CN108440567A - A kind of new synthetic method of Cefprozil - Google Patents
A kind of new synthetic method of Cefprozil Download PDFInfo
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- CN108440567A CN108440567A CN201810287720.9A CN201810287720A CN108440567A CN 108440567 A CN108440567 A CN 108440567A CN 201810287720 A CN201810287720 A CN 201810287720A CN 108440567 A CN108440567 A CN 108440567A
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- cefprozil
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- phpg
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- alkali
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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
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, 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
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention belongs to pharmaceutical synthesis preparing technical fields, and in particular to a kind of new Cefprozil synthesis preparation method patent application.This method technical thought is：In aprotic solvent, to acyl Ammonia parent nucleus in β（7 amino 3（The third 1 alkenyls of Z）4 cephalosporanic acids）Alkali substitution reaction is carried out, branch D D-pHPG derivatives are then added and carry out condensation reaction to prepare Cefprozil.In general, preparation method provided herein, reaction raw materials are easy to get, and reaction condition is mildly easy to control；Main material residual is relatively low after reaction, the cost pressure that main material is brought can be greatly lowered, and Cefprozil yield is higher；This method process route is relatively simple simultaneously, only two-step reaction can be obtained high-quality Cefprozil product, it generally can preferably overcome in existing Cefprozil preparation method that yield is relatively low, unstable quality defect, there is preferable practical value and production to promote and apply meaning.
Description
Technical field
The invention belongs to pharmaceutical synthesis preparing technical fields, and in particular to a kind of new Cefprozil synthesis preparation method is special
Profit application.
Background technology
Cefprozil（Cefprozil), chemical name is：(6R, 7R) -7 [(R) -2- amino -2-（To hydroxy-pheny）Second
Acylamino-] -8- oxo -3- propylene -5- thia -1- azabicyclos -（4,2,0）- 2 carboxylic acids of oct-2-ene-hydrate, molecular formula:
C18H19N3O5S·H2O.Cefprozil is second generation cephalosporin class antibiotic, has broad-spectrum antibacterial action, in children market
It is upper that there are preferable security advantages, thus application is relatively broad.
The preparation process route of existing Cefprozil is mainly：D-pHPG dane potassium salts generate Deng with pivaloyl chloride
Sylvite acid anhydrides, then with 7- amino -3-（1 alkenyl of Z- propyl-s）- 4- cephalosporanic acids react, and generate 7-【2- M Crs-amino-
2-（To hydroxy-pheny）Acetylamino】- 8- oxo -3- acrylic -5- thia -1- azabicyclo -2- alkene -2- carboxylic acids, further
It after sour water solution, is added dropwise in n,N-Dimethylformamide, prepares hydrate Cefprozil, specific synthetic route is shown
Meaning is as follows：
。
Although the process route is using more universal, it can be found that 7- amino -3- in final product in actual production
（1 alkenyl of Z- propyl-s）- 4- cephalosporanic acids residual is often higher, causes the yield of final Cefprozil relatively low, while also making final head
The quality of spore propylene can not be effectively ensured, thus it is necessary to further improve or inquire into for the preparation process pole of Cefprozil
New preparation process.
Invention content
The application is designed to provide a kind of new Cefprozil synthetic method, so as to partly solve existing cephalo third
The lower defect of yield in alkene preparation process.
Details are as follows for the technical solution that the application is taken.
A kind of Cefprozil new synthetic method, technical thought are：In aprotic solvent, to the interior acyl Ammonia parent nucleus of β-
（7- amino -3-（1 alkenyl of Z- propyl-s）- 4- cephalosporanic acids）Alkali substitution reaction is carried out, then carries out condensation reaction to prepare cephalo
Propylene specifically comprises the following steps：
（One）Alkali substitution reaction
In aprotic solvent, under the conditions of -70 ~ 0 DEG C（It is preferred that under the conditions of -40 ~ 0 DEG C）, beta-lactam parent nucleus 7- amino-is added
3-（1 alkenyl of Z- propyl-s）- 4- cephalosporanic acids（Compound（1））, big steric hindrance Ammonia non-nucleophilic alkali is then slowly added dropwise, carries out alkali
Substitution reaction is reacted after basic dissolved clarification and is terminated, prepares compound（3）；
With molar ratio computing, beta-lactam parent nucleus：Non- compatibility alkali=1:1.05~1.3；
The aprotic solvent is dichloromethane, dichloroethanes, DMF, DMAC, acetone, THF, stupid, toluene, ethyl acetate, acetonitrile
Middle one or more arbitrary proportion mixture；
The big steric hindrance Ammonia non-nucleophilic alkali is：11 carbon -7- alkene of 1,8- diazabicylos, lithium diisopropylamine or N, N-
Diisopropylethylamine, it is preferred to use 1,8- diazabicylo, 11 carbon -7- alkene；
- 7 alkene of 11 carbon of 1,8- diazabicylos is used with big steric hindrance Ammonia non-nucleophilic alkali（Compound（2））For, react road
Line is schematically as follows：
。
（Two）Condensation reaction
Under the conditions of -80 ~ 0 DEG C（It is preferred that under the conditions of -60 ~ -30 DEG C）, by step（One）Middle gained dissolved clarification liquid is with branch D- to hydroxyl
Base phenylglycine derivatives mix, and are reacted 3 ~ 5 hours under clear state；
With molar ratio computing, compound（3）Burden control with D-pHPG derivative is 1:1.02 ~ 1.05 are advisable,
Derivative object amount is easy to cause the raising of final products related substances when excessive, influence final product quality；
Under stirring, hydrochloric acid is added to 1 ~ 10mol concentration（It is preferred that 5mol concentration）It is extracted（This process, that is, sour water solution, is answered
Ensure hydrolysis completely and walk before can neutralizing to react excessive alkali）, pH to 3.5 ~ 6.5 is adjusted, crystallization precipitation is carried out, will be precipitated
Crystallization be filtered, be prepared Cefprozil after being dried under reduced pressure（Compound（5））；
The branch D-pHPG derivative is：D-pHPG glycol ester, D-pHPG first
Ester, D-pHPG ethyl ester or D-pHPG are acylated ester, it is preferred to use D-pHPG glycol ester；
NH is used when adjusting pH3Or organic base carry out pH adjustings, adjust pH the purpose of be that solution ph is made to be consistent with substance isoelectric point,
Consequently facilitating crystallization is precipitated；
D-pHPG glycol ester is used with branch D-pHPG derivative（Compound（4））For, tool
Precursor reactant route is schematically as follows：
。
It is to help with non-nucleophilic alkali in the presence of non-protonic solvent in Cefprozil synthetic method provided herein
Solvent, first to beta-lactam parent nucleus（7- amino -3-（1 alkenyl of Z- propyl-s）- 4- cephalosporanic acids）Dissolving modification is carried out, then
With side chain D-pHPG esters（Branch D-pHPG esters）Condensation, to obtain high-quality cephalo third
Alkene.
In general, preparation method provided herein, reaction raw materials are easy to get, and reaction condition is mildly easy to control；Instead
Main material residual is relatively low after answering, and the cost pressure that main material is brought can be greatly lowered, and Cefprozil yield is higher；
This method process route is relatively simple simultaneously, and only two-step reaction can be obtained high-quality Cefprozil product, generally can be preferable
Overcome in existing Cefprozil preparation method that yield is relatively low, unstable quality defect, there is preferable practical value and production to push away
Wide application value.
Specific implementation mode
Explanation is further explained to the application with reference to specific embodiment.
Embodiment 1
The Cefprozil synthetic method that the present embodiment is provided, specific steps are described below.
（One）Alkali substitution reaction
Using dichloromethane as aprotic solvent, dichloromethane 95ml is added in the reactor of a drying, beta-lactam is added
Class parent nucleus 7- amino -3-（1 alkenyl of Z- propyl-s）Under the conditions of -30 DEG C, the big non-parent of steric hindrance Ammonia is slowly added dropwise in -4- cephalosporanic acids 10g
Nuclearity alkali 1, -7 alkene 6.4g of 11 carbon of 8- diazabicylos carry out alkali substitution reaction, are stirred to react until dissolved clarification.
（Two）Condensation reaction
- 30 DEG C of conditions are kept, in step（One）Branch D-pHPG derivative is slowly added dropwise in middle gained dissolved clarification liquid
D-pHPG glycol ester 14.2ml, the reaction was complete（HPLC detects noresidue）Afterwards（It takes around 4 hours or so）, add
Enter 5mol HCL extractions, leads to NH3PH to 5.0 or so is adjusted, crystallization is precipitated, is dried under reduced pressure after crystallization is filtered, cephalo of weighing to obtain
Propylene dry product about 13.4g（Calculation shows that molar yield 68.44%）.
Embodiment 2
The there is provided Cefprozil preparation method of the present embodiment is same as Example 1, and only adjustment member parameter is as follows：
Step（One）In, it is lithium diisopropylamine, dosage 4.7g to adjust big steric hindrance Ammonia non-nucleophilic alkali；It is final to obtain head
Spore propylene product about 13.2g（Calculation shows that molar yield 67.42%）.
Embodiment 3
The there is provided Cefprozil preparation method of the present embodiment is same as Example 1, and only adjustment member parameter is as follows：
Step（One）In, it is n,N-diisopropylethylamine, dosage 5.4g to adjust big steric hindrance Ammonia non-nucleophilic alkali；
Step（Two）In, pH to 5.0 or so is adjusted using triethylamine, crystallization is precipitated, it is final to obtain Cefprozil finished product about 13.2g
（Calculation shows that molar yield 67.42%）.
Claims (7)
1. a kind of new synthetic method of Cefprozil, which is characterized in that specifically comprise the following steps：
（One）Alkali substitution reaction
In aprotic solvent, beta-lactam parent nucleus 7- amino -3- is added（1 alkenyl of Z- propyl-s）- 4- cephalosporanic acids, -70 ~ 0
Under the conditions of DEG C, big steric hindrance Ammonia non-nucleophilic alkali is added, carries out alkali substitution reaction；
With molar ratio computing, beta-lactam parent nucleus：Non- compatibility alkali=1:1.05~1.3；
The aprotic solvent is dichloromethane, dichloroethanes, DMF, DMAC, acetone, THF, stupid, toluene, ethyl acetate, acetonitrile
Middle one or more arbitrary proportion mixture；
The big steric hindrance Ammonia non-nucleophilic alkali is：11 carbon -7- alkene of 1,8- diazabicylos, lithium diisopropylamine or N, N-
Diisopropylethylamine；
（Two）Condensation reaction
Under the conditions of -80 ~ 0 DEG C, in step（One）Reaction solution in be added branch D-pHPG derivative, reaction 3 ~
5 hours, after, hydrochloric acid is added and is extracted, then adjusts pH to 3.5 ~ 6.5, carries out crystallization precipitation, the crystallization that will be precipitated
It is filtered, is prepared Cefprozil after being dried under reduced pressure；
The branch D-pHPG derivative is：D-pHPG glycol ester, D-pHPG first
Ester, D-pHPG ethyl ester or D-pHPG are acylated ester.
2. the new synthetic method of new Cefprozil as described in claim 1, which is characterized in that step（One）In, reaction condition
For：- 40 ~ 0 DEG C, the big steric hindrance Ammonia non-nucleophilic alkali is 1,8- diazabicylos, 11 carbon -7- alkene, and reaction route is：
。
3. the new synthetic method of Cefprozil as claimed in claim 1 or 2, which is characterized in that step（Two）In, reaction condition
For：- 60 ~ -30 DEG C, the branch D-pHPG derivative is：D-pHPG glycol ester reacts road
Line is：
。
4. the new synthetic method of Cefprozil as claimed in claim 1 or 2, which is characterized in that step（Two）In, it is used when adjusting pH
NH3Or organic base is adjusted.
5. the new synthetic method of Cefprozil as claimed in claim 1 or 2, which is characterized in that step（One）In, each material and use
Amount is：
The aprotic solvent is dichloromethane, dosage 95ml；Beta-lactam parent nucleus 7- amino -3-（1 alkenyl of Z- propyl-s）-
4- cephalosporanic acids, dosage 10g；Big steric hindrance Ammonia non-nucleophilic alkali is -7 alkene of 1,8- diazabicylos, 11 carbon, and dosage is
6.4g。
6. the new synthetic method of Cefprozil as claimed in claim 1 or 2, which is characterized in that step（One）In, each material and use
Amount is：
The aprotic solvent is dichloromethane, dosage 95ml；Beta-lactam parent nucleus 7- amino -3-（1 alkenyl of Z- propyl-s）-
4- cephalosporanic acids, dosage 10g；Big steric hindrance Ammonia non-nucleophilic alkali is lithium diisopropylamine, dosage 4.7g.
7. the new synthetic method of Cefprozil as claimed in claim 1 or 2, which is characterized in that step（One）In, each material and use
Amount is：
The aprotic solvent is dichloromethane, dosage 95ml；Beta-lactam parent nucleus 7- amino -3-（1 alkenyl of Z- propyl-s）-
4- cephalosporanic acids, dosage 10g；Big steric hindrance Ammonia non-nucleophilic alkali is n,N-diisopropylethylamine, dosage 5.4g.
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| CN201810287720.9A CN108440567A (en) | 2018-04-03 | 2018-04-03 | A kind of new synthetic method of Cefprozil |
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| CN201810287720.9A CN108440567A (en) | 2018-04-03 | 2018-04-03 | A kind of new synthetic method of Cefprozil |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102030762A (en) * | 2010-12-02 | 2011-04-27 | 苏州致君万庆药业有限公司 | Preparation method of cefprozil |
| CN104193766A (en) * | 2014-08-27 | 2014-12-10 | 庄妍 | Method for preparing cefetamet acid |
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2018
- 2018-04-03 CN CN201810287720.9A patent/CN108440567A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102030762A (en) * | 2010-12-02 | 2011-04-27 | 苏州致君万庆药业有限公司 | Preparation method of cefprozil |
| CN104193766A (en) * | 2014-08-27 | 2014-12-10 | 庄妍 | Method for preparing cefetamet acid |
Non-Patent Citations (1)
| Title |
|---|
| 吴明书，等: "头孢丙烯原料药的合成工艺", 《科技展望》 * |
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Application publication date: 20180824 |