Refining method of tebipenem pivoxil

Abstract

The present invention provides a tebipenem pivoxil refining method, which comprises: dissolving a tebipenem pivoxil crude product in a benign solvent to obtain a crude product solution, adding a poor solvent to the crude product solution to carry out crystallization, and separating the obtained crystal to obtain the refined tebipenem pivoxil, the solvent I is a C1-C6 alkyl ester solvent of acetic acid, the solvent II is a C1-C6 saturated chain monohydric alcohol solvent, and the poor solvent is a C4-C8 chain alkane solvent. The refining method provided by the invention can effectively reduce the use amount of the solvent, and the obtained refined tebipenem pivoxil product is high in yield and good in purity, so that the refining method is very suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical chemistry, and in particular to a method for refining tipipenam ester. Background Art

[0002] Tebipenem ester (also known as: Tebipenem ester, Tebipenem Pivoxil, Tebipenem Pivoxil, etc., English name: Tebipenem Pivoxil), chemical name is (4R, 5S, 6S)-3-[[1-(4,5-dihydro-2-thiazolyl)-3-azaalkyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (2,2-dimethyl-1-oxopropoxy) methyl ester, its structural formula is:

[0003]

[0004] Tipopenem ester was developed by Wyeth Lederle of Japan and licensed to Meiji Seika Co., Ltd. of Japan in March 2002. The fine particles of Tipopenem ester developed by it were first launched in Japan in August 2009. Tipopenem ester is hydrolyzed by esterase after oral administration to release the active parent drug Tipopenem. Compared with Tipopenem, Tipopenem ester has better absorption kinetics and stability. It is the first oral preparation used to treat pneumonia, otitis media and sinusitis in children, with the advantages of few side effects and safe medication.

[0005] U.S. Patent (US5534510) and European Patent (EP0632039) report the synthesis method of tibipenem ester: tibipenem is dissolved in a sodium bicarbonate aqueous solution and then freeze-dried, dissolved in DMF and reacted with iodomethyl pivalate, after the reaction is completed, ethyl acetate is added for extraction, washed with water and dried, concentrated and passed through a silica gel column to obtain tibipenem ester. This preparation method requires column chromatography, is time-consuming and labor-intensive, and is not suitable for industrial scale-up production.

[0006] Japanese patent (JP3317649B2) reports: After concentrating the ethyl acetate solution of tipipenam ester, an amorphous compound is obtained, and then the compound is dissolved in ethyl acetate or ethanol, cooled and crystallized to obtain a crystalline compound with yields of 44% and 59%, respectively. This method has a low yield and is not suitable for industrial scale-up production.

[0007] Chinese patent (CN106083858B) reports: the ethyl acetate solution of tipenem ester after the reaction is dried and concentrated, acetone is added to dissolve it, isopropyl ether is added to crystallize it, filtered, and dried to obtain tipenem ester. This method does not undergo crude product crystallization and decolorization treatment, and impurities and color are uncontrollable, which is not conducive to the quality stability between batches after industrialization. Summary of the invention

[0008] In order to solve the problems of low yield, uncontrollable impurities, poor quality stability, etc. that are easy to occur during the refining of tipipenam ester in the prior art, the purpose of the present invention is to provide a refining method of tipipenam ester, which has a series of advantages such as high product yield, high purity, good particle size, low solvent consumption, and easy industrial scale-up production.

[0009] The method for refining tebipenem ester provided by the present invention comprises: dissolving a crude tebipenem ester in a benign solvent to obtain a crude solution, then adding a poor solvent to the crude solution for crystallization, and separating the obtained crystals to obtain the refined tebipenem ester; wherein the benign solvent consists of a solvent I and a solvent II, the solvent I is a C1-C6 alkyl ester solvent of acetic acid, the solvent II is a C1-C6 saturated chain monohydric alcohol solvent, and the poor solvent is a C4-C8 chain alkane solvent.

[0010] The inventors have found through extensive research that tebipenem ester is moderately soluble in solvent I, easily soluble in solvent II, and insoluble in poor solvents. When solvent I is used alone to dissolve the crude product of tebipenem ester and then a poor solvent is added for crystallization, the amount of solvent used is large, and the yield of the refined product is not high. When solvent II is used alone for refining, the crystal yield is low because the crude product has a large solubility in alcohol solvents. At the same time, the product obtained by refining with a single solvent also has defects such as fine solid powder, easy agglomeration, and poor fluidity. The refining method provided by the present invention uses solvent I and solvent II to form a benign solvent together, which has suitable solubility for the crude product of tebipenem ester, and then uses an alkane solvent for crystallization, which can greatly improve the yield of the crystalline product, and can also effectively control the impurities, color and particle size of the product, and comprehensively improve the product quality. In addition, the refined method provided by the present invention is significantly reduced in the amount of solvent used, so that the production cost can be reduced, which is conducive to industrial production.

[0011] In the refining method provided by the present invention, the solvent I can be a C1-C6 alkyl ester solvent of acetic acid, which can be expressed as: CH3COO-C1-C6 alkyl, wherein the C1-C6 alkyl includes but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl and other groups. In some preferred embodiments, the solvent I can be one or more of methyl acetate, ethyl acetate, isopropyl acetate, and tert-butyl acetate.

[0012] In the purification method provided by the present invention, the solvent II may be a C1-C6 saturated chain monohydric alcohol solvent, which may be expressed as: C m H 2m+1OH, wherein m can be 1, 2, 3, 4, 5 or 6. In some preferred embodiments, the solvent II can be one or more of methanol, ethanol, isopropanol, and tert-butanol.

[0013] In the purification method provided by the present invention, the volume ratio of the solvent I to the solvent II can be 2 to 10:1, for example, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1 or any volume ratio interval. In some preferred embodiments, the volume ratio of the solvent I to the solvent II can be 3 to 6:1.

[0014] In the refining method provided by the present invention, the mass ratio of the benign solvent to the crude product of teprenyl ester can be 8 to 25: 1, for example, about 8: 1, about 9: 1, about 10: 1, about 11: 1, about 12: 1, about 13: 1, about 14: 1, about 15: 1, about 16: 1, about 17: 1, about 18: 1, about 19: 1, about 20: 1, about 21: 1, about 22: 1, about 23: 1, about 24: 1, about 25: 1 or any mass ratio interval. In some preferred embodiments, the mass ratio of the benign solvent to the crude product of teprenyl ester can be 10 to 20: 1.

[0015] In the purification method provided by the present invention, the poor solvent may be a C4-C8 chain alkane solvent, which can be expressed as: C n H 2n+2 , wherein n can be 1, 2, 3, 4, 5 or 6. In some preferred embodiments, the poor solvent can be one or both of n-hexane and n-heptane.

[0016] In the refining method provided by the present invention, the mass ratio of the poor solvent to the crude product of tebipenem ester can be 8 to 40: 1, for example, about 8: 1, about 10: 1, about 12: 1, about 15: 1, about 18: 1, about 20: 1, about 22: 1, about 25: 1, about 28: 1, about 30: 1, about 32: 1, about 35: 1, about 38: 1, about 40: 1 or any mass ratio interval. In some preferred embodiments, the mass ratio of the poor solvent to the crude product of tebipenem ester can be 10 to 30: 1.

[0017] In the purification method provided by the present invention, the crude tipenem ester can be dissolved in the benign solvent at a temperature of 20 to 40° C. to obtain the crude product solution.

[0018] In the purification method provided by the present invention, the crude product solution can be crystallized by adding a poor solvent at a temperature of -10 to 10° C. In some preferred embodiments, the poor solvent can be added dropwise.

[0019] The refining method provided by the present invention may further include: before adding the poor solvent, decolorizing the crude solution. In some preferred embodiments, the decolorization process may be: adding activated carbon to the crude solution (the amount of which may be 1 to 10 wt.% of the crude quality of tebipenem ester, for example, 5 to 8 wt.%) and stirring (for example, stirring for 20 to 60 minutes), and then removing the activated carbon.

[0020] In the purification method provided by the present invention, the crude tibipenem ester can be prepared by reacting tibipenem hydrate and chloromethyl pivalate, and the reaction formula is as follows:

[0021]

[0022] In the refining method provided by the present invention, the desired material can be obtained through a separation step, and the separation equipment or method can be a common equipment or method in the art, including but not limited to natural sedimentation, (normal pressure or vacuum) filtration, centrifugation and the like and their common equipment.

[0023] The technical solution provided by the present invention has the following advantages:

[0024] (1) The purification method provided by the present invention uses a mixed solvent of alcohols and esters as a benign solvent, which can effectively reduce the amount of solvent used, and the obtained refined product of tebipenem ester has a high yield and low loss, thereby significantly reducing the production cost of tebipenem ester.

[0025] (2) The refined product of tipipenam ester obtained by the refining method of the present invention also has good appearance (white crystals), excellent purity (HPLC purity ≥99.7%, unknown single impurity ≤0.1%) and outstanding stability, and is very suitable for storage and formulation development.

[0026] (3) The refined product of tipipenam ester obtained by the refining method of the present invention has good granularity and strong fluidity, and is convenient for industrial scale-up drying, packaging and granulation.

[0027] (4) The purification method provided by the present invention has simple process, mild conditions, strong operability, and is very suitable for industrial production. It provides a way to expand the production and application of tebipenem ester, and thus has important economic and social value. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is a particle size detection diagram of the tipipenam ester crystals prepared in Example 1.

[0029] Figure 2 This is the HPLC detection spectrum of the tebipenem ester crystals prepared in Example 1. DETAILED DESCRIPTION

[0030] The technical solution of the present invention is further described in detail below in conjunction with specific embodiments.

[0031] Unless otherwise specified, the raw materials or reagents used in the examples and comparative examples of the present invention are commercially available products.

[0032] The percentages used in the embodiments and comparative examples of the present invention are all mass percentages unless otherwise specified.

[0033] Preparation Example Preparation of crude product of tebipenem

[0034] Add 10.0 g (0.022 mol) of tibipenem tetrahydrate, 25 ml of DMF, 6.0 g (0.046 mol) of N,N-diisopropylethylamine and 10.0 g (0.044 mol, benzyltriethylammonium chloride) of TEBAC into a 100 ml four-necked flask, heat to 25-30 ° C, and after dissolving, add 6.0 g (0.04 mol) of chloromethyl pivalate dropwise. After adding, heat to 30-40 ° C, keep warm for 4 hours, and monitor by TLC (developing solvent: methanol: ethyl acetate = 4:1, v / v) until the reaction is complete. The reaction solution was cooled to about 20°C, added to 50ml of water and 50ml of ethyl acetate, and the pH was adjusted to 4.0±0.1 with 1M citric acid solution, separated, the organic layer was discarded, 50ml of ethyl acetate was added to the aqueous layer, 1M K2CO3 solution was added dropwise under stirring, the pH was adjusted to 7.6±0.15, separated, and the aqueous layer was discarded. The organic layer was dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, 39ml of isopropyl ether was added and cooled to room temperature to precipitate solids, filtered, and the filter cake was dried to obtain 9.2g of crude tebipenem ester, the purity of which was 99.02% by HPLC, and the palladium residue was 56ppm.

[0035] Example 1

[0036] Add 150 ml of methyl acetate and 30 ml of methanol to the reaction flask, control the internal temperature to 30-40 ° C, add 15 g of the crude product of tipipenam ester obtained in the preparation example, stir to dissolve, add 1 g of activated carbon, stir to decolorize for 30 min, filter to remove the activated carbon, control the internal temperature to 0-10 ° C, slowly add 300 ml of n-hexane dropwise, stir for 6-10 h after addition, filter, rinse the filter cake with a small amount of n-hexane, and dry to obtain 14.5 g of white crystals of tipipenam ester, with a weight yield of 97%, a purity of 99.87% detected by HPLC, and a palladium residue of 0.46 ppm.

[0037] 1H NMR (DMSO-d6) δ: 5.896-5.884ppm (1H, d), 5.750-5.738ppm (1H, d), 5.084-5.074p pm (1H, d), 4.375-4.287ppm (3H, m), 4.196-4.172ppm (1H, m), 3.977-3.943ppm (1H, m), 3.893-3.863ppm (2H, t), 3.755-3.715ppm (2H, m), 3.366-3.294ppm (3H, m), 3.2 54-3.237ppm (1H, m), 1.149ppm (9H, s), 1.131ppm (3H, d), 1.105-1.090ppm (3H, m).

[0038] 13 C NMR(DMSO-d6)δ: 176.47ppm(1C), 174.34ppm(1C), 163.00ppm(1C), 159.49ppm(1C) , 152.67ppm(1C), 123.48ppm(1C), 79.83ppm(1C), 64.64ppm(1C), 61.38ppm(1C), 6 0.36ppm(1C), 60.14ppm(1C), 58.14ppm(1C), 55.99ppm(1C), 43.49ppm(1C), 40.51 ppm(1C), 38.65ppm(1C), 33.00(1C), 26.77ppm(3C), 22.21ppm(1C), 17.16ppm(1C).

[0039] MS(EI): m / z[M] + =498.2, molecular formula: C 22 H 31 N3O6S2.

[0040] Example 2

[0041] Add 225 ml of methyl acetate and 75 ml of methanol to the reaction flask, control the internal temperature to 30-40 ° C, add 15 g of the crude product of teprenyl ester obtained in the preparation example, stir to dissolve, add 1 g of activated carbon, stir to decolorize for 30 min, filter to remove the activated carbon, control the internal temperature to -5-5 ° C, slowly add 600 ml of n-heptane dropwise, stir for 6-10 h after addition, filter, rinse the filter cake with a small amount of n-heptane, and dry to obtain 13.6 g of white crystalline particles of teprenyl ester, with a weight yield of 90%, a purity of 99.78% detected by HPLC, and a palladium residue of 0.85 ppm.

[0042] Example 3

[0043] 200 ml of ethyl acetate and 50 ml of ethanol were added to the reaction flask, the internal temperature was controlled at 20-30 ° C, 15 g of the crude product of tipipenam ester obtained in the preparation example was added, and the solution was stirred to dissolve. 1 g of activated carbon was added, and the mixture was stirred for 30 min for decolorization. The activated carbon was removed by filtration, the internal temperature was controlled at -10-0 ° C, 600 ml of n-hexane was slowly added dropwise, and the mixture was stirred for 6-10 h after addition. The mixture was filtered, and the filter cake was washed with a small amount of n-hexane and dried to obtain 14.3 g of white crystalline particles of tipipenam ester, with a weight yield of 95%, a purity of 99.80% detected by HPLC, and a palladium residue of 0.74 ppm.

[0044] Example 4

[0045] Add 225 ml of isopropyl acetate and 75 ml of isopropanol to the reaction flask, control the internal temperature to 30-40 ° C, add 15 g of the crude product of teprenyl ester obtained in the preparation example, stir to dissolve, add 1 g of activated carbon, stir to decolorize for 30 min, filter to remove the activated carbon, control the internal temperature to 0-10 ° C, slowly add 600 ml of n-heptane dropwise, stir for 6-10 h after addition, filter, rinse the filter cake with a small amount of n-heptane, and dry to obtain 14.1 g of white crystalline particles of teprenyl ester, with a weight yield of 94%, a purity of 99.73% detected by HPLC, and a palladium residue of 0.32 ppm.

[0046] Example 5

[0047] 225 ml of tert-butyl acetate and 40 ml of tert-butyl alcohol were added to the reaction flask, the internal temperature was controlled at 30-40 ° C, 15 g of the crude product of tipipenam ester prepared in the preparation example was added, stirred to dissolve, 1 g of activated carbon was added, and the mixture was stirred for 30 min for decolorization. The activated carbon was removed by filtration, the internal temperature was controlled at 0-10 ° C, 500 ml of n-hexane was slowly added dropwise, and the mixture was stirred for 6-10 h after addition. The mixture was filtered, the filter cake was rinsed with a small amount of n-hexane, and dried to obtain 13.7 g of white crystalline particles of tipipenam ester, with a weight yield of 91%, a purity of 99.84% detected by HPLC, and a palladium residue of 0.49 ppm.

[0048] Comparative Example 1

[0049] A single solvent I was used as a benign solvent.

[0050] 1800 ml of ethyl acetate was added to the reaction flask, the internal temperature was controlled at 30-40 ° C, 15 g of the crude product of tipipenam ester obtained in the preparation example was added, and the solution was stirred to dissolve. 1 g of activated carbon was added, and the mixture was stirred for 30 min for decolorization. The activated carbon was removed by filtration, the internal temperature was controlled at 0-10 ° C, 3000 ml of n-hexane was slowly added dropwise, and the mixture was stirred for 6-10 h after addition. The mixture was filtered, and the filter cake was washed with a small amount of n-hexane and dried to obtain 12.8 g of white powder of tipipenam ester, with a weight yield of 85%, a purity of 99.08% detected by HPLC, and a palladium residue of 0.72 ppm.

[0051] From Comparative Example 1, it can be found that when ethyl acetate is used as a single solvent to dissolve the crude product, the amount of solvent used is large, the product yield is low, and the purity improvement is not obvious. Moreover, as shown in the results in Table 1, the obtained crystal particles are fine and even have agglomeration, and the fluidity is poor, which is not conducive to cost control and scale-up production.

[0052] Comparative Example 2

[0053] Add 50 ml of ethanol to the reaction flask, control the internal temperature to 30-40° C., add 15 g of the crude product of tipipenam ester obtained in the preparation example, stir to dissolve, add 1 g of activated carbon, stir to decolorize for 30 min, filter to remove the activated carbon, control the internal temperature to 0-10° C., stir for 6-10 h after addition, filter, rinse the filter cake with a small amount of ethanol, and dry to obtain 12.1 g of tipipenam ester as a white solid, with a weight yield of 81%, a purity of 99.87% detected by HPLC, and a palladium residue of 0.42 ppm.

[0054] From Comparative Example 2, it can be found that the use of ethanol as a single solvent for refining has an ideal purity but a significantly lower product yield. As shown in the results in Table 1, compared with the crystals of Comparative Example 1, the crystals obtained in Comparative Example 2 have finer particles and poor fluidity, which is not conducive to cost control and scale-up production.

[0055] Comparative Example 3

[0056] Add 150 ml of methyl acetate and 30 ml of methanol to the reaction flask, control the internal temperature to 50 ° C, add 15 g of the crude product of teprenyl ester obtained in the preparation example, stir to dissolve, add 1 g of activated carbon, stir to decolorize for 30 minutes, filter to remove the activated carbon, control the internal temperature to 0-10 ° C, slowly add 300 ml of n-hexane dropwise, stir for 6-10 hours after addition, filter, rinse the filter cake with a small amount of n-hexane, and dry to obtain 13.0 g of white crystals of teprenyl ester, with a weight yield of 87%, a purity of 98.24% detected by HPLC, and a palladium residue of 0.94 ppm.

[0057] It can be found from Comparative Example 2 that when the crude tipipenam ester is dissolved at a higher temperature (50° C.), more impurities will be formed, the chromatographic purity will deteriorate, and the yield will also decrease significantly.

[0058] Comparative Example 4

[0059] Add 150 ml of methyl acetate and 30 ml of methanol to the reaction flask, control the internal temperature to 30-40 ° C, add 15 g of the crude product of teprenyl ester obtained in the preparation example, stir to dissolve, add 1 g of activated carbon, stir to decolorize for 30 min, filter to remove the activated carbon, control the internal temperature to about 20 ° C, slowly add 300 ml of n-hexane dropwise, stir for 6-10 hours after addition, filter, rinse the filter cake with a small amount of n-hexane, and dry to obtain 13.5 g of white crystals of teprenyl ester, with a weight yield of 90%, a purity of 99.73% detected by HPLC, and a palladium residue of 0.71 ppm.

[0060] From Comparative Example 3, it can be found that increasing the temperature for dropping n-hexane has a certain effect on the product yield, but has little effect on the chromatographic purity.

[0061] Test Example 1: Particle Size Detection

[0062] The products prepared in the examples and comparative examples were respectively subjected to wet method testing using a Malvern 3000 particle size analyzer. The test results are shown in Table 1.

[0063] Table 1. Particle size test results

[0064] Serial number d(0.1) d(0.5) d(0.9) Example 1 199.560μm 339.500μm 494.996μm Example 2 187.451μm 347.320μm 515.531μm Example 3 193.874μm 368.894μm 506.946μm Example 4 181.693μm 354.367μm 498.157μm Example 5 188.379μm 367.549μm 521.445μm Comparative Example 1 48.312μm 105.331μm 167.982μm Comparative Example 2 40.884μm 89.765μm 140.342μm

[0065] The particle size detection diagram of the crystal prepared in Example 1 is as follows Figure 1 As shown, it can be seen that the tebipenem axetil crystalline particles prepared by the present invention have good granularity.

[0066] Test Example 2: Stability Test

[0067] The crystal particles prepared in Example 1 were subjected to a long-term stability test (storage temperature of 20-25° C., humidity of 60±5% RH). The test results are shown in Table 2.

[0068] Table 2. Stability test results

[0069] Storage time Main component content Largest single unknown impurity Appearance 0 months 99.86％ 0.028％ White 3 months 99.87％ 0.030％ White 6 months 99.86％ 0.029％ White 12 months 99.86％ 0.031％ White 24 months 99.85％ 0.031％ White

[0070] It can be seen from the results in Table 2 that the crystalline particles of tipipenam ester prepared in the present invention have excellent stability and will not deteriorate significantly after being placed for a long time.

[0071] Unless otherwise defined, the terms used in the present invention have the meanings commonly understood by those skilled in the art.

[0072] The embodiments described in the present invention are for illustrative purposes only and are not intended to limit the scope of protection of the present invention. Those skilled in the art may make various other substitutions, changes and improvements within the scope of the present invention. Therefore, the present invention is not limited to the above embodiments, but is only limited by the claims.

Claims

1. A method for refining tipenem ester, characterized in that: The crude product of tibipenem exicon is dissolved in a benign solvent to obtain a crude product solution, and then a poor solvent is added to the crude product solution for crystallization, and the obtained crystals are separated to obtain the refined tibipenem exicon; wherein the benign solvent is composed of solvent I and solvent II, the solvent I is a C1-C6 alkyl ester solvent of acetic acid, the solvent II is a C1-C6 saturated chain monohydric alcohol solvent, and the poor solvent is a C4-C8 chain alkane solvent.

2. The refining method according to claim 1, characterized in that The solvent I is one or more of methyl acetate, ethyl acetate, isopropyl acetate, and tert-butyl acetate; the solvent II is one or more of methanol, ethanol, isopropanol, and tert-butanol.

3. The refining method according to claim 2, characterized in that: The volume ratio of the solvent I to the solvent II is 2 to 10:1, preferably 3 to 6:

1.

4. The refining method according to any one of claims 1 to 3, characterized in that: The mass ratio of the benign solvent to the crude product of tipipenam ester is 8 to 25:1, preferably 10 to 20:

1.

5. The refining method according to any one of claims 1 to 4, characterized in that: The poor solvent is one or both of n-hexane and n-heptane.

6. The refining method according to claim 5, characterized in that: The mass ratio of the poor solvent to the crude product of tipipenam ester is 8 to 40:1, preferably 10 to 30:

1.

7. The refining method according to any one of claims 1 to 6, characterized in that: The crude product of tebipenem is dissolved in the benign solvent at a temperature of 20 to 40° C. to obtain the crude product solution.

8. The refining method according to any one of claims 1 to 7, characterized in that: The crude product solution is added with a poor solvent at a temperature of -10 to 10° C. for crystallization; preferably, the poor solvent is added dropwise.

9. The refining method according to any one of claims 1 to 8, characterized in that: The refining method further comprises: before adding the poor solvent, decolorizing the crude product solution; Preferably, the decolorization process is: adding activated carbon to the crude product solution and stirring, and then removing the activated carbon.

10. The refining method according to any one of claims 1 to 9, characterized in that: The crude product of tibipenem ester is prepared by reacting tibipenem hydrate with chloromethyl pivalate;

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