JPS59163370A - Preparation of 0-(aminomethyl)phenylacetic lactam - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an intermediate for cephalosporin antibiotics simply in high yield, by using an easily and inexpensively obtainable O-(halomethyl)phenylacetic ester as a raw material, reacting it with ammonia. CONSTITUTION:An O-(halomethyl)phenylacetic ester shown by the formula I (X is halogen; R is lower alkyl) is reacted with ammonia in water or an alcoholic solvent at 40-80 deg.C, preferably at 60-70 deg.C, to give a compound shown by the formula II. During the reaction, gaseous ammonia as ammonia is blown on the reaction solution, ammonia water, or a solution such as ammonia-methanol solution, etc. of ammonia in a solvent may be used. An amount of ammonia used is theroretically >=2 times the molar amount of the compound shown by the formula I , practically preferably >=3 times the molar amount. Water is practically preferable as the reaction solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing 0-(aminomethyl)phenylacetic acid lactam, more specifically, the present invention relates to a novel method for producing 0-(aminomethyl)phenylacetic acid lactam, and more specifically, the present invention relates to a novel method for producing 0-(aminomethyl)phenylacetic acid lactam, more specifically, general formula CI) (wherein, X represents a halogen atom, and R represents a lower alkyl group). The present invention relates to a method for producing 0-(aminomethyl)phenylacetic acid lactam represented by the formula, which comprises reacting 0-(halogenated methyl)phenylacetic acid ester represented by the following formula with ammonia.

Examples of the halogen atom represented by X in the general formula CI) include chlorine, bromine, and iodine, but chlorine is practically preferred. Examples of the alkyl group represented by R include lower alkyl groups such as methyl, ethyl, and propyl, but a methyl group is practically preferred.

O-(aminomethyl,)phenylacetic acid lactam is easily converted to 0-(aminomethyl)phenylacetic acid by hydrolysis (Japanese Patent Application Laid-Open No. 49-24975), which is an intermediate among cephalosporin antibiotics. It is a compound that is useful as a body.

The following methods are known as methods for producing lactam 0-(aminomethyl)phenylacetate.

(1) (% 1977-24975, 1977-11235
7) (2) (Japanese Unexamined Patent Publication No. 57-149271) In the method (1), it is difficult to obtain raw materials and it is necessary to use high-purity raw materials. ) There are problems such as the risk of generation and the complicated post-treatment of the reaction.

In method (2), the reaction time is very long and a large amount of polyphosphoric acid is used as a dehydrating agent, so there are problems in terms of wastewater management.As explained above, both methods have many problems, and It cannot be said that it is an excellent method.

The present inventors conducted various studies on a method for producing 0-(aminomethyl)phenylacetic acid lactam with a simple operation and good yield, and as a result, discovered a new production method and completed the present invention.

That is, the present invention produces 0-(aminomethyl)phenylacetic acid, which is characterized by using an inexpensive material as a starting material and subjecting 0-(halogenated methyl)phenylacetic acid ester, which can be easily and relatively inexpensively obtained, to an ammoniato reaction. This is a method for producing 2cutam.

The raw material o-<no-methyl phenylacetate is produced from fallen trees according to the following reaction formula.

(In the formula, Y represents a chlorine or bromine atom, and R represents a lower alkyl group.) In either method, 0-(halogenated methyl ) phenylacetic acid ester can be obtained.

In carrying out the method of the present invention, O'7( Produce lactam (aminomethyl)phenylacetate.

As the reaction solvent, water or a lower alcohol such as methanol can be used, but in practice water can be used to obtain the desired product in a sufficiently good yield, and post-treatment is also easy. Gaseous ammonia may be blown into the ammonia, or ammonia dissolved in a solvent such as aqueous ammonia or ammonia-methanol solution may be used.

The amount of ammonia used should theoretically be at least twice the mole of 0'-(halogenated methyl)phenylacetate, but practically it is preferably at least three times the mole.

The reaction temperature is preferably 40 to 80°C, particularly 60 to 70°C. If the reaction temperature is below 40°C, it will take a long time to complete the reaction.
When the reaction temperature is 80° C. or higher, a large amount of ammonia is lost to the outside of the reaction system.

The reaction time varies depending on the reaction temperature or the amount of ammonia used, but it is usually completed in 30 minutes to several hours.

After the reaction, in the case of an aqueous solvent, the precipitated crystals are filtered and washed, or extracted with an organic solvent such as chloroform and the solvent is distilled off to obtain 〇-(aminomethyl)phenylacetic acid lactam. You can get it. In the case of using an alcohol solvent, after the reaction, the reaction solution is concentrated, the residue is extracted with an organic solvent such as chloroform, and the solvent is distilled off.
-(Aminomethyl)phenylacetic acid lactam can be obtained.

As explained above, the method of the present invention uses a substance that can be easily and relatively inexpensively obtained as a starting material, and the desired product can be obtained in a good yield under safe and mild conditions, and post-treatment is also easy. This is an extremely excellent method from an industrial perspective.

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

Example 1 0-(chloromethyl)phenylacetic acid methyl ester 63
．． 245.8 f of 83 thiammonia water (equivalent to 1.2 moles) was added to 4r (purity '94.0, equivalent to 0.3 moles) and held at 60° C. for 2 hours with stirring. Thereafter, the mixture was cooled to room temperature, and the precipitated crystals were collected, washed with a small amount of toluene, and dried to obtain the desired crystal 34.61. Yield 78.5% Slight yellow needle crystals m, p 152-154°C Provisional spectrum (δ, CDCt3) 3.56 (2H,s), 4.48 (2H,s),
7.12 (4H, m) , 8.42 (IH, s
) Elemental analysis value (as C9H9NO) Calculated value: C73,45, H6,16, N9.52 Analysis value: C73,63, H6,09, N 9.4 0 Example 2 Methyl 0-(chloromethyl)phenylacetate ester 63
．． 12.5 to 4f (purity 94.0%, equivalent to 0.3 mol)
% aqueous ammonia (equivalent to 1.2 mmol) was added, and the mixture was maintained at 60° C. for 2 hours while stirring. After that, it was cooled to room temperature and chloroform 15Qrn1. chloroform was distilled off from this extracted layer to obtain a residue 42.8.

As a result of analyzing the residue by liquid chromatography, the target product 38. It contained Of. Yield: 86.0 Example 3 0-(chloromethyl)phenylacetic acid ethyl ester 22
．． 5tC purity 94.5chi, 0.1 molar phase) to 12.5
% ammonia water (equivalent to 68.Of f'0.5 mo#) was added and maintained at 65°C for 1.5 hours with stirring. After that, it was cooled to room temperature and extracted with 50 ml of chloroform, and from this extracted layer Chloroform was distilled off, and the residue was washed and filtered with 50 bottles of toluene, and after drying, 12.2 f of slightly yellowish green crystals were obtained. Yield: 82.9% Example 4 0-(Chloromethyl)phenylacetic acid 21. 1r (purity 9
85.0 r (equivalent to 0.5 mol) of a 10% ammonia-methanol solution was added to 4.0 IO (equivalent to 1 mol) and held at 45 to 50° C. for 2 hours while stirring.

Thereafter, methanol was distilled off, 20 ml of water was added to the residue, extracted with 5 ml of chloroform, and the extracted layer was concentrated.

The resulting residue was then washed and filtered with 5QmR of toluene to obtain 11.7r of slightly yellowish green crystals. Yield 79.5chi Applicant: Nippon Soda Co., Ltd. Agent: Haruno Ito: Yoshimi Yokoyama

Claims (2)

[Claims] (1) A formula characterized in that 0-(halogenated methyl)phenylacetic acid ester represented by the general formula (wherein, X represents a halogen atom and R represents a lower alkyl group) is reacted with ammonia. A method for producing the 0-(aminomethyl)phenylacetic acid lactam shown below. (2) The method according to claim 1, wherein x is a chlorine atom and R is a methyl group.