetic acid can be isolated.

Before filtration, 1 to 3 molar equivalents of the chlorosulfonyl isocyanate used, preferably 1.8 to
2.2 Add an equivalent amount of alkali to neutralize hydrochloric acid and sulfuric acid in the system to reduce the acid odor and corrosiveness of the hydrolyzed solution and increase the amount of carbamoyloxyacetic acid deposited due to the salting-out effect. be able to. The alkali at this time is preferably an alkali metal hydroxide or an alkali metal carbonate.

In the process of producing carbamoyloxyacetic acid, when the carbamoyloxyacetic acid ester is to be isolated, water is added to this reaction solution and the mixture is stirred while maintaining 0 to 100 ° C, preferably 5 to 25 ° C. Produces carbamoyloxyacetic acid ester. As a method of adding water, water may be added to the reaction solution or the reaction solution may be added to water. The amount of water at that time is 1 to 10 times the weight of the chlorosulfonyl isocyanate used, preferably 2 to 3
It is double weight. The reaction time is 15 minutes to 8 hours, preferably 30 minutes to 2 hours.

The carbamoyloxyacetic acid ester thus obtained can be isolated by separating and concentrating the mixed organic layers.

The carbamoyloxyacetic acid ester can selectively hydrolyze the ester portion by stirring with water under acidic conditions at 0 to 100 ° C., preferably 25 to 50 ° C.

The acid used at this time is preferably a mineral acid such as hydrochloric acid or sulfuric acid, an organic acid such as p-toluenesulfonic acid, or a strongly acidic ion exchange resin. The amount of acid used is 0.2-based on the hydrolyzable carbamoyloxyacetic acid ester.
It is 5 molar equivalents, preferably 0.5 to 3 molar equivalents. When a strongly acidic ion exchange resin is used, the amount used relative to the carbamoyloxyacetic acid ester to be hydrolyzed is 0.5 to 10 times molar equivalent, preferably 1 to 3 times molar equivalent, based on the total exchange capacity of the ion exchange resin used.

The amount of water used for the hydrolysis of the carbamoyloxyacetic acid ester is 1 to 20 times by weight, preferably 5 to 10 times the weight of the carbamoyloxyacetic acid ester used.
It is twice the weight.

The reaction time of hydrolysis is not particularly limited, but it is 1 hour to 7 days, preferably 2 hours to 24 hours.

When using a strongly acidic ion exchange resin, a method of stirring the carbamoyloxyacetic acid ester and the strongly acidic ion exchange resin together with water, or a method of circulating an aqueous solution of the carbamoyloxyacetic acid ester in a packed column of the strongly acidic ion exchange resin. Is preferred.

The carbamoyloxyacetic acid produced by hydrolysis is precipitated by concentrating the hydrolyzed solution, and can be isolated by filtration.

[0022]

EXAMPLES The present invention will be specifically described with reference to the following examples. The present invention is not limited to these examples.

Example 1 (Synthesis of carbamoyloxyacetic acid from methyl glycolate) A 200 ml four-necked flask equipped with a stirrer was equipped with a thermometer and the inside of the system was replaced with nitrogen. 90 ml of methylene chloride, 31.36 g of methyl glycolate (98% by gas chromatograph analysis)
(Purity, 0.341 mol) was added, and under ice cooling, 30 ml (48.78 g, 0.345 mol) of chlorosulfonyl isocyanate was added dropwise over 1 hour while maintaining the temperature at 5 to 10 ° C.

After completion of dropping, the mixture was stirred for 1.5 hours under ice cooling.
On the other hand, 100 ml of water was placed in a 500 ml four-necked flask equipped with a thermometer and a stirrer, and ice-cooled to 10 ° C or lower while stirring. The above-mentioned reaction solution was added to this over 35 minutes while maintaining the temperature at 15 to 18 ° C. After completion of the dropping, the mixture was stirred at room temperature for 1 hour and then left standing overnight to precipitate white crystals.

While stirring the system again, 110.4 g (0.69 mol) of 25% aqueous sodium hydroxide solution was added over 20 minutes while maintaining the temperature at 25 ° C. or lower, and then the mixture was stirred under ice cooling for 30 minutes. White crystals were filtered and dried under reduced pressure at 50 ° C. to obtain 30.51 g of carbamoyloxyacetic acid. The purity of this crystal was 96.2% by high performance liquid chromatography. The yield is 72.3%, and the NMR data are as follows.

1H-NMR (DMSO-d6); 4.38ppm (s, 2H), 6.
5-6.9ppm (bd, 2H), 12.3-13.5ppm (bs, 1H) 13C-NMR (DMSO-d6); 60.2ppm, 156.2ppm, 170.4ppm Example 2 (Synthesis of carbamoyloxyacetate) 100ml Three A thermometer was attached to the necked flask, a stirrer was placed therein, and the inside of the system was replaced with nitrogen. Methylene chloride 30 ml, ethyl glycolate 5.02 g (96 by gas chromatographic analysis
% Purity, 46.3 mmol) was added and the system was ice-cooled.

[0027] Here, 5 m of chlorosulfonyl isocyanate
l (57.4 mmol) was added, and the mixture was stirred under ice cooling for 1.5 hours. After that, 10 ml of water was added and the mixture was stirred for 30 minutes. After liquid separation, methylene chloride extraction was performed, and the organic layers were collectively concentrated to give 5.56 g of white crystals.
I got The yield is 78.4%, and the NMR data are as follows.

1H-NMR (DMSO-d6); 1.29ppm (t, 3H), 4.
23ppm (q, 2H), 4.58ppm (s, 2H), 5.1-5.5ppm (bs, 2H) 13C-NMR (DMSO-d6); 13.8ppm, 6 0.9ppm, 61.1ppm,
156.3ppm, 168.6ppm Example 3 (hydrolysis of ethyl carbamoyloxyacetate 1) 1.006 g (6.84 mmol) of ethyl carbamoyloxyacetate obtained by the method of Example 2 was dissolved in 10.3 ml of 1N hydrochloric acid,
The mixture was stirred at 25 to 35 ° C for 24 hours. Liquid chromatographic analysis of this liquid showed that 2-carbamoyloxyacetic acid was produced in a yield of 99%.

Example 4 (Hydrolysis of ethyl carbamoyloxyacetate 2) In a 200 ml four-necked flask equipped with a thermometer, a stirrer and a Dimroth condenser, 7.50 g of ethyl carbamoyloxyacetate obtained by the method of Example 2 (51.0 mmol), strongly acidic ion exchange resin (Amberlite IR-120B) 75 ml, water 70 ml
Was added and the mixture was stirred at 48 ° C for 8 hours.

The resin was then filtered and washed thoroughly with 100 ml of water. The mother liquor and the washing liquid were combined, concentrated under reduced pressure to 80 g, and this was washed twice with 50 ml of methylene chloride. The aqueous layer was further concentrated under reduced pressure to 21.84 g and ice-cooled to precipitate white crystals. This was filtered and dried to obtain 2.88 g of 2-carbamoyloxyacetic acid. The purity was 99.3% and the yield was 63.5%.

Example 5 (Hydrolysis of ethyl carbamoyloxyacetate 3) According to the method of Example 2, a strongly acidic ion-exchange resin packed column (Amberlite IR-120B, 60 ml) adjusted to 44 ° C. using a thermostatic bath was used. Obtained ethyl carbamoyloxyacetate 10.0
A solution prepared by dissolving 3 g (68.2 mmol) in 100 ml of water was circulated using a metering pump. After circulating for 16 hours at SV = 8 / h, the reaction solution was taken and the packed column was washed with 100 ml of water.

When the washing solution and the reaction solution were analyzed by high performance liquid chromatography, 84.3% of the yield of carbamoyloxyacetic acid was produced.

Example 6 (Synthesis of 2-carbamoyloxyacetic acid using isopropyl glycolate) A 100 ml four-necked flask equipped with a stirrer was equipped with a thermometer and the system was replaced with nitrogen. To this, 50 ml of methylene chloride and 10.24 g of isopropyl glycolate (93% purity by gas chromatographic analysis, 80.6 mmol) were added, and under ice-cooling 7.0 ml of chlorosulfonyl isocyanate (11.38 g, 80.4 mmol)
The solution was added dropwise over 20 minutes while maintaining 10 ° C.

After the dropping, the mixture was stirred under ice cooling for 30 minutes and then at room temperature for 1 hour. After adding 50 ml of methylene chloride, water
30 ml was added dropwise, and the mixture was stirred for 1.5 hours at room temperature. After separating the liquid,
The aqueous layer was extracted twice with 50 ml of methylene chloride, all the organic layers were combined, dried over magnesium sulfate, and concentrated to obtain 12.55 g of a colorless oil. The oil crystallized in the refrigerator overnight.

12.14 g of this crystal was taken, 100 ml of water,
After adding 6.2 ml of concentrated hydrochloric acid and stirring at 45 ° C. for 17 hours, this solution was washed with methylene chloride. When the water layer after washing was analyzed by high performance liquid chromatography, 6.60 g (55.4 mmo
The carbamoyloxyacetic acid of l) was produced. The conversion yield based on isopropyl glycolate was 71.1%.

Example 7 (Synthesis of 2-carbamoyloxyacetic acid from butyl glycolate) A 200 ml four-necked flask equipped with a stirrer was equipped with a thermometer and the inside of the system was replaced with nitrogen. 60 ml of methylene chloride and 29.43 g of butyl glycolate (98% by gas chromatography analysis)
Purity (0.218 mol) was added, and 20 ml (0.230 mol) of chlorosulfonyl isocyanate was added dropwise over 1 hour under ice cooling while maintaining 5 to 10 ° C. After completion of the dropping, the mixture was stirred for 1.5 hours under ice cooling.

On the other hand, 67 ml of water was placed in a 500 ml four-necked flask equipped with a thermometer and a stirrer and ice-cooled to 10 ° C. or lower while stirring, and the reaction solution was heated to 15-18 ° C. Add over 30 minutes while holding. After completion of dropping, the mixture was stirred at room temperature for 1 hour, then at 42-44 ° C for 12.5 hours, and then left at room temperature for 4 days. While stirring the system again, 73.6 g (0.46 mol) of 25% aqueous sodium hydroxide solution was added over 20 minutes while maintaining the temperature at 25 ° C or lower, and then the mixture was stirred under ice cooling for 30 minutes. The white crystals were filtered and dried under reduced pressure at 50 ° C to obtain 19.71 g of carbamoyloxyacetic acid. The purity of this crystal was 95.0% by high performance liquid chromatography. The yield was 72%.

[0038]

INDUSTRIAL APPLICABILITY According to the present invention, carbamoyloxyacetic acid and carbamoyloxyacetic acid ester useful as raw materials for penem antibiotics can be easily and inexpensively produced.

Claims (3)

[Claims] 1. Formula (1): HO—CH ₂ —COOR (1) [wherein R represents an alkyl group having 1 to 6 carbon atoms, an optionally substituted phenyl group or a benzyl group] (2): H ₂ NOC—O—CH ₂ —COOR (2) [wherein R is an alkyl group having 1 to 6 carbon atoms, substituted with Represents a phenyl group or a benzyl group which may be present], and then hydrolyzes the obtained carbamoyloxyacetic acid ester, and then produces carbamoyloxyacetic acid. 2. The method for producing carbamoyloxyacetic acid according to claim 1, wherein the carbamoyloxyacetic acid ester is isolated and then hydrolyzed under acidic conditions. 3. Formula (2): H ₂ NOC—O—CH ₂ —COOR (2) [wherein R represents an alkyl group having 1 to 6 carbon atoms, an optionally substituted phenyl group or a benzyl group. Represents] carbamoyloxyacetic acid ester.