CN111118098A - Preparation method of 3-hydroxymethyl cefazolin - Google Patents
Preparation method of 3-hydroxymethyl cefazolin Download PDFInfo
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- CN111118098A CN111118098A CN201911353150.XA CN201911353150A CN111118098A CN 111118098 A CN111118098 A CN 111118098A CN 201911353150 A CN201911353150 A CN 201911353150A CN 111118098 A CN111118098 A CN 111118098A
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Abstract
The invention discloses a preparation method of 3-hydroxymethyl cefazolin, which comprises the steps of dropwise adding 7-ACA solution into a tetrazoleacetic acid mixed anhydride solution for condensation reaction, adjusting pH phase after reaction, then adding purified water for phase separation, combining water phases, adding an organic solvent for phase separation, concentrating to obtain a primary purified water phase and a secondary purified water phase respectively, adjusting pH of the secondary purified water phase, adding cephalosporin C deacetylase, then adding a dispersing agent into the filtered water phase, cooling, growing crystals, filtering, washing and drying until the water content is less than 1.0%. The method replaces the traditional strong alkaline hydrolysis process, the wastewater discharge can be reduced by 80%, the cephalosporin C deacetylase after enzymolysis can be recycled, the solvent residue is less than 5%, the concentration weight loss ratio is 2-5%, the influence of various solvents on the activity of the cephalosporin C deacetylase is thoroughly solved, the enzyme dosage and the enzyme reutilization activity are ensured, the cost is reduced, the reaction condition is mild, the product conversion rate is up to more than 90%, the product purity is not lower than 98%, and the subsequent structural analysis and pharmacological research are facilitated.
Description
Technical Field
The invention belongs to the field of chemical drug synthesis, and particularly relates to a preparation method of 3-hydroxymethyl cefazolin, a key known impurity in the quality research of cefazolin sodium.
Background
Ceftizolin Sodium (the common name in English is Cefazolin Sodium), which was originally developed by Nippon Tectoria, is the first generation of cephalosporin when being first marketed in Japan in 1971, has a wide antibacterial spectrum, is a leading antibiotic for treating gram-positive bacteria in international and domestic clinical medicine, is clinically applied to infections of respiratory tract, genitourinary system, skin soft tissue, bones, joints, biliary tract and the like caused by sensitive bacteria, can also be used for endocarditis, septicemia, pharynx and ear infections, and can also be used as a preventive medicine before surgical operations.
In the synthesis route of cefazolin sodium at home and abroad, 7-ACA is mostly adopted as a starting material, D-7ACA is impurities introduced in the fermentation process of 7-ACA, and because the structures are similar and are not easy to separate, in the process of synthesizing the cefazolin sodium by 7-ACA, the D-7ACA generates 3-hydroxymethyl cefazolin along with amidation reaction of 7-amino, and main process impurities in the generated cefazolin sodium, namely cefazolin impurity E in the cefazolin sodium in United states pharmacopoeia.
At present, the national requirements for impurities in medicines are more strict, and particularly, the impurities in the medicines are required to be synthesized, structurally analyzed and subjected to pharmacological research, and impurity reference substances are adopted to carry out impurity research as far as possible. The content of 3-hydroxymethyl cefazolin generated in the synthesis process of cefazolin sodium is low, and the separation is inconvenient; however, no synthetic preparation method for 3-hydroxymethyl cefazolin exists at present, which is not beneficial to the related research of impurities.
Disclosure of Invention
Aiming at the defect that structural analysis and pharmacological research are limited due to the fact that a synthetic preparation method of 3-hydroxymethyl cefazolin sodium is unavailable at present, the invention provides a synthetic method of 3-hydroxymethyl cefazolin with high conversion rate and high purity.
The chemical reaction equation of the invention is as follows:
the preparation method of the 3-hydroxymethyl cefazolin is characterized by comprising the following steps:
a. preparation of 7-ACA solution: adding 7-ACA into dichloromethane or chloroform at the temperature of-20 to-40 ℃, then dropwise adding tetramethylguanidine until the solution is dissolved and clarified to obtain a 7-ACA solution, wherein the molar ratio of the 7-ACA to the tetramethylguanidine is 1:1.2 to 1.6, and the mass part ratio of the 7-ACA to the dichloromethane or chloroform is 1:9.3 to 17.0;
b. preparing a tetrazoleacetic acid mixed anhydride solution: under the condition of-20 to-60 ℃, after adding tetrazoleacetic acid into dichloromethane or chloroform, sequentially adding N, N-dimethylacetamide, triethylamine, a catalyst and pivaloyl chloride, controlling the temperature to be-20 to-28 ℃, stirring for 1.5 hours to obtain a tetrazoleacetic acid mixed anhydride solution, wherein the molar ratio of the tetrazoleacetic acid to 7-ACA is 1.05 to 1.50:1, the mass part ratio of the dichloromethane or chloroform to the tetrazoleacetic acid is 20.0 to 24.0:1, the mass part ratio of the N, N-dimethylacetamide to the tetrazoleacetic acid is 1.10 to 1.30:1, the mass part ratio of the triethylamine to the tetrazoleacetic acid is 0.8 to 1.0:1, the mass part ratio of the catalyst to the tetrazoleacetic acid is 0.02 to 0.08:1, the molar ratio of the pivaloyl chloride to the tetrazoleacetic acid is 0.6 to 1.0:1, and the catalyst is pyridine, 2, 6-lutidine or N-methylmorpholine;
c. 3-hydroxymethyl cefazolin preparation:
1. dropwise adding a 7-ACA solution into a tetrazoleacetic acid mixed anhydride solution at the temperature of-40 ℃ to-50 ℃, adjusting the temperature to-10 ℃ to-35 ℃ for condensation reaction, adding purified water after reacting for 1h, adjusting the pH value to 6.0-8.0 by using inorganic base, standing for phase separation, adding the purified water into an organic phase, adjusting the pH value to 6.0-8.0 by using the inorganic base, standing for phase separation, and combining two water phases for later use, wherein the inorganic base is sodium carbonate, sodium bicarbonate or sodium hydroxide;
2. adding an organic solvent into the combined water phase, standing and phase splitting to obtain a primary purified water phase, wherein the volume ratio of the organic solvent to the water phase is 0.4-1.0: 1, and the organic solvent is dichloromethane, ethyl acetate or chloroform;
3. concentrating the primary purified water phase at the external temperature of 30-45 ℃ and under the reduced pressure of-0.095 Mpa until the weight reduction ratio is 2-5% to obtain a secondary purified water phase;
4. controlling the temperature to be 20-30 ℃, dropwise adding ammonia water into the secondary purified water phase to adjust the pH value to be 7.0-7.8, then adding cephalosporin C deacetylase, dropwise adding ammonia water to keep the pH value to be 7.0-7.8 under the condition of 20-30 ℃, filtering, then adding a dispersing agent into the filtered water phase, controlling the temperature to be 10-25 ℃, dropwise adding inorganic acid to reach the pH value of 1.7-2.2, then cooling to 0-5 ℃, then growing crystals for 30min, filtering, washing, and drying under the vacuum condition of 25-35 ℃ and-0.095 Mpa until the moisture content is less than 1.0%, wherein the mass part ratio of the cephalosporin C deacetylase to 7-ACA is 0.40-0.70: 1, the mass part ratio of the dispersing agent to 7-ACA is 2.0-5.0: 1, the dispersing agent is dichloromethane, ethyl acetate or chloroform, and the inorganic acid is hydrochloric acid, sulfuric acid or phosphoric acid.
The invention achieves the technical progress that:
(1) the invention takes 7-ACA as raw material, generates 3-acetoxymethyl cefazolin by condensation reaction with tetrazoleacetic acid, and generates the target product 3-hydroxymethyl cefazolin by enzymolysis reaction.
(2) According to the invention, through twice purification of the aqueous phase before enzymolysis, the extraction ratio of the aqueous phase is refined to be 0.4-1.0: 1, the solvent residue is less than 5%, and the solvent residue is effectively reduced; as the concentration and purification steps are added, the concentration weight loss ratio is 2-5%, the influence of various solvents on the activity of the cephalosporin C deacetylase in the early synthesis process is thoroughly solved, the enzyme dosage and the activity of enzyme reutilization are ensured, and the cost is reduced.
(3) The invention replaces the traditional chemical synthesis method through enzymolysis reaction, has mild reaction conditions, reduces the product damage, improves the product conversion rate and leads the conversion rate to be as high as more than 90 percent.
(4) Due to the structural difference between 3-hydroxymethyl cefazolin and cefazolin, oily substances are separated out from normal crystallization, and due to the fact that the dispersing agent is introduced into the water phase during crystallization, normal crystallization is ensured, separation of the oily substances is avoided, and the yield of a target product is over 80%.
(5) The route of the invention omits the protection step of 3-position hydroxyl, reduces the reaction steps, simultaneously adopts enzymatic synthesis to replace chemical synthesis, has mild reaction conditions, effectively reduces the side reaction of product decomposition, has high reaction conversion rate, and has the purity of the crystal liquid product as high as 97 percent, so the purity (HPLC) of the product is not lower than 98 percent and can reach 99.2 percent at most.
(6) The invention solves the preparation problem of the reference substance of main process impurities in the registration and declaration process of cefazolin sodium, and is beneficial to subsequent structural analysis and pharmacological research.
Drawings
FIG. 1 is a diagram of MS of 3-hydroxymethyl cefazolin according to the present invention.
FIG. 2 is a HNMR picture of 3-hydroxymethyl cefazolin of the present invention.
FIG. 3 is a CNMR map of cefazolin-hydroxymethyl.
Detailed Description
Example 1:
a. preparation of 7-ACA solution: under the condition of-20 to-40 ℃, sequentially adding 250ml of chloroform and 35.4g of 7-ACA (molecular weight of 272.3, 0.13mol) into a 500ml four-mouth bottle, controlling the temperature to be-15 to 20 ℃, dropwise adding 23.0g of tetramethylguanidine (molecular weight of 115.18, 0.20 mol) until the mixture is dissolved and clarified to obtain a 7-ACA solution, and then cooling to-25 ℃ for later use;
b. preparing a tetrazoleacetic acid mixed anhydride solution: under the condition of-20 to-60 ℃, adding 280ml of chloroform, 17.5g of tetrazoleacetic acid (molecular weight 128.09, 0.14 mol) and 19.3g of N, N-dimethylacetamide (molecular weight 87.12, 0.22 mol) in another 1L four-mouth bottle in sequence, stirring for 10min at the temperature of-20 to-25 ℃, dropwise adding 14.0g of triethylamine (molecular weight 101, 0.14 mol) within about 15min, adding 0.4g of pyridine and 19.5g of pivaloyl chloride (molecular weight 155.0, 0.13mol) after the tetrazoleacetic acid is dissolved, and stirring for 1.5h at the temperature of-20 to-28 ℃ to obtain a tetrazoleacetic acid mixed anhydride solution;
c. 3-hydroxymethyl cefazolin preparation:
1. transferring the 7-ACA solution into a tetrazoleacetic acid mixed anhydride solution for about 5min at the temperature of between 40 ℃ below zero and 50 ℃ below zero, adjusting the temperature to between 10 ℃ below zero and 35 ℃ below zero to perform condensation reaction, stirring for 1h, adding 380ml of purified water at the temperature of between 10 ℃ and 20 ℃, adjusting the pH to between 6.0 and 7.0 by using a 7 mass percent sodium bicarbonate aqueous solution, stirring for hydrolysis for 10min, standing for phase separation, adding 120ml of purified water into the organic phase after phase separation, adjusting the pH to between 6.0 and 8.0 by using a 7 mass percent sodium bicarbonate aqueous solution, stirring for 10min, standing for phase separation, and combining the two aqueous phases for later use;
2. adding 250ml of dichloromethane solvent into the combined water phase, stirring for 15min, standing and phase splitting to obtain a primary purified water phase;
3. concentrating the primary purified water phase at the external temperature of 30-45 ℃ and under the pressure of-0.095 Mpa until the weight reduction ratio is 3% to obtain a secondary purified water phase, wherein the concentration of the 3-acetoxymethyl cefazolin intermediate in the secondary water phase is 7% -10%;
4. controlling the temperature to be 20-30 ℃, dropwise adding 3M ammonia water into the secondary purified water phase to adjust the pH value to be 7.0-7.8, adding 15g of cephalosporin C deacetylase, dropwise adding 3M ammonia water to keep the pH value to be 7.0-7.8 at the temperature of 20-30 ℃, filtering after the pH value is stable, then adding 60ml of dispersant chloroform into the filtered water phase, controlling the temperature to be 10-25 ℃, dropwise adding 4M hydrochloric acid water solution to the pH value of 1.8, cooling to 0-5 ℃, then growing crystals for 30min, carrying out suction filtration and washing, drying the filter cake under the reduced pressure of 0.095Mpa at the temperature of 25-30 ℃ by using an oven, and drying the filter cake under the reduced pressure of 0.095MpaDrying for 4h until the water content is reduced<After 1.0%, 29.1g of target product is obtained, and the purity (HPLC) of the target product, namely 3-hydroxymethyl cefazolin, is 98.9% through detection. MS and NMR detection prove that the target product prepared in the embodiment has the structure of 3-hydroxymethyl cefazolin, MS,1HNMR、13The detection spectra of CNMR are shown in FIGS. 1-3.
Example 2:
a. preparation of 7-ACA solution: under the condition of-20 to-40 ℃, 400ml of dichloromethane and 35.4g of 7-ACA are sequentially added into a 500ml four-mouth bottle, the temperature is controlled to be-15 to 20 ℃, 20.0g of tetramethylguanidine is dropwise added until the mixture is dissolved and clarified to obtain a 7-ACA solution, and then the temperature is reduced to-25 ℃ for later use;
b. preparing a tetrazoleacetic acid mixed anhydride solution: under the condition of-20 to-60 ℃, adding 350ml of dichloromethane, 21.78g of tetrazoleacetic acid (0.17 mol) and 26.5g of N, N-dimethylacetamide (0.30 mol) into another 1L four-mouth bottle in sequence, controlling the temperature to be-20 to-25 ℃, stirring for 10min, dropwise adding 21.5g of triethylamine (0.20 mol) within about 15min, adding 1.74g of 2, 6-dimethylpyridine and 21.7g of pivaloyl chloride (0.14 mol) after the tetrazoleacetic acid is dissolved, controlling the temperature to be-20 to-28 ℃, and stirring for 1.5h to obtain a tetrazoleacetic acid mixed anhydride solution;
c. 3-hydroxymethyl cefazolin preparation:
1. transferring 7-ACA solution into tetrazoleacetic acid mixed anhydride for about 5min at the temperature of-40 to-50 ℃, adjusting the temperature to-10 to-35 ℃ for condensation reaction, stirring for 1h, adding 350ml of purified water at the temperature of 10 to 20 ℃, adjusting the pH to 6.0 to 8.0 by using a 10 mass percent sodium carbonate aqueous solution, stirring for hydrolysis for 10min, standing for phase separation, adding 120ml of purified water into the phase-separated organic phase, adjusting the pH to 6.0 to 8.0 by using a 10 mass percent sodium carbonate aqueous solution, stirring for 10min, standing for phase separation, and combining the two water phases for later use;
2. adding 200ml of ethyl acetate solvent into the combined water phase, stirring for 15min, standing and phase splitting to obtain a primary purified water phase;
3. concentrating the primary purified water phase at an external temperature of 40-0.095 Mpa under reduced pressure until the weight reduction ratio is 4% to obtain a secondary purified water phase, wherein the concentration of the 3-acetoxymethyl cefazolin intermediate in the secondary water phase is 7-10%;
4. controlling the temperature to be 23-28 ℃, dropwise adding 3M ammonia water into the secondary purified water phase to adjust the pH value to be 7.0-7.8, adding 23g of cephalosporin C deacetylase, dropwise adding 3M ammonia water to keep the pH value to be 7.0-7.8 at the temperature of 20-30 ℃, filtering after the pH value is stable, adding 120ml of dispersant dichloromethane into the filtered water phase, then controlling the temperature to be 10-25 ℃, dropwise adding 4M phosphoric acid water solution to be pH2.2, cooling to be 0-5 ℃, then growing crystals for 30min, carrying out suction filtration and washing, drying the filter cake in an oven at 25-30 ℃ and 0.095MPa under reduced pressure for 4h until the moisture content is less than 1.0%, obtaining 29.0g of a target product, and detecting that the purity (HPLC) of the target product 3-hydroxymethyl ceftizolid is 99.2%.
Example 3:
a. preparation of 7-ACA solution: under the condition of-20 to-40 ℃, sequentially adding 320ml of dichloromethane and 35.4g of 7-ACA into a 500ml four-mouth bottle, controlling the temperature to be-15 to 20 ℃, then dropwise adding 18.1g of tetramethylguanidine until the mixture is dissolved and clarified to obtain a 7-ACA solution, and then cooling to-25 ℃ for later use;
b. preparing a tetrazoleacetic acid mixed anhydride solution: under the condition of-20 to-60 ℃, adding 450ml of dichloromethane, 25.0g of tetrazoleacetic acid and 28g of N, N-dimethylacetamide into another 1L four-necked bottle, controlling the temperature to be-20 to-25 ℃, stirring for 10min, dropwise adding 22.5g of triethylamine within about 15min, after the tetrazoleacetic acid is dissolved, sequentially adding 2.0g of N-methylmorpholine and 23.25g of pivaloyl chloride, controlling the temperature to be-20 to-28 ℃, and stirring for 1.5h to obtain a tetrazoleacetic acid mixed anhydride solution;
c. 3-hydroxymethyl cefazolin preparation:
1. transferring 7-ACA solution into tetrazoleacetic acid mixed anhydride at the temperature of-40 ℃ to-50 ℃ for about 5min, adjusting the temperature to-10 ℃ to-35 ℃ for condensation reaction, stirring for 1h, adding 400ml of purified water at the temperature of 10-20 ℃, adjusting the pH to 6.0-8.0 by using 8% sodium hydroxide aqueous solution, stirring for hydrolysis for 10min, standing for phase separation, adding 120ml of purified water into the organic phase after phase separation, adjusting the pH to 6.0-8.0 by using 8% sodium hydroxide aqueous solution, stirring for 10min, standing for phase separation, and combining the two aqueous phases for later use;
2. adding 250ml of chloroform solvent into the combined water phase, stirring for 15min, standing and phase splitting to obtain a primary purified water phase;
3. concentrating the primary purified water phase at the external temperature of 40 ℃ and under the reduced pressure of-0.095 Mpa until no bubbles emerge and the concentration is 4 percent, thus obtaining a secondary purified water phase, wherein the concentration of the 3-acetoxymethyl cefazolin intermediate in the secondary water phase is 7 to 10 percent;
4. controlling the temperature to be 23-28 ℃, dropwise adding 3M ammonia water into the secondary purified water phase to adjust the pH value to be 7.0-7.8, adding 19g of cephalosporin C deacetylase, dropwise adding 3M ammonia water to keep the pH value to be 7.0-7.8 at the temperature of 20-30 ℃, filtering after the pH value is stable, adding 180ml of dispersant ethyl acetate into the filtered water phase, then controlling the temperature to be 10-25 ℃, dropwise adding 4M sulfuric acid water solution to the pH value of 1.8, cooling to 0-5 ℃, then growing crystals for 30min, carrying out suction filtration and washing, drying the filter cake in an oven at the temperature of 25-30 ℃ and the pressure of 0.095MPa for 4h under reduced pressure until the moisture content is less than 1.0%, obtaining 28.7g of a target product, and detecting that the purity (HPLC) of the target product 3-hydroxymethyl ceftizolid in the embodiment is 98.8%.
Example 4:
a. preparation of 7-ACA solution: under the condition of-20 to-40 ℃, 400ml of dichloromethane and 35.4g of 7-ACA are sequentially added into a 500ml four-mouth bottle, the temperature is controlled to be-15 to 20 ℃, 21.0g of tetramethylguanidine is dropwise added until the mixture is dissolved and clarified to obtain a 7-ACA solution, and then the temperature is reduced to-25 ℃ for later use;
b. preparing a tetrazoleacetic acid mixed anhydride solution: under the condition of-20 to-60 ℃, sequentially adding 370ml of dichloromethane, 23.3g of tetrazoleacetic acid and 30.0g of N, N-dimethylacetamide into another 1L four-necked bottle, controlling the temperature to be-20 to-25 ℃, stirring for 10min, dropwise adding 21.0g of triethylamine within about 15min, after the tetrazoleacetic acid is dissolved, sequentially adding 1.4g of pyridine and 27.6g of pivaloyl chloride, controlling the temperature to be-20 to-28 ℃, and stirring for 1.5h to obtain a tetrazoleacetic acid mixed anhydride solution;
c. 3-hydroxymethyl cefazolin preparation:
1. transferring 7-ACA solution into a tetrazoleacetic acid mixed anhydride solution for about 5min at the temperature of between 40 ℃ below zero and 50 ℃ below zero, carrying out condensation reaction at the temperature of between 10 ℃ below zero and 35 ℃ below zero, stirring for 1h, adding 450ml of purified water at the temperature of between 10 ℃ and 20 ℃, adjusting the pH to be 6.0 to 7.0 by using a 7 mass percent sodium bicarbonate aqueous solution, stirring for hydrolysis for 10min, standing for phase separation, adding 100ml of purified water into the phase-separated organic phase, adjusting the pH to be 6.0 to 8.0 by using a 7 mass percent sodium bicarbonate aqueous solution, stirring for 10min, standing for phase separation, and combining the two water phases for later use;
2. adding 500ml of dichloromethane solvent into the combined water phase, stirring for 15min, standing and phase splitting to obtain a primary purified water phase;
3. concentrating the primary purified water phase at the external temperature of 30-45 ℃ and under the pressure of-0.095 Mpa until the weight reduction ratio is 5% to obtain a secondary purified water phase, wherein the concentration of the 3-acetoxymethyl cefazolin intermediate in the secondary water phase is 7% -10%;
4. controlling the temperature to be 20-30 ℃, dropwise adding 3M ammonia water into the secondary purified water phase to adjust the pH value to be 7.0-7.8, then adding 24.0g of cephalosporin C deacetylase, dropwise adding 3M ammonia water to keep the pH value to be 7.0-7.8 at the temperature of 20-30 ℃, filtering after the pH value is stabilized, then adding 150ml of dispersant ethyl acetate into the filtered water phase, controlling the temperature to be 10-25 ℃, dropwise adding 4M sulfuric acid water solution to the pH value of 1.8, then cooling to 0-5 ℃, growing crystals for 30min, carrying out suction filtration and washing, drying a filter cake in an oven at the temperature of 25-30 ℃ and 0.095MPa under reduced pressure for 4h until the moisture content is less than 1.0%, and obtaining 29.9g of a target product, wherein the purity (HPLC) of the target product 3-hydroxymethyl cefazolin the embodiment is 98.9% by detection.
Example 5:
a. preparation of 7-ACA solution: sequentially adding 300ml of chloroform and 35.4g of 7-ACA into a 500ml four-mouth bottle at the temperature of-20 to-30 ℃, controlling the temperature to be-15 to-10 ℃, dropwise adding 18.8g of tetramethylguanidine until the mixture is dissolved and clarified to obtain a 7-ACA solution, and then cooling to-25 ℃ for later use;
b. preparing a tetrazoleacetic acid mixed anhydride solution: under the condition of-40 to-60 ℃, 295ml of chloroform, 20.0g of tetrazoleacetic acid and 24.0g of N, N-dimethylacetamide are sequentially added into another 1L four-necked bottle, the temperature is controlled to be-20 to-25 ℃, stirring is carried out for 10min, 16.5g of triethylamine is dropwise added within about 15min, after the tetrazoleacetic acid is dissolved, 1.0g of 2, 6-dimethylpyridine and 22.3g of pivaloyl chloride are sequentially added, and stirring is carried out for 1.5h at the temperature of-20 to-28 ℃ to obtain a tetrazoleacetic acid mixed anhydride solution;
c. 3-hydroxymethyl cefazolin preparation:
1. transferring 7-ACA solution into a tetrazoleacetic acid mixed anhydride solution for about 5min at the temperature of between 40 ℃ below zero and 50 ℃ below zero, carrying out condensation reaction at the temperature of between 10 ℃ below zero and 35 ℃ below zero, stirring for 1h, adding 400ml of purified water at the temperature of between 10 ℃ and 20 ℃, adjusting the pH to be 6.0 to 7.0 by using a sodium carbonate aqueous solution with the mass concentration of 10%, stirring for hydrolysis for 10min, standing for phase separation, adding 100ml of purified water into the phase-separated organic phase, adjusting the pH to be 6.0 to 8.0 by using a sodium carbonate aqueous solution with the mass concentration of 10%, stirring for 10min, standing for phase separation, and combining the two water phases for later use;
2. adding 350ml of chloroform solvent into the combined water phase, stirring for 15min, standing and phase splitting to obtain a primary purified water phase;
3. concentrating the primary purified water phase at the external temperature of 30-45 ℃ and under the pressure of-0.095 Mpa until the weight reduction ratio is 3% to obtain a secondary purified water phase, wherein the concentration of the 3-acetoxymethyl cefazolin intermediate in the secondary water phase is 7% -10%;
4. controlling the temperature to be 20-30 ℃, dropwise adding 3M ammonia water into the secondary purified water phase to adjust the pH value to be 7.0-7.8, then adding 17.7g of cephalosporin C deacetylase, dropwise adding 3M ammonia water to keep the pH value to be 7.0-7.8 at the temperature of 20-30 ℃, filtering after the pH value is stable, then adding 70ml of dispersant chloroform into the filtered water phase, then controlling the temperature to be 10-25 ℃, dropwise adding 4M hydrochloric acid water solution to reach the pH value of 1.8, then cooling to 0-5 ℃, then growing crystals for 30min, then carrying out suction filtration and washing, drying the filter cake for 4h at the temperature of 25-30 ℃ and under the pressure of 0.095MPa by using an oven until the moisture content is less than 1.0% to obtain a target product 29.4g, and detecting that the purity (HPLC) of the target product 3-hydroxymethyl cefazolin the embodiment is 99.0%.
Example 6:
a. preparation of 7-ACA solution: under the condition of-30 to-40 ℃, sequentially adding 430ml of dichloromethane and 35.4g of 7-ACA into a 500ml four-mouth bottle, controlling the temperature to be-15 to-10 ℃, dropwise adding 23.8g of tetramethylguanidine until the mixture is dissolved and clarified to obtain a 7-ACA solution, and then cooling to-25 ℃ for later use;
b. preparing a tetrazoleacetic acid mixed anhydride solution: under the condition of-20 to-40 ℃, adding 400ml of dichloromethane, 24.8g of tetrazoleacetic acid and 27.8g of N, N-dimethylacetamide into another 1L four-necked bottle in sequence, controlling the temperature to be-20 to-25 ℃, stirring for 10min, dropwise adding 19.8g of triethylamine within about 15min, after the tetrazoleacetic acid is dissolved, sequentially adding 2, 6-dimethylpyridine and 21.0g of pivaloyl chloride, controlling the temperature to be-20 to-28 ℃, and stirring for 1.5h to obtain a tetrazoleacetic acid mixed anhydride solution;
c. 3-hydroxymethyl cefazolin preparation:
1. transferring 7-ACA solution into a tetrazoleacetic acid mixed anhydride solution for about 5min at the temperature of between 40 ℃ below zero and 50 ℃ below zero, carrying out condensation reaction at the temperature of between 20 ℃ below zero and 35 ℃ below zero, stirring for 1h, adding 400ml of purified water at the temperature of between 10 ℃ and 20 ℃, adjusting the pH to be 6.0 to 7.0 by using a 7 mass percent sodium bicarbonate aqueous solution, stirring for hydrolysis for 10min, standing for phase separation, adding 100ml of purified water into the phase-separated organic phase, adjusting the pH to be 6.0 to 8.0 by using a 7 mass percent sodium bicarbonate aqueous solution, stirring for 10min, standing for phase separation, and combining the two water phases for later use;
2. adding 300ml of ethyl acetate solvent into the combined water phase, stirring for 15min, standing and phase splitting to obtain a primary purified water phase;
3. concentrating the primary purified water phase at the external temperature of 30-45 ℃ and under the pressure of-0.095 Mpa until the weight reduction ratio is 4% to obtain a secondary purified water phase, wherein the concentration of the 3-acetoxymethyl cefazolin intermediate in the secondary water phase is 7% -10%;
4. controlling the temperature to be 20-30 ℃, dropwise adding 3M ammonia water into the secondary purified water phase to adjust the pH value to be 7.0-7.8, then adding 19.5g of cephalosporin C deacetylase, dropwise adding 3M ammonia water to keep the pH value to be 7.0-7.8 at the temperature of 20-30 ℃, filtering after the pH value is stabilized, then adding 200ml of dispersant ethyl acetate into the filtered water phase, controlling the temperature to be 10-25 ℃, dropwise adding 4M phosphoric acid water solution to reach the pH value of 1.8, then cooling to 0-5 ℃, growing crystals for 30min, carrying out suction filtration and washing, drying a filter cake in an oven at the temperature of 25-30 ℃ and under the pressure of 0.095MPa for 4h under reduced pressure until the moisture content is less than 1.0% to obtain a target product 29.3g, and detecting that the purity (HPLC) of the target product 3-hydroxymethyl azoline in the embodiment is 99.1%.
Claims (1)
1. A preparation method of 3-hydroxymethyl cefazolin is characterized by comprising the following steps:
a. preparation of 7-ACA solution: adding 7-ACA into dichloromethane or chloroform at the temperature of-20 to-40 ℃, then dropwise adding tetramethylguanidine until the solution is dissolved and clarified to obtain a 7-ACA solution, wherein the molar ratio of the 7-ACA to the tetramethylguanidine is 1:1.2 to 1.6, and the mass part ratio of the 7-ACA to the dichloromethane or chloroform is 1:9.3 to 17.0;
b. preparing a tetrazoleacetic acid mixed anhydride solution: under the condition of-20 to-60 ℃, after adding tetrazoleacetic acid into dichloromethane or chloroform, sequentially adding N, N-dimethylacetamide, triethylamine, a catalyst and pivaloyl chloride, controlling the temperature to be-20 to-28 ℃, stirring for 1.5 hours to obtain a tetrazoleacetic acid mixed anhydride solution, wherein the molar ratio of the tetrazoleacetic acid to 7-ACA is 1.05 to 1.50:1, the mass part ratio of the dichloromethane or chloroform to the tetrazoleacetic acid is 20.0 to 24.0:1, the mass part ratio of the N, N-dimethylacetamide to the tetrazoleacetic acid is 1.10 to 1.30:1, the mass part ratio of the triethylamine to the tetrazoleacetic acid is 0.8 to 1.0:1, the mass part ratio of the catalyst to the tetrazoleacetic acid is 0.02 to 0.08:1, the molar ratio of the pivaloyl chloride to the tetrazoleacetic acid is 0.6 to 1.0:1, and the catalyst is pyridine, 2, 6-lutidine or N-methylmorpholine;
c. 3-hydroxymethyl cefazolin preparation:
dropwise adding a 7-ACA solution into a tetrazoleacetic acid mixed anhydride solution at the temperature of-40 ℃ to-50 ℃, adjusting the temperature to-10 ℃ to-35 ℃ for condensation reaction, adding purified water after reacting for 1h, adjusting the pH value to 6.0-8.0 by using inorganic base, standing for phase separation, adding the purified water into an organic phase, adjusting the pH value to 6.0-8.0 by using the inorganic base, standing for phase separation, and combining two water phases for later use, wherein the inorganic base is sodium carbonate, sodium bicarbonate or sodium hydroxide;
adding an organic solvent into the combined water phase, standing and phase splitting to obtain a primary purified water phase, wherein the volume ratio of the organic solvent to the water phase is 0.4-1.0: 1, and the organic solvent is dichloromethane, ethyl acetate or chloroform;
concentrating the primary purified water phase at the external temperature of 30-45 ℃ and under the reduced pressure of-0.095 Mpa until the weight reduction ratio is 2-5% to obtain a secondary purified water phase;
controlling the temperature to be 20-30 ℃, dropwise adding ammonia water into the secondary purified water phase to adjust the pH value to be 7.0-7.8, then adding cephalosporin C deacetylase, dropwise adding ammonia water to keep the pH value to be 7.0-7.8 under the condition of 20-30 ℃, filtering, then adding a dispersing agent into the filtered water phase, controlling the temperature to be 10-25 ℃, dropwise adding inorganic acid to reach the pH value of 1.7-2.2, then cooling to 0-5 ℃, then growing crystals for 30min, filtering, washing, and drying under the vacuum condition of 25-35 ℃ and-0.095 Mpa until the moisture content is less than 1.0%, wherein the mass part ratio of the cephalosporin C deacetylase to 7-ACA is 0.40-0.70: 1, the mass part ratio of the dispersing agent to 7-ACA is 2.0-5.0: 1, the dispersing agent is dichloromethane, ethyl acetate or chloroform, and the inorganic acid is hydrochloric acid, sulfuric acid or phosphoric acid.
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| CN107964558A (en) * | 2017-11-07 | 2018-04-27 | 河北九派制药股份有限公司 | A kind of cefotiam hydrochloride impurity takes off the preparation method of tetrazole Cefotiam |
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