CN103694257A - Preparation method of 7-amino-3-chloro-3-cephem-4-carboxylic acid - Google Patents
Preparation method of 7-amino-3-chloro-3-cephem-4-carboxylic acid Download PDFInfo
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- CN103694257A CN103694257A CN201310723331.3A CN201310723331A CN103694257A CN 103694257 A CN103694257 A CN 103694257A CN 201310723331 A CN201310723331 A CN 201310723331A CN 103694257 A CN103694257 A CN 103694257A
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- phenylacetylamino
- chloro
- cephalo ring
- reaction
- carboxylic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/59—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3 with hetero atoms directly attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention relates to a preparation method of 7-amino-3-chloro-3-cephem-4-carboxylic acid. The preparation method takes 7-phenacetylamino-3-hydroxyl-3-cephem-4-diphenylmethyl carboxylate as a starting material and comprises the following steps: (1) chloridizing the starting material to obtain 7-phenacetylamino-3-chloro-3-cephem-4-diphenylmethyl carboxylate; (2) removing diphenylmethyl on the C-4 site to obtain 7-phenacetylamino-3-chloro-3-cephem-4-carboxylic acid; (3) removing phenylacetyl on the C-7 site to obtain 7-amino-3-chloro-3-cephem-4-carboxylic acid. In the whole process route, the reaction conditions are mild; the raw materials are cheap and easy to obtain; severe harmful substances are not used; the preparation method is low in pollution, saves resources, and is high in product yield, low in cost and suitable for industrial production.
Description
Technical field
The present invention relates to a kind of method of preparing 7-ACCA, 7-ACCA is the crucial parent nucleus of preparing cephalosporin antibiotics cefaclor, is called for short 7-ACCA.Cefaclor is a kind of oral broad-spectrum cephalosporin microbiotic, has the advantages such as good effect, safety, sensitization be low.
Background technology
Cefaclor, because good effect, safety, sensitization are low, is suitable for all kinds of crowds, has children's microbiotic laudatory title.At present, the main dependence on import of the cefaclor of China, output in domestic is not high, and major cause is that to produce the technology of parent nucleus 7-ACCA of cefaclor immature, can not produce in enormous quantities, has restricted the development that cefaclor is produced.Prepare 7-ACCA mainly with 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-diphenylmethyl carboxylate or 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-carboxy acid mutual-nitro carbobenzoxy as initial feed.Existing preparation 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-diphenylmethyl carboxylate and 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-carboxy acid mutual-nitro carbobenzoxy's Technology, be the method transforming with penicilline g potassium ring expansion, a kind of is the method transforming with 7-APA transformation.
At application publication number, be that in the 7-ACCA preparation method described in the patent application of CN 103387584 A, the operational path from 3-hydroxy-cepham to 7-ACCA is as follows:
In this operational path, used the hazardous chemicals such as phosphorus trichloride, phosphorus pentachloride, environmental pollution is very large, large to safety in production pressure, severe reaction conditions.
Authorizing publication No., be that the 7-ACCA preparation method operational path described in the patent of CN 102220403 B is as follows:
In this operational path, in chlorination link, used triphosgene, but long reaction time, cost improves; Removing phenylacetyl link, used penicillin G acylase, but yield needs to improve.
Summary of the invention
Target of the present invention is to provide a kind of reaction conditions gentleness, safety, pollution is little, energy-conservation, yield is high, production cost the is low method of preparing 7-ACCA.
Method of the present invention comprises the following steps:
1. according to 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-diphenylmethyl carboxylate: the quality proportioning of dimethyl formamide: sulfur oxychloride: dimethyl sulfone=1:5-40:0.3-3:0.005-0.016, takes respectively material standby, the dimethyl formamide of 1/3rd dehydration is added in empty container, then add sulfur oxychloride, control temperature at 0-30 ℃, stir 0.5-2 hour, the dimethyl formamide of remaining 2/3rds dehydration is added to another empty container, add again 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-diphenylmethyl carboxylate, add dimethyl sulfone simultaneously, control temperature at 20-25 ℃, stirring and dissolving, then the dimethyl formamide preparing and sulfur oxychloride solution are added to this solution above, stir and control temperature at 0-30 ℃, after stirring reaction 2-8 hour, add frozen water cooling, obtain the chloro-3-cephalo ring-4-of 7-phenylacetylamino-3-diphenylmethyl carboxylate solid, filter and use a small amount of clear water to clean, then vacuum-drying.
This step, also can be according to 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-diphenylmethyl carboxylate: the quality proportioning of dimethyl formamide: sulfur oxychloride: dimethyl sulfone=1:5-40:0.3-3:0.005-0.016, first the dimethyl formamide of whole dehydrations and sulfur oxychloride are added in empty container, control temperature at 0-30 ℃, stir 0.5-2 hour, add again dimethyl sulfone, add 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-diphenylmethyl carboxylate simultaneously, stir and control temperature at 0-30 ℃, after stirring reaction 2-8 hour, add frozen water cooling, obtain the chloro-3-cephalo ring-4-of 7-phenylacetylamino-3-diphenylmethyl carboxylate solid, filter and use a small amount of clear water to clean, then vacuum-drying.
2. according to the chloro-3-cephalo ring-4-of 7-phenylacetylamino-3-diphenylmethyl carboxylate: the quality proportioning of p-cresol=1:2-10, the chloro-3-cephalo ring-4-of 7-phenylacetylamino-3-diphenylmethyl carboxylate is added in empty container, add again p-cresol, keep temperature 45-50 ℃, stir after 0.5-2 hour, according to the chloro-3-cephalo ring-4-of 7-phenylacetylamino-3-diphenylmethyl carboxylate: the mass ratio of ethyl acetate: 5% sodium hydrogen carbonate solution=1:5-15:10-30 adds ethyl acetate and the extraction of 5% sodium hydrogen carbonate solution, the water layer that extraction is obtained is again according to the chloro-3-cephalo ring-4-of 7-phenylacetylamino-3-diphenylmethyl carboxylate: the mass ratio of ethyl acetate=1:10-20, be extracted with ethyl acetate three times, then according to the chloro-3-cephalo ring-4-of 7-phenylacetylamino-3-diphenylmethyl carboxylate: ethyl acetate: the mass ratio of 2 equivalent concentration aqueous hydrochloric acid=1:5-15:0.2-0.5, in the aqueous solution of extraction, add ethyl acetate and 2 centinormal 1 aqueous hydrochloric acids, be uniformly mixed liquid, collected organic layer carries out vacuum concentration, then in concentrated solution, add diethyl ether, obtain the chloro-3-cephalo ring-4-of 7-phenylacetylamino-3-carboxylic acid solid, filter, with diethyl ether, wash, dry.
3. prepare respectively 3mL/L ammonia soln, 5mol/L aqueous hydrochloric acid, 0.05mol/L boric acid aqueous solution standby, according to the chloro-3-cephalo ring-4-of 7-phenylacetylamino-3-carboxylic acid: immobilized penicillin G acylase IPA-750: the quality proportioning of boric acid aqueous solution=1:0.65-1:12-18, in empty container, add 0.05mol/L boric acid aqueous solution, with 3mL/L ammonia soln adjust pH to 7.8, add 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-carboxylic acid, stir, then add immobilized penicillin G acylase IPA-750, control temperature at 28 ℃, stir and drip 3mL/L ammonia soln, adjusting rate of addition makes pH value remain on 8.0, until drip the speed of ammonia soln, be adjusted into zero and pH value remains on 8.0 when constant, reaction finishes, filtered and recycled immobilized penicillin G acylase IPA-750, according to the stop buffer after filtering: the volume ratio of methyl alcohol=5:4 adds methyl alcohol, stirs, and ice bath is cooled to 0～10 ℃, with 6 mol/ L aqueous hydrochloric acids, regulate pH value to 4.5-3.5, crystallization 3 hours, then filtration, vacuum-drying, obtain 7-amino-3-hydroxyl-3-cephalo ring-4-carboxylic acid.
The operational path of the method for preparing 7-ACCA provided by the invention is as follows:
The preparation method of 7-ACCA provided by the invention, the hazardous and noxious substances such as use chlorine, phosphorus pentachloride have been avoided, reaction process is at normal temperature or close to carrying out under normal temperature condition, and reaction conditions is gentle, and the reaction times is shorter, raw materials used being easy to obtains, with low cost, pollute little, save energy, yield is high, is applicable to suitability for industrialized production.
Embodiment
Example 1:
At 20-25 ℃ of temperature, in empty container, add the dimethyl formamide of 60mL dehydration, then add 7g sulfur oxychloride, control temperature at 25-30 ℃, stir one hour, then dimethyl formamide and 18g 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-diphenylmethyl carboxylate of 120mL dehydration are added to another empty container, control temperature at 20-25 ℃, stirring and dissolving, the dimethyl formamide preparing above and sulfur oxychloride solution are added to this solution, add 168mg dimethyl sulfone simultaneously, cooling down, control temperature at 25 ℃, stir 6 hours, add 1.5 liters of frozen water coolings, to isolated solid filtering, with a small amount of clear water, rinse, then vacuum-drying, obtain the chloro-3-cephalo ring-4-of 17.36g 7-phenylacetylamino-3-diphenylmethyl carboxylate.
By the chloro-3-cephalo ring-4-of the 17.36g 7-phenylacetylamino-3-diphenylmethyl carboxylate making, 90mL p-cresol adds empty container, control temperature at 45-50 ℃, stirring reaction 1 hour, add 180mL ethyl acetate and 360mL 5% sodium bicarbonate aqueous solution extraction, the water layer of extraction is extracted three times by 260mL ethyl acetate again, in the aqueous solution of extraction, add 180mL ethyl acetate and the centinormal 1 aqueous hydrochloric acid of 5mL 2, be uniformly mixed liquid, collected organic layer carries out vacuum concentration, then in concentrated solution, add 260mL diethyl ether, to the solid filtering obtaining, with diethyl ether, wash, dry, obtain the chloro-3-cephalo ring-4-of 10.92g7-phenylacetylamino-3-carboxylic acid.
Prepare respectively 3mol/L ammonia soln, 5mol/L aqueous hydrochloric acid, 0.05mol/L boric acid aqueous solution standby; In empty container, add 160mL0.05mol/L boric acid aqueous solution, with 3mol/L ammonia soln adjust pH to 7.8, then the 10.92g7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-carboxylic acid that adds preparation, stir, then add 7.5g immobilized penicillin G acylase IPA-750, control temperature at 28 ℃, stir and drip 3mL/L ammonia soln, adjusting rate of addition makes pH value remain on 8.0, until drip the speed of 3mL/L ammonia soln, be adjusted into zero and pH value remains on 8.0 when constant, reaction finishes, filtered and recycled immobilized penicillin G acylase; According to the stop buffer after filtering: the volume ratio of methyl alcohol=5:4 adds methyl alcohol, stirs, and ice bath is cooled to 0～10 ℃, with 6 mol/ L aqueous hydrochloric acids, regulate pH value to 4.5-3.5, crystallization 3 hours, then filtration, vacuum-drying, obtain 6.57g 7-amino-3-hydroxyl-3-cephalo ring-4-carboxylic acid.
Example 2:
At 20-25 ℃ of temperature, in empty container, add 2000mL dehydration dimethyl formamide, at room temperature add 78g sulfur oxychloride, control temperature at 30 ℃, stir one hour, then add 1900mg dimethyl sulfone and 200g 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-diphenylmethyl carboxylate, control temperature at 25 ℃, stir 7 hours, add 15 liters of frozen water, to isolated solid filtering, with a small amount of clear water, rinse, then vacuum-drying, obtains the chloro-3-cephalo ring-4-of 184.26g 7-phenylacetylamino-3-diphenylmethyl carboxylate.
By the chloro-3-cephalo ring-4-of the 184.26g 7-phenylacetylamino-3-diphenylmethyl carboxylate making, 960mL p-cresol adds empty flask, control temperature at 45-50 ℃, stirring reaction half an hour, add 1900mL ethyl acetate and 3800mL 5% sodium bicarbonate aqueous solution extraction, the water layer of extraction is extracted three times by 2760mL ethyl acetate again, in the aqueous solution of extraction, add 1900mL ethyl acetate and the centinormal 1 aqueous hydrochloric acid of 55mL 2, be uniformly mixed liquid, collected organic layer carries out vacuum concentration, then in concentrated solution, add 2760mL diethyl ether, to the solid filtering obtaining, with diethyl ether, wash, dry, obtain the chloro-3-cephalo ring-4-of 112.44g7-phenylacetylamino-3-carboxylic acid.
Prepare respectively 3mol/L ammonia soln, 5mol/L aqueous hydrochloric acid, 0.05mol/L boric acid aqueous solution standby; In empty flask, add 1700mL0.05mol/L boric acid aqueous solution, with 3mol/L ammonia soln adjust pH to 7.8, then the 112.44g 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-carboxylic acid that adds preparation, stir, then add 78g immobilized penicillin G acylase IPA-750, control temperature at 28 ℃, stir and drip 3mL/L ammonia soln, adjusting rate of addition makes pH value remain on 8.0, until drip the speed of 3mL/L ammonia soln, be adjusted into zero and pH value remains on 8.0 when constant, reaction finishes, filtered and recycled immobilized penicillin G acylase; According to the stop buffer after filtering: the volume ratio of methyl alcohol=5:4 adds methyl alcohol, stirs, and ice bath is cooled to 0～10 ℃, with 6 mol/ L aqueous hydrochloric acids, regulate pH value to 4.5-3.5, crystallization 3 hours, then filtration, vacuum-drying, obtain 72.56g7-amino-3-hydroxyl-3-cephalo ring-4-carboxylic acid.
Claims (4)
1. a method of preparing 7-ACCA, comprises the following steps:
Step 1: 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-diphenylmethyl carboxylate (II) reacts with dimethyl formamide and sulfur oxychloride, the dimethyl sulfone of dehydration; obtain 7-phenylacetylamino-3-chloro-3-cephalo ring-4-diphenylmethyl carboxylate (III); after having reacted; cooling down; to the chloro-3-cephalo ring-4-of the 7-phenylacetylamino-3-obtaining diphenylmethyl carboxylate solid filtering; and with a small amount of clear water, clean then vacuum-drying;
Step 2: 7-phenylacetylamino-3-chloro-3-cephalo ring-4-diphenylmethyl carboxylate (III) removes diphenyl-methyl with p-cresol, obtain 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid (IV), after having reacted, extraction, concentrated, crystallization, filter, be dried crystal;
Step 3: 7-phenylacetylamino-3-chloro-3-cephalo ring-4-carboxylic acid (IV) is used immobilized penicillin G acylase IPA-750; remove phenylacetyl; obtain product 7-ACCA (I), after having reacted, crystallization, filtration, vacuum-drying.
2. preparation method according to claim 1, it is characterized in that, in step 1, materials quality proportioning is: 7-phenylacetylamino-3-hydroxyl-3-cephalo ring-4-diphenylmethyl carboxylate: the dimethyl formamide of dehydration: sulfur oxychloride: dimethyl sulfone=1:5-40:0.3-3:0.005-0.016, temperature of reaction is 0-30 ℃, and the reaction times is 2-8 hour.
3. preparation method according to claim 1, it is characterized in that, in step 2, materials quality proportioning is: the chloro-3-cephalo ring-4-of 7-phenylacetylamino-3-diphenylmethyl carboxylate: p-cresol=1:2-10, temperature of reaction is 45-50 ℃, and the reaction times is 0.5-2 hour.
4. preparation method according to claim 1, is characterized in that, in step 3, reaction is carried out in rare boric acid aqueous solution, and the concentration of boric acid aqueous solution is 0.05mol/L; Materials quality proportioning is: the chloro-3-cephalo ring-4-of 7-phenylacetylamino-3-carboxylic acid: immobilized penicillin G acylase IPA-750: boric acid aqueous solution=1:0.65-1:12-18; During reaction, continuing to add concentration is that the ammoniacal liquor of 5mol/L is controlled pH value at 7.8-8.2, and temperature of reaction is 26-34 ℃, reaction times 1-2 hour.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104725425A (en) * | 2015-04-09 | 2015-06-24 | 山东罗欣药业集团股份有限公司 | Preparation method for ceftaroline fosamil |
| CN109266713A (en) * | 2018-11-12 | 2019-01-25 | 齐鲁安替制药有限公司 | A kind of preparation method suitable for industrial Cefaclor |
| CN111979287A (en) * | 2020-09-21 | 2020-11-24 | 湖北凌晟药业有限公司 | Preparation method of 7-phenylacetylamino-3-nor-3-cephem-4-carboxylic acid |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103387584A (en) * | 2013-07-17 | 2013-11-13 | 盐城开元医药化工有限公司 | Synthetic method of 7-amino-3-chloro-3-cephem-4-carboxylic acid |
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- 2013-12-25 CN CN201310723331.3A patent/CN103694257A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103387584A (en) * | 2013-07-17 | 2013-11-13 | 盐城开元医药化工有限公司 | Synthetic method of 7-amino-3-chloro-3-cephem-4-carboxylic acid |
Non-Patent Citations (2)
| Title |
|---|
| 张越等: "3-氯头孢烯酸的合成", 《精细化工》, vol. 22, no. 2, 28 February 2005 (2005-02-28) * |
| 白金龙: "7-AVCA与7-ACCA的合成工艺研究", 《中国优秀硕士学位论文全文数据库工程科技Ⅰ辑》, 15 August 2010 (2010-08-15) * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104725425A (en) * | 2015-04-09 | 2015-06-24 | 山东罗欣药业集团股份有限公司 | Preparation method for ceftaroline fosamil |
| CN104725425B (en) * | 2015-04-09 | 2017-01-04 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of Ceftaroline Fosamil |
| CN109266713A (en) * | 2018-11-12 | 2019-01-25 | 齐鲁安替制药有限公司 | A kind of preparation method suitable for industrial Cefaclor |
| CN111979287A (en) * | 2020-09-21 | 2020-11-24 | 湖北凌晟药业有限公司 | Preparation method of 7-phenylacetylamino-3-nor-3-cephem-4-carboxylic acid |
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Application publication date: 20140402 |