Preparation technology of cefpodoxime nucleus 7-AMCA

Abstract

The invention discloses a preparation process of cefpodoxime nucleus 7-AMCA, and relates to the technical field of 7-AMCA. The technical scheme is: add dimethyl carbonate and boron trifluoride-dimethyl carbonate complex to reaction bottle A, and drip alkylating agent; add D-7ACA, react at room temperature; add purified water, sodium pyrosulfite and disodium edetate to reaction bottle B; transfer the feed liquid in reaction bottle B to reaction bottle A, add organic solvent to the mixed solution for extraction and separation at room temperature to obtain aqueous phase; drip alkaline solution to the aqueous phase, adjust pH to 2.8-3, cool and grow crystals; drip alkaline solution again, adjust pH to 4.5-5.2, cool and grow crystals; filter out the mother liquor, wash it until colorless, drain it after rinsing with organic solvent, and vacuum dry it to obtain cefpodoxime nucleus 7-AMCA. The present invention uses D-7ACA as the starting material, improves the process flow, optimizes the preparation process of 7-AMCA, and achieves the purpose of improving product quality and yield.

Description

Technical Field

[0001] The invention relates to the technical field of 7-AMCA, and in particular to a preparation process of cefpodoxime mother nucleus 7-AMCA. Background Art

[0002] Amino-3-methoxymethyl-3-cephem-4-carboxylic acid (7-AMCA for short) is a key intermediate for the synthesis of the third-generation antibacterial drug cefpodoxime proxetil. Cefpodoxime proxetil has inhibitory effects on most Gram-negative and Gram-positive bacteria, rarely has drug resistance, and is stable to β-lactamase. It is mainly used to treat upper and lower respiratory tract infections, urinary tract infections, otitis media, skin and soft tissue infections, scarlet fever, etc. At present, most 7-AMCA is converted from 7-aminocephalosporanic acid (7-ACA for short), and a few 7-AMCA are prepared using D-7ACA as the starting material. For example: Chinese invention patent CN102746322A discloses a method for preparing 7-amino-3-methoxymethyl-2-cephem-2-carboxylic acid, a cephalosporin intermediate, using 7-ACA as a substrate, boron trifluoride-methanol as a catalyst, dimethyl carbonate or cyclopentane as an organic solvent, and methoxy alkali metal as a methylating agent for reaction, and the product is obtained by crystallization, filtration, washing, and drying, and the yield can reach 84%. However, due to the strong base effect of sodium methoxide, this patent is easy to cause local over-alkalinity, thereby forming a large amount of lactone and causing β-lactam ring opening, so that the purity of the product is very low, only 97.9%, and industrial mass production is uncontrollable; and the production process uses dangerous and expensive methoxy alkali metals, and the production cost is high. Chinese invention patent CN105669701A discloses a method for synthesizing a cefpodoxime axetil intermediate, using 7-ACA as a starting material, methoxysulfonic acid as a catalyst, trimethyl borate as a methylating agent, and methanol as a solvent to prepare 7-AMCA. The methoxysulfonic acid used in this method is expensive, and the chlorosulfonic acid used is a highly toxic reagent that is difficult to purchase and store; the product yield obtained by this method is 66.88%, and the liquid phase purity is 95-96%.

[0003] US invention patent US4482710A discloses a preparation process of 3-alkoxymethyl cephalosporin derivatives, wherein the 7-amino group of 7-ACA is protected by phenylacetyl group to prepare 7-amino-3-methoxymethyl-3-cephem carboxylic acid; the 3-acetoxy group is converted into a methoxy group by the action of methanol-sodium bicarbonate or methanol-calcium chloride, and the protecting group is removed. However, this method is cumbersome and has many steps, resulting in a low product yield (only 20%).

[0004] Chinese invention patent CN106046024A discloses a method for preparing cefpodoxime axetil, using D-7ACA as raw material, trimethyl orthoformate as methylating agent, boron trifluoride / ether as catalyst, and acetonitrile as solvent to prepare 7-AMCA. This method needs to be carried out at a low temperature of -30~-20℃, has strict requirements on equipment, and the mixed solvent of ether and acetonitrile is not easy to recycle and has safety hazards, and there is also the problem of low product yield.

[0005] European invention patent EP0204657A2 discloses a preparation process of 7-ACA derivatives, which uses 7-ACA as a raw material and reacts with boron trifluoride-methanol in sulfolane to produce 7-AMCA. However, this process requires the use of dangerous gaseous boron trifluoride, which poses a safety hazard.

[0006] In summary, in view of the above-mentioned problems existing in the existing preparation process of 7-AMCA, it is urgent to develop an environmentally friendly, economically feasible and high-purity preparation process of 7-AMCA. Summary of the invention

[0007] The technical problem to be solved by the present invention is: to overcome the shortcomings of the prior art, to provide a preparation process of cefpodoxime mother nucleus 7-AMCA, to use 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid (D-7ACA) as a starting material, to improve the process flow and optimize the preparation process of cefpodoxime mother nucleus 7-AMCA in view of the shortcomings of the prior art, so as to achieve the purpose of improving product quality and yield.

[0008] The technical solution of the present invention is:

[0009] The preparation process of cefpodoxime mother nucleus 7-AMCA comprises the following steps:

[0010] S1: Dimethyl carbonate and boron trifluoride-dimethyl carbonate complex are sequentially added to reaction flask A, and an alkylating agent is added dropwise, and the mixture is stirred after the addition; D-7ACA is added, and the reaction is carried out at room temperature;

[0011] S2 Add purified water to reaction bottle B, then add sodium pyrosulfite and disodium edetate;

[0012] S3: transferring the feed liquid in reaction bottle B to reaction bottle A, controlling the temperature at room temperature, adding an organic solvent to the obtained mixed solution for extraction and separation, and obtaining an aqueous phase;

[0013] S4: adding alkaline solution to the aqueous phase, adjusting the pH to 2.8-3, cooling and growing the crystal; adding alkaline solution again, adjusting the pH to 4.5-5.2, cooling and growing the crystal;

[0014] After S5 crystal growth is completed, the mother liquor is filtered out, and the mother liquor is washed until colorless, and finally rinsed with an organic solvent and then dried by vacuum drying to obtain the cefpodoxime mother nucleus 7-AMCA.

[0015] Preferably, in step S1, the temperature is 10-15°C when the alkylating agent is added dropwise, and after adding D-7ACA, the temperature is raised to 20-25°C for reaction.

[0016] Preferably, in step S1, when the residual amount of D-7ACA is less than 0.2 g / L after HPLC analysis during the reaction process, the reaction is terminated.

[0017] Preferably, in step S1, the mass ratio of dimethyl carbonate, boron trifluoride-dimethyl carbonate complex and D-7ACA is (4-5):(4-5):1; the alkylating agent is trimethyl orthoborate or trimethyl orthoformate, and the mass ratio of the alkylating agent to D-7ACA is (0.5-1):1.

[0018] Preferably, in step S2, the mass ratio of the purified water to D-7ACA is (15-17):1; the mass ratio of the sodium metabisulfite to purified water is 1:(150-200), and the mass ratio of disodium edetate to purified water is 1:(500-1000).

[0019] Preferably, in step S3, the organic solvent is dichloromethane or ethyl acetate, and the mass ratio of the organic solvent to D-7ACA is (10-13):1.

[0020] Preferably, in step S4, the aqueous phase is cooled to 20-25° C. before the alkaline solution is added dropwise.

[0021] Preferably, in step S4, the alkaline solution is a 15-20 wt.% sodium carbonate solution.

[0022] Preferably, in step S4, the temperature of the first cooling and crystal growing is 10-15°C, and the crystal growing time is 0.8-1.2h; the temperature of the second cooling and crystal growing is 0-5°C, and the crystal growing time is 0.8-1.2h.

[0023] Preferably, in step S5, the washing liquid used for washing the mother liquor is an organic solvent and water in a volume ratio of 1:(1-3); the organic solvent is methanol, ethanol or acetone; and the organic solvent is acetone.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] 1. The present invention uses 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid (D-7ACA) as a starting material, improves the process flow and optimizes the preparation process of cefpodoxime mother nucleus 7-AMCA in view of the deficiencies of the prior art, so as to achieve the purpose of improving product quality and yield.

[0026] 2. When preparing the cefpodoxime nucleus 7-AMCA, the present invention reduces the solution system distribution ratio and improves the yield and quality of the product by adding an extraction and liquid separation step. At the same time, the present invention needs to control the low temperature when dropping the alkaline solution for crystallization for the first time, so that the precipitated 7-AMCA product has a good appearance. In addition, the present invention changes the particle size and impurity encapsulation of the 7-AMCA product during the crystallization process by eluting the mother liquor with an organic solvent, thereby reducing the influence of impurities on the crystallization process. The present invention uses a washing liquid composed of an organic solvent and water to wash the mother liquor, which further reduces the polymer and impurity content in the 7-AMCA product. The prepared product has a good appearance, high purity, and slow degradation under high temperature conditions.

[0027] 3. Although the preparation process of the present invention still uses D-7ACA as a raw material to prepare 7-AMCA, the strong acid catalyst is precipitated in the form of salt by dropping an alkaline solution in the later stage of the reaction, thereby improving the yield of the product; at the same time, the alkaline solution used in the present invention has low pollution, which reduces the difficulty of recovering wastewater in the later stage. In addition, the preparation process of the present invention avoids the degradation of the β-lactam ring under strong alkaline conditions, improves the yield, and the obtained product has high purity and good stability. DETAILED DESCRIPTION

[0028] In order to enable persons skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention.

[0029] Unless otherwise specified, the raw materials used in the following examples are commercially available products.

[0030] Example 1

[0031] The preparation process of the cefpodoxime mother core 7-AMCA of the present embodiment comprises the following steps:

[0032] S1: Add 155g of dimethyl carbonate and 160g of boron trifluoride-dimethyl carbonate complex to a 500mL four-necked reaction bottle A, control the temperature at 10°C, dropwise add 25g of trimethyl orthoformate, and stir for 60min after the dropwise addition; add 34g of D-7ACA, and raise the temperature to 20°C; detect the reaction end point by HPLC, and terminate the reaction when the residual amount of D-7ACA is less than 0.2g / L;

[0033] S2 Add 560 mL of purified water to a 1000 mL four-necked reaction flask B, then add 3 g of sodium pyrosulfite and 0.6 g of disodium edetate, and stir for 20 min;

[0034] S3: Transfer the feed liquid in the four-necked reaction flask B to the four-necked reaction flask A, and control the temperature at 20° C.; add 300 mL of dichloromethane to the obtained mixed solution for extraction and separation to obtain an aqueous phase;

[0035] S4 controlled the temperature at 20°C, added 18wt.% sodium carbonate solution to the aqueous phase, adjusted the pH to 2.9, cooled to 12°C, and allowed to grow for 1h; then continued to add 18wt.% sodium carbonate solution, adjusted the pH to 4.7, cooled to 2°C, and allowed to grow for 1h;

[0036] After S5 crystal growth was completed, the mother liquor was filtered out and washed with a washing solution consisting of ethanol and water in a volume ratio of 1:1 until it was colorless. Finally, it was rinsed with acetone and dried, and vacuum dried at 50°C to obtain 29.8 g of white crystalline powder, i.e., cefpodoxime mother nucleus 7-AMCA, with a yield of 87.6% and a purity of 98.1%.

[0037] Example 2

[0038] The preparation process of the cefpodoxime mother core 7-AMCA of the present embodiment comprises the following steps:

[0039] S1: Add 136g of dimethyl carbonate and 170g of boron trifluoride-dimethyl carbonate complex to a 500mL four-necked reaction bottle A, control the temperature at 15°C, dropwise add 17g of trimethyl orthoformate, and stir for 60min after the addition; raise the temperature to 25°C, add 34g of D-7ACA; detect the reaction end point by HPLC, and terminate the reaction when the residual amount of D-7ACA is less than 0.2g / L;

[0040] S2 Add 510 mL of purified water to a 1000 mL four-necked reaction flask B, then add 3.4 g of sodium pyrosulfite and 1 g of disodium edetate, and stir for 20 min;

[0041] S3: transfer the feed liquid in the four-necked reaction flask B to the four-necked reaction flask A, and control the temperature at 20°C after the transfer; add 340 mL of dichloromethane to the obtained mixed solution for extraction and separation to obtain an aqueous phase;

[0042] S4: Control the temperature at 22°C, add 15wt.% sodium carbonate solution to the water phase, adjust the pH to 2.8, cool to 10°C, and grow crystals for 0.8h; then continue to add 15wt.% sodium carbonate solution, adjust the pH to 4.5, cool to 0°C, and grow crystals for 0.8h;

[0043] After S5 crystal growth was completed, the mother liquor was filtered out and washed with a washing solution consisting of methanol and water in a volume ratio of 1:3 until it was colorless. Finally, it was rinsed with acetone and dried, and vacuum dried at 50°C to obtain 28.9 g of white crystalline powder, i.e., cefpodoxime mother nucleus 7-AMCA, with a yield of 85% and a purity of 98.4%.

[0044] Example 3

[0045] The preparation process of the cefpodoxime mother core 7-AMCA of the present embodiment comprises the following steps:

[0046] S1: Add 170g of dimethyl carbonate and 136g of boron trifluoride-dimethyl carbonate complex to a 500mL four-necked reaction bottle A, control the temperature at 12°C, dropwise add 34g of trimethyl orthoborate, and stir for 60min after the addition; raise the temperature to 22°C, add 34g of D-7ACA; detect the reaction end point by HPLC, and terminate the reaction when the residual amount of D-7ACA is less than 0.2g / L;

[0047] S2 Add 578 mL of purified water to a 1000 mL four-necked reaction flask B, then add 2.9 g of sodium pyrosulfite and 0.6 g of disodium edetate, and stir for 20 min;

[0048] S3: transfer the feed liquid in the four-necked reaction bottle B to the four-necked reaction bottle A, and control the temperature at 20° C.; add 490 mL of ethyl acetate to the obtained mixed solution, extract and separate the liquid, and obtain an aqueous phase;

[0049] S4 controlled the temperature at 25°C, added 20wt.% sodium carbonate solution to the aqueous phase, adjusted the pH to 3, cooled to 15°C, and allowed to grow for 1.2h; then continued to add 20wt.% sodium carbonate solution, adjusted the pH to 5.2, cooled to 5°C, and allowed to grow for 1.2h;

[0050] After S5 crystal growth was completed, the mother liquor was filtered out and washed with a washing solution consisting of acetone and water in a volume ratio of 1:2 until it was colorless. Finally, it was rinsed with acetone and dried, and vacuum dried at 50°C to obtain 29.5 g of white crystalline powder, i.e., cefpodoxime mother nucleus 7-AMCA, with a yield of 86% and a purity of 99.2%.

[0051] Comparative Example 1

[0052] The difference between Comparative Example 1 and Example 1 is that in step S2, disodium edetate is used instead of sodium pyrosulfite.

[0053] Finally, 26.8 g of yellow crystalline powder, namely cefpodoxime nucleus 7-AMCA, was prepared with a yield of 78.8% and a purity of 94.8%.

[0054] In Comparative Example 1, disodium edetate was used alone without sodium pyrosulfite, which failed to effectively inhibit the generation of oxide impurities, resulting in a high oxide content in the obtained product, resulting in poor product quality.

[0055] Comparative Example 2

[0056] The difference between Comparative Example 2 and Example 1 is that in step S2, sodium pyrosulfite is used instead of disodium edetate.

[0057] Finally, 27.5 g of light yellow crystalline powder, namely cefpodoxime nucleus 7-AMCA, was prepared with a yield of 80.9% and a purity of 95.8%.

[0058] Comparative Example 2 uses sodium metabisulfite alone without using disodium edetate, which cannot effectively remove metal ions that may be contained in purified water, resulting in the generation of non-specific impurities and poor product quality.

[0059] Comparative Example 3

[0060] The difference between Comparative Example 3 and Example 1 is that in step S3, the mixed solution is not subjected to extraction and separation, and in step S4, the sodium carbonate solution is directly added dropwise to the mixed solution.

[0061] Finally, 12.7 g of light yellow crystalline powder, namely cefpodoxime nucleus 7-AMCA, was prepared with a yield of 37.3% and a purity of 97.8%.

[0062] In Comparative Example 3, the mixed solution was not extracted and separated, so that part of the material was dissolved in the organic phase and could not be precipitated during the final crystallization, resulting in a low yield of the final prepared product.

[0063] Comparative Example 4

[0064] The difference between Comparative Example 4 and Example 1 is that in step S4, no second crystal growing is performed.

[0065] Finally, 28.3 g of light yellow crystalline powder, namely cefpodoxime nucleus 7-AMCA, was prepared with a yield of 83.2% and a purity of 98.4%.

[0066] Comparative Example 4 did not perform secondary crystal growth, but directly performed filtration, resulting in some materials not being precipitated into the mother liquor, ultimately leading to a slightly lower product yield.

[0067] Comparative Example 5

[0068] The difference between Comparative Example 5 and Example 1 is that in step S4, 18 wt.% sodium carbonate solution is added dropwise for the first time to adjust the pH to 3.2; and 18 wt.% sodium carbonate solution is added dropwise for the second time to adjust the pH to 5.8.

[0069] Finally, 27.6 g of light yellow crystalline powder, namely cefpodoxime nucleus 7-AMCA, was prepared with a yield of 81.1% and a purity of 98.6%.

[0070] In Comparative Example 5, when the 18 wt.% sodium carbonate solution was added for the second time, the pH was adjusted too high, causing part of the precipitated material to dissolve, ultimately resulting in a slightly lower product yield.

Claims

1. A process for preparing cefpodoxime nucleus 7-AMCA, characterized in that: The following steps are involved: S1: Add dimethyl carbonate and boron trifluoride-dimethyl carbonate complex into reaction flask A in sequence, add alkylating agent dropwise at a temperature of 10-15°C, and stir after adding; add D-7ACA, and heat to 20-25°C for reaction; S2 Add purified water to reaction bottle B, then add sodium pyrosulfite and disodium edetate; S3: transferring the feed liquid in reaction bottle B to reaction bottle A, controlling the temperature at room temperature, adding an organic solvent to the obtained mixed solution for extraction and separation, and obtaining an aqueous phase; S4: adding alkaline solution to the aqueous phase, adjusting the pH to 2.8-3, cooling and growing the crystal; adding alkaline solution again, adjusting the pH to 4.5-5.2, cooling and growing the crystal; After the crystal growth in S5 is completed, the mother liquor is filtered out, and the mother liquor is washed until colorless, and finally rinsed with an organic solvent, dried, and vacuum dried to obtain the cefpodoxime mother nucleus 7-AMCA; In step S1, the mass ratio of dimethyl carbonate, boron trifluoride-dimethyl carbonate complex and D-7ACA is (4-5):(4-5):1; the alkylating agent is trimethyl orthoborate or trimethyl orthoformate, and the mass ratio of the alkylating agent to D-7ACA is (0.5-1):

1.

2. The preparation process of cefpodoxime mother nucleus 7-AMCA as claimed in claim 1, characterized in that, In step S1, after the reaction process is analyzed by HPLC, when the residual amount of D-7ACA is less than 0.2 g / L, the reaction is terminated.

3. The preparation process of cefpodoxime nucleus 7-AMCA as claimed in claim 1, characterized in that: In step S2, the mass ratio of the purified water to D-7ACA is (15-17):1; the mass ratio of the sodium metabisulfite to purified water is 1:(150-200), and the mass ratio of disodium edetate to purified water is 1:(500-1000).

4. The preparation process of cefpodoxime nucleus 7-AMCA as claimed in claim 1, characterized in that: In step S3, the organic solvent is dichloromethane or ethyl acetate, and the mass ratio of the organic solvent to D-7ACA is (10-13):

1.

5. The preparation process of cefpodoxime nucleus 7-AMCA as claimed in claim 1, characterized in that: In step S4, the water phase is cooled to 20-25°C before the alkaline solution is added dropwise.

6. The process for preparing the cefpodoxime nucleus 7-AMCA according to claim 1, characterized in that: In step S4, the alkaline solution is a 15-20 wt.% sodium carbonate solution.

7. The process for preparing the cefpodoxime nucleus 7-AMCA according to claim 1, characterized in that: In step S4, the temperature of the first cooling and crystal growing is 10-15°C, and the crystal growing time is 0.8-1.2h; the temperature of the second cooling and crystal growing is 0-5°C, and the crystal growing time is 0.8-1.2h.

8. The process for preparing the cefpodoxime nucleus 7-AMCA according to claim 1, characterized in that: In step S5, the washing liquid used for washing the mother liquor is an organic solvent and water in a volume ratio of 1:(1-3); the organic solvent is methanol, ethanol or acetone; and the organic solvent is acetone.