CN109336905A

CN109336905A - The synthetic method of Cefazolin Intermediate TDA

Info

Publication number: CN109336905A
Application number: CN201811581537.6A
Authority: CN
Inventors: 张艳红; 张立明
Original assignee: Zibo Xin Xin Medical Technology Service Co Ltd
Current assignee: Zibo Xin Xin Medical Technology Service Co Ltd
Priority date: 2018-12-24
Filing date: 2018-12-24
Publication date: 2019-02-15

Abstract

The present invention relates to medical synthesis technical fields, and in particular to a kind of synthetic method of Cefazolin Intermediate TDA.The synthetic method of the Cefazolin Intermediate TDA is, using phosphate buffer and acetone as solvent, using 7-ACA and thiadiazoles as raw material, reacts under catalyst of triethylamine or ammonium hydroxide effect, obtains TDA.Synthetic method of the invention makees solvent by using phosphate buffer, to maintain the stabilization of reacting liquid pH value, it solves the problems, such as to add lye repeatedly because pH is reduced in reaction process, simple process, solvent are mild, reduce the use of organic solvent, the high income of the TDA of synthesis, purity is high, color are good.

Description

The synthetic method of Cefazolin Intermediate TDA

Technical field

The present invention relates to medical synthesis technical fields, and in particular to a kind of synthetic method of Cefazolin Intermediate TDA.

Background technique

Cefazolin sodium belongs to first generation cephalosporin class antibiotic, because its is cheap and therapeutic effect is good, in clinic On have a wide range of applications.TDA is the important intermediate for producing Cefazolin, and 7-amino-cephalosporanic acid 3 are contracted by thiadiazoles It closes chaining and forms TDA.The quality of TDA is most important to the purity and yield of Cefazolin sodium.Synthesis TDA common method master at present There are Aqueous phase and catalysis method, Aqueous phase takes water as a solvent, and alkali used is often sodium bicarbonate, ammonium hydroxide, triethylamine etc., this method cost Low, reaction condition is mild, and pollution is small, small to actual bodily harm；Catalysis method common solvent is acetonitrile, ether, tetrahydrofuran etc., yield 5-7% high compared with Aqueous phase, but that there are toxicity is big for used catalyst boron trifluoride, and by-product is difficult to recycle, and is unfavorable for environmental protection.

A kind of synthetic method of Cefazolin sodium Intermediate TDA is disclosed in patent CN201210112682.6, with acetone, Second is cured, ether, dimethyl carbonate, methylene chloride or chloroform are that solvent, 7-ACA and thiadiazoles are packed into according to the weight ratio of 1:1.2 In reaction vessel, it is passed through boron triflouride gas into reaction vessel, controls the temperature in reaction vessel between 0-50 DEG C, reaction It remains to 7-ACA less than 1% within 1-8 hours, crystallization is hydrolyzed to reactant using sodium carbonate, sodium bicarbonate or ammonium hydroxide, then Finished product TDA is obtained by suction filtration, washing and drying process.It is disclosed in patent CN20111024214.5 and a kind of prepares cephalo azoles The method of woods sodium compound uses dimethyl carbonate for solvent, and boron trifluoride is catalyst, the weight of 7-ACA and thiadiazoles 1:0.5 Amount ratio is reacted, and is carried out crystallization to reactant with ammonium hydroxide after reaction, using filter, washing, drying, is obtained TDA.It is above-mentioned Boron trifluoride catalyst is all made of in scheme, boron trifluoride is toxic and price is high, also needs to handle containing boride after reaction Waste, higher cost are not suitable for large-scale production.

A kind of synthetic method of Cefazolin Intermediate TDA is disclosed in patent CN201010014470.4, using cephalo Rhzomorph C is oxidized to GL-7-ACA through D-AAO, then reacts with 2- methyl-5-sulfydryl-1,3,4-thiadiazole, uses GL-7-ACA ACY sloughs glutaryl and obtains TDA.The technical solution uses biological enzyme reaction synthesis, environmentally protective nothing Pollution, solves the problems, such as that consumption of organic solvent is big in chemical production, but it needs first to synthesize GL-7-ACA, then synthesizes GL- TDA finally just synthesizes TDA, and synthesis step is more, and whole yield is lower, is unfavorable for industrialized production.

Therefore, seeking one kind, there is high yield, high quality, the simple synthetic method of reaction process to seem most important.

Summary of the invention

In view of the deficiencies of the prior art, the object of the present invention is to provide a kind of synthetic method of Cefazolin Intermediate TDA, Simple process, solvent are mild, reduce the use of organic solvent, the high income of the TDA of preparation is with high purity, and color is good.

The synthetic method of Cefazolin Intermediate TDA of the present invention, using phosphate buffer and acetone as solvent, with 7-ACA and thiadiazoles are raw material, react under the action of catalyst, obtain TDA；

The catalyst is triethylamine or ammonium hydroxide, preferably triethylamine.

Wherein, the mass ratio of 7-ACA and thiadiazoles is 1:0.5-1.

The mass ratio of 7-ACA and catalyst is 1:0.8-1.0.

Preferably, the synthetic method of the Cefazolin Intermediate TDA, comprising the following steps:

(1) it prepares phosphate buffer: buffer substance being dissolved in purified water, is shaken up, phosphate-buffered is made in constant volume Liquid, pH value 7.6-8.0.

(2) it synthesizes TDA: phosphate buffer and acetone being mixed, thiadiazoles and catalyst is sequentially added, is warming up to 60- 70 DEG C, 7-ACA is added, reacts 1.5-3h, adds Sodium Metabisulfite and EDTA, the reaction was continued to 7-ACA residual quantity < 1.0%, reaction terminates, and is down to room temperature, and it is 3.8-4.0 that dilute hydrochloric acid, which is added, and adjusts pH value, under the conditions of 20-25 DEG C, crystallization 30- 50min, then it is cooled to 0-5 DEG C, it filters, washes 2-3 times, acetone is washed 2-3 times, is dried in vacuo to get TDA product.

Buffer substance is one of potassium dihydrogen phosphate, sodium dihydrogen phosphate and disodium hydrogen phosphate, phosphoric acid hydrogen two in step (1) The mixture of one of potassium, sodium hydroxide.

The mixed volume ratio of phosphate buffer and acetone is 4-9:1 in step (2).

Sodium Metabisulfite in step (2), EDTA, 7-ACA mass ratio be 0.03-0.05:0.02-0.05:1.

The concentration of dilute hydrochloric acid is 15-20% in step (2).

Compared with prior art, the invention has the following beneficial effects:

(1) present invention can keep the stabilization of reacting liquid pH value, using phosphate buffer as solvent to solve to react The problem of adding lye repeatedly because of pH reduction in the process；

(2) a small amount of acetone is added in a solvent, it is miscellaneous can to remove in the reaction part during synthesizing TDA by the present invention Matter, to improve product purity；

(3) TDA yield prepared by the present invention can reach 110~115%, and purity is higher than 98%, and color is good, technique letter used List, solvent are mild, meet the energy-saving and emission-reduction requirement of country's promotion, mitigate environmental protection pressure, are suitable for industrialized production.

Specific embodiment

The present invention will be further described with reference to embodiments, but protection scope of the present invention is not limited only to this, the neck Domain professional changes to made by technical solution of the present invention, is within the scope of protection of the invention interior.

Embodiment 1

(1) phosphate buffer is prepared

Dipotassium hydrogen phosphate 0.59g, potassium dihydrogen phosphate 0.41g are weighed, purified water is added to dissolve and is settled to 1000mL, is shaken up The phosphate buffer that pH value is 7.8, it is spare.

(2) TDA is synthesized

500mL three-necked flask is taken, the phosphate buffer 1 80mL of Fresh is added, acetone 60mL is added while stirring Thiadiazoles 12g, is slowly added dropwise triethylamine 8g in 35 DEG C, is warming up to 60 DEG C wait be added dropwise, and 7- is added after all dissolutions ACA12g reacts 2h, adds Sodium Metabisulfite 0.6g, EDTA0.6g, and the reaction was continued, sample detection, remains < to 7-ACA 1.0%, reaction terminates, and is cooled to room temperature, in reaction solution be added dropwise 15% dilute hydrochloric acid adjust pH value be 3.8, growing the grain 30min, Ice water is cooled to 5 DEG C again, filters, and is washed 2 times with 100mL, 200mL acetone is washed 3 times, and TDA dry product is dried in vacuo to obtain in 60 DEG C 13.70g, yield are 1.14 (in terms of 7-ACA), content 98.3%.

Embodiment 2

(1) phosphate buffer is prepared

Disodium hydrogen phosphate 0.48g, potassium dihydrogen phosphate 0.41g are weighed, purified water is added to dissolve and is settled to 1000mL, is shaken up The phosphate buffer that pH is 8.0, it is spare.

(2) TDA is synthesized

500mL three-necked flask is taken, the phosphate buffer 260mL of Fresh is added, acetone 40mL is added while stirring Thiadiazoles 8g, is slowly added dropwise triethylamine 10.2g in 35 DEG C, is warming up to 65 DEG C wait be added dropwise, and 7- is added after all dissolutions ACA12g reacts 2h, adds Sodium Metabisulfite 0.6g, EDTA0.45g, and the reaction was continued, sample detection, remains to 7-ACA < 1.0%, reaction terminates, and is cooled to room temperature, and the dilute hydrochloric acid adjusting pH value that 18% is added dropwise in reaction solution is 4.0, growing the grain 40min, then ice water are cooled to 5 DEG C, filter, and are washed 2 times with 150mL, 200mL acetone is washed 3 times, is dried in vacuo to obtain TDA in 60 DEG C Dry product 13.62g, yield are 1.135 (in terms of 7-ACA), content 98.2%.

Embodiment 3

(1) phosphate buffer is prepared

Dipotassium hydrogen phosphate 2.72g is weighed, adds purified water to dissolve and is settled to 100mL.100mL is taken, 0.20mol hydroxide is added Sodium solution 84.8mL is added water and is diluted to the phosphate buffer that 400mL is 7.6 to get pH, spare.

(2) TDA is synthesized

500mL three-necked flask is taken, the phosphate buffer 270mL of Fresh is added, acetone 30mL is added while stirring Thiadiazoles 6g, is slowly added dropwise ammonium hydroxide 12g in 35 DEG C, is warming up to 68 DEG C wait be added dropwise, and 7-ACA12g is added after all dissolutions, 2.5h is reacted, Sodium Metabisulfite 0.36g, EDTA0.24g are added.Sample detection remains < 1.0%, reaction knot to 7-ACA Beam is cooled to room temperature, and it is 3.9 that certain 20% salt acid for adjusting pH value is added dropwise in reaction solution, and growing the grain 50min, then ice water are cooled to 0 DEG C, filter, with 120mL wash 2 times, 200mL acetone is washed 3 times, be dried in vacuo in 60 DEG C TDA dry product 13.35g, yield are 1.11 (in terms of 7-ACA), content 98.0%.

Claims

1. a kind of synthetic method of Cefazolin Intermediate TDA, it is characterised in that: using phosphate buffer and acetone as solvent, Using 7-ACA and thiadiazoles as raw material, reacts under the action of catalyst, obtain TDA；

The catalyst is ammonium hydroxide or triethylamine.

2. the synthetic method of Cefazolin Intermediate TDA according to claim 1, it is characterised in that: 7-ACA and thiadiazoles Mass ratio be 1:0.5-1.

3. the synthetic method of Cefazolin Intermediate TDA according to claim 1, it is characterised in that: 7-ACA and catalyst Mass ratio be 1:0.8-1.0.

4. the synthetic method of Cefazolin Intermediate TDA according to claim 1, it is characterised in that: the following steps are included:

(1) it prepares phosphate buffer: buffer substance being dissolved in purified water, is shaken up, phosphate buffer is made；

(2) it synthesizes TDA: phosphate buffer and acetone being mixed, thiadiazoles and catalyst is sequentially added, is warming up to 60-70 DEG C, 7-ACA is added, reacts 1.5-3h, adds Sodium Metabisulfite and EDTA, the reaction was continued to 7-ACA residual quantity < 1.0%, instead It should terminate, be down to room temperature, it is 3.8-4.0 that dilute hydrochloric acid, which is added, and adjusts pH value, crystallization, then is cooled to 0~5 DEG C, filters, washs, does It is dry to get TDA product.

5. the synthetic method of Cefazolin Intermediate TDA according to claim 4, it is characterised in that: buffering in step (1) Substance is one of potassium dihydrogen phosphate, sodium dihydrogen phosphate and one of disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium hydroxide Mixture.

6. the synthetic method of Cefazolin Intermediate TDA according to claim 4, it is characterised in that: phosphoric acid in step (1) The pH value of salt buffer is 7.6-8.0.

7. the synthetic method of Cefazolin Intermediate TDA according to claim 4, it is characterised in that: phosphoric acid in step (2) The mixed volume ratio of salt buffer and acetone is 4-9:1.

8. the synthetic method of Cefazolin Intermediate TDA according to claim 4, it is characterised in that: laid particular stress in step (2) Sodium sulfite, EDTA, 7-ACA mass ratio be 0.03-0.05:0.02-0.05:1.

9. the synthetic method of Cefazolin Intermediate TDA according to claim 4, it is characterised in that: dilute salt in step (2) The concentration of acid is 15-20%.

10. the synthetic method of Cefazolin Intermediate TDA according to claim 4, it is characterised in that: analysis in step (2) Brilliant temperature is 20-25 DEG C, and the crystallization time is 30-50min.