CN102220403B - Method for preparing 7-ACCA - Google Patents
Method for preparing 7-ACCA Download PDFInfo
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- CN102220403B CN102220403B CN 201110095656 CN201110095656A CN102220403B CN 102220403 B CN102220403 B CN 102220403B CN 201110095656 CN201110095656 CN 201110095656 CN 201110095656 A CN201110095656 A CN 201110095656A CN 102220403 B CN102220403 B CN 102220403B
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- phenylacetylamino
- carboxylic acid
- chloro
- cephalo ring
- nitrobenzyl ester
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Abstract
The invention relates to an important intermediate 7-ACCA of cephalosporin cefaclor, comprising the following steps of: 1) preparation of 3-amino-2-ethoxyformyl anesthesin; 2) preparation of 2-ethoxybenzimidazole-4-carboxylic acid ethyl ester; 3) preparation of candesartan cyclic compound. According to the invention, the benzimidazole ring is constructed, tetraehtyl orthocarbonate is avoided, and intramolecular dehydration is accomplished; and alkylation is accomplished in the final stage and cyanobromobiphenyl is introduced to minimize the consumption of cyanobromobiphenyl as well as the cost of the candesartan cyclic compound.
Description
Technical field
The present invention relates to the preparation method of an important intermediate 7-ACCA of antibacterial cephalosporin element cefaclor.
Background technology
Cefaclor is a kind of extensive pedigree antibiotic that is widely used, in this class medicine that has gone on the market, and good effect, market obtains unprecedented development.This medicine synthetic, key or the preparation of intermediate 7-ACCA.
7-ACCA chemical name: 7-ACCA
Structural formula is as follows:
At present, 7-ACCA's is synthetic, and common method can be summarized as two kinds of A, B:
A kind of is route take 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-carboxylic acid phenylbenzene methyl esters as raw material, at first by the chlorination of phosphorus oxychloride, makes 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid phenylbenzene methyl esters; Pass through again trichlorinated elimination, slough diphenyl-methyl, obtain 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid; Finally by crossing immobilized penicillin G acylase, slough the toluylic acid base, thereby obtain 7-ACCA.
Operational path A is as follows:
Another kind be take 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-carboxylic acid to the route of nitrobenzyl ester as raw material, at first by the chlorination of chlorine, make 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid to the nitrobenzyl ester; Pass through again the elimination of triphenyl phosphite, slough the toluylic acid base, obtain 7-amino-3-hydroxyl-3-cephalo ring-4-carboxylic acid to the nitrobenzyl ester; Finally by the effect of crossing vat powder, slough nitrobenzyl, thereby obtain 7-ACCA.
Operational path B is as follows:
Above-mentioned the first operational path, phenylacetylamino-3-hydroxyl-3-cephalo ring-4-carboxylic acid phenylbenzene methyl esters is raw material, causes the final raw materials cost of 7-ACCA higher, also uses simultaneously the phosphorus oxychloride hazardous chemical owing to selecting 7-.
The second operational path, although phenylacetylamino-3-hydroxyl-3-cephalo ring-4-carboxylic acid is raw material to the nitrobenzyl ester to select 7-, but also relate to hazardous chemical chlorine, meanwhile, slough the toluylic acid base with the chemical cracking method, produce a large amount of high pollution waste water, give environmental protection with very large pressure, increased the weight of production cost.
Summary of the invention
Technical problem to be solved by this invention is the above-mentioned shortcoming and defect that overcomes existing synthesis technique, provides a kind of lower production cost, the preparation method of oligosaprobic 7-ACCA.
The present invention is that the solution that problem adopts of the above-mentioned proposition of solution is: the preparation method of 7-ACCA includes following steps:
1) preparation of 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid:
Press 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid to the nitrobenzyl ester: water: acetone: the proportioning of vat powder=1: 1.5～2: 4～5: 1.5～2, get 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid to the nitrobenzyl ester, to wherein adding entry, acetone and vat powder, stir lower dilute ammonia solution accent pH to 7.0～7.2 that drip, 40～45 ℃ of control temperature, reacted 3～6 hours, filter, gained filtrate drips dilute hydrochloric acid, transfer pH to 2～3, crystallization, suction filtration, washing and drying get 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid;
2) preparation of 7-ACCA (7-ACCA):
Press 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid: water: the proportioning of immobilized penicillin G acylase=1: 15～20: 0.25～0.3; get 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid; to wherein adding entry; stir lower dilute sodium bicarbonate solution accent pH to 7.0～7.2 that drip; material dissolution; add immobilized penicillin G acylase; stir lower dilute sodium carbonate solution accent pH to 7.9～8.0 that drip; suction filtration after reaction is finished; dezymotize, filtrate drips dilute hydrochloric acid, transfers pH to 2～3; crystallization, suction filtration, washing and drying get the 7-ACCA product.
Press such scheme, described 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid is to the preparation method of nitrobenzyl ester:
1. press 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-carboxylic acid to the nitrobenzyl ester: trichloromethane: triphosgene: DMF=1: 6～10: 1.1～1.5: 1.2～1.7 proportioning, get trichloromethane, triphosgene and DMF, under-1 ℃～1 ℃ temperature, then stirring reaction 1～3 hour adds 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-carboxylic acid to the nitrobenzyl ester, 53 ℃～57 ℃ of control temperature, stirring reaction 8～12 hours obtains reacting feed liquid;
2. press 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-carboxylic acid to the nitrobenzyl ester: the weight proportion of NaOH solution=1: 2～4, to react feed liquid slowly pours in the NaOH solution, control pH12～13,23 ℃～27 ℃ of control temperature, stirring reaction 1～3 hour, static, layering removes trichloromethane under reduced pressure;
3. press 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-carboxylic acid to the nitrobenzyl ester: the weight proportion of methyl alcohol=1: 2～4, add methyl alcohol, crystallisation by cooling, filtration, washing and drying get 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid to the nitrobenzyl ester.
Primitive reaction principle of the present invention is: take 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-carboxylic acid to the nitrobenzyl ester as starting raw material; Carry out chlorination by triphosgene, make 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid to the nitrobenzyl ester; Through the effect of vat powder, slough nitrobenzyl, make 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid; Finally by crossing immobilized penicillin G acylase, slough the toluylic acid base, thereby obtain 7-ACCA;
Operational path C of the present invention is as follows:
Preparation method of the present invention, more existing technical scheme is at first in the chloro link of 3-OH, avoid high-risk chlorination reagent, select triphosgene (triphosgene, chemical name, two (trichloromethyl) carbonic ether is called for short BTC), realize that chlorinated effluent carries out the green discharging with the form of sodium chloride solution; Next is to the elimination of nitrobenzyl and toluylic acid base, adopts respectively vat powder and immobilized penicillin G acylase, finishes the cracking of relevant protecting group at aqueous phase and eliminates, and makes 7-ACCA, green, environmental protection, economy.
Embodiment
In order to understand better the present invention, further set forth content of the present invention below in conjunction with test example, but content of the present invention not only is confined to the following examples.
Embodiment 1:
1) 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid is to the preparation of nitrobenzyl ester:
Get the trichloromethane of 400g, triphosgene (the triphosgene of 68g, chemical name, two (trichloromethyl) carbonic ether is called for short BTC), the DMF of 72g, 0 ± 1 ℃ of control temperature, stirring reaction 2 hours, the 7-phenylacetylamino of adding 60g-3-hydroxyl-3-cephalo ring-4-carboxylic acid is to the nitrobenzyl ester, 55 ± 2 ℃ of control temperature, stirring reaction 10 hours obtains reacting feed liquid and slowly pours in the NaOH solution of 150g (10%, mass percent concentration), control pH12～13,25 ± 2 ℃ of control temperature, stirring reaction 1 hour is static, layering, remove trichloromethane under reduced pressure, add methyl alcohol 150g, crystallisation by cooling, filter, washing and dry, obtain that the 7-phenylacetylamino-3-chloro-3-cephalo ring-the 4-carboxylic acid is to nitrobenzyl ester product 54.7g, purity is more than 98%;
2) preparation of 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid:
To 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid to adding entry 150g among the nitrobenzyl ester 100g, acetone 400g, vat powder 150g stirs lower dilute ammonia solution accent pH to 7.0～7.2 that drip, 40～45 ℃ of control temperature, reacted 3 hours, and filtered, filtrate drips dilute hydrochloric acid, transfer pH to 2～3, crystallization, suction filtration, washing and drying get 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid product 47.8g, and purity is more than 98.5%;
3) preparation of 7-ACCA (7-ACCA):
In 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid 40g, add water 650g; stir the lower dilute sodium bicarbonate solution (8% that drips; mass percent concentration) transfers pH to 7.0～7.2; material dissolution; add immobilized penicillin G acylase 10g; stir the lower dilute sodium carbonate solution (9%, mass percent concentration) that drips and transfer pH to 7.9～8.0, when pH can stablize 10 minutes when constant; proved response is complete; suction filtration is dezymotized, and filtrate drips dilute hydrochloric acid; transfer pH to 2～3; crystallization; suction filtration; washing and dry gets 7-ACCA product 17.7g, and purity is more than 98.5%.
Embodiment 2:
1) 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid is to the preparation of nitrobenzyl ester:
Get the trichloromethane of 5000g, triphosgene (the triphosgene of 800g, chemical name, two (trichloromethyl) carbonic ether is called for short BTC), the DMF of 1000g, 0 ± 1 ℃ of control temperature, stirring reaction 3 hours, the 7-phenylacetylamino of adding 600g-3-hydroxyl-3-cephalo ring-4-carboxylic acid is to the nitrobenzyl ester, 55 ± 2 ℃ of control temperature, stirring reaction 12 hours obtains reacting feed liquid and slowly pours in the NaOH solution of 2000g (10%, mass percent concentration), control pH12～13,25 ± 2 ℃ of control temperature, stirring reaction 1 hour is static, layering, remove trichloromethane under reduced pressure, add methyl alcohol 2000g, crystallisation by cooling, filter, washing and dry, obtain that the 7-phenylacetylamino-3-chloro-3-cephalo ring-the 4-carboxylic acid is to nitrobenzyl ester product 550g, purity is more than 98%;
2) preparation of 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid:
7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid is to adding entry 1800g among the nitrobenzyl ester 1000g, acetone 4500g, vat powder 1600g stirs lower dilute ammonia solution accent pH to 7.0～7.2 that drip, 40～45 ℃ of control temperature, reacted 4 hours, and filtered, filtrate drips dilute hydrochloric acid, transfer pH to 2～3, crystallization, suction filtration, washing and drying get 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid product 475g, and purity is more than 98.5%;
3) preparation of 7-ACCA (7-ACCA):
In 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid 1000g, add water 18000g; stir the lower dilute sodium bicarbonate solution (8% that drips; mass percent concentration) transfers pH to 7.0～7.2; material dissolution; add immobilized penicillin G acylase 280g; stir the lower dilute sodium carbonate solution (9%, mass percent concentration) that drips and transfer pH to 7.9～8.0, when pH can stablize 10 minutes when constant; proved response is complete; suction filtration is dezymotized, and filtrate drips dilute hydrochloric acid; transfer pH to 2～3; crystallization; suction filtration; washing and dry gets 7-ACCA product 443g, and purity is more than 98.5%.
Embodiment 3:
1) 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid is to the preparation of nitrobenzyl ester:
Get the trichloromethane of 2000g, triphosgene (the triphosgene of 430g, chemical name, two (trichloromethyl) carbonic ether is called for short BTC), the DMF of 450g, 0 ± 1 ℃ of control temperature, stirring reaction 3 hours, the 7-phenylacetylamino of adding 300g-3-hydroxyl-3-cephalo ring-4-carboxylic acid is to the nitrobenzyl ester, 55 ± 2 ℃ of control temperature, stirring reaction 12 hours obtains reacting feed liquid and slowly pours in the NaOH solution of 1000g (10%, mass percent concentration), control pH12～13,25 ± 2 ℃ of control temperature, stirring reaction 1 hour is static, layering, remove trichloromethane under reduced pressure, add methyl alcohol 700g, crystallisation by cooling, filter, washing and dry, obtain that the 7-phenylacetylamino-3-chloro-3-cephalo ring-the 4-carboxylic acid is to nitrobenzyl ester product 270g, purity is more than 98%;
2) preparation of 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid:
To 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid to adding entry 800g among the nitrobenzyl ester 500g, acetone 2200g, vat powder 750g stirs lower dilute ammonia solution accent pH to 7.0～7.2 that drip, 40～45 ℃ of control temperature, reacted 6 hours, and filtered, filtrate drips dilute hydrochloric acid, transfer pH to 2～3, crystallization, suction filtration, washing and drying get 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid product 240g, and purity is more than 98.5%;
3) preparation of 7-ACCA (7-ACCA):
In 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid 200g, add water 3500g; stir the lower dilute sodium bicarbonate solution (8% that drips; mass percent concentration) transfers pH to 7.0～7.2; material dissolution; add immobilized penicillin G acylase 55g; stir the lower dilute sodium carbonate solution (9%, mass percent concentration) that drips and transfer pH to 7.9～8.0, when pH can stablize 10 minutes when constant; proved response is complete; suction filtration is dezymotized, and filtrate drips dilute hydrochloric acid; transfer pH to 2～3; crystallization; suction filtration; washing and dry gets 7-ACCA product 85.7g, and purity is more than 98.5%.
Claims (1)
1.7-ACCA the preparation method, include following steps:
1) preparation of 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid:
Press 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid to the nitrobenzyl ester: the proportioning of water: acetone: vat powder=1:1.5～2:4～5:1.5～2, get 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid to the nitrobenzyl ester, to wherein adding entry, acetone and vat powder, stir lower dilute ammonia solution accent pH to 7.0～7.2 that drip, 40～45 ℃ of control temperature, reacted 3～6 hours, filter, gained filtrate drips dilute hydrochloric acid, transfer pH to 2～3, crystallization, suction filtration, washing and drying get 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid; Described 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid is to the preparation method of nitrobenzyl ester:
1. press 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-carboxylic acid to the nitrobenzyl ester: the proportioning of trichloromethane: triphosgene: DMF=1:6～10:1.1～1.5:1.2～1.7, get trichloromethane, triphosgene and DMF, under-1 ℃～1 ℃ temperature, then stirring reaction 1～3 hour adds 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-carboxylic acid to the nitrobenzyl ester, 53 ℃～57 ℃ of control temperature, stirring reaction 8～12 hours obtains reacting feed liquid;
2. press 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-carboxylic acid to the nitrobenzyl ester: the weight proportion of NaOH solution=1:2～4, to react feed liquid slowly pours in the NaOH solution, control pH12～13,23 ℃～27 ℃ of control temperature, stirring reaction 1～3 hour, static, layering removes trichloromethane under reduced pressure;
3. press 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-carboxylic acid to the weight proportion of nitrobenzyl ester: methyl alcohol=1:2～4, add methyl alcohol, crystallisation by cooling, filtration, washing and drying get 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid to the nitrobenzyl ester;
2) preparation of 7-ACCA:
Press 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid: the proportioning of water: immobilized penicillin G acylase=1:15～20:0.25～0.3; get 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid; to wherein adding entry; stir lower dilute sodium bicarbonate solution accent pH to 7.0～7.2 that drip; material dissolution; add immobilized penicillin G acylase; stir lower dilute sodium carbonate solution accent pH to 7.9～8.0 that drip; suction filtration after reaction is finished; dezymotize, filtrate drips dilute hydrochloric acid, transfers pH to 2～3; crystallization, suction filtration, washing and drying get the 7-ACCA product.
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| CN 201110095656 CN102220403B (en) | 2011-04-18 | 2011-04-18 | Method for preparing 7-ACCA |
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| CN 201110095656 CN102220403B (en) | 2011-04-18 | 2011-04-18 | Method for preparing 7-ACCA |
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| CN102220403B true CN102220403B (en) | 2013-03-06 |
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| CN102703559B (en) * | 2012-06-18 | 2013-09-11 | 山东诚创医药技术开发有限公司 | Preparation method for 7 beta-amino-3-[4-(1-methyl-4-pyridinium)-2-thiazole sulfenyl]-3-cephem-4-carboxylate acidification matter |
| CN103387584B (en) * | 2013-07-17 | 2015-02-25 | 盐城开元医药化工有限公司 | Synthetic method of 7-amino-3-chloro-3-cephem-4-carboxylic acid |
| CN103571907B (en) * | 2013-10-30 | 2016-01-13 | 苏州中联化学制药有限公司 | A kind of separation of enzymatic clarification cefaclor and purification process |
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