CN105566350A - Synthetic method of cefoperazone acid - Google Patents
Synthetic method of cefoperazone acid Download PDFInfo
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- CN105566350A CN105566350A CN201511010943.3A CN201511010943A CN105566350A CN 105566350 A CN105566350 A CN 105566350A CN 201511010943 A CN201511010943 A CN 201511010943A CN 105566350 A CN105566350 A CN 105566350A
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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
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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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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- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a synthetic method of cefoperazone acid. The method comprises the steps of: reacting raw materials of 7-ACA and 1-methyl-5-mercapto tetrazole under the catalysis of boron trifluoride acetonitrile to obtain 7-ACT; dissolving the 7-ACT in a mixed solution of acetonitrile and N,O-(bis) trimethylsilyl acetamide to obtain a 7-ACT amino alkylate solution; mixing HO-EPCP, an organic solvent and a catalyst, adding phosphorus oxychloride for reaction at the temperature of -25 to -20 DEG C, wherein when the residue amount of HO-EPCP in the reaction solution is no more than 0.5%, the reaction is complete, so as to prepare a HO-EPCP acyl chloride solution; mixing and reacting 7-ACT amino alkylate solution with HO-EPCP acyl chloride solution, adding an aqueous solution of sodium bicarbonate after the reaction, standing foe stratification, filtering a lower layer material, adding water, crystallizing, filtering, washing and drying to obtain the cefoperazone acid. The method has the advantages of simpleness, high yield and stable intermediate.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of synthetic method of cefoperazone acid.
Background technology
T-1551 is the third generation cephalosporin that the development of Japan folic hill chemical industrial company finds, there is the features such as has a broad antifungal spectrum, anti-microbial effect be strong, strong to β-lactamase tolerance, all effect is had to gram-positive microorganism and Gram-negative bacteria, be used for the treatment of respiratory tract infection disease, biliary tract infection disease, gynecological infections disease, surgical infection disease etc., enter and be hydrolyzed to cefoperazone through nonspecific esterase after in body and play a role.
Cefoperazone acid (Cefoperazone), chemical name is 7-(((4-ethyl-2,3-dioxo-1-piperazinyl) formamido group) (4-hydroxy phenyl) kharophen)-3-((1-methyl isophthalic acid H-tetrazolium-5-base) thiomethyl)-8-oxo-5-sulphur-1-azabicyclo (4.2.0) oct-2-ene-2-formic acid, be the raw material of synthesis T-1551, its structural formula is:
At present, the synthetic method of cefoperazone acid mainly contains chloride method, mixed anhydride method, thioester method, amino-substituent distribution condensation method, there is the defects such as raw materials cost is high, acyl chlorides compound intermediate unstable, product yield is low, severe reaction conditions, poor product quality in existing synthetic method, is unfavorable for large-scale industrial production.
Summary of the invention
The object of the invention is intended to the synthetic method providing a kind of cefoperazone acid.
Based on above object, the present invention takes following technical scheme:
A synthetic method for cefoperazone acid, comprises the following steps:
(1) under boron trifluoride acetonitrile catalysis, with 7-ACA and 1-methyl-5-mercapto tetrazole for raw material reaction obtains 7-ACT;
(2) 7-ACT of step (1) is dissolved in acetonitrile and N, in the mixed solution of O-(two) trimethyl silane yl acetamide, obtain 7-ACT aminoalkyl group compound solution, described acetonitrile, 7-ACT and N, the amount ratio of O-(two) trimethyl silane yl acetamide is 70 ~ 90ml:13 ~ 15g:13 ~ 15g, and the amino in 7-ACT and carboxylic group are protected;
(3) by HO-EPCP, organic solvent and catalyst mix, add phosphorus oxychloride and react, HO-EPCP residual quantity≤0.5% in reaction soln, is considered as reacting completely, obtained HO-EPCP acyl chlorides compound solution; Described organic solvent is N, N-N,N-DIMETHYLACETAMIDE and acetonitrile, described catalyzer is trimethylchlorosilane, temperature of reaction is-25 ~-20 DEG C, the amount ratio of described N,N-dimethylacetamide, acetonitrile, trimethylchlorosilane, HO-EPCP and phosphorus oxychloride is 45 ~ 60ml:25 ~ 40ml:8 ~ 10g:15 ~ 16g:7.5 ~ 8.5g;
(4) by the HO-EPCP acyl chlorides compound solution hybrid reaction of 7-ACT aminoalkyl group compound solution in step (2) and step (3), temperature of reaction is-30 ~-25 DEG C, the sodium bicarbonate aqueous solution is added after reaction, stratification, take off layered material liquid after filtering, add water crystallization, filtration, wash, be drying to obtain cefoperazone acid white crystal.
Further, in step (2), the amount ratio of acetonitrile, 7-ACT and N, O-(two) trimethyl silane yl acetamide is 70 ~ 90ml:14g:14g.
Further, in step (3), the amount ratio of N,N-dimethylacetamide, acetonitrile, trimethylchlorosilane, HO-EPCP and phosphorus oxychloride is 45 ~ 60ml:25 ~ 40ml:8g:15g:8.1g.
Further, HPLC is adopted to detect to HO-EPCP residual quantity in described reaction soln in step (3).
Further, in step (4), 7-ACT aminoalkyl group compound mixes for 1:1 ~ 2 in molar ratio with HO-EPCP acyl chlorides compound.
Adopt HPLC to detect HO-EPCP residual quantity in the HO-EPCP acyl chlorides compound solution in step (3), its detecting step is:
1) 0.16g p-Chlorobenzoic acid amide is dissolved in 25ml acetonitrile and 5mlN, in the mixed solution of N-N,N-DIMETHYLACETAMIDE, then add the HO-EPCP acyl chlorides compound solution of 3g step (3), after reaction 20min, be diluted to 50ml with the methanol aqueous solution that concentration is 50%, obtain solution to be measured;
2) chromatographic condition: using octadecylsilane chemically bonded silica as weighting agent; With 0.025mol/L phosphoric acid solution-acetonitrile (volume ratio is for 87:13) for moving phase; Flow velocity is 1.5ml/min, and inspection wavelength is 278nm.Get 20 microlitre step 1) solution to be measured, after organic membrane filtration, sample detection, calculates HO-EPCP residual content (area normalization method).
Chemical equation of the present invention is as follows:
Compared with prior art, the present invention has following beneficial effect:
1) preparation method of the present invention is simple, product yield is high, intermediate is stable, in HO-EPCP acyl chloride reaction, under the katalysis of trimethylchlorosilane, acyl chloride reaction carries out more thorough, not only the transformation efficiency of HO-EPCP acyl chlorides compound improves 3%, and HO-EPCP acyl chlorides compound zero solution in 24h, improve the stability of HO-EPCP acyl chlorides compound.
2) product adds the sodium bicarbonate aqueous solution before crystallization, stratification, the by product silicon ether that reaction generates effectively is separated, and solves the problem of the easy gel of cefoperazone acid crystal in later crystallization process, improve the yield of cefoperazone acid, product purity reaches more than 99%.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further details.
Embodiment 1
(1) by 65g boron trifluoride acetonitrile and the mixing of 6.8g1-methyl-5-mercapto tetrazole, stir 30min, then 14g7-ACA is added, react 1h at 30 DEG C after, proceed in 100g purified water and be hydrolyzed, at 10 DEG C, add weak ammonia and occur to there being crystal, growing the grain 30min, continue to add weak ammonia and regulate pH to 3.0, after growing the grain 1h, suction filtration is after 60% aqueous acetone solution washs by concentration, be dried to moisture≤1%, obtain 16.1g white solid 7-ACT, its purity >99%, mass yield 115%;
(2) get 7-ACT, 77ml acetonitrile of 14g step (1), the mixing of 14gN, O-(two) trimethyl silane yl acetamide, at temperature is 25 DEG C, stirring and dissolving, to clarification, obtains 7-ACT aminoalkyl group compound solution, is cooled to 0 DEG C, for subsequent use;
(3) by 15.5gHO-EPCP, 45mlN, N-N,N-DIMETHYLACETAMIDE, 25ml acetonitrile and 8g trimethylchlorosilane mix, after stirring and dissolving, be cooled to-20 DEG C, then add 8.1g phosphorus oxychloride, insulation reaction, HPLC tracing detection reaction soln, HO-EPCP residual quantity <0.5% in reaction soln, is considered as reacting completely, reaction stops, and obtains HO-EPCP acyl chlorides compound solution;
(4) at-30 DEG C, 7-ACT aminoalkyl group compound solution in step (2) is added drop-wise in the HO-EPCP acyl chlorides compound solution of step (3) and carries out condensation reaction, drip off reaction 2h; After reaction terminates, adding 60ml concentration is the 10% sodium bicarbonate aqueous solution, stir 10min, static layering, takes off layered material liquid after membrane filtration, at 25 DEG C, after dripping 130ml purified water, growing the grain 60min, then adds 330ml purified water, is cooled to 5 DEG C, growing the grain 2h, filter, be after the acetonitrile-water mixing solutions washing leaching cake of 20% by mass concentration, be dried to moisture≤6%, obtain 24.5g white crystal cefoperazone acid, its purity >99%, mass yield 175%, two step mass yields 201%.
Embodiment 2
(1) by 65g boron trifluoride acetonitrile and the mixing of 6.8g1-methyl-5-mercapto tetrazole, stir 30min, then add 14g7-ACA, react 1h at 30 DEG C after, proceed in 100g purified water and be hydrolyzed, at 10 DEG C, add weak ammonia to occur to there being crystal, growing the grain 30min, continues to add weak ammonia and regulates pH to 3.0, after growing the grain 1h, suction filtration, with concentration be 60% aqueous acetone solution washing after, be dried to moisture≤1%, obtain 7-ACT;
(2) get 7-ACT, 90ml acetonitrile of 14g step (1), the mixing of 14gN, O-(two) trimethyl silane yl acetamide, at temperature is 25 DEG C, stirring and dissolving, to clarification, obtains 7-ACT aminoalkyl group compound solution, is cooled to 0 DEG C, for subsequent use;
(3) by 15gHO-EPCP, 60mlN, N-N,N-DIMETHYLACETAMIDE, 40ml acetonitrile and 8g trimethylchlorosilane mix, after stirring and dissolving, be cooled to-20 DEG C, then add 8.1g phosphorus oxychloride, insulation reaction, HPLC tracing detection reaction soln, HO-EPCP residual quantity <0.5% in reaction soln, is considered as reacting completely, reaction stops, and obtains HO-EPCP acyl chlorides compound solution;
(4) at-30 DEG C, 7-ACT aminoalkyl group compound solution in step (2) is added drop-wise in the HO-EPCP acyl chlorides compound solution of step (3) and carries out condensation reaction, drip off reaction 2h; After reaction terminates, adding 60ml concentration is the 10% sodium bicarbonate aqueous solution, stir 10min, static layering, takes off layered material liquid after membrane filtration, at 25 DEG C, after dripping 130ml purified water, growing the grain 60min, then adds 330ml purified water, is cooled to 5 DEG C, growing the grain 2h, filter, be after the acetonitrile-water mixing solutions washing leaching cake of 20% by mass concentration, be dried to moisture≤6%, obtain 24g white crystal cefoperazone acid, its purity >99%, mass yield 171%, two step mass yields 197%.
Embodiment 3
(1) by 65g boron trifluoride acetonitrile and the mixing of 6.8g1-methyl-5-mercapto tetrazole, stir 30min, then add 14g7-ACA, react 1h at 30 DEG C after, proceed in 100g purified water and be hydrolyzed, at 10 DEG C, add weak ammonia to occur to there being crystal, growing the grain 30min, continues to add weak ammonia and regulates pH to 3.0, after growing the grain 1h, suction filtration, with concentration be 60% aqueous acetone solution washing after, be dried to moisture≤1%, obtain 7-ACT;
(2) get 7-ACT, 70ml acetonitrile of 13g step (1), the mixing of 13gN, O-(two) trimethyl silane yl acetamide, at temperature is 25 DEG C, stirring and dissolving, to clarification, obtains 7-ACT aminoalkyl group compound solution, is cooled to 0 DEG C, for subsequent use;
(3) by 16gHO-EPCP, 60mlN, N-N,N-DIMETHYLACETAMIDE, 40ml acetonitrile and 10g trimethylchlorosilane mix, after stirring and dissolving, be cooled to-25 DEG C, then add 7.5g phosphorus oxychloride, insulation reaction, HPLC tracing detection reaction soln, HO-EPCP residual quantity <0.5% in reaction soln, is considered as reacting completely, reaction stops, and obtains HO-EPCP acyl chlorides compound solution;
(4) at-25 DEG C, 7-ACT aminoalkyl group compound solution in step (2) is added drop-wise in the HO-EPCP acyl chlorides compound solution of step (3) and carries out condensation reaction, drip off reaction 2h; After reaction terminates, adding 60ml concentration is the 10% sodium bicarbonate aqueous solution, stirs 10min, static layering, takes off layered material liquid after membrane filtration, at 25 DEG C, after dripping 130ml purified water, growing the grain 60min, then adds 330ml purified water, be cooled to 5 DEG C, growing the grain 2h, filter, be after the acetonitrile-water mixing solutions washing leaching cake of 20% by mass concentration, be dried to moisture≤6%, obtain white crystal cefoperazone acid, its purity >99%.
Embodiment 4
(1) by 65g boron trifluoride acetonitrile and the mixing of 6.8g1-methyl-5-mercapto tetrazole, stir 30min, then add 14g7-ACA, react 1h at 30 DEG C after, proceed in 100g purified water and be hydrolyzed, at 10 DEG C, add weak ammonia to occur to there being crystal, growing the grain 30min, continues to add weak ammonia and regulates pH to 3.0, after growing the grain 1h, suction filtration, with concentration be 60% aqueous acetone solution washing after, be dried to moisture≤1%, obtain 7-ACT;
(2) get 7-ACT, 90ml acetonitrile of 15g step (1), the mixing of 15gN, O-(two) trimethyl silane yl acetamide, at temperature is 25 DEG C, stirring and dissolving, to clarification, obtains 7-ACT aminoalkyl group compound solution, is cooled to 0 DEG C, for subsequent use;
(3) by 16gHO-EPCP, 50mlN, N-N,N-DIMETHYLACETAMIDE, 30ml acetonitrile and 9g trimethylchlorosilane mix, after stirring and dissolving, be cooled to-20 DEG C, then add 8.5g phosphorus oxychloride, insulation reaction, HPLC tracing detection reaction soln, HO-EPCP residual quantity <0.5% in reaction soln, is considered as reacting completely, reaction stops, and obtains HO-EPCP acyl chlorides compound solution;
(4) at-30 DEG C, 7-ACT aminoalkyl group compound solution in step (2) is added drop-wise in the HO-EPCP acyl chlorides compound solution of step (3) and carries out condensation reaction, drip off reaction 2h; After reaction terminates, adding 60ml concentration is the 10% sodium bicarbonate aqueous solution, stirs 10min, static layering, takes off layered material liquid after membrane filtration, at 25 DEG C, after dripping 130ml purified water, growing the grain 60min, then adds 330ml purified water, be cooled to 5 DEG C, growing the grain 2h, filter, be after the acetonitrile-water mixing solutions washing leaching cake of 20% by mass concentration, be dried to moisture≤6%, obtain white crystal cefoperazone acid, its purity >99%.
Claims (5)
1. a synthetic method for cefoperazone acid, is characterized in that, comprises the following steps:
(1) under boron trifluoride acetonitrile catalysis, with 7-ACA and 1-methyl-5-mercapto tetrazole for raw material reaction obtains 7-ACT;
(2) 7-ACT of step (1) is dissolved in acetonitrile and N, in the mixed solution of O-(two) trimethyl silane yl acetamide, obtain 7-ACT aminoalkyl group compound solution, the amount ratio of described acetonitrile, 7-ACT and N, O-(two) trimethyl silane yl acetamide is 70 ~ 90ml:13 ~ 15g:13 ~ 15g;
(3) by HO-EPCP, organic solvent and catalyst mix, add phosphorus oxychloride and react, HO-EPCP residual quantity≤0.5% in reaction soln, is considered as reacting completely, obtained HO-EPCP acyl chlorides compound solution; Described organic solvent is N, N-N,N-DIMETHYLACETAMIDE and acetonitrile, catalyzer is trimethylchlorosilane, temperature of reaction is-25 ~-20 DEG C, the amount ratio of described N,N-dimethylacetamide, acetonitrile, trimethylchlorosilane, HO-EPCP and phosphorus oxychloride is 45 ~ 60ml:25 ~ 40ml:8 ~ 10g:15 ~ 16g:7.5 ~ 8.5g;
(4) by the HO-EPCP acyl chlorides compound solution hybrid reaction of 7-ACT aminoalkyl group compound solution in step (2) and step (3), temperature of reaction is-30 ~-25 DEG C, the sodium bicarbonate aqueous solution is added after reaction, stratification, take off layered material liquid after filtering, add water crystallization, filtration, wash, be drying to obtain cefoperazone acid white crystal.
2. the synthetic method of cefoperazone acid according to claim 1, is characterized in that, in step (2), the amount ratio of acetonitrile, 7-ACT and N, O-(two) trimethyl silane yl acetamide is 70 ~ 90ml:14g:14g.
3. the synthetic method of cefoperazone acid according to claim 2, it is characterized in that, in step (3), the amount ratio of N,N-dimethylacetamide, acetonitrile, trimethylchlorosilane, HO-EPCP and phosphorus oxychloride is 45 ~ 60ml:25 ~ 40ml:8g:15g:8.1g.
4. the synthetic method of cefoperazone acid according to claim 3, is characterized in that, adopts HPLC to detect in step (3) to HO-EPCP residual quantity in described reaction soln.
5. the synthetic method of the cefoperazone acid according to claim 1,2,3 or 4, is characterized in that, in step (4), 7-ACT aminoalkyl group compound mixes for 1:1 ~ 2 in molar ratio with HO-EPCP acyl chlorides compound.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111499658A (en) * | 2020-04-25 | 2020-08-07 | 广东赛法洛药业有限公司 | New indications of cefoperazone medicinal preparation for treating endometritis and other gynecological genital tract infections |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1508071A (en) * | 1976-01-19 | 1978-04-19 | Toyama Chemical Co Ltd | Cephalosporins and process for producing the same |
| US20100068197A1 (en) * | 2008-07-11 | 2010-03-18 | Myriad Pharmaceuticals, Inc. | Pharmaceutical compounds as inhibitors of cell proliferation and the use thereof |
| CN102432554A (en) * | 2011-12-27 | 2012-05-02 | 山东鑫泉医药有限公司 | Method for synthesizing D(-)-alpha-(4-ethyl-2,3-dioxypiperazine-1-methanamide) hydroxyphenylacetic acid (HO-EPCP) |
| CN102532168A (en) * | 2011-12-27 | 2012-07-04 | 山东鑫泉医药有限公司 | Synthesis method of cefoperazone acid |
-
2015
- 2015-12-30 CN CN201511010943.3A patent/CN105566350B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1508071A (en) * | 1976-01-19 | 1978-04-19 | Toyama Chemical Co Ltd | Cephalosporins and process for producing the same |
| US20100068197A1 (en) * | 2008-07-11 | 2010-03-18 | Myriad Pharmaceuticals, Inc. | Pharmaceutical compounds as inhibitors of cell proliferation and the use thereof |
| CN102432554A (en) * | 2011-12-27 | 2012-05-02 | 山东鑫泉医药有限公司 | Method for synthesizing D(-)-alpha-(4-ethyl-2,3-dioxypiperazine-1-methanamide) hydroxyphenylacetic acid (HO-EPCP) |
| CN102532168A (en) * | 2011-12-27 | 2012-07-04 | 山东鑫泉医药有限公司 | Synthesis method of cefoperazone acid |
Non-Patent Citations (3)
| Title |
|---|
| SAIKAWA, ISAMU等，: ""Studies on b-lactam antibiotics for medicinal purpose. VIII. Synthesis of 7-[D(-)-α-(4-alkyl-2,3-dioxo-1-piperazinecarboxamido)phenylacetamido]-cephalosporanic acids and structure-antibacterial activity"", 《YAKUGAKU ZASSHI》 * |
| 徐云根等，: ""头孢哌酮合成工艺的改进"", 《中国药科大学学报》 * |
| 韩新正等，: ""头孢哌酮酸合成新方法"", 《广东化工》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111499658A (en) * | 2020-04-25 | 2020-08-07 | 广东赛法洛药业有限公司 | New indications of cefoperazone medicinal preparation for treating endometritis and other gynecological genital tract infections |
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