CN110204556B - Preparation method of (RS) -methoxy cefoxitin - Google Patents
Preparation method of (RS) -methoxy cefoxitin Download PDFInfo
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- CN110204556B CN110204556B CN201910640215.2A CN201910640215A CN110204556B CN 110204556 B CN110204556 B CN 110204556B CN 201910640215 A CN201910640215 A CN 201910640215A CN 110204556 B CN110204556 B CN 110204556B
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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
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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
- C07D501/57—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with a further substituent in position 7, e.g. cephamycines
Abstract
The invention discloses a preparation method of (RS) -methoxy cefoxitin, which is characterized by comprising the following steps: (1) taking thiophene as an initial raw material, taking n-heptane as a reaction solvent, reacting with trichloroacetaldehyde, and distilling under reduced pressure after the reaction is finished to obtain the compound; (2) the product obtained in the previous step reacts with methanol in the presence of alkaline substances to prepare (RS) -alpha-methoxy-2-thiopheneacetic acid; (3) dissolving (RS) -alpha-methoxy-2-thiopheneacetic acid in an organic solvent, adding a first organic base, stirring and clarifying, and then dropwise adding methylsulfonyl chloride or pivaloyl chloride for later use; adding HACA and an organic solvent into another reaction vessel, adding a second organic base, and stirring until the mixture is clear for later use; slowly dripping the solution B into the solution A at the temperature of below-30 ℃; then dropwise adding chlorosulfonyl isocyanate to react to obtain off-white crystalline powder; (4) and (3) reacting the off-white crystalline powder with sodium methoxide to obtain the product. The product has high purity.
Description
Technical Field
The invention relates to a preparation method of (RS) -methoxy cefoxitin, belonging to the field of impurity analysis in drug synthesis.
Background
Cefoxitin (Cefoxitin), chemically (6R,7S) -3-carbamoyloxymethyl-7-methoxy-8-oxo-7- [2- (2-thienyl) acetamido ] -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, is a semi-synthetic cephalosporin antibiotic developed by Merck, USA.
In the process of research and development of new drugs, the quality of the drugs is an important standard for measuring the quality of the drugs, and the quality of the drugs is determined by the curative effect and the toxic and side effects of the drugs, namely the effectiveness and the safety of the drugs. The content of the effective components of the medicine is an important mark for reflecting the purity of the medicine, and impurities in the medicine directly influence the curative effect of the medicine and can cause toxic and side effects. The impurities of the medicine are other chemical substances except the introduced or generated medicine in the processes of production, storage and transportation, and the existence of the impurities not only affects the purity of the medicine, but also brings non-therapeutic active toxic and side effects and must be controlled. For safe and effective use of drugs, the quality standards of the drugs have strict regulations on the purity of the active ingredients of the drugs and the limits of impurities.
For drug developers, the main work is not only how to obtain high-quality drug Substances (APIs) and develop efficient synthesis processes, but also how to study the types and sources of impurities in the drug substances and how to control the generation of process impurities. Usually, researchers can firstly orient impurities generated in a synthesis process, and secondly develop an efficient impurity synthesis route so as to obtain a large amount of impurity reference substances and ensure the development of quality detection work (such as impurity HPLC positioning, impurity content measurement and the like) of each batch of raw material medicines.
(R, S) -methoxy cefoxitin
(6R,7S) -3-carbamoyloxymethyl-7-methoxy-7- ((2RS) -2-methoxy-2- (thiophen-2-yl) -acetylamino) -8-oxo-5-thio-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid
(6R,7S)-3-((carbamoyloxy)methyl)-7-methoxy-7-((2RS)-2-methoxy-2-(thiophen-2-yl)-acetyl)amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
The impurity is specifically defined as E, F by European pharmacopoeia and is an important impurity needing to be researched in the quality control of cefoxitin medicaments, the preparation method of the impurity compound is determined, a qualified reference substance is provided, and the impurity compound can play a positive role in the quality control of cefoxitin and other medicaments.
Disclosure of Invention
Aiming at the technical problems, the invention aims to provide a preparation method of (RS) -methoxy cefoxitin.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a preparation method of (RS) -methoxy cefoxitin is characterized by comprising the following steps:
(1) taking thiophene as a starting material, taking n-heptane as a reaction solvent, reacting with chloral, and distilling under reduced pressure after the reaction is finished to obtain (RS) -alpha-trichloromethyl-2-thiophene methanol;
(2) reacting the (RS) -alpha-trichloromethyl-2-thiophene methanol obtained in the step (1) with methanol in the presence of an alkaline substance to prepare (RS) -alpha-methoxy-2-thiophene phenylacetic acid;
(3) dissolving (RS) -alpha-methoxy-2-thiopheneacetic acid in an organic solvent, cooling to below-10 ℃ under the protection of nitrogen, adding a first organic base, stirring for clarification, cooling to-50 to-60 ℃, dropwise adding methylsulfonyl chloride or pivaloyl chloride, reacting at below-35 ℃, and obtaining a solution A for later use after the reaction is finished;
adding hydroxymethyl-7-aminocephalosporanic acid and an organic solvent into another reaction vessel, stirring under the protection of nitrogen, cooling to below 0 ℃, adding a second organic base, and stirring until the mixture is clear to obtain a solution B for later use;
slowly dripping the solution B into the solution A at the temperature of below-30 ℃; controlling the temperature to be below 30 ℃ below zero for reaction, then cooling to be below 40 ℃ below zero, adding acid liquor, continuing the reaction, then dropwise adding chlorosulfonyl isocyanate, and continuing the reaction at about 30 ℃ below zero; finally adding water, adjusting the pH value to 2-3, standing for layering after the reaction is finished, drying and decoloring the organic phase, filtering, adding acetone and methanol into the filtrate, dropwise adding a first organic base, separating out crystals, filtering and drying to obtain white-like crystalline powder;
(4) dissolving the obtained white-like crystalline powder in an organic solvent and methanol, cooling to-60 to-80 ℃ under the protection of nitrogen, adding a methanol solution of sodium methoxide, dropwise adding tert-butyl hypochlorite after the addition, stirring for reaction, adding sodium metabisulfite after the reaction is finished, stirring, adjusting the pH value to 6-7 with acetic acid, heating to 0-5 ℃, adjusting the pH value to 1-2, standing for layering, washing an organic layer, adding saturated sodium bicarbonate to adjust the pH value to 7-8, layering, adjusting the pH value to 1-2 with a water layer, extracting with ethyl acetate, drying the ethyl acetate layer, filtering, and concentrating under reduced pressure to obtain an oily crude product.
The reaction formula of each step is as follows:
in the step (1), the molar ratio of the thiophene to the chloral is 1: 1-1.2. Is beneficial to the reaction and improves the yield.
The specific operation steps of the step (1) are as follows: adding thiophene, n-heptane and chloral into a reaction vessel, stirring, heating to reflux reaction, cooling after the reaction is finished, concentrating under reduced pressure to recover the solvent, distilling the residue under reduced pressure, and collecting 1.0mmHg fractions at 98-100 ℃ to obtain RS) -alpha-trichloromethyl-2-thiophenemethanol.
In the step (2), the alkaline substance is potassium hydroxide or sodium hydroxide, and the molar ratio of the (R, S) -alpha-trichloromethyl-2-thiophene methanol to the alkaline substance is 1: 3-5.
The specific operation steps of the step (2) are as follows: adding methanol and alkaline substances into a reaction vessel, stirring and dissolving, cooling to-5-0 ℃, adding a methanol solution of (R, S) -alpha-trichloromethyl-2-thiophenemethanol, stirring, heating and refluxing for reaction, cooling to room temperature after the reaction is finished, concentrating under reduced pressure to remove an organic solvent, then adding methyl tert-butyl ether or petroleum ether or isopropyl ether, stirring, adjusting the pH to 2.5-3.5 with a hydrochloric acid solution, separating an organic layer, extracting a water layer with methyl tert-butyl ether or petroleum ether or isopropyl ether, combining the organic layers, washing with brine, drying, filtering, and concentrating to obtain (RS) -alpha-methoxy-2-thiopheneacetic acid.
The organic solvent is dichloromethane or chloroform. In the step (3), the first organic base is one of diisopropylamine, triethylamine, tributylamine and diisopropylethylamine, the molar ratio of the (RS) -alpha-methoxy-2-thiopheneacetic acid to the first organic base is 1:1-1.2, and the molar ratio of the (RS) -alpha-methoxy-2-thiopheneacetic acid to methylsulfonyl chloride or pivaloyl chloride is 1: 1-1.1.
In the step (3), the second organic base is one of tetramethylguanidine, triethylamine, diisopropylethylamine, tributylamine and diisopropylamine, and the molar ratio of the hydroxymethyl-7-aminocephalosporanic acid to the second organic base is 1: 1.1-1.3;
the acid solution is one of methanesulfonic acid, hydrochloric acid, phosphoric acid, formic acid and acetic acid;
the molar ratio of the (RS) -alpha-methoxy-2-thiopheneacetic acid to the acid solution is 1: 1-1.1;
the molar ratio of the (RS) -alpha-methoxy-2-thiopheneacetic acid to the chlorosulfonyl isocyanate is 1: 1.5-1.6.
In the step (4), the molar ratio of the off-white crystalline powder to the sodium methoxide is 1: 3-4; the molar ratio of the white-like crystalline powder to tert-butyl hypochlorite is 1: 2-3; the molar ratio of the white-like crystalline powder to the sodium metabisulfite is 1: 1.2-2.
And purifying the crude oily matter by silica gel column chromatography. After purification by silica gel column chromatography, the purity can reach more than 98 percent.
Has the advantages that: the preparation method provided by the invention is simple in steps, low in cost and suitable for large-scale preparation. The purity of the finally prepared methyl sulfamate can reach more than 98.0 percent by carefully controlling and adjusting the reaction metering, the reaction solvent, the reaction temperature and the adding sequence of the reaction materials of each step. Provides a theoretical basis for the safe use of the medicine, provides effective data support for the quality standard of the cefoxitin medicine, and provides effective guarantee for the clinical safe use of the medicine.
Detailed Description
The invention is further illustrated by the following examples:
example 1
Preparation chemical reaction formula of (RS) -alpha-trichloromethyl-2-thiophene methanol
Adding 84g (1.0mol) of thiophene, 500ml of n-heptane and 147g (1.0mol) of chloral into a 1000ml three-necked bottle, stirring, heating to reflux, cooling to room temperature after reaction, concentrating under reduced pressure to recover the solvent, distilling the residue under reduced pressure, collecting 98-100 ℃ and 1.0mmHg fractions, wherein the yield is about 46 g.
Example 2
Preparation of (RS) -alpha-trichloromethyl-2-thiophenemethanol
Adding 84g (1.0mol) of thiophene, 500ml of n-heptane and 147g (1.2mol) of chloral into a 1000ml three-necked bottle, stirring, heating to reflux, cooling to room temperature after reaction, concentrating under reduced pressure to recover the solvent, distilling the residue under reduced pressure, collecting 98-100 ℃ and 1.0mmHg fractions, wherein the yield is about 52 g.
Example 3
Preparation chemical reaction formula of (RS) -alpha-methoxy-2-thiopheneacetic acid
Adding 100ml of methanol and 11.2g (0.2mol) of potassium hydroxide into a 500ml three-neck flask under the protection of nitrogen, stirring for dissolving, cooling to-5-0 ℃, adding a solution of 11.6g (0.05mol) of (R, S) -alpha-trichloromethyl-2-thiophene methanol in 30ml of methanol, stirring, slowly heating to reflux, cooling to room temperature after reaction, removing the solvent by reduced pressure concentration, adding 50ml of methyl tert-butyl ether into the residue, adjusting the pH to 3.0 by using 0.1N diluted hydrochloric acid under stirring, separating an organic layer, extracting a water layer by using methyl tert-butyl ether again, combining the organic layers, washing with brine, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain about 6.2g of a product.
Example 4
(RS) -alpha-methoxy-2-thiopheneacetic acid
Adding 100ml of methanol and 0.25mol of sodium hydroxide into a 500ml three-neck flask under the protection of nitrogen, stirring for dissolving, cooling to-5-0 ℃, adding a solution of 11.6g (0.05mol) of (R, S) -alpha-trichloromethyl-2-thiophene methanol in 30ml of methanol, stirring, slowly heating to reflux, cooling to room temperature after the reaction is finished, concentrating under reduced pressure to remove the solvent, adding 50ml of isopropyl ether, adjusting the pH to 2.5 by using 0.1N dilute hydrochloric acid under stirring, separating an organic layer, extracting a water layer by using the isopropyl ether, combining the organic layers, washing by using brine, drying by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain about 5.9g of a product.
Example 5
(RS) -alpha-methoxy-2-thiopheneacetic acid
Adding 100ml of methanol and 8.4g (0.15mol) of potassium hydroxide into a 500ml three-neck flask under the protection of nitrogen, stirring for dissolving, cooling to-5-0 ℃, adding a solution of 11.6g (0.05mol) of (R, S) -alpha-trichloromethyl-2-thiophene methanol in 30ml of methanol, stirring, slowly heating to reflux, cooling to room temperature after reaction, removing the solvent by reduced pressure concentration, adding 50ml of petroleum ether (boiling point of 60-90 ℃), adjusting the pH to 3.5 by using 1N diluted hydrochloric acid under stirring, separating an organic layer, extracting a water layer by using the petroleum ether, combining the organic layers, washing with brine, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain about 6.15g of a product.
Example 6
Preparation of diisopropylamine (6R,7S) -3-carbamoyloxymethyl-7- ((2RS) -2-methoxy-2- (thiophen-2-yl) -acetylamino) -8-oxo-5-thio-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate
1. Chemical reaction formula
17.2g (0.1mol) (RS) -alpha-methoxy-2-thiopheneacetic acid and 200ml dichloromethane are added into a 500ml four-mouth reaction bottle, and the mixture is stirred and cooled to below minus 10 ℃ under the protection of nitrogen. 11.1g (0.11mol) of diisopropylamine was added thereto, and the mixture was dissolved with stirring to clarify. Cooling to-50 deg.C, adding dropwise 12g (0.105mol) methanesulfonyl chloride, reacting at-35 deg.C, cooling to-45 deg.C to obtain solution A.
Adding 23.2g (0.1mol) of HACA (hydroxymethyl-7-aminocephalosporanic acid) and 100ml of dichloromethane into a 250ml three-neck bottle, stirring and cooling to below 0 ℃ under the protection of nitrogen; adding 13.8g (0.12mol) of tetramethylguanidine, and stirring until the mixture is dissolved and clarified; cooling to-45 deg.C to obtain solution B.
Slowly dripping the solution B into the solution A at the temperature below minus 30 ℃; controlling the temperature below minus 30 ℃ to react for 3-4 hours, cooling to minus 40 ℃, adding 9.6g (0.1mol) of methanesulfonic acid, reacting for 20 minutes, dropwise adding 21.2g (0.15mol) of chlorosulfonyl isocyanate, and reacting for 2 hours at about minus 30 ℃; 150ml of water was added, and the pH was adjusted to 2 with sodium hydrogencarbonate to conduct a reaction for 60 minutes. Standing for layering, separating an organic phase, washing with water twice, each time washing with 150ml, adding 30g of anhydrous sodium sulfate and 2g of activated carbon, stirring for 30 minutes, filtering, adding 250ml of acetone 50ml of methanol into a filtrate, dropwise adding 11.1g (0.11mol) of diisopropylamine, precipitating crystals, stirring for 30 minutes, filtering, and washing with acetone. The wet product was dried under vacuum to obtain 40g of off-white crystalline powder with a yield of 75%.
Example 7
Preparation of triethylamine (6R,7S) -3-carbamoyloxymethyl-7- ((2RS) -2-methoxy-2- (thiophen-2-yl) -acetylamino) -8-oxo-5-thio-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate salt
17.2g (0.1mol) (RS) -alpha-methoxy-2-thiopheneacetic acid and 200ml dichloromethane are added into a 500ml four-mouth reaction bottle, and the mixture is stirred and cooled to below minus 10 ℃ under the protection of nitrogen. 0.12mol of triethylamine is added, stirred, dissolved and clarified. Cooling to-50 deg.C, adding 0.11mol of pivaloyl chloride dropwise, reacting at-35 deg.C, and cooling to-45 deg.C to obtain solution A.
Adding 23.2g (0.1mol) of HACA (hydroxymethyl-7-aminocephalosporanic acid) and 100ml of dichloromethane into a 250ml three-neck bottle, stirring and cooling to below 0 ℃ under the protection of nitrogen; adding 0.13mol of triethylamine, and stirring until the triethylamine is dissolved and clarified; cooling to-45 deg.C to obtain solution B.
Slowly dripping the solution B into the solution A at the temperature below minus 30 ℃; controlling the temperature below minus 30 ℃ to react for 3-4 hours, cooling to minus 40 ℃, adding 0.11mol of hydrochloric acid to react for 20 minutes, dropwise adding 22.6g (0.16mol) of chlorosulfonyl isocyanate, and reacting for 2 hours at about minus 30 ℃; 150ml of water was added, and the reaction was carried out for 60 minutes while adjusting the pH to 2.5 with sodium hydrogencarbonate. Standing for layering, separating an organic phase, washing with water twice, each time washing with 150ml, adding 30g of anhydrous sodium sulfate and 2g of activated carbon, stirring for 30 minutes, filtering, adding 250ml of acetone 50ml of methanol into a filtrate, dropwise adding 0.12mol of triethylamine, precipitating crystals, stirring for 30 minutes, filtering, and washing with acetone. The wet product was vacuum-dried to obtain 38.9g of off-white crystalline powder.
Example 8
Preparation of tributylamine (6R,7S) -3-carbamoyloxymethyl-7- ((2RS) -2-methoxy-2- (thiophen-2-yl) -acetylamino) -8-oxo-5-thio-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate
17.2g (0.1mol) (RS) -alpha-methoxy-2-thiopheneacetic acid and 200ml dichloromethane are added into a 500ml four-mouth reaction bottle, and the mixture is stirred and cooled to below minus 10 ℃ under the protection of nitrogen. Adding 0.12mol of tributylamine, stirring, dissolving and clarifying. Cooling to-50 deg.C, adding 0.108mol of pivaloyl chloride dropwise, reacting at-35 deg.C, and cooling to-45 deg.C to obtain solution A.
Adding 23.2g (0.1mol) of HACA (hydroxymethyl-7-aminocephalosporanic acid) and 100ml of dichloromethane into a 250ml three-neck bottle, stirring and cooling to below 0 ℃ under the protection of nitrogen; adding 0.11mol of tributylamine, and stirring until the tributylamine is dissolved and clarified; cooling to-45 deg.C to obtain solution B.
Slowly dripping the solution B into the solution A at the temperature below minus 30 ℃; controlling the temperature below minus 30 ℃ to react for 3-4 hours, cooling to minus 40 ℃, adding 0.105mol of formic acid, reacting for 20 minutes, dropwise adding 0.16mol of chlorosulfonyl isocyanate, and reacting for 2 hours at about minus 30 ℃; 150ml of water was added, and the reaction was carried out for 60 minutes while adjusting the pH to 2.5 with sodium hydrogencarbonate. Standing for layering, separating an organic phase, washing with water twice, each time washing with 150ml, adding 30g of anhydrous sodium sulfate and 2g of activated carbon, stirring for 30 minutes, filtering, adding 250ml of acetone 50ml of methanol into a filtrate, dropwise adding 0.115mol of tributylamine, separating out crystals, stirring for 30 minutes, filtering, and washing with acetone. The wet product was vacuum-dried to obtain 39.2g of off-white crystalline powder.
Example 9
Preparation of (6R,7S) -3-carbamoyloxymethyl-7- ((2RS) -2-methoxy-2- (thiophen-2-yl) -acetylamino) -8-oxo-5-thio-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid cyclohexylamine salt
17.2g (0.1mol) (RS) -alpha-methoxy-2-thiophene phenylacetic acid and 200ml chloroform are added into a 500ml four-mouth reaction bottle and stirred and cooled to below minus 10 ℃. 0.1mol of diisopropylethylamine is added, stirred, dissolved and clarified. Cooling to-50 deg.C, adding dropwise 0.1mol of methanesulfonyl chloride, reacting at-35 deg.C, and cooling to-45 deg.C to obtain solution A.
Adding 23.2g (0.1mol) of HACA (hydroxymethyl-7-aminocephalosporanic acid) and 100ml of chloroform into a 250ml three-neck bottle, stirring and cooling to below 0 ℃ under the protection of nitrogen; adding 0.11mol of diisopropylethylamine, and stirring until the solution is clear; cooling to-45 deg.C to obtain solution B.
Slowly dripping the solution B into the solution A at the temperature below minus 30 ℃; controlling the temperature below minus 30 ℃ to react for 3-4 hours, cooling to minus 40 ℃, adding 0.1mol of acetic acid, reacting for 20 minutes, dropwise adding 22.6g (0.15mol) of chlorosulfonyl isocyanate, and reacting for 2 hours at about minus 30 ℃; 150ml of water was added, and the reaction was carried out for 60 minutes while adjusting the pH to 2.5 with sodium hydrogencarbonate. Standing for layering, separating an organic phase, washing with water twice, each time washing with 150ml, adding 30g of anhydrous sodium sulfate and 2g of activated carbon, stirring for 30 minutes, filtering, adding 250ml of acetone 50ml of methanol into a filtrate, dropwise adding 0.115mol of cyclohexylamine, separating out crystals, stirring for 30 minutes, filtering, and washing with acetone. The wet product was vacuum-dried to obtain 40.2g of off-white crystalline powder.
Example 10
Preparation of diisopropylamine (6R,7S) -3-carbamoyloxymethyl-7- ((2RS) -2-methoxy-2- (thiophen-2-yl) -acetylamino) -8-oxo-5-thio-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate
17.2g (0.1mol) (RS) -alpha-methoxy-2-thiophene phenylacetic acid and 200ml chloroform are added into a 500ml four-mouth reaction bottle and stirred and cooled to below minus 10 ℃. 0.115mol of diisopropylethylamine is added, stirred, dissolved and clarified. Cooling to-50 deg.C, adding dropwise 0.105mol of methanesulfonyl chloride, reacting at-35 deg.C, cooling to-45 deg.C to obtain solution A.
Adding 23.2g (0.1mol) of HACA (hydroxymethyl-7-aminocephalosporanic acid) and 100ml of dichloromethane into a 250ml three-neck bottle, stirring and cooling to below 0 ℃ under the protection of nitrogen; adding 0.12mol of diisopropylamine, and stirring until the mixture is dissolved and clarified; cooling to-45 deg.C to obtain solution B.
Slowly dripping the solution B into the solution A at the temperature of below minus 30 ℃; controlling the temperature below minus 30 ℃ to react for 3-4 hours, cooling to minus 40 ℃, adding 0.1mol of phosphoric acid, reacting for 20 minutes, dropwise adding 22.6g (0.15mol) of chlorosulfonyl isocyanate, and reacting for 2 hours at about minus 30 ℃; 150ml of water was added, and the reaction was carried out for 60 minutes while adjusting the pH to 3 with sodium hydrogencarbonate. Standing for layering, separating an organic phase, washing with water twice, each time washing with 150ml, adding 30g of anhydrous sodium sulfate and 2g of activated carbon, stirring for 30 minutes, filtering, adding 250ml of acetone 50ml of methanol into a filtrate, dropwise adding 0.115mol of diisopropylamine, precipitating crystals, stirring for 30 minutes, filtering, and washing with acetone. The wet product was vacuum-dried to obtain 40.2g of off-white crystalline powder.
Example 11
Chemical reaction formula for preparing (R, S) -methoxy cefoxitin
Procedure of operation
Into a 50ml three-necked flask was added 5.3g (0.01mol) of the above-obtained off-white crystalline powder of (6R,7S) -3-carbamoyloxymethyl-7- ((2RS) -2-methoxy-2- (thiophen-2-yl) -acetylamino) -8-oxo-5-thio-1-azabicyclo [ 4.2.0%]The preparation method comprises the following steps of stirring diisopropyl amine salt of octyl-2-ene-2-carboxylic acid, 50ml of dichloromethane and 5ml of methanol, cooling to-70 ℃ under the protection of nitrogen, adding a solution of 1g (0.03mol) of sodium methoxide and 20ml of methanol, dropwise adding a solution of 2.73g (0.025mol) of tert-butyl hypochlorite at about-70 ℃, stirring for about 1 hour, adding 2.8g (0.015mol) of sodium metabisulfite, stirring for 10 minutes, adjusting the pH value to be 6-7 by using acetic acid, heating, dropwise adding hydrochloric acid with the mass concentration of 5% at 0-5 ℃ to adjust the pH value to be 1-2, standing to separate an organic layer, extracting a water layer once by using dichloromethane, combining the organic layers, and washing once by using water. And adjusting the pH value of the organic layer to 7-8 by using a saturated sodium bicarbonate solution, separating the organic layer, adjusting the pH value of the water layer to 1-2 by using 10% hydrochloric acid, extracting by using ethyl acetate, drying the ethyl acetate layer by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain about 4.4g of a light yellow oily substance, and purifying the crude product by using a silica gel column chromatography to obtain 3.5g of a product. (eluent ethyl acetate-petroleum ether ═ 6: 1). The purity is 98.0%. Through MS,1H-NMR and13the C-NMR structure was confirmed to be consistent with the spectrum of the control.
Example 12
Preparation of (R, S) -methoxy cefoxitin
Into a 50ml three-necked flask was charged 5.3g (0.01mol) of the obtained off-white crystalline powder of (6R,7S) -3-carbamoyloxymethyl-7- ((2RS) -2-methoxy-2- (thien-2-yl) -acetamido)Yl) -8-oxo-5-thio-1-azabicyclo [4.2.0]The preparation method comprises the following steps of stirring diisopropylamine salt of octyl-2-ene-2-carboxylic acid, 50ml of chloroform and 5ml of methanol, cooling to-60 ℃ under the protection of nitrogen, adding a solution of 0.04mol of sodium methoxide and 20ml of methanol, dropwise adding a 0.02mol of tert-butyl hypochlorite solution at about-60 ℃ after the addition is finished, stirring for about 1 hour, adding 0.012mol of sodium metabisulfite, stirring for 10 minutes, adjusting the pH value to be 6-7 by using acetic acid, heating, dropwise adding 5% hydrochloric acid at 0-5 ℃ to adjust the pH value to be 1-2, standing to separate an organic layer, extracting a water layer once by using trichloromethane, combining the organic layers, and washing once by using water. Adjusting the pH value of an organic layer to 7-8 by using a saturated sodium bicarbonate solution, separating the organic layer, adjusting the pH value of a water layer to 1-2 by using 10% hydrochloric acid, extracting by using ethyl acetate, drying an ethyl acetate layer by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain about 3.8g of a light yellow oily substance, and purifying a crude product by using a silica gel column chromatography to obtain 2.56g of a product. (eluent ethyl acetate-petroleum ether ═ 6: 1). The purity is 98.2%. Through MS,1H-NMR and13the C-NMR structure was confirmed to be consistent with the spectrum of the control.
Example 13
Preparation of (R, S) -methoxy cefoxitin
Into a 50ml three-necked flask was added 5.3g (0.01mol) of the above-obtained off-white crystalline powder of (6R,7S) -3-carbamoyloxymethyl-7- ((2RS) -2-methoxy-2- (thiophen-2-yl) -acetylamino) -8-oxo-5-thio-1-azabicyclo [ 4.2.0%]The preparation method comprises the following steps of stirring diisopropylamine salt of octyl-2-ene-2-carboxylic acid, 50ml of chloroform and 5ml of methanol, cooling to-80 ℃ under the protection of nitrogen, adding a solution of 0.035mol of sodium methoxide and 20ml of methanol, dropwise adding a 0.03mol of tert-butyl hypochlorite solution at-80 ℃ after the addition is finished, stirring for about 1 hour, adding 0.02mol of sodium metabisulfite, stirring for 10 minutes, adjusting the pH value to be 6-7 by using acetic acid, heating, dropwise adding 5% hydrochloric acid at 0-5 ℃ to adjust the pH value to be 1-2, standing to separate an organic layer, extracting a water layer once by using trichloromethane, combining the organic layers, and washing once by using water. Adjusting pH of the organic layer to 7-8 with saturated sodium bicarbonate solution, separating organic layer, adjusting pH of the water layer to 1-2 with 10% hydrochloric acid, extracting with ethyl acetate, drying the ethyl acetate layer with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain yellowish oily substance about 3.9g, and subjecting the crude product to silica gel column chromatographyPurification gave 2.95 g. (eluent ethyl acetate-petroleum ether ═ 6: 1). The purity is 98.0%. From MS to MS,1H-NMR and13the C-NMR structure was confirmed to be consistent with the spectrum of the control.
The present invention is not limited to the above-described embodiments, and those skilled in the art will understand that: various changes, modifications, substitutions and alterations can be made to the embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.
Claims (9)
1. A preparation method of (RS) -methoxy cefoxitin is characterized by comprising the following steps:
(1) taking thiophene as a starting material, taking n-heptane as a reaction solvent, reacting with chloral, and distilling under reduced pressure after the reaction is finished to obtain (RS) -alpha-trichloromethyl-2-thiophene methanol;
(2) reacting the (RS) -alpha-trichloromethyl-2-thiophene methanol obtained in the step (1) with methanol in the presence of an alkaline substance to prepare (RS) -alpha-methoxy-2-thiophene phenylacetic acid;
(3) dissolving (RS) -alpha-methoxy-2-thiopheneacetic acid in an organic solvent, cooling to below-10 ℃ under the protection of nitrogen, adding a first organic base, stirring for clarification, cooling to-50 to-60 ℃, dropwise adding methylsulfonyl chloride or pivaloyl chloride, reacting at below-35 ℃, and obtaining a solution A for later use after the reaction is finished;
adding hydroxymethyl-7-aminocephalosporanic acid and an organic solvent into another reaction vessel, stirring under the protection of nitrogen, cooling to below 0 ℃, adding a second organic base, and stirring until the mixture is clear to obtain a solution B for later use;
slowly dripping the solution B into the solution A at the temperature of below-30 ℃; controlling the temperature to be below 30 ℃ below zero for reaction, then cooling to be below 40 ℃ below zero, adding acid liquor, continuing the reaction, then dropwise adding chlorosulfonyl isocyanate, and continuing the reaction at about 30 ℃ below zero; finally adding water, adjusting the pH value to 2-3, standing for layering after the reaction is finished, drying and decoloring the organic phase, filtering, adding acetone and methanol into the filtrate, dropwise adding a first organic base, separating out crystals, filtering and drying to obtain white-like crystalline powder;
(4) dissolving the obtained white-like crystalline powder in an organic solvent and methanol, cooling to-60 to-80 ℃ under the protection of nitrogen, adding a methanol solution of sodium methoxide, dropwise adding tert-butyl hypochlorite after the addition, stirring for reaction, adding sodium metabisulfite after the reaction is finished, stirring, adjusting the pH value to 6-7 with acetic acid, heating to 0-5 ℃, adjusting the pH value to 1-2, standing for layering, washing an organic layer, adding saturated sodium bicarbonate to adjust the pH value to 7-8, layering, adjusting the pH value to 1-2 with a water layer, extracting with ethyl acetate, drying the ethyl acetate layer, filtering, and concentrating under reduced pressure to obtain an oily crude product;
in the step (1), the molar ratio of the thiophene to the chloral is 1: 1-1.2.
2. The process for the preparation of (RS) -methoxy cefoxitin according to claim 1, wherein: the specific operation steps of the step (1) are as follows: adding thiophene, n-heptane and chloral into a reaction vessel, stirring, heating to reflux reaction, cooling after the reaction is finished, concentrating under reduced pressure to recover the solvent, distilling the residue under reduced pressure, and collecting 1.0mmHg fractions at 98-100 ℃ to obtain (RS) -alpha-trichloromethyl-2-thiophenemethanol.
3. Process for the preparation of (RS) -methoxy cefoxitin according to any one of claims 1-2, characterized in that: in the step (2), the alkaline substance is potassium hydroxide or sodium hydroxide, and the molar ratio of the (R, S) -alpha-trichloromethyl-2-thiophene methanol to the alkaline substance is 1: 3-5.
4. The process for the preparation of (RS) -methoxycefoxitin according to claim 3, wherein the specific steps of step (2) are: adding methanol and alkaline substances into a reaction vessel, stirring and dissolving, cooling to-5-0 ℃, adding a methanol solution of (R, S) -alpha-trichloromethyl-2-thiophenemethanol, stirring, heating for reflux reaction, cooling to room temperature after the reaction is finished, removing the organic solvent by vacuum concentration, then adding methyl tert-butyl ether or petroleum ether or isopropyl ether, stirring, adjusting the pH to 2.5-3.5 by using a hydrochloric acid solution, separating an organic layer, extracting a water layer by using the methyl tert-butyl ether or the petroleum ether or the isopropyl ether, combining the organic layers, washing with brine, drying, filtering, and concentrating to obtain (RS) -alpha-methoxy-2-thiopheneacetic acid.
5. The process for the preparation of (RS) -methoxycefoxitin according to claim 4, wherein: the organic solvent is dichloromethane or chloroform.
6. The process for the preparation of (RS) -methoxycefoxitin according to claim 5, wherein: in the step (3), the first organic base is one of diisopropylamine, triethylamine, tributylamine and diisopropylethylamine, the molar ratio of the (RS) -alpha-methoxy-2-thiopheneacetic acid to the first organic base is 1:1-1.2, and the molar ratio of the (RS) -alpha-methoxy-2-thiopheneacetic acid to methylsulfonyl chloride or pivaloyl chloride is 1: 1-1.1.
7. The process for the preparation of (RS) -methoxycefoxitin according to claim 6, wherein: in the step (3), the second organic base is one of tetramethylguanidine, triethylamine, diisopropylethylamine, tributylamine and diisopropylamine, and the molar ratio of the hydroxymethyl-7-aminocephalosporanic acid to the second organic base is 1: 1.1-1.3;
the acid solution is one of methanesulfonic acid, hydrochloric acid, phosphoric acid, formic acid and acetic acid;
the molar ratio of the (RS) -alpha-methoxy-2-thiopheneacetic acid to the acid solution is 1: 1-1.1;
the molar ratio of the (RS) -alpha-methoxy-2-thiopheneacetic acid to the chlorosulfonyl isocyanate is 1: 1.5-1.6.
8. The process for the preparation of (RS) -methoxy cefoxitin according to claim 7, wherein: in the step (4), the molar ratio of the off-white crystalline powder to the sodium methoxide is 1: 3-4; the molar ratio of the white-like crystalline powder to tert-butyl hypochlorite is 1: 2-3; the molar ratio of the white-like crystalline powder to the sodium metabisulfite is 1: 1.2-2.
9. The process for the preparation of (RS) -methoxy cefoxitin according to claim 8, wherein: and purifying the crude oily matter by silica gel column chromatography.
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