A preparation method and application of an oxygen cephalosporin intermediate OZ

Abstract

The present invention provides a method for preparing an oxygen cephalosporin intermediate OZ, the preparation method comprising using a compound shown in formula I as a raw material, triphenylphosphine as a desulfurizing agent, toluene and dichloroethane as solvents for reflux reaction, and preparing an oxygen cephalosporin intermediate OZ shown in formula II. The present invention tests the effects of different organic phosphines on the reaction. According to liquid phase reaction monitoring data, triphenylphosphine is the best. By using a specific precipitation solvent, the crystallization effect is good, and the purity of the product is improved. At the same time, the present invention tests the effects of different organic solvents on the reaction. Among them, a mixed solvent of toluene and dichloroethane is the best for the reaction, and the reaction conversion rate can reach more than 80%. The present invention has a short process route, mild reaction control conditions, simple operation, high yield, low cost, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediate preparation, and particularly relates to a preparation method and application of an oxycephalosporin intermediate OZ. Background Art

[0002] Oxycephalosporin intermediate OZ, chemical name: [1R-[1a,5a,6(R)]]-a-(1-methylvinyl)-3-(4-methylphenyl)-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-ene-6-acetic acid (diphenyl) methyl ester, molecular formula: C 29 H 26 O4N2, molecular weight: 466.19, CAS number: 67978-05-6, properties: white or off-white crystalline powder, easily soluble in dichloromethane, acetone, acetonitrile; poorly soluble in methanol, ethanol, cyclohexane; insoluble in water. The molecular structure is as follows:

[0003]

[0004] Fluoxetine sodium is an oxacephalosporin antibiotic developed and marketed by Shionogi Pharmaceutical Co., Ltd. in Japan in 1988. The finished product is used as an injection in the form of sodium salt. It is very stable to beta-lactamase, and its antibacterial spectrum is similar to other third-generation cephalosporins, mainly including Staphylococcus, Streptococcus (except Enterococcus), Streptococcus pneumoniae, Peptostreptococcus, Catarrhalis, Neisseria gonorrhoeae, Escherichia coli, Klebsiella, Proteus, Haemophilus influenzae, and Bacteroides.

[0005] Latamoxef sodium is an oxycephalosporin antibiotic developed by Shionogi Pharmaceutical Co., Ltd. of Japan. It was first launched in Germany in 1981 and has good antibacterial effects on a variety of Gram-negative bacteria. Escherichia coli, influenza bacillus, Klebsiella, various types of Proteus, Enterobacter, Citrobacter, Serratia, etc. are highly sensitive to latamoxef sodium. It also has good antibacterial effects on anaerobic bacteria (Bacteroides), which is better than other first, second and third generation cephalosporins. Latamoxef sodium has strong resistance to β-lactamase and low drug resistance. Latamoxef sodium has poor effects on Pseudomonas aeruginosa and Acinetobacter. Its effect on Gram-positive bacteria such as Staphylococcus aureus and Pneumococcus is weaker than that of cephalothin, cefazolin and penicillin.

[0006] Fluoxetine sodium or fluoxetine sodium is used for pneumonia, tracheitis, pleurisy, skin and soft tissue infections, bone and joint infections, infections of the five senses, wounds, etc. caused by the above-mentioned sensitive bacteria. It can also be used for sepsis and meningitis. It has good effects on lower respiratory tract infections, abdominal infections, biliary tract infections, and genitourinary system infections.

[0007] Currently, there are no patents or literature reports on the synthesis method of the oxycephalosporin intermediate OZ, and there is a lack of mature and production-applicable process technology in the synthesis process technology. Summary of the invention

[0008] The invention aims to provide a preparation method of an oxygen cephalosporin intermediate OZ and application thereof. The oxygen cephalosporin intermediate YGH is subjected to desulfurization and cyclization under the action of an organic phosphine, and the proportion of the organic phosphine is adjusted to obtain an oxygen cephalosporin intermediate OZ with high conversion rate and high target purity. The invention has a short process route, mild reaction control conditions, simple operation, high yield, low cost and is suitable for industrial production.

[0009] In order to achieve the above object, the present invention provides the following technical solutions:

[0010] A method for preparing an oxygen cephalosporin intermediate OZ, the method comprising: using a compound shown in formula I as a raw material, triphenylphosphine as a desulfurizing agent, toluene and dichloroethane as solvents for reflux reaction, and preparing an oxygen cephalosporin intermediate OZ shown in formula II;

[0011] The chemical reaction formula is as follows

[0012]

[0013] Furthermore, the method specifically includes the following steps:

[0014] (1) Adding a compound of formula I into a reaction vessel, wherein the compound of formula I is an oxocephalexin intermediate YGH, adding toluene and dichloroethane, adding triphenylphosphine, heating to 110° C. under stirring, and reflux reaction for 5.5-6.5 hours to obtain a reaction solution;

[0015] (2) cooling the reaction solution and pouring it into a distillation container, stirring and concentrating it in vacuum until the volume of the solution is reduced by three quarters and the fluidity is poor, and stirring and crystallizing is performed: adding a crystallization solvent to the reaction solution, adjusting the temperature to 10-15° C., and stirring at 60-70 rpm for 30-40 min; continuing to cool to 0-5° C., stirring at 60-70 rpm for 30-40 min; filtering to obtain a filter cake;

[0016] (3) The filter cake is washed with methanol to obtain a white solid, and the product oxycephalosporin intermediate OZ is obtained.

[0017] Furthermore, the reflux reaction process is monitored by HPLC sampling, and the reaction is terminated when the residual amount of the oxocephalexin intermediate YGH is less than 0.5%.

[0018] Furthermore, the reaction solution was cooled to below 25°C.

[0019] Furthermore, the reaction solution was cooled to 20°C.

[0020] Furthermore, the molar ratio of the oxygen cephalosporin intermediate YGH to triphenylphosphine is (37-39):(58-60).

[0021] Furthermore, the molar ratio of the oxacephalosporin intermediate YGH to triphenylphosphine is 38.7:59.

[0022] During the experiment, it was found that the types of desulfurizer and solvent affect the conversion rate of the reaction. According to the liquid phase reaction monitoring data, the desulfurizer is triphenylphosphine, toluene and dichloroethane mixed solvent. The two are compounded and work synergistically, with the best reaction effect and a conversion rate of more than 85%. The conversion rate of tributylphosphine is about 75-80%, and other phosphine reagents react poorly, with conversion rates below 60%.

[0023] Furthermore, the sum of the masses of toluene and ethylene dichloride is 15-25 times the mass of the oxycephalosporin intermediate YGH.

[0024] Furthermore, the volume ratio of toluene to ethylene dichloride is (0.8-1.2):1.

[0025] Furthermore, the volume ratio of toluene to ethylene dichloride is 1:1.

[0026] Furthermore, the mass ratio of the crystallization solvent to the oxygen cephalosporin intermediate YGH is (11-13):20.

[0027] Furthermore, the crystallization solvent is a mixture of methanol, N-methylpyrrolidone and acetonitrile in a volume ratio of (4-4.5):1:(0.4-0.6).

[0028] Furthermore, the crystallization solvent is a mixture of methanol, N-methylpyrrolidone and acetonitrile in a volume ratio of 4.3:1:0.5.

[0029] The inventors found that in the post-processing process, the reaction byproduct triphenylphosphine of the triphenylphosphine system is difficult to separate from the product OZ, which will affect the purity of the product oxygen cephalosporin intermediate OZ. The present invention has found through a large number of experiments that the use of a mixed solvent of methanol, N-methylpyrrolidone and acetonitrile in which the product has different solubility as a precipitation solvent, and the use of a gradient cooling method to precipitate crystals can improve the purity of the oxygen cephalosporin intermediate OZ. Analysis is that the mixed solvent can adjust the polarity of the solvent, combined with factors such as the temperature during crystallization, thereby affecting the formation and growth process of the crystal, through the influence of these comprehensive factors, the crystal can be formed more well during the crystallization process, thereby removing impurities and impure substances, and improving the purity and efficiency of the crystal.

[0030] The present invention also provides the use of the oxycephalosporin intermediate OZ in the preparation of oxycephalosporin drugs.

[0031] Furthermore, the oxacephalosporin drug is fluoxetine sodium or latamoxetine sodium.

[0032] Compared with the prior art, the advantages and beneficial effects of the present invention are:

[0033] 1. Currently, there is no special research on the synthesis process technology of this product. The present invention is to develop a new synthesis process for the oxygen cephalosporin intermediate OZ. The key points of the synthesis method are short process route and mild reaction control conditions. Through this technical research and invention, highly toxic chemical raw materials are removed, and the organic solvent used is simple and easy to recover and separate.

[0034] 2. The present invention tests the effects of different organic phosphines on the reaction, including triphenylphosphine, triethyl phosphite, tripropylphosphine, and tributylphosphine. According to the liquid phase reaction monitoring data, triphenylphosphine is the best, with a reaction conversion rate of 80-85%, and tributylphosphine has a reaction conversion rate of 75-80%. Other phosphine reagents have poor reactions, with conversion rates all below 60%. In the post-processing process, the reaction byproduct triphenylphosphine sulfide of the triphenylphosphine system is difficult to separate from the product OZ. The present invention selects a specific precipitation solvent to improve the purity of OZ, which is as high as more than 99%.

[0035] 3. The present invention tests the effects of different organic solvents on the reaction, including toluene, ethylene dichloride, ethyl acetate, and isobutanol; among them, a mixed solvent of toluene and ethylene dichloride has the best effect on the reaction.

[0036] The invention has a short synthesis route, mild reaction control conditions, a simple reaction solvent system, and is easy to separate and recycle; a high reaction conversion rate and stable product quality. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 The present invention is a flow chart of the preparation method.

[0038] Figure 2 The high performance liquid chromatography (HPLC) of the oxygen cephalosporin intermediate YGH used in the present invention.

[0039] Figure 3 This is the NMR image of the oxycephalosporin intermediate OZ of Example 1.

[0040] Figure 4 This is the high performance liquid chromatography of the oxycephalosporin intermediate OZ of Example 1. DETAILED DESCRIPTION

[0041] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0042] The compound represented by formula I of the present invention: the oxygen cephalosporin intermediate YGH was purchased from Hubei Xinrunde Chemical Co., Ltd.

[0043] Example 1

[0044] This embodiment provides a method for preparing an oxocephalosporin intermediate OZ, the preparation method comprising the following steps:

[0045] (1) Add 38.7 mmol of the oxycephalosporin intermediate YGH to a 1000 mL clean and dry four-necked reaction flask, add 200 mL of toluene, 200 mL of dichloroethane, and 59 mmol of triphenylphosphine, and heat the contents of the reaction flask to 110° C. in an oil bath while stirring, and reflux for 6 hours; monitor the reaction process by sampling with HPLC, and terminate the reaction when the residual YGH is less than 0.5%, obtain a reaction solution, and cool the reaction solution to 20° C.;

[0046] (2) The reaction solution was poured into a distillation reaction bottle, and vacuum concentrated to dryness with poor fluidity under stirring, and stirred for crystallization: a crystallization solvent was added to the reaction solution, the mass ratio of the crystallization solvent to the oxygen cephalosporin intermediate YGH was 3:5, and the crystallization solvent was a mixture of methanol, N-methylpyrrolidone and acetonitrile in a volume ratio of 4.3:1:0.5. The temperature was adjusted to 13°C, and the mixture was stirred at 65 rpm for 35 minutes; the temperature was further lowered to 3°C, and the mixture was stirred at 65 rpm for 35 minutes; the filter cake was obtained, and the filter cake was washed three times with 30 mL of 3°C methanol to obtain a white solid, which was vacuum dried at 35°C for 2 hours to obtain the product oxygen cephalosporin intermediate OZ, with a reaction conversion rate of 85.3% and a purity of 99.1%.

[0047] like Figure 2 As shown, the raw material oxygen cephalosporin intermediate YGH used in the present invention has high purity. Figure 3 The structure of the product of the present invention can be obtained by Figure 4 It can be seen that the purity of the product prepared in Example 1 is above 99%.

[0048] Example 2

[0049] This embodiment provides a method for preparing an oxocephalosporin intermediate OZ, the preparation method comprising the following steps:

[0050] (1) Add 37 mmol of the oxygen cephalosporin intermediate YGH to a 1000 mL clean and dry four-necked reaction flask, add 190 mL of toluene, 210 mL of dichloroethane, and 58 mmol of triphenylphosphine, and heat the material temperature in the reaction flask to 110° C. in an oil bath while stirring, and reflux, and reflux for 5.8 hours; the reaction process is monitored by HPLC sampling, and the reaction is completed when the YGH residue is less than 0.5%, and a reaction solution is obtained, and the reaction solution is cooled to 20° C.;

[0051] (2) The reaction solution was poured into a distillation reaction bottle, and vacuum concentrated to dryness with poor fluidity under stirring, and stirred for crystallization: a crystallization solvent was added to the reaction solution, the mass ratio of the crystallization solvent to the oxygen cephalosporin intermediate YGH was 11:20, and the crystallization solvent was a mixture of methanol, N-methylpyrrolidone and acetonitrile in a volume ratio of 4:1:0.4. The temperature was adjusted to 15°C, and the mixture was stirred at 60 rpm for 30 minutes; the temperature was further lowered to 5°C, and the mixture was stirred at 60 rpm for 30 minutes; a filter was filtered to obtain a filter cake, and the filter cake was washed three times with 30 mL of 5°C methanol to obtain a white solid, which was vacuum dried at 35°C for 2 hours to obtain the product oxygen cephalosporin intermediate OZ, with a reaction conversion rate of 83.5% and a purity of 99.3%.

[0052] Example 3

[0053] This embodiment provides a method for preparing an oxocephalosporin intermediate OZ, the preparation method comprising the following steps:

[0054] (1) Add 37 mmol of the oxygen cephalosporin intermediate YGH to a 1000 mL clean and dry four-necked reaction flask, add 210 mL of toluene, 190 mL of dichloroethane, and 60 mmol of triphenylphosphine, and heat the material temperature in the reaction flask to 110° C. in an oil bath while stirring, and reflux, and reflux for 6.2 hours; the reaction process is monitored by HPLC sampling, and the reaction is completed when the YGH residue is less than 0.5%, and a reaction solution is obtained, and the reaction solution is cooled to 20° C.;

[0055] (2) The reaction solution was poured into a distillation reaction bottle, and vacuum concentrated to dryness with poor fluidity under stirring, and stirred for crystallization: a crystallization solvent was added to the reaction solution, the mass ratio of the crystallization solvent to the oxygen cephalosporin intermediate YGH was 13:20, and the crystallization solvent was a mixture of methanol, N-methylpyrrolidone and acetonitrile in a volume ratio of 4.5:1:0.4. The temperature was adjusted to 10°C, and the mixture was stirred at 70 rpm for 40 minutes; the temperature was further lowered to 0°C, and the mixture was stirred at 70 rpm for 40 minutes; a filter was obtained to obtain a filter cake, and the filter cake was washed three times with 30 mL of 0°C methanol to obtain a white solid, which was vacuum dried at 35°C for 2 hours to obtain the product oxygen cephalosporin intermediate OZ, with a reaction conversion rate of 84.1% and a purity of 99.2%.

[0056] Comparative Example 1

[0057] The difference between this comparative example and Example 1 is that the solvent used in the reaction is toluene.

[0058] A method for preparing an oxycephalosporin intermediate OZ, the method comprising the following steps:

[0059] (1) Add 38.7 mmol of the oxygen cephalosporin intermediate YGH, 400 mL of toluene, and 59 mmol of triphenylphosphine to a 1000 mL clean and dry four-necked reaction flask, heat the reaction flask to 110° C. in an oil bath under stirring, and reflux for 6 hours; monitor the reaction process by HPLC sampling, and terminate the reaction when the YGH residue is less than 0.5%, obtain a reaction solution, and cool the reaction solution to 20° C.;

[0060] (2) The reaction solution was poured into a distillation reaction bottle, and vacuum concentrated to dryness with poor fluidity under stirring, and stirred for crystallization: a crystallization solvent was added to the reaction solution, the mass ratio of the crystallization solvent to the oxygen cephalosporin intermediate YGH was 3:5, and the crystallization solvent was a mixture of methanol, N-methylpyrrolidone and acetonitrile in a volume ratio of 4.3:1:0.5. The temperature was adjusted to 13°C, and the mixture was stirred at 65 rpm for 35 minutes; the temperature was further lowered to 3°C, and the mixture was stirred at 65 rpm for 35 minutes; the filter cake was obtained, and the filter cake was washed three times with 30 mL of 3°C methanol to obtain a white solid, which was vacuum dried at 35°C for 2 hours to obtain the product oxygen cephalosporin intermediate OZ, with a reaction conversion rate of 78.6% and a purity of 96.2%.

[0061] Comparative Example 2

[0062] The difference between this comparative example and Example 1 is that the solvent used in the reaction is ethylene dichloride.

[0063] A method for preparing an oxycephalosporin intermediate OZ, the method comprising the following steps:

[0064] (1) Add 38.7 mmol of the oxygen cephalosporin intermediate YGH, 400 mL of dichloroethane, and 59 mmol of triphenylphosphine to a 1000 mL clean and dry four-necked reaction flask, heat the reaction flask to 110° C. in an oil bath under stirring, and reflux for 6 hours; monitor the reaction process by HPLC sampling, and terminate the reaction when the YGH residue is less than 0.5%, obtain a reaction solution, and cool the reaction solution to 20° C.;

[0065] (2) The reaction solution was poured into a distillation reaction bottle, and vacuum concentrated to dryness with poor fluidity under stirring, and stirred for crystallization: a crystallization solvent was added to the reaction solution, the mass ratio of the crystallization solvent to the oxygen cephalosporin intermediate YGH was 3:5, and the crystallization solvent was a mixture of methanol, N-methylpyrrolidone and acetonitrile in a volume ratio of 4.3:1:0.5. The temperature was adjusted to 13°C, and the mixture was stirred at 65 rpm for 35 minutes; the temperature was further lowered to 3°C, and the mixture was stirred at 65 rpm for 35 minutes; the filter cake was obtained, and the filter cake was washed three times with 30 mL of 3°C methanol to obtain a white solid, which was vacuum dried at 35°C for 2 hours to obtain the product oxygen cephalosporin intermediate OZ, with a reaction conversion rate of 79.7% and a purity of 96.0%.

[0066] Comparative Example 3

[0067] The difference between this comparative example and Example 1 is that the solvent used in the reaction is ethyl acetate.

[0068] A method for preparing an oxycephalosporin intermediate OZ, the method comprising the following steps:

[0069] (1) Add 38.7 mmol of the oxygen cephalosporin intermediate YGH, 400 mL of ethyl acetate, and 59 mmol of triphenylphosphine to a 1000 mL clean and dry four-necked reaction flask, heat the reaction flask to 110° C. in an oil bath under stirring, and reflux for 6 hours; monitor the reaction process by HPLC sampling, and terminate the reaction when the YGH residue is less than 0.5%, obtain a reaction solution, and cool the reaction solution to 20° C.;

[0070] (2) The reaction solution was poured into a distillation reaction bottle, and vacuum concentrated to dryness with poor fluidity under stirring, and stirred for crystallization: a crystallization solvent was added to the reaction solution, the mass ratio of the crystallization solvent to the oxygen cephalosporin intermediate YGH was 3:5, and the crystallization solvent was a mixture of methanol, N-methylpyrrolidone and acetonitrile in a volume ratio of 4.3:1:0.5. The temperature was adjusted to 13°C, and the mixture was stirred at 65 rpm for 35 minutes; the temperature was further lowered to 3°C, and the mixture was stirred at 65 rpm for 35 minutes; the filter cake was obtained, and the filter cake was washed three times with 30 mL of 3°C methanol to obtain a white solid, which was dried at 35°C in vacuum for 2 hours to obtain the product oxygen cephalosporin intermediate OZ, with a reaction conversion rate of 75.8% and a purity of 95.6%.

[0071] Comparative Example 4

[0072] The difference between this comparative example and Example 1 is that the solvent used in the reaction is isobutanol.

[0073] A method for preparing an oxycephalosporin intermediate OZ, the method comprising the following steps:

[0074] (1) Add 38.7 mmol of the oxygen cephalosporin intermediate YGH, 400 mL of isobutyl alcohol, and 59 mmol of triphenylphosphine to a 1000 mL clean and dry four-necked reaction flask, heat the reaction flask to 110° C. in an oil bath under stirring, and reflux for 6 hours; monitor the reaction process by HPLC sampling, and terminate the reaction when the YGH residue is less than 0.5%, obtain a reaction solution, and cool the reaction solution to 20° C.;

[0075] (2) The reaction solution was poured into a distillation reaction bottle, and vacuum concentrated to dryness with poor fluidity under stirring, and stirred for crystallization: a crystallization solvent was added to the reaction solution, the mass ratio of the crystallization solvent to the oxygen cephalosporin intermediate YGH was 3:5, and the crystallization solvent was a mixture of methanol, N-methylpyrrolidone and acetonitrile in a volume ratio of 4.3:1:0.5. The temperature was adjusted to 13°C, and the mixture was stirred at 65 rpm for 35 minutes; the temperature was further lowered to 3°C, and the mixture was stirred at 65 rpm for 35 minutes; the filter cake was obtained, and the filter cake was washed three times with 30 mL of 3°C methanol to obtain a white solid, which was dried at 35°C in vacuum for 2 hours to obtain the product oxygen cephalosporin intermediate OZ, with a reaction conversion rate of 74.9% and a purity of 95.7%.

[0076] Comparative Example 5

[0077] The difference between this comparative example and Example 1 is that the amounts of toluene and ethylene dichloride used are different.

[0078] A method for preparing an oxycephalosporin intermediate OZ, the method comprising the following steps:

[0079] (1) Add 38.7 mmol of the oxygen cephalosporin intermediate YGH to a 1000 mL clean and dry four-necked reaction flask, add 100 mL of toluene, 300 mL of dichloroethane, and 59 mmol of triphenylphosphine, and heat the material temperature in the reaction flask to 110° C. in an oil bath while stirring, and reflux, and reflux for 6 hours; the reaction process is monitored by HPLC sampling, and the reaction is completed when the YGH residue is less than 0.5%, and a reaction solution is obtained, and the reaction solution is cooled to 20° C.;

[0080] (2) The reaction solution was poured into a distillation reaction bottle, and vacuum concentrated to dryness with poor fluidity under stirring, and stirred for crystallization: a crystallization solvent was added to the reaction solution, the mass ratio of the crystallization solvent to the oxygen cephalosporin intermediate YGH was 3:5, and the crystallization solvent was a mixture of methanol, N-methylpyrrolidone and acetonitrile in a volume ratio of 4.3:1:0.5. The temperature was adjusted to 13°C, and the mixture was stirred at 65 rpm for 35 minutes; the temperature was further lowered to 3°C, and the mixture was stirred at 65 rpm for 35 minutes; the filter cake was obtained, and the filter cake was washed three times with 30 mL of 3°C methanol to obtain a white solid, which was vacuum dried at 35°C for 2 hours to obtain the product oxygen cephalosporin intermediate OZ, with a reaction conversion rate of 81.4% and a purity of 96.6%.

[0081] Comparative Example 6

[0082] The difference between this comparative example and Example 1 is that the amounts of toluene and ethylene dichloride used are different.

[0083] A method for preparing an oxycephalosporin intermediate OZ, the method comprising the following steps:

[0084] (1) Add 38.7 mmol of the oxygen cephalosporin intermediate YGH to a 1000 mL clean and dry four-necked reaction flask, add 300 mL of toluene, 100 mL of dichloroethane, and 59 mmol of triphenylphosphine, and heat the material temperature in the reaction flask to 110° C. in an oil bath under stirring, and reflux for 6 hours; the reaction process is monitored by HPLC sampling, and the reaction is completed when the YGH residue is less than 0.5%, and the reaction solution is obtained, and the reaction solution is cooled to 20° C.;

[0085] (2) The reaction solution was poured into a distillation reaction bottle, and vacuum concentrated to dryness with poor fluidity under stirring, and stirred for crystallization: a crystallization solvent was added to the reaction solution, the mass ratio of the crystallization solvent to the oxygen cephalosporin intermediate YGH was 3:5, and the crystallization solvent was a mixture of methanol, N-methylpyrrolidone and acetonitrile in a volume ratio of 4.3:1:0.5. The temperature was adjusted to 13°C, and the mixture was stirred at 65 rpm for 35 minutes; the temperature was further lowered to 3°C, and the mixture was stirred at 65 rpm for 35 minutes; the filter cake was obtained, and the filter cake was washed three times with 30 mL of 3°C methanol to obtain a white solid, which was vacuum dried at 35°C for 2 hours to obtain the product oxygen cephalosporin intermediate OZ, with a reaction conversion rate of 81.3% and a purity of 96.0%.

[0086] Comparative Example 7

[0087] The difference between this comparative example and Example 1 is that the desulfurizing agent is triethyl phosphite.

[0088] A method for preparing an oxycephalosporin intermediate OZ, the method comprising the following steps:

[0089] (1) Add 38.7 mmol of the oxygen cephalosporin intermediate YGH to a 1000 mL clean and dry four-necked reaction flask, add 200 mL of toluene, 200 mL of dichloroethane, and 59 mmol of triphenylphosphine, and heat the material temperature in the reaction flask to 110° C. in an oil bath under stirring, and reflux for 6 hours; the reaction process is monitored by HPLC sampling, and the reaction is completed when the YGH residue is less than 0.5%, and the reaction solution is obtained, and the reaction solution is cooled to 20° C.;

[0090] (2) The reaction solution was poured into a distillation reaction bottle, and vacuum concentrated to dryness with poor fluidity under stirring, and stirred for crystallization: a crystallization solvent was added to the reaction solution, the mass ratio of the crystallization solvent to the oxygen cephalosporin intermediate YGH was 3:5, and the crystallization solvent was a mixture of methanol, N-methylpyrrolidone and acetonitrile in a volume ratio of 4.3:1:0.5. The temperature was adjusted to 13°C, and the mixture was stirred at 65 rpm for 35 minutes; the temperature was further lowered to 3°C, and the mixture was stirred at 65 rpm for 35 minutes; the filter cake was obtained, and the filter cake was washed three times with 30 mL of 3°C methanol to obtain a white solid, which was dried at 35°C in vacuum for 2 hours to obtain the product oxygen cephalosporin intermediate OZ, with a reaction conversion rate of 55.5% and a purity of 97.6%.

[0091] Comparative Example 8

[0092] The difference between this comparative example and Example 1 is that the desulfurizing agent is tripropyl phosphine.

[0093] A method for preparing an oxycephalosporin intermediate OZ, the method comprising the following steps:

[0094] (1) Add 38.7 mmol of the oxygen cephalosporin intermediate YGH to a 1000 mL clean and dry four-necked reaction flask, add 200 mL of toluene, 200 mL of dichloroethane, and 59 mmol of triphenylphosphine, and heat the material temperature in the reaction flask to 110° C. in an oil bath under stirring, and reflux for 6 hours; the reaction process is monitored by HPLC sampling, and the reaction is completed when the YGH residue is less than 0.5%, and the reaction solution is obtained, and the reaction solution is cooled to 20° C.;

[0095] (2) The reaction solution was poured into a distillation reaction bottle, and vacuum concentrated to dryness with poor fluidity under stirring, and stirred for crystallization: a crystallization solvent was added to the reaction solution, the mass ratio of the crystallization solvent to the oxygen cephalosporin intermediate YGH was 3:5, and the crystallization solvent was a mixture of methanol, N-methylpyrrolidone and acetonitrile in a volume ratio of 4.3:1:0.5. The temperature was adjusted to 13°C, and the mixture was stirred at 65 rpm for 35 minutes; the temperature was further lowered to 3°C, and the mixture was stirred at 65 rpm for 35 minutes; the filter cake was obtained, and the filter cake was washed three times with 30 mL of 3°C methanol to obtain a white solid, which was vacuum dried at 35°C for 2 hours to obtain the product oxygen cephalosporin intermediate OZ, with a reaction conversion rate of 58.8% and a purity of 95.9%.

[0096] Comparative Example 9

[0097] The difference between this comparative example and Example 1 is that the desulfurizing agent is tributylphosphine.

[0098] A method for preparing an oxycephalosporin intermediate OZ, the method comprising the following steps:

[0099] (1) Add 38.7 mmol of the oxygen cephalosporin intermediate YGH to a 1000 mL clean and dry four-necked reaction flask, add 200 mL of toluene, 200 mL of dichloroethane, and 59 mmol of triphenylphosphine, and heat the material temperature in the reaction flask to 110° C. in an oil bath under stirring, and reflux for 6 hours; the reaction process is monitored by HPLC sampling, and the reaction is completed when the YGH residue is less than 0.5%, and the reaction solution is obtained, and the reaction solution is cooled to 20° C.;

[0100] (2) The reaction solution was poured into a distillation reaction bottle, and vacuum concentrated to dryness with poor fluidity under stirring, and stirred for crystallization: a crystallization solvent was added to the reaction solution, the mass ratio of the crystallization solvent to the oxygen cephalosporin intermediate YGH was 3:5, and the crystallization solvent was a mixture of methanol, N-methylpyrrolidone and acetonitrile in a volume ratio of 4.3:1:0.5. The temperature was adjusted to 13°C, and the mixture was stirred at 65 rpm for 35 minutes; the temperature was further lowered to 3°C, and the mixture was stirred at 65 rpm for 35 minutes; the filter cake was obtained, and the filter cake was washed three times with 30 mL of 3°C methanol to obtain a white solid, which was vacuum dried at 35°C for 2 hours to obtain the product oxygen cephalosporin intermediate OZ, with a reaction conversion rate of 78.8% and a purity of 99.4%.

[0101] Comparative Example 10

[0102] The difference between this comparative example and Example 1 is that the crystallization solvent is methanol.

[0103] A method for preparing an oxycephalosporin intermediate OZ, the method comprising the following steps:

[0104] (1) Add 38.7 mmol of the oxygen cephalosporin intermediate YGH to a 1000 mL clean and dry four-necked reaction flask, add 200 mL of toluene, 200 mL of dichloroethane, and 59 mmol of triphenylphosphine, and heat the material temperature in the reaction flask to 110° C. in an oil bath under stirring, and reflux for 6 hours; the reaction process is monitored by HPLC sampling, and the reaction is completed when the YGH residue is less than 0.5%, and the reaction solution is obtained, and the reaction solution is cooled to 20° C.;

[0105] (2) The reaction liquid was poured into a distillation reaction bottle, and vacuum concentrated to dryness with poor fluidity under stirring, and stirred for crystallization: a crystallization solvent was added to the reaction liquid, the mass ratio of the crystallization solvent to the oxygen cephalosporin intermediate YGH was 3:5, the crystallization solvent was methanol, the temperature was adjusted to 13°C, and the mixture was stirred at 65 rpm for 35 minutes; the temperature was further lowered to 3°C, and the mixture was stirred at 65 rpm for 35 minutes; the filter cake was obtained, and the filter cake was washed three times with 30 mL of 3°C methanol to obtain a white solid, which was vacuum dried at 35°C for 2 hours to obtain the product oxygen cephalosporin intermediate OZ, with a reaction conversion rate of 85.2% and a purity of 93.2%.

[0106] Comparative Example 11

[0107] The difference between this comparative example and Example 1 is that the crystallization solvent is cyclohexane.

[0108] A method for preparing an oxycephalosporin intermediate OZ, the method comprising the following steps:

[0109] (1) Add 38.7 mmol of the oxygen cephalosporin intermediate YGH to a 1000 mL clean and dry four-necked reaction flask, add 200 mL of toluene, 200 mL of dichloroethane, and 59 mmol of triphenylphosphine, and heat the material temperature in the reaction flask to 110° C. in an oil bath under stirring, and reflux for 6 hours; the reaction process is monitored by HPLC sampling, and the reaction is completed when the YGH residue is less than 0.5%, and the reaction solution is obtained, and the reaction solution is cooled to 20° C.;

[0110] (2) The reaction liquid was poured into a distillation reaction bottle, and vacuum concentrated to dryness with poor fluidity under stirring, and stirred for crystallization: a crystallization solvent was added to the reaction liquid, the mass ratio of the crystallization solvent to the oxygen cephalosporin intermediate YGH was 3:5, and the crystallization solvent was cyclohexane. The temperature was adjusted to 13°C, and the mixture was stirred at 65 rpm for 35 minutes; the temperature was further lowered to 3°C, and the mixture was stirred at 65 rpm for 35 minutes; the filter cake was obtained, and the filter cake was washed three times with 30 mL of 3°C methanol to obtain a white solid, which was vacuum dried at 35°C for 2 hours to obtain the product oxygen cephalosporin intermediate OZ, with a reaction conversion rate of 85.1% and a purity of 90.5%.

[0111] Comparative Example 12

[0112] The difference between this comparative example and Example 1 is that the crystallization solvent is a mixture of methanol and N-methylpyrrolidone in a volume ratio of 4.3:1.

[0113] A method for preparing an oxycephalosporin intermediate OZ, the method comprising the following steps:

[0114] (1) Add 38.7 mmol of the oxygen cephalosporin intermediate YGH to a 1000 mL clean and dry four-necked reaction flask, add 200 mL of toluene, 200 mL of dichloroethane, and 59 mmol of triphenylphosphine, and heat the material temperature in the reaction flask to 110° C. in an oil bath under stirring, and reflux for 6 hours; the reaction process is monitored by HPLC sampling, and the reaction is completed when the YGH residue is less than 0.5%, and the reaction solution is obtained, and the reaction solution is cooled to 20° C.;

[0115] (2) The reaction solution was poured into a distillation reaction bottle, and vacuum concentrated to dryness with poor fluidity under stirring, and stirred for crystallization: a crystallization solvent was added to the reaction solution, the mass ratio of the crystallization solvent to the oxygen cephalosporin intermediate YGH was 3:5, and the crystallization solvent was a mixture of methanol and N-methylpyrrolidone in a volume ratio of 4.3:1. The temperature was adjusted to 13°C, and the mixture was stirred at 65 rpm for 35 minutes; the temperature was further lowered to 3°C, and the mixture was stirred at 65 rpm for 35 minutes; a filter was filtered to obtain a filter cake, and the filter cake was washed three times with 30 mL of 3°C methanol to obtain a white solid, which was dried at 35°C in vacuum for 2 hours to obtain the product oxygen cephalosporin intermediate OZ, with a reaction conversion rate of 85.2% and a purity of 95.4%.

[0116] Comparative Example 13

[0117] The difference between this comparative example and Example 1 is that the crystallization solvent is a mixture of methanol and acetonitrile in a volume ratio of 4.3:0.5.

[0118] A method for preparing an oxycephalosporin intermediate OZ, the method comprising the following steps:

[0119] (1) Add 38.7 mmol of the oxygen cephalosporin intermediate YGH to a 1000 mL clean and dry four-necked reaction flask, add 200 mL of toluene, 200 mL of dichloroethane, and 59 mmol of triphenylphosphine, and heat the material temperature in the reaction flask to 110° C. in an oil bath under stirring, and reflux for 6 hours; the reaction process is monitored by HPLC sampling, and the reaction is completed when the YGH residue is less than 0.5%, and the reaction solution is obtained, and the reaction solution is cooled to 20° C.;

[0120] (2) The reaction solution was poured into a distillation reaction bottle, and vacuum concentrated to dryness with poor fluidity under stirring, and stirred for crystallization: a crystallization solvent was added to the reaction solution, the mass ratio of the crystallization solvent to the oxygen cephalosporin intermediate YGH was 3:5, and the crystallization solvent was a mixture of methanol and acetonitrile in a volume ratio of 4.3:0.5. The temperature was adjusted to 13°C, and the mixture was stirred at 65 rpm for 35 minutes; the temperature was further lowered to 3°C, and the mixture was stirred at 65 rpm for 35 minutes; the filter cake was obtained, and the filter cake was washed three times with 30 mL of 3°C methanol to obtain a white solid, which was vacuum dried at 35°C for 2 hours to obtain the product oxygen cephalosporin intermediate OZ, with a reaction conversion rate of 85.3% and a purity of 95.0%.

[0121] Comparative Example 14

[0122] The difference between this comparative example and Example 1 is that the crystallization solvent is a mixture of methanol, N-methylpyrrolidone and acetonitrile in a volume ratio of 5:1:0.2.

[0123] A method for preparing an oxycephalosporin intermediate OZ, the method comprising the following steps:

[0124] (1) Add 38.7 mmol of the oxygen cephalosporin intermediate YGH to a 1000 mL clean and dry four-necked reaction flask, add 200 mL of toluene, 200 mL of dichloroethane, and 59 mmol of triphenylphosphine, and heat the material temperature in the reaction flask to 110° C. in an oil bath under stirring, and reflux for 6 hours; the reaction process is monitored by HPLC sampling, and the reaction is completed when the YGH residue is less than 0.5%, and the reaction solution is obtained, and the reaction solution is cooled to 20° C.;

[0125] (2) The reaction solution was poured into a distillation reaction bottle, and vacuum concentrated to dryness with poor fluidity under stirring, and stirred for crystallization: a crystallization solvent was added to the reaction solution, the mass ratio of the crystallization solvent to the oxygen cephalosporin intermediate YGH was 3:5, and the crystallization solvent was a mixture of methanol, N-methylpyrrolidone and acetonitrile in a volume ratio of 5:1:0.2. The temperature was adjusted to 13°C, and the mixture was stirred at 65 rpm for 35 minutes; the temperature was further lowered to 3°C, and the mixture was stirred at 65 rpm for 35 minutes; the filter cake was obtained, and the filter cake was washed three times with 30 mL of 3°C methanol to obtain a white solid, which was vacuum dried at 35°C for 2 hours to obtain the product oxygen cephalosporin intermediate OZ, with a reaction conversion rate of 85.3% and a purity of 95.9%.

[0126] The conversion rates and purities of Examples 1-3 are shown in Table 1.

[0127] Table 1

[0128] sample Conversion Rate % purity% Example 1 85.3 99.5 Example 2 83.5 99.1 Example 3 84.1 99.3

[0129] It can be seen from the results that the oxygen cephalosporin intermediate OZ prepared in Examples 1-3 of the present invention has a reaction conversion rate of 80-85% and a purity of more than 99%. It can be seen from Comparative Examples 1-2 that the reaction solvents using toluene and dichloroethane alone have a reaction conversion rate lower than 80%, and the purity also decreases. Analysis shows that the by-products increase, affecting the crystallization effect. According to Comparative Examples 3-4, when the solvents are ethyl acetate and isobutanol, the conversion rate and purity are lower. According to Comparative Examples 5-6, the ratio of toluene and dichloroethane affects the conversion rate and purity of the reaction. According to Comparative Examples 7-9, the conversion rate and purity of the products using triethyl phosphite and tripropyl phosphine as desulfurizers are relatively low, and the product purity using tributyl phosphine is higher, but the conversion rate is lower than that using triphenyl phosphine. Considering the production benefits and cost issues in industrial production, the present invention selects triphenyl phosphine as a desulfurizer. It can be seen from Comparative Examples 10-11 that the purity of only using methanol or cyclohexane as the precipitation solvent is less than 95%, but methanol is better than cyclohexane. It can be seen from Comparative Examples 12 and 13 that the purity of the product can be improved by compounding methanol with N-methylpyrrolidone or acetonitrile as the precipitation solvent, but the effect is lower than that of the embodiment. It can be seen from Comparative Example 14 that changing the ratio of the three solvents of the precipitation solvent affects the purity of the product.

[0130] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing an oxygen cephalosporin intermediate OZ, characterized in that: The preparation method comprises the steps of using the compound shown in formula I as a raw material, triphenylphosphine as a desulfurizing agent, and toluene and dichloroethane as solvents for a reflux reaction to prepare an oxycephalosporin intermediate OZ shown in formula II; The chemical reaction formula is as follows: ; The preparation method of the oxocephalosporin intermediate OZ specifically comprises the following steps: (1) Adding a compound of formula I into a reaction vessel, wherein the compound of formula I is an oxocephalexin intermediate YGH, adding toluene and dichloroethane, and then adding triphenylphosphine, mixing, heating to 110° C. with stirring, and reflux reaction for 5.5-6.5 hours to obtain a reaction solution; (2) Cooling the reaction solution and pouring it into a distillation container, stirring and concentrating it in vacuum until the volume of the solution is reduced by three quarters, and stirring and crystallizing: adding a crystallization solvent to the reaction solution, adjusting the temperature to 10-15°C, and stirring at 60-70rpm for 30-40min; continuing to cool to 0-5°C, stirring at 60-70rpm for 30-40min; filtering to obtain a filter cake; (3) The filter cake is washed with methanol to obtain a white solid, and the oxocephalexin intermediate OZ is obtained; The volume ratio of toluene to ethylene dichloride is (0.8-1.2):1; The crystallization solvent is a mixture of methanol, N-methylpyrrolidone and acetonitrile in a volume ratio of (4-4.5):1:(0.4-0.6).

2. The method for preparing the oxocephalosporin intermediate OZ according to claim 1, characterized in that: The reaction solution was cooled to below 25°C and then poured into a distillation container.

3. The method for preparing the oxocephalosporin intermediate OZ according to claim 1, characterized in that: The molar ratio of the oxygen cephalosporin intermediate YGH to triphenylphosphine is (37-39): (58-60).

4. The method for preparing the oxocephalosporin intermediate OZ according to claim 1, characterized in that: The sum of the masses of the toluene and the ethylene dichloride is 15-25 times the mass of the oxygen cephalosporin intermediate YGH.

5. The method for preparing the oxocephalosporin intermediate OZ according to claim 1, characterized in that: The mass ratio of the crystallization solvent to the oxygen cephalosporin intermediate YGH is (11-13):20.

Images