CN101058584A - Method of preparing cefprozil parent nucleus 7-amino-3-propenylcephalosporanic acid - Google Patents
Method of preparing cefprozil parent nucleus 7-amino-3-propenylcephalosporanic acid Download PDFInfo
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- CN101058584A CN101058584A CN 200710093818 CN200710093818A CN101058584A CN 101058584 A CN101058584 A CN 101058584A CN 200710093818 CN200710093818 CN 200710093818 CN 200710093818 A CN200710093818 A CN 200710093818A CN 101058584 A CN101058584 A CN 101058584A
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Abstract
The invention discloses a new making method of cepham propone parent nucleus 7-amino-3-propenyl cepham alkyl acid (7-APCA), which comprises the following steps: reacting 7-ACA(2) protected by silicane and substituted by iodine with triphenylphosphor in the solvent during -10-120 deg. c; obtaining the compound (3); reserving the compound (3) in the alkaline metal salt; reacting the compound (3) and acetaldehyde to obtain the compound (4); crystallizing the compound (4) through removing the protector; obtaining the product to synthesize the cepham propone.
Description
Technical field
The present invention relates to the novel method of a kind of preparation Prozef parent nucleus 7-amino-3-propenylcephalosporaacid acid (7-APCA), structure is shown in (1).Described Prozef parent nucleus is the raw material that is used to prepare Prozef.
Background technology
Prozef (Cefprozil) chemical name is (6R, 7R)-7-(R)-2-amino-2-(p-hydroxybenzene) acetylaminohydroxyphenylarsonic acid 8-oxo-3-(1-propenyl)-5-thia-1-azabicyclo (4.2.0) oct-2-ene-2-carboxylic acid monohydrate, be s-generation oral cephalosporin, have broad-spectrum antibacterial action.
At present, the method for the synthetic 7-APCA that has reported is to adopt the GCLE route substantially, as U.S. Pat 4694079, US2004132992, Chinese patent publication number CN1694888 etc.Synthetic route is as follows:
Is the synthetic 7-APCA of raw material with GCLE, synthesis yield is all on the low side, and the mol yield and exists synthesis step long about 60%, shortcoming such as more than complicated operation and the three waste discharge.
Summary of the invention
The purpose of this invention is to provide the novel method that a kind of yield is higher, cost is lower, operational path simply synthesizes 7-APCA, raw materials used 7-ACA is cheap, the domestic market is in liberal supply.Solving GCLE higher with price at present, that the source of goods lacks is that raw material synthesizes 7-APCA, and the yield that technology exists is on the low side, and cost is higher, problems such as quality instability.
Technical solution of the present invention is: the novel method of a kind of preparation Prozef parent nucleus 7-amino-3-propenylcephalosporaacid acid [7-APCA (1)].
May further comprise the steps:
(i) in the presence of solvent, in-10～120 ℃ of scopes, 7-amino-cephalosporanic acid [7-ACA (2)] is protected through silanization, iodine replaces, obtain compound (3), the i.e. trimethyl silicon based amino of 7--8-oxo-3-triphenyl phosphorus methylene radical-5-thia-1-azabicyclo (4.2.0) oct-2-ene-trimethyl silicon based ester of 2-carboxylic acid with the triphenyl phosphorus reaction;
(ii) compound (3) is in the presence of an alkali metal salt, carry out propylene reaction (Wittig reaction) with acetaldehyde, obtain compound (4), i.e. the trimethyl silicon based amino of 7--8-oxo-3-propenyl-5-thia-1-azabicyclo (4.2.0) oct-2-ene-trimethyl silicon based ester of 2-carboxylic acid;
(iii) to slough front three through deprotection agent silica-based for compound (4), and crystallization obtains purpose product 7-APCA (1).
Synthetic route through the synthetic 7-APCA of 7-ACA is as follows:
Employed solvent is meant methylene dichloride, ethylene dichloride, N in the step (i), dinethylformamide (DMF), N, N-diethylformamide (DMAC), dimethyl sulfoxide (DMSO) (DMSO), acetone, acetonitrile, ethyl acetate, propyl acetate, butylacetate, tetrahydrofuran (THF), benzene, toluene equal solvent, or any mixture of two or more solvent wherein.
Employed silanization protective material is meant trimethylchlorosilane, bromotrimethylsilane, Iodotrimethylsilane, hexamethyldisilazane (HMDS), hexamethyl two silicon ureas, N in the step (i); the two pivalyl amine of O-, the silica-based imidazoles of N-front three etc., or the mixture of two or more silanizing agent wherein.
Iodine replace to adopt Iodotrimethylsilane (iodine silane can the silanization protection, also can iodo).
An alkali metal salt of step described in (ii) is meant lithium chloride, lithiumbromide, lithium iodide, Lithium Sulphate, lithium nitrate, lithium formate, lithium acetate, sodium iodide, potassiumiodide etc.
The desiliconization alkanisation protectant method of step described in (iii) is meant and adopts the small-molecule substance that contains reactive hydrogen; the silica-based group from its protection of front three that replaces is escaped; the used reactive hydrogen small-molecule substance that contains is meant: methyl alcohol, ethanol, water, hydrochloric acid, sulfuric acid etc., or its mixture.
In the present invention, range of reaction temperature between-10～120 ℃, wherein the Silanization reaction temperature between-10～120 ℃, preferred 0～60 ℃; The iodine replacement reaches and triphenyl phosphorus salt-forming reaction temperature is-5～50 ℃, preferred 0～40 ℃; The propylene temperature of reaction is 0～50 ℃, preferred 5～40 ℃.
The invention has the beneficial effects as follows: the inventive method adopts the method for the treatment of different things alike from the synthetic 7-APCA of 7-ACA, can obtain in a step, and the compound that obtains in the reaction (3), compound (4) all need not separate and directly carry out next step reaction.Yield of the present invention is higher, cost is lower, operational path is simple, and raw materials used 7-ACA is cheap, the domestic market is in liberal supply.
Adopt the synthetic 7-APCA of 7-ACA than adopting the synthetic 7-APCA raw materials cost of GCLE can descend more than 30% at present, the economic benefit of being brought is conspicuous.
Embodiment
Following examples are detailed description of the invention, but the invention is not restricted to following examples.
Embodiment 1:
Under step 1 room temperature; in the dry reaction bottle, add 7-ACA 12g, methylene dichloride 100ml, hexamethyldisilazane (HMDS) 10g; trimethylchlorosilane 1ml; under the nitrogen protection, be warming up to 40-55 ℃, refluxed 7～8 hours; when detection backflow tail gas does not almost have ammonia to overflow; stop to reflux, be cooled to 0～5 ℃, obtain the silanization solution of 7-ACA.Add triphenyl phosphorus 13.5g in the reaction solution, added Iodotrimethylsilane 11.5g at about 10 minutes, temperature must not be higher than 5 ℃.Finish, 5-10 ℃ of insulation reaction 3～5 hours, sampling detected the residual 0.5g/L (HPLC) that is less than of 7-ACA, and reaction finishes, and is cooled to-5～0 ℃, obtains the mixed solution of compound (3).
Step 2 adds DMF87ml in the mixing solutions of the compound (3) that step 1 obtains, 0～2 ℃ of temperature control adds Lithium chloride (anhydrous) 2.6g, stirs 15 minutes.Add anhydrous acetaldehyde 10.1ml, reinforced process temperature is controlled at-2～2 ℃, keeps this thermotonus 14～16 hours, the residual 3g/L (HPLC) that is less than of detection compound (3), and reaction finishes, and obtains the mixed solution of compound (4).
The mixed solution of the compound that step 3 obtains step 2 (4) carries out vacuum distilling, removes methylene dichloride, and distillation temperature is controlled at below 50 ℃, and distillation finishes, and reduces to room temperature, adds gac 5g, stirs 30 minutes, filters.Filtrate adds methyl alcohol 100ml, is warming up to 35～40 ℃, and insulated and stirred 30 minutes is cooled to 0～5 ℃, stirs 1 hour, filters, and uses the 50ml methanol wash.35 ℃ of vacuum-drying 7～8 hours obtains 7-APCA9.8g, purity 95% (HPLC is suitable/anti-=92.5/7.5).Yield 77%.
Embodiment 2:
Under step 1 room temperature, add 7-ACA12g in the dry reaction bottle, methylene dichloride 100ml is cooled to 0～5 ℃, adds, and triphenyl phosphorus 13.5g in about 10 minutes, adds Iodotrimethylsilane 33g, and temperature must not be higher than 5 ℃.Finish, 5-10 ℃ of insulation reaction 3～5 hours, sampling detected the residual 0.5g/L (HPLC) that is less than of 7-ACA, and reaction finishes, and is cooled to-5～0 ℃, obtains the mixed solution of compound (3).
Subsequent operations comes to the same thing with embodiment one.
Embodiment 3:
Step 1, step 2 are with embodiment 1.
The mixed solution of the compound that step 3 obtains step 2 (4) carries out vacuum distilling, removes methylene dichloride, and distillation temperature is controlled at below 50 ℃, and distillation finishes, and reduces to room temperature, adds gac 5g, stirs 30 minutes, filters.Filtrate adds entry 400ml, is warming up to 35～40 ℃, and insulated and stirred 30 minutes is cooled to 0～5 ℃, stirs 1 hour, filters, with 50ml water and 100ml washing with acetone.35 ℃ of vacuum-drying 7～8 hours obtains 7-APCA10.2g, purity 95.5% (HPLC is suitable/anti-=92.5/7.5).Yield 78%.
Embodiment 4:
Step 1 is with embodiment 2, and step 2 is with embodiment 1, and step 3 is with embodiment 3, and the result is identical with embodiment 3.
Embodiment 5: an alkali metal salt that adds in the step 2 is a Lithium Sulphate, and all the other are with embodiment 1.
Embodiment 6: the deprotection agent in the step 3 is ethanol and a hydrochloric acid mixture in proportion, and all the other are with embodiment 1.
Embodiment 7: solvent is selected DMAC and acetone mixture in proportion for use in the step 1, and all the other are with embodiment 1.
Embodiment 8: the silanization protective material is N in the step 1, the mixture of the two pivalyl amine of O-, the silica-based imidazoles of N-front three, and all the other are with embodiment 1.
Claims (10)
1, a kind of method for preparing Prozef parent nucleus 7-amino-3-propenylcephalosporaacid acid is characterized in that may further comprise the steps:
A, in the presence of solvent, in-10～120 ℃ of scopes, 7-amino-cephalosporanic acid is protected through silanization, iodine replaces, and obtains the trimethyl silicon based amino of 7--8-oxo-3-triphenyl phosphorus methylene radical-5-thia-1-azabicyclo (4.2.0) oct-2-ene-trimethyl silicon based ester of 2-carboxylic acid with the triphenyl phosphorus reaction;
The trimethyl silicon based amino of b, 7--8-oxo-3-triphenyl phosphorus methylene radical-5-thia-1-azabicyclo (4.2.0) oct-2-ene-trimethyl silicon based ester of 2-carboxylic acid is in the presence of an alkali metal salt, carry out the propylene reaction with acetaldehyde, obtain the trimethyl silicon based amino of 7--8-oxo-3-propenyl-5-thia-1-azabicyclo (4.2.0) oct-2-ene-trimethyl silicon based ester of 2-carboxylic acid;
It is silica-based that the trimethyl silicon based amino of c, 7--8-oxo-3-propenyl-5-thia-1-azabicyclo (4.2.0) oct-2-ene-the trimethyl silicon based ester of 2-carboxylic acid is sloughed front three through deprotection agent, and crystallization obtains purpose product 7-amino-3-propenylcephalosporaacid acid.
2, a kind of method for preparing Prozef parent nucleus 7-amino-3-propenylcephalosporaacid acid according to claim 1, it is characterized in that, employed solvent is meant methylene dichloride, ethylene dichloride, N among the step a, dinethylformamide, N, a kind of, the mixture of two or more solvent arbitrarily in N-diethylformamide, dimethyl sulfoxide (DMSO), acetone, acetonitrile, ethyl acetate, propyl acetate, butylacetate, tetrahydrofuran (THF), benzene, the toluene.
3, a kind of method for preparing Prozef parent nucleus 7-amino-3-propenylcephalosporaacid acid according to claim 1; it is characterized in that; employed silanization protective material is meant trimethylchlorosilane, bromotrimethylsilane, Iodotrimethylsilane, hexamethyldisilazane, hexamethyl two silicon ureas, N among the step a; the mixture of a kind of, two or more silanizing agent in the two pivalyl amine of O-, the silica-based imidazoles of N-front three, iodine replaces needs to add the reaction reagent Iodotrimethylsilane.
4, a kind of method for preparing Prozef parent nucleus 7-amino-3-propenylcephalosporaacid acid according to claim 1, it is characterized in that an alkali metal salt described in the step b is meant a kind of in lithium chloride, lithiumbromide, lithium iodide, Lithium Sulphate, lithium nitrate, lithium formate, lithium acetate, sodium iodide, the potassiumiodide.
5, a kind of method for preparing Prozef parent nucleus 7-amino-3-propenylcephalosporaacid acid according to claim 1; it is characterized in that; the deprotection of the deprotection agent described in the step c is meant; employing contains the small-molecule substance of reactive hydrogen; the silica-based group from its protection of front three that replaces is escaped, and the used reactive hydrogen small-molecule substance that contains is meant: a kind of or its two or more mixtures in methyl alcohol, ethanol, water, hydrochloric acid, the sulfuric acid.
6, a kind of method for preparing Prozef parent nucleus 7-amino-3-propenylcephalosporaacid acid according to claim 1 is characterized in that step a Silanization reaction temperature is between-10～120 ℃.
7, a kind of method for preparing Prozef parent nucleus 7-amino-3-propenylcephalosporaacid acid according to claim 6 is characterized in that step a Silanization reaction temperature is at 0～60 ℃.
8, a kind of method for preparing Prozef parent nucleus 7-amino-3-propenylcephalosporaacid acid according to claim 1 is characterized in that, the iodine replacement reaches and triphenyl phosphorus salt-forming reaction temperature is-5～50 ℃.
9, a kind of method for preparing Prozef parent nucleus 7-amino-3-propenylcephalosporaacid acid according to claim 8 is characterized in that, the iodine replacement reaches and triphenyl phosphorus salt-forming reaction temperature is 0～40 ℃.
10, a kind of method for preparing Prozef parent nucleus 7-amino-3-propenylcephalosporaacid acid according to claim 1 is characterized in that the propylene temperature of reaction is 5～40 ℃.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102443013A (en) * | 2010-10-10 | 2012-05-09 | 石药集团中奇制药技术（石家庄）有限公司 | Method for preparing cefprozil dimethyl formamide solvate |
| CN102911187A (en) * | 2012-10-11 | 2013-02-06 | 南通康鑫药业有限公司 | Recovery method of cefprozil |
| CN104844623A (en) * | 2015-05-22 | 2015-08-19 | 齐鲁安替制药有限公司 | Synthesis method of high-purity 7-amino-3-propylene-1-yl-3-cephem-4-carboxylic acid |
| CN105001238A (en) * | 2015-07-21 | 2015-10-28 | 河北九天生物制品有限公司 | Method for preparing cefprozil mother nucleus 7-amino-3-acryl cephalosporanic acid |
| CN108017658A (en) * | 2017-12-26 | 2018-05-11 | 山东裕欣药业有限公司 | A kind of synthetic method of Cefprozil |
| CN108017657A (en) * | 2017-12-26 | 2018-05-11 | 山东裕欣药业有限公司 | A kind of process for purification of Cefprozil |
| CN109232608A (en) * | 2018-11-14 | 2019-01-18 | 湖北凌晟药业有限公司 | A kind of preparation method of Cefprozil |
| CN110526964A (en) * | 2015-04-17 | 2019-12-03 | 南京济朗生物科技有限公司 | The quick non-invasive monitoring technology of women luteal function |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4694079A (en) * | 1985-07-29 | 1987-09-15 | Bristol-Myers Company | 3-propenyl cephalosporin solvates |
| US6903211B2 (en) * | 2002-10-30 | 2005-06-07 | Orchid Chemicals & Pharmaceuticals Limited | Process for the preparation of 3-propenyl cephalosporin DMF solvate |
-
2007
- 2007-05-23 CN CN200710093818A patent/CN101058584B/en not_active Expired - Fee Related
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102443013A (en) * | 2010-10-10 | 2012-05-09 | 石药集团中奇制药技术（石家庄）有限公司 | Method for preparing cefprozil dimethyl formamide solvate |
| CN102443013B (en) * | 2010-10-10 | 2014-09-17 | 石药集团中奇制药技术（石家庄）有限公司 | Method for preparing cefprozil dimethyl formamide solvate |
| CN102911187A (en) * | 2012-10-11 | 2013-02-06 | 南通康鑫药业有限公司 | Recovery method of cefprozil |
| CN102911187B (en) * | 2012-10-11 | 2015-03-11 | 南通康鑫药业有限公司 | Recovery method of cefprozil |
| CN110526964A (en) * | 2015-04-17 | 2019-12-03 | 南京济朗生物科技有限公司 | The quick non-invasive monitoring technology of women luteal function |
| CN104844623A (en) * | 2015-05-22 | 2015-08-19 | 齐鲁安替制药有限公司 | Synthesis method of high-purity 7-amino-3-propylene-1-yl-3-cephem-4-carboxylic acid |
| CN105001238B (en) * | 2015-07-21 | 2017-10-20 | 河北九天生物制品有限公司 | The method of the propenylcephalosporaacid acid of 7 amino of Cefprozil parent nucleus 3 processed |
| CN105001238A (en) * | 2015-07-21 | 2015-10-28 | 河北九天生物制品有限公司 | Method for preparing cefprozil mother nucleus 7-amino-3-acryl cephalosporanic acid |
| CN108017658A (en) * | 2017-12-26 | 2018-05-11 | 山东裕欣药业有限公司 | A kind of synthetic method of Cefprozil |
| CN108017657A (en) * | 2017-12-26 | 2018-05-11 | 山东裕欣药业有限公司 | A kind of process for purification of Cefprozil |
| CN108017657B (en) * | 2017-12-26 | 2020-05-19 | 山东裕欣药业有限公司 | Refining method of cefprozil |
| CN108017658B (en) * | 2017-12-26 | 2020-06-16 | 山东裕欣药业有限公司 | Synthesis method of cefprozil |
| CN109232608A (en) * | 2018-11-14 | 2019-01-18 | 湖北凌晟药业有限公司 | A kind of preparation method of Cefprozil |
| CN109232608B (en) * | 2018-11-14 | 2020-04-28 | 湖北凌晟药业有限公司 | Preparation method of cefprozil |
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Assignee: Weiqida Pharmaceutical Ind Co., Ltd. Assignor: Shanghai Junjie Biochemistry Technology Co., Ltd. Contract record no.: 2011990000264 Denomination of invention: Method of preparing cefprozil parent nucleus 7-amino-3-propenylcephalosporanic acid Granted publication date: 20100526 License type: Exclusive License Open date: 20071024 Record date: 20110415 |
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