CN1660801A

CN1660801A - Technique for preparing N-carbobenzoxy-5 phenyl-L-cysteine

Info

Publication number: CN1660801A
Application number: CN 200410089193
Authority: CN
Inventors: 高玉冠; 仲全福
Original assignee: Individual
Current assignee: Individual
Priority date: 2004-12-07
Filing date: 2004-12-07
Publication date: 2005-08-31

Abstract

A process for preparing N-benzoxycarbonyl-S-phenyl-L-cysteine includes synthesizing phenylamine diazonium salt from sodium nitrate and phenylamine, reacting on the solution of L-cysteine to obtain coarse S-phenyl-L-cysteine (PC), refining, dissolving, reacting on the solution of benzyl chloroformate, removing solvent, washing to obtain N-benzoxycarbonyl-S-phenyl-L-cysteine, adding solvent, acidifying, filter and baking. It can be used as the basic raw material for preparing anti-AIDS and antineoplastic medicines.

Description

The preparation technology of N-carbobenzoxy-(Cbz)-S phenyl-L-halfcystine

Technical field

The present invention relates to the preparation technology that basic material N-carbobenzoxy-(Cbz)-the S phenyl-the L-halfcystine is new of a kind of anti-AIDS and antitumor drug.

Background technology

The method of producing N-carbobenzoxy-(Cbz)-S phenyl-L-halfcystine (CBZ-PC) product in the world at present has two kinds.A kind of is that the employing Serine is a raw material; with carbobenzoxy-(Cbz) N is protected earlier; make CBZ-PC with the reaction of thiophenol sodium again through the synthetic N-carbobenzoxy-(Cbz) of Mitsunobu reaction-L-Serine-β lactone then; be called for short the Serine route; this route synthetic CBZ-PC product purity height; content 〉=99%, but Serine expensive raw material price, the cost height.Another kind method is to be raw material with the L-halfcystine, in the presence of cuprous chloride, react with diazonium salt, make CBZ-PC with sodium sulphite decopper(ing), neutralization, this method is called for short diazonium, condensation route, in recent years, domestic and international primary study diazonium, condensation route, though this route L-halfcystine raw material is cheap, but because the reaction yield too low (36%) of L-halfcystine and diazonium salt, the CBZ-PC overall yield has only 25%, the more important thing is that the CBZ-PC quality product is not high, content only about 98%, does not satisfy customer requirements (more than 99%).Therefore, both at home and abroad the expert concentrates one's energy to improve the quality of diazonium, condensation route synthetic CBZ-PC, strives reaching and surpasses Serine route (content 〉=99%); Improve productive rate, reduce cost and the Serine route is competed.

Summary of the invention

At the deficiency that exists in the prior art, the object of the present invention is to provide the preparation method of a kind of low cost, high-quality CBZ-PC.

The present invention is achieved through the following technical solutions:

Chemical reaction related among the preparation technology of a kind of N-carbobenzoxy-(Cbz) of the present invention-S-phenyl-L-halfcystine is as follows:

Diazonium:

Condensation:

The preparation technology of a kind of N-carbobenzoxy-(Cbz)-S-phenyl-L-halfcystine comprises the steps:

A, elder generation synthesize diazonium salt of aniline with Sodium Nitrite and aniline, be under the condition that exists of-5 ℃-5 ℃, cuprous chloride in temperature then, the diazonium salt of aniline that obtains is added drop-wise in the solution of L-halfcystine and reacts, reacted 1-20 hour, through sodium sulphite decopper(ing), sodium hydroxide solution be neutralized to PH5-7, suction filtration obtains thick S-phenyl-L-halfcystine (PC);

B, the thick S-phenyl-L-halfcystine that will make dissolve in alkaline solution, and it is refining to add gac and reductive agent, and being neutralized to pH value with acid again is 5-7, suction filtration, dry purified S-phenyl-L-halfcystine (PC), its content 〉=99.5%, fusing point 200-204 ℃, productive rate 50%;

C, purified S-phenyl-L-halfcystine is dissolved in the dilute alkaline soln, in this solution, drip the chloroformic acid benzyl ester solution that has solvent again, (because phenyl chloroformate is very active, the reaction by product is many, products obtained therefrom is of poor quality, therefore adopt the method for adding solvent that reaction is relaxed, suppress to pay reaction).Drip dilute alkaline soln simultaneously, make PH remain on 10-12, the reaction times is 1-5 hour, and layering was desolvated, got N-carbobenzoxy-(Cbz)-S phenyl-L-halfcystine solution with toluene wash after reaction was finished;

D, in N-carbobenzoxy-(Cbz)-S-phenyl-L-halfcystine solution, add one or more mixtures in toluene, tetracol phenixin, ethylene dichloride, the water solvent, through hcl acidifying to PH2, N-carbobenzoxy-(Cbz)-S-phenyl-L-halfcystine crystal is separated out, suction filtration, dry the finished product.Product content reaches 99.5%, productive rate 96%.

The solvent that adds in chloroformic acid benzyl ester solution in the described C step is one or more the mixture in ethylene dichloride, methylene dichloride, toluene, the dimethylbenzene.Wherein the weight ratio of solvent and chloroformic acid benzyl ester is: 1-10: 1.

The preparation technology of N-carbobenzoxy-(Cbz) of the present invention-S phenyl-L-halfcystine (CBZ-PC) is owing to adopt the refining PC of the method for alkali-soluble acid analysis, adopt the method for solvent cut chloroformic acid benzyl ester and the method for solvent acidizing crystal moulding, make synthesis technique of the present invention have work simplification, equip advantages such as simple, easy to operate, safe, the prepared CBZ-PC good product quality of the inventive method, reach 99.5%, productive rate 96%, overall yield can reach 48%, makes production cost reduce greatly.

Description of drawings

Fig. 1 is a process flow sheet of the present invention.

Embodiment

How further specify the present invention below in conjunction with accompanying drawing and specific embodiment realizes:

Embodiment 1

The sulfuric acid of 52g (28ml) is dissolved in the water of 275ml, adds the 22.5g aniline solution, be cooled to the 8.75g Sodium Nitrite is dissolved in the water of 40ml below 5 ℃, be added drop-wise to and get diazonium salt of aniline in the above-mentioned solution;

The L-cysteine hydrochloride (0.17mol) that 30g is contained a crystal water is dissolved in the 225g water, add 30% technical hydrochloric acid 11g, add the 4.25g cuprous chloride again, be cooled to below 5 ℃, the above-mentioned diazonium salt that makes is added drop-wise in this solution, drip off the back and under this temperature, continue reaction 6 hours, again reactant is warming up to 85 ℃-90 ℃, be incubated 1 hour, be cooled to again about 60 ℃ and add sodium sulfide solution till do not have precipitation and generate, suction filtration, solution is neutralized to PH5-7 with 30% sodium hydroxide, suction filtration is dissolved in thick PC in the sodium hydroxide solution, adds 5g gac and reductive agent decolorizing and refining, suction filtration, with the hydrochloric acid PH5-7 that neutralizes, then highly purified PC separates out suction filtration to solution again, oven dry, get PC15g, purity 99.5%, fusing point 200-204 ℃, productive rate 50%.

The above-mentioned 6gPC that makes (0.03mol) is added in the 20ml water, the sodium hydroxide 20ml of adding 7%, dripping ethylene dichloride (20ml) solution that contains the 6g chloroformic acid benzyl ester below 5 ℃, drip 7% sodium hydroxide solution simultaneously, regulate PH=10-12, reacted again 2 hours after dripping off, layering is desolvated, CBZ-PC solution with toluene wash once adds the 10ml tetracol phenixin again, with hcl acidifying to PH=2, cooling, crystallization, dry product C BZ-PC9.6g, recording content is 99.5%, fusing point 94-95 ℃, and productive rate 96%.

Embodiment 2

Additive method is identical with embodiment 1, and just the solution after the toluene wash that will make with embodiment 1 same procedure adds the toluene of 100ml, again with hcl acidifying to PH2, stirring at normal temperature crystallization, suction filtration dry CBZ-PC9.0g, content is 99.30%, fusing point is 93.5-94.5 ℃, and productive rate is 89%.

Embodiment 3

Additive method is identical with embodiment 1, just the solution after the toluene wash that will make with embodiment 1 same procedure adds the tetracol phenixin of 5ml and the ethylene dichloride of 40ml, be acidified to PH2, be cooled to 5 ℃, stirred crystallization, filtering drying gets CBZ-PC7.4g, and content is 99.61%, fusing point is 94-95.5 ℃, and productive rate is 73.4%.

Embodiment 4

Additive method is identical with embodiment 2, and just chloroformic acid benzyl ester solution is made into 6g chloroformic acid benzyl ester and 10ml toluene, and the CBZ-PC8.5g that makes, content are 98.98%, and fusing point is 93-94 ℃, and productive rate is 85%.

Claims

1, the preparation technology of a kind of N-carbobenzoxy-(Cbz)-S-phenyl-L-halfcystine comprises the steps:

A, elder generation synthesize diazonium salt of aniline with Sodium Nitrite and aniline, be under the condition that exists of-5 ℃-5 ℃, cuprous chloride in temperature then, the diazonium salt of aniline that obtains is added drop-wise in the solution of L-halfcystine and reacts, reaction finishes after decopper(ing), suction filtration, obtain thick S-phenyl-L-halfcystine with the alkali neutralization;

B, the thick S-phenyl-L-halfcystine that will make dissolve in alkaline solution, and it is refining to add gac and reductive agent, and being neutralized to pH value with acid again is 5-7, get purified S-phenyl-L-halfcystine;

C, purified S-phenyl-L-halfcystine is dissolved in the dilute alkaline soln, in this solution, drip the chloroformic acid benzyl ester solution that has solvent again, drip dilute alkaline soln simultaneously, make PH remain on 10-12, branch desolvated, gets N-carbobenzoxy-(Cbz)-S-phenyl-L-halfcystine solution with toluene wash after reaction was finished;

D, in N-carbobenzoxy-(Cbz)-S-phenyl-L-halfcystine solution, add one or more mixtures in toluene, tetracol phenixin, ethylene dichloride, the water solvent, after acidifying, separate out N-carbobenzoxy-(Cbz)-S phenyl-L-halfcystine crystal.

2, the preparation technology of a kind of N-carbobenzoxy-(Cbz) according to claim 1-S-phenyl-L-halfcystine, it is characterized in that: the reaction times in the described A step is 1-20 hour.

3, the preparation technology of a kind of N-carbobenzoxy-(Cbz) according to claim 1-S-phenyl-L-halfcystine is characterized in that: the solvent that adds in chloroformic acid benzyl ester solution in the described C step is one or more the mixture in ethylene dichloride, methylene dichloride, toluene, the dimethylbenzene.

4, according to the preparation technology of claim 1 or 3 described a kind of N-carbobenzoxy-(Cbz)-S-phenyl-L-halfcystines, it is characterized in that: the weight ratio of described solvent and chloroformic acid benzyl ester is: 1-10: 1.

5, the preparation technology of a kind of N-carbobenzoxy-(Cbz) according to claim 1-S-phenyl-L-halfcystine, it is characterized in that: the reaction times in the described C step is 1-5 hour.