CN108659008B - Application process of cefprozil mother liquor - Google Patents
Application process of cefprozil mother liquor Download PDFInfo
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- CN108659008B CN108659008B CN201810367881.9A CN201810367881A CN108659008B CN 108659008 B CN108659008 B CN 108659008B CN 201810367881 A CN201810367881 A CN 201810367881A CN 108659008 B CN108659008 B CN 108659008B
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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
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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
- C07D501/02—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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Abstract
The invention discloses a process for mechanically applying cefprozil mother liquor, which comprises the following steps of (1) adding saturated FeCl into cefprozil mother liquor3Regulating pH value of solution, and (2) reacting in cefprozil synthesisAdding the cefprozil mother liquor treated in the step (1) into a reaction solution, heating, stirring at a controlled temperature, standing, and separating; (3) cooling the aqueous phase layer after liquid separation in the step (2) to below-5 ℃, adding dimethylformamide at controlled temperature, adding acetone washing liquid, stirring, filtering, and collecting filtrate; (4) cooling the filtrate, dropwise adding ammonia water, adjusting the pH value, cooling, stirring, filtering, collecting a filter cake, washing with dimethylformamide, washing with acetone, and vacuum-drying to obtain a cefprozil crude product; and (5) refining the cefprozil crude product. The application process is simple, the operation is convenient, the use amount of dimethylformamide and acetone is greatly reduced, and the economic benefit and the environmental benefit are obvious.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a process for mechanically applying cefprozil mother liquor.
Background
Cefprozil (Cefprozil) chemical name: (6R,7R) -7 [ R) -2-amino-2- (p-hydroxy-phenyl) acetamido ] -8-oxo-3-propene-5-thia-1-azabicyclo- (4,2,0) oct-2-ene-2-carboxylic acid-purified hydrate, a second generation of novel broad spectrum oral cephalosporin developed by Bestol-Myer Squibb, USA and marketed in 1992, commonly used for upper and lower respiratory tract infections, urinary system infections and intestinal infections in adults, otitis media, tonsillitis, pneumonia and the like in children, and for processes currently used in industrial production, wherein a certain amount of cefprozil often remains in a cefprozil mother liquor and a lotion after synthesis and is used in the lotion, if the dimethyl formamide is not recycled, serious environmental pollution is caused, and a large amount of dimethyl formamide and acetone are required to be used during recycling, so that resource waste is caused.
The synthesis of cefprozil reported in US200511357 and Chinese CN101024649 mainly uses cefprozil nucleus as initial raw material, and adopts Wittig reaction to introduce propenyl at 3-position, remove protecting group at 7-position, introduce side chain, finally remove protecting group on 7-position side chain amino and 4-position carboxyl under the action of acid, and hydrolyze to obtain cefprozil monohydrate, and the total yield is low by adopting these methods.
World patents WO2004083172A2 and WO2004110399A2 disclose that 7-APRA reacts with hexamethyldisilazane and trimethylchlorosilane to prepare a protective group mixed solution, p-hydroxyphenylglycine sodium salt reacts with ethyl chloroformate to generate corresponding active ester mixed solution, the protective group mixed solution and the active ester mixed solution undergo a condensation reaction in a one-pot method, cefprozil is obtained by hydrolysis (the synthetic route is as follows), the yield is improved to about 132 percent, but more cefprozil can remain in mother liquor.
Chinese patent CN102911187A, cooling the cefprozil refined mother liquor, adding dimethylformamide and acetone for treatment to obtain cefprozil dimethylformamide solvate, and refining to obtain cefprozil, wherein the method needs to consume a large amount of solvent and energy, and the quality of the obtained product does not meet the requirements of new pharmacopoeia.
The information disclosed in this background section is only for enhancement of understanding of the general background of the invention and should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person skilled in the art.
Disclosure of Invention
The invention aims to provide a cefprozil mother liquor applying process which is simple and convenient to operate, greatly reduces the using amount of dimethylformamide and acetone, and has obvious economic and environmental benefits.
In order to realize the purpose, the invention provides a cefprozil mother liquor recycling process, which comprises the following steps:
(1) adding saturated FeCl into cefprozil mother liquor3Adjusting the pH value of the solution;
(2) adding the cefprozil mother liquor treated in the step (1) into a reaction solution after the synthesis reaction of cefprozil is finished, heating to 5-8 ℃, controlling the temperature, stirring for 28-32min, standing, and separating liquid;
(3) cooling the water phase layer after liquid separation in the step (2) to below-5 ℃, further controlling the temperature to 0-10 ℃, adding dimethylformamide, controlling the temperature to 0-5 ℃, adding acetone washing liquid, stirring for 28-32min, filtering, and collecting filtrate;
(4) cooling the filtrate to 10-20 ℃, dropwise adding ammonia water, adjusting the pH value to 6.3-6.8, cooling to 0-5 ℃, stirring for 1.5-2.5h, filtering, collecting a filter cake, washing the filter cake with dimethylformamide, washing with acetone, and vacuum-drying at the temperature of below 50 ℃ for 8-10h to obtain a cefprozil crude product; and
(5) heating purified water to 45 ℃, slowly adding the cefprozil crude product, controlling the temperature to 35-45 ℃, stirring for 28-32min, cooling to 0-5 ℃, stirring for 2h, performing suction filtration, washing with acetone, and performing vacuum drying at 38-42 ℃ for 3h to obtain a cefprozil product;
wherein saturated FeCl is added3The purpose of the solution is: the complex is crystallized with impurities such as 7-aminocephalosporanic acid (7-ACA) and the like, thereby removing impuritiesThe purpose is to;
in the step (2), the cefprozil synthesis reaction is as follows: reacting 7-APRA (cefprozil nucleus) with hexamethyldisilazane and trimethylchlorosilane to prepare a protective group mixed solution, reacting p-hydroxyphenylglycine dane potassium salt with ethyl chloroformate to generate a corresponding active ester mixed solution, carrying out a condensation reaction on the protective group mixed solution and the active ester mixed solution, and hydrolyzing to obtain cefprozil;
in the step (3), the addition amount of the dimethylformamide is 8-15 times of the amount of the 7-APRA in the cefprozil synthesis reaction in the step (2), and the addition amount of the acetone washing liquid is 2-5 times of the amount of the 7-APRA in the cefprozil synthesis reaction in the step (2);
in the step (4), the addition amount of the dimethylformamide is 1-3 times of the amount of 7-APRA in the cefprozil synthesis reaction in the step (2); the addition amount of the acetone is 1-3 times of the amount of the 7-APRA in the cefprozil synthesis reaction in the step (2).
Preferably, in the above technical scheme, the cefprozil mother liquor in step (1) is mother liquor obtained by refining cefprozil crude product with purified water in step (5), that is, cefprozil crude product refined mother liquor.
Preferably, in the above technical solution, the saturated FeCl in step (1)3The dosage of the solution is 0.08-0.11 time of the dosage of the cefprozil mother liquor.
Preferably, in the above technical scheme, hydrochloric acid is added in the step (1) to adjust the pH value to 0.8-1.2.
Preferably, in the above technical scheme, the stirring is performed for 30min under the controlled temperature in the step (2).
Preferably, in the above technical scheme, the acetone washing liquid in step (3) is a washing liquid obtained by washing the filter cake with dimethylformamide and acetone in step (4) of the cefprozil mother liquor applying process; the acetone washing liquid mainly comprises cefprozil, purified water, dimethylformamide and ammonium chloride.
Preferably, in the above technical scheme, stirring is carried out for 30min in the step (3).
Preferably, in the above technical scheme, the stirring is carried out for 2 hours in the step (4).
Preferably, in the above technical scheme, the stirring in the step (5) is carried out for 30 min.
Preferably, in the technical scheme, the cefprozil product is obtained by vacuum drying at 40 ℃ for 3h in the step (5).
Compared with the prior art, the invention has the following beneficial effects:
(1) the process for mechanically applying the cefprozil mother liquor greatly reduces the dosage of dimethylformamide and acetone: dimethyl formamide and acetone are required to be added when the mother liquor is recovered in the prior art, but the mother liquor is directly used (the mother liquor is not required to be recovered) without using the two solvents, so that the use amounts of dimethyl formamide and acetone are greatly reduced; in addition, the mother liquor generated by the prior art needs to be added with dimethyl formamide and acetone to prepare a crude product, and then is refined to prepare the cefprozil, but before the cefprozil mother liquor is hydrolyzed by adding hydrochloric acid, the cefprozil mother liquor is used for replacing purified water, so that the product yield can be improved, and the use of dimethyl formamide and acetone during mother liquor recovery can be saved;
(2) the invention discloses a cefprozil mother liquor recycling process, under the condition of not changing cefprozil reaction process, adding treated cefprozil crude product refined mother liquor and acetone washing liquor to obtain cefprozil crude product; the cefprozil product is obtained after the crude product is refined, and the yield is greatly improved;
(3) the invention omits the complicated mother liquor recovery operation, can improve the yield by about 10 percent on the basis of unchanged original reaction process, and the obtained product quality conforms to the standard of new pharmacopoeia.
Detailed Description
The following detailed description of specific embodiments of the invention is provided, but it should be understood that the scope of the invention is not limited to the specific embodiments.
Throughout the specification and claims, unless explicitly stated otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or component but not the exclusion of any other element or component.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1:
taking 28.4g of 7-APRA (cefprozil mother nucleus), respectively adding 200mL of dichloromethane, 15g of hexamethyldisilazane, 9.8g of trimethylchlorosilane and 1g of imidazole into a three-necked bottle A, and heating until reflux reaction is carried out for 3 hours;
taking 91.2g of p-hydroxyphenylglycine dane potassium salt, adding 200mL of dichloromethane and 150mL of DMF (dimethylformamide) into a three-necked flask B, cooling to-50 ℃, dropwise adding ethyl chloroformate, controlling the temperature to-33-43 ℃, and reacting for 3 hours;
cooling the active ester in the three-mouth bottle B to below-50 ℃ after the reaction, dripping the protective base mixed solution in the three-mouth bottle A, controlling the temperature to be below-50 ℃ after dripping, reacting for 2 hours to prepare cefprozil, and adding 110mL of cefprozil crude product refined mother solution and 9mL of saturated FeCl into the reaction solution for preparing cefprozil3Adding hydrochloric acid into the solution to adjust the pH value to 1.0, heating to 5-8 ℃, stirring at a controlled temperature for 30min, standing, separating liquid, cooling a water phase to below-5 ℃, adding dimethylformamide at a controlled temperature of 0-10 ℃, adding an acetone washing solution at a controlled temperature of 0-5 ℃, stirring for 30min, filtering, collecting filtrate, cooling the filtrate to 15 ℃, dropwise adding ammonia water, adjusting the pH value to 6.5, cooling to 0-5 ℃, stirring for 2h, filtering, collecting a filter cake, washing the filter cake with dimethylformamide, washing with acetone, and drying under vacuum at the temperature of 50 ℃ for 8-10h to obtain 57.2g of cefprozil crude product;
heating purified water to 45 ℃, slowly adding the crude product, controlling the temperature to 35 ℃, stirring for 30min, cooling to 0-5 ℃, stirring for 2h, performing suction filtration, washing with acetone, and performing vacuum drying at 40 ℃ for 3h to obtain 42g of cefprozil product, wherein the yield is 147.9%, and the product purity is 99.8%.
Example 2:
taking 28.4g7-APRA, respectively adding 200mL dichloromethane, 15.5g hexamethyldisilazane, 9.8g trimethylchlorosilane and 1g imidazole into a three-necked bottle A, and heating to reflux for reaction for 3 h;
taking 91.2g of p-hydroxyphenylglycine dane potassium salt, adding 200mL of dichloromethane and 150mLDMF into a three-necked bottle B, cooling to-50 ℃, dropwise adding ethyl chloroformate, controlling the temperature to-33-43 ℃, and reacting for 3 hours;
cooling the active ester in the three-necked bottle B after the reaction to below-50 ℃, dropwise adding the protecting group mixed solution in the three-necked bottle A, reacting for 2 hours at the temperature of-50 ℃ after dropwise adding the active ester to obtain cefprozil, and adding 100mL of cefprozil crude product refined mother liquor and 11mL of saturated FeCl into the reaction solution for preparing cefprozil3Adding hydrochloric acid into the solution to adjust the pH value to 0.8, heating to 8 ℃, stirring for 30min, standing, separating liquid, cooling a water phase to below-5 ℃, controlling the temperature to be 0-10 ℃, adding dimethylformamide, adding an acetone washing solution at 0-5 ℃, stirring for 30min, filtering, collecting a filtrate, cooling the filtrate to 17 ℃, dropwise adding ammonia water, adjusting the pH value to 6.3, cooling to 0-5 ℃, stirring for 2h, filtering, collecting a filter cake, washing the filter cake with dimethylformamide, washing with acetone, and vacuum-drying for 8-10h below 50 ℃ to obtain 56.8g of a cefprozil crude product;
heating purified water to 45 ℃, slowly adding the crude product, controlling the temperature to 35 ℃, stirring for 30min, cooling to 0-5 ℃, stirring for 2h, performing suction filtration, washing with acetone, and performing vacuum drying for 3h at 40 ℃ to obtain 41.2g of cefprozil product, wherein the yield is 145%, and the product purity is 99.8%.
Example 3:
taking 28.4g7-APRA, respectively adding 200mL dichloromethane, 15.3g hexamethyldisilazane, 9.8g trimethylchlorosilane and 1g imidazole into a three-necked bottle A, and heating to reflux for reaction for 3 h;
taking 91.2g of p-hydroxyphenylglycine dane potassium salt, adding 200mL of dichloromethane and 150mLDMF into a three-necked bottle B, cooling to-50 ℃, dropwise adding ethyl chloroformate, controlling the temperature to-33-43 ℃, and reacting for 3 hours;
cooling the active ester in the three-necked bottle B after the reaction to below-50 ℃, dropwise adding the protective base mixed solution in the A, controlling the temperature to be below-50 ℃ after dropwise adding, reacting for 2 hours to obtain cefprozil, and adding 120mL of cefprozil crude product refined mother solution and 10mL of saturated FeCl into the reaction solution for preparing cefprozil3Adding hydrochloric acid into the solution to adjust pH to 0.9, heating to 6, stirring for 30min, standing, separating, and cooling water phaseControlling the temperature to be below-5 ℃, adding dimethylformamide and acetone washing liquor at 0 ℃, stirring for 30min, filtering, collecting filtrate, cooling the filtrate to 17 ℃, dropwise adding ammonia water, adjusting the pH value to 6.5, cooling to 0-5 ℃, stirring for 2h, filtering, collecting filter cakes, washing the filter cakes by using dimethylformamide, washing by using acetone, and drying in vacuum for 8-10h at the temperature of below 50 ℃ to obtain 57.1g of cefprozil crude product;
heating purified water to 45 ℃, slowly adding the crude product, controlling the temperature to 35 ℃, stirring for 30min, cooling to 0-5 ℃, stirring for 2h, performing suction filtration, washing with acetone, and performing vacuum drying for 3h at 40 ℃ to obtain 42.1g of cefprozil product, wherein the yield is 148.2%, and the product purity is 99.7%.
The foregoing descriptions of specific exemplary embodiments of the present invention have been presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to explain certain principles of the invention and its practical application to enable one skilled in the art to make and use various exemplary embodiments of the invention and various alternatives and modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims and their equivalents.
Claims (6)
1. The process for mechanically applying cefprozil mother liquor is characterized by comprising the following steps:
(1) adding saturated FeCl into cefprozil mother liquor3A solution;
(2) adding the cefprozil mother solution treated in the step (1) into a reaction solution after the synthesis reaction of cefprozil is finished, adding hydrochloric acid to adjust the pH value to 1.0, heating to 5-8 ℃, stirring at a controlled temperature for 28-32min, standing, and separating liquid;
(3) cooling the water phase layer after liquid separation in the step (2) to below-5 ℃, further controlling the temperature of the water phase layer to 0-10 ℃, adding dimethylformamide, controlling the temperature to 0-5 ℃, adding acetone washing liquid, stirring for 28-32min, filtering, and collecting filtrate;
(4) cooling the filtrate to 10-20 ℃, dropwise adding ammonia water, adjusting the pH value to 6.3-6.8, cooling to 0-5 ℃, stirring for 1.5-2.5h, filtering, collecting a filter cake, washing the filter cake with dimethylformamide, washing with acetone, and vacuum-drying at the temperature of below 50 ℃ for 8-10h to obtain a cefprozil crude product; and
(5) heating purified water to 45 ℃, slowly adding the cefprozil crude product, controlling the temperature to 35-45 ℃, stirring for 28-32min, cooling to 0-5 ℃, stirring for 2h, performing suction filtration, washing with acetone, and performing vacuum drying at 38-42 ℃ for 3h to obtain a cefprozil product;
wherein, the cefprozil mother liquor in the step (1) is mother liquor obtained by adding purified water to a cefprozil crude product in the step (5) and refining the cefprozil mother liquor;
the acetone washing liquid in the step (3) is the washing liquid obtained by washing the filter cake with dimethylformamide and acetone in the step (4) of the cefprozil mother liquor applying process;
the saturated FeCl in the step (1)3The dosage of the solution is 0.08-0.11 time of the dosage of the cefprozil mother liquor.
2. The process for mechanically applying cefprozil mother liquor according to claim 1, wherein in step (2), the temperature is controlled and the stirring is carried out for 30 min.
3. The process for recycling cefprozil mother liquor according to claim 1, wherein the stirring in step (3) is carried out for 30 min.
4. The process for recycling cefprozil mother liquor as claimed in claim 1, wherein the stirring in step (4) is carried out for 2 hours.
5. The process for recycling cefprozil mother liquor as claimed in claim 1, wherein the stirring in step (5) is carried out for 30 min.
6. The process for recycling cefprozil mother liquor according to claim 1, wherein the cefprozil product is obtained by vacuum drying at 40 ℃ for 3h in step (5).
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| US6903211B2 (en) * | 2002-10-30 | 2005-06-07 | Orchid Chemicals & Pharmaceuticals Limited | Process for the preparation of 3-propenyl cephalosporin DMF 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 |
| CN102911187B (en) * | 2012-10-11 | 2015-03-11 | 南通康鑫药业有限公司 | Recovery method of cefprozil |
| CN107501296B (en) * | 2017-09-01 | 2019-11-19 | 天俱时工程科技集团有限公司 | From the method for Cefprozil crystalline mother solution recycling Cefprozil |
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