CN1091439C - Method for producing N-benzyloxycarbony I S-phenyl L-cysteine - Google Patents

Abstract

The present invention discloses s production method for N-benzyloxycarbony S-phenyl L-cysteine, which comprises the steps that L-cysteine is used as raw material, is in reaction with cupric sulfate, and then is in reaction with aniline diazotization solution so as to generate midbodies; products are obtained by the reaction between the midbodies and benzyl chloroformate. The present invention has the advantages of simple production technology, high product yield higher than 27% and low toxicity and risk reduction in production processes because no ether is used.

Description

The production method of N-benzyloxycarbony I S-phenyl L-cysteine

The present invention relates to a kind of pharmaceutical intermediate.

The production method of N-benzyloxycarbony I S-phenyl L-cysteine in the prior art, complex procedures, yield are low, are generally about 10%, and the employing ether is a raw material, and toxicity is big, the production cost height.

The object of the present invention is to provide the production method of a kind of product yield height, N-benzyloxycarbony I S-phenyl L-cysteine that toxicity is little.

Technical solution of the present invention is:

The production method of N-benzyloxycarbony I S-phenyl L-cysteine, the difference of itself and prior art is: in turn include the following steps:

1. cysteine hydrochloride and copper-bath react under-5～8 ℃ of conditions, and reaction formula is:

2. in above-mentioned resultant, add the reaction of aniline diazotization liquid again, and through feeding hydrogen sulfide, decolorization filtering, drying to such an extent that intermediate sulfur phenenyl L-halfcystine reaction formula is as follows:

3. above-mentioned reaction gained intermediate sulfur phenenyl L-halfcystine is dissolved with sodium hydroxide solution, with the chloroformic acid benzyl ester reaction, get the N-benzyloxycarbony I S-phenyl L-cysteine under-5～5 ℃ of temperature, reaction formula is:

The 1. middle reaction times of step is 20～50 minutes, and the step reaction times 2. is 3～5 hours, and the step reaction times 3. is 1～3 hour, and pH value is 7～10 during reaction.

3. react through step obtain N-benzyloxycarbony I S-phenyl L-cysteine product after, be neutralized to PH3.0～2.5 with sulfuric acid, after filtration, crystallization, dry product.

Production technique of the present invention is simple, and product yield height can reach more than 27%, owing to do not adopt ether, so production process toxicity is little, reduces dangerous.

The invention will be further described below in conjunction with embodiment.

Embodiment:

The sulfuric acid that in reaction flask, adds 210gL-cysteine hydrochloride and 550ml left and right sides 1.5N, be cooled to-5～8 ℃ (-5 ,-2,0,3,5,8 ℃ of examples), drip copper-bath (150g copper sulfate is dissolved in 550ml1.5N sulfuric acid), dropwise, insulation reaction 20～50 minutes (example 20,30,40,50 minutes), reaction formula is:

Then, in above-mentioned reaction solution, add aniline diazotization liquid 1800ml again, and keep 3～5 hours (example 3,4,5 hours) of reaction, with above-mentioned reacting liquid filtering, filtrate is warming up to 45～70 ℃ (45,55,63,70 ℃ of examples), feeds hydrogen sulfide to saturated, adding decolorizing with activated carbon after the ordinary method degassing handles, refilter, oven dry promptly gets intermediate sulfur phenenyl L-halfcystine, its mp is 173～176 ℃, (α)=+ 60～+ 80 degree, (1NHCL, 1% concentration) reaction formula is:

Above-mentioned intermediate sulfur phenenyl L-halfcystine water 1000ml is disperseed (is example with the 100g intermediate), be cooled to 6～10 ℃ (6,7,8,9,10 ℃ of examples), add the 2N dissolution of sodium hydroxide, be cooled to-5～5 ℃ (-5 ,-2,0,2,4,5 ℃ of examples), add chloroformic acid benzyl ester 65ml, react 1～3 hour (example 1,2,3 hours), generate N-benzyloxycarbony I S-phenyl L-cysteine product, reaction formula is:

Be neutralized to PH=3.0～2.5 with 1.5N sulfuric acid then, filter, dry, promptly get N-benzyloxycarbony I S-phenyl L-cysteine product, yield reaches more than 27%, and the mp of product is 93～95 ℃, (α)=-60～85 degree (in 1% methanol solution).

Claims (3)

1, the production method of N-benzyloxycarbony I S-phenyl L-cysteine is characterized in that: in turn include the following steps:

1. cysteine hydrochloride and copper-bath react under-5～8 ℃ of conditions, and reaction formula is:

2. in above-mentioned resultant, add aniline diazotization liquid reaction again, and through feed hydrogen sulfide, decolorization filtering, dry intermediate sulfur phenenyl L-halfcystine, reaction formula is as follows:

3. above-mentioned reaction gained intermediate sulfur phenenyl L-halfcystine is dissolved with sodium hydroxide solution, with the chloroformic acid benzyl ester reaction, get the N-benzyloxycarbony I S-phenyl L-cysteine under-5～5 ℃ of temperature, reaction formula is:

2, the production method of N-benzyloxycarbony I S-phenyl L-cysteine according to claim 1 is characterized in that:

The 1. middle reaction times of step is 20～50 minutes; The step reaction times 2. is 3～5 hours; The step reaction times 3. is 1～3 hour, and pH value is 7～10 during reaction.

3, the production method of N-benzyloxycarbony I S-phenyl L-cysteine according to claim 1, it is characterized in that: 3. react through step obtain N-benzyloxycarbony I S-phenyl L-cysteine product after, be neutralized to PH3.0～2.5 with sulfuric acid, after filtration, crystallization, dry product.