Preparation method of tebipenem pivoxil intermediate

Abstract

The invention relates to the technical field of medicine synthesis, in particular to a preparation method of a tebipenem pivoxil intermediate. The preparation method is mild in reaction condition, simple to operate, low in cost and suitable for industrialization, and the obtained tebipenem pivoxil intermediate is high in purity and high in yield.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and particularly relates to a preparation method of a tebipenem pivoxil intermediate. Background Art

[0002] As a new member of carbapenem antibiotics, Tebipenem pivoxil has strong antibacterial activity against both Gram-positive and Gram-negative bacteria. It is sensitive to Staphylococcus aureus pyogenes, Streptococcus pneumoniae, Streptococcus spp. and Moraxella catarrhalis (Branhamella spp.), and has good efficacy against penicillin-sensitive drug-resistant Streptococcus pneumoniae and Haemophilus influenzae. Tebipenem pivoxil granules, the world's first orally administered carbapenem antibiotic, have the advantages of strong compliance in clinical use, low inhibitory concentration, not easily leading to the emergence of bacterial drug resistance, small side effects, high drug safety, etc., and can be used for the treatment of ear, nose, throat and upper respiratory tract infections in pediatric patients, including persistent otitis media and bacterial pneumonia.

[0003] Compound I is an important intermediate for the synthesis of tebipenem pivoxil:

[0004]

[0005] Currently, there are two common preparation methods for Compound I:

[0006] Method 1: Patent WO2012139414A1 discloses that starting from I-6a, compound II-6 is obtained through a catalytic hydrogenation reaction. The synthetic route is as follows:

[0007]

[0008] This reaction not only requires nitrogen replacement several times, but also requires hydrogen replacement several times. The hydrogen reaction has high requirements for equipment and site, high equipment cost, cumbersome process operation, and there are great potential safety hazards in industrial production.

[0009] Method 2: Patent US5783703A uses tetrahydrofuran and water as reaction solvents, and a method catalyzed by zinc powder / buffer salt is used to prepare the tebipenem pivoxil intermediate. However, tetrahydrofuran and water have good miscibility, and the by-products generated in the reaction are easily soluble in tetrahydrofuran. It is difficult to completely remove the washing impurities and tetrahydrofuran, which brings difficulties to purification and crystallization. When using zinc powder as a catalyst, the dosage of zinc powder is large, and it is difficult to remove the zinc mud in the post-treatment. The solid waste generated is difficult to treat, which is not conducive to industrialization, and the subsequent resin purification yield is low, only 64%.

[0010] There are many difficult problems to be solved when the above two routes are used for industrial production. Therefore, it is an urgent problem to be solved in this field to develop a preparation method of the intermediate of tibipenem pivoxil with mild reaction conditions, simple operation, low cost, suitable for industrialization, and high product purity and high yield. Summary of the Invention

[0011] The purpose of the present invention is to provide a preparation method of the intermediate of tibipenem pivoxil.

[0012] To achieve the above purpose, the technical solution of the present invention is as follows:

[0013] A preparation method of the intermediate of tibipenem pivoxil, comprising the following steps: The compound of formula II undergoes a transfer hydrogenation reaction under the action of a catalyst and a hydrogen source to obtain the compound of formula I:

[0014]

[0015] Among them, the hydrogen source is not hydrogen.

[0016] Further, the hydrogen source is selected from any one or more of triethylsilane, trimethylsilane, tribenzylsilane, diphenylmethylsilane, dihydropyridine, cyclohexene, cyclohexadiene, tetrahydronaphthalene, pyrrolidine, formic acid, ammonium formate;

[0017] Preferably, the hydrogen source is selected from any one or more of triethylsilane, cyclohexene, tetrahydronaphthalene, pyrrolidine, formic acid, ammonium formate;

[0018] More preferably, the hydrogen source is selected from triethylsilane.

[0019] Further, the molar ratio of the hydrogen source to the compound II is 5-30:1;

[0020] Preferably, the molar ratio of the hydrogen source to the compound II is 10:1.

[0021] Further, the catalyst is selected from any one or more of 10% palladium on carbon, platinum on carbon, palladium hydroxide, platinum oxide, palladium oxide;

[0022] Preferably, the catalyst is selected from 10% palladium on carbon.

[0023] Further, the mass ratio of the catalyst to the compound II is 0.1-2.0:1;

[0024] Preferably, the mass ratio of the catalyst to the compound II is 0.2:1.

[0025] Furthermore, the reaction solvent used in the transfer hydrogenation reaction is selected from any one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, acetone, butanone, tetrahydrofuran, dioxane, ethyl acetate, propyl acetate, dichloromethane, chloroform, methanol, ethanol, propanol, butanol, and water;

[0026] Preferably, the reaction solvent used in the transfer hydrogenation reaction is selected from any one or more of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, acetone, dioxane, and methanol;

[0027] More preferably, the reaction solvent used in the transfer hydrogenation reaction is selected from N,N-dimethylformamide and N,N-dimethylacetamide.

[0028] Furthermore, the volume ratio of the reaction solvent used in the transfer hydrogenation reaction to Compound II is 1-20:1.

[0029] Furthermore, the temperature of the transfer hydrogenation reaction is 0-80 °C;

[0030] Preferably, the temperature of the transfer hydrogenation reaction is 0-50 °C;

[0031] Preferably, the temperature of the transfer hydrogenation reaction is 20-25 °C.

[0032] Furthermore, the preparation method further comprises a post-treatment step: after the transfer hydrogenation reaction is completed, the hydrogenation reaction solution is filtered, and an organic solvent is added to the filtrate for crystallization to obtain a crude product of the temocillin intermediate;

[0033] Preferably, the organic solvent is selected from any one or more of ethyl acetate, isopropyl acetate, methyl tert-butyl ether, tetrahydrofuran, acetone, acetonitrile, and n-butanol.

[0034] Furthermore, the preparation method further comprises a purification step: the obtained crude product is slurried with purified water, filtered, the filtrate is taken, and after the filtrate is cooled to 0-5 °C, a crystallization solvent is added, and crystallization is carried out with stirring to obtain a purified temocillin intermediate;

[0035] Preferably, the crystallization solvent is selected from any one or more of acetone, tetrahydrofuran, acetonitrile, isopropanol, and tert-butanol;

[0036] More preferably, the crystallization solvent is selected from acetone.

[0037] The present invention provides a preparation method of a temocillin intermediate, which does not require special reaction equipment and sites, has mild reaction conditions, is simple to operate, has low cost, is suitable for industrialization, and the obtained product has high purity and high yield. Description of the Drawings

[0038] Figure 1 It is the high performance liquid chromatography (HPLC) chromatogram of the compound of Formula I in Example 1;

[0039] Figure 2 It is the high performance liquid chromatography (HPLC) chromatogram of the compound of Formula I in Comparative Example 1;

[0040] Figure 3 It is the high performance liquid chromatography (HPLC) chromatogram of the compound of Formula I in Comparative Example 2. Detailed Embodiments

[0041] The present invention will be described in detail below. However, the present invention may be embodied in many different forms and should not be limited to the embodiments described herein. The purpose of providing these embodiments is to make the disclosed content more complete and comprehensive. The reagents and raw materials used, except for those provided for the preparation method, are all commercially available. Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the technical field to which the subject matter of the claims belongs.

[0042] Unless otherwise specified, the terms used herein have the following meanings:

[0043] Belonging to "hydrogen source" means a compound that can provide hydrogen in a transfer hydrogenation reaction.

[0044] The present invention provides a method for preparing a temocillin intermediate, comprising the following steps: The compound of Formula II undergoes a transfer hydrogenation reaction under the action of a catalyst and a hydrogen source to obtain the compound of Formula I:

[0045]

[0046] In certain embodiments, the hydrogen source is selected from any one or more of triethylsilane, trimethylsilane, tribenzylsilane, diphenylmethylsilane, dihydropyridine, cyclohexene, cyclohexadiene, tetrahydronaphthalene, pyrrolidine, formic acid, ammonium formate.

[0047] In certain embodiments, the hydrogen source is selected from any one or more of triethylsilane, cyclohexene, tetrahydronaphthalene, pyrrolidine, formic acid, ammonium formate.

[0048] In certain embodiments, the hydrogen source is selected from triethylsilane.

[0049] In certain embodiments, the molar ratio of the hydrogen source to Compound II is 5 - 30:1, such as 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1.

[0050] In some embodiments, the molar ratio of the hydrogen source to Compound II is 10:1.

[0051] In some embodiments, the catalyst is selected from any one or more of 10% palladium on carbon, platinum on carbon, palladium hydroxide, platinum oxide, and palladium oxide.

[0052] In some embodiments, the catalyst is selected from 10% palladium on carbon.

[0053] In some embodiments, the mass ratio of the catalyst to Compound II is 0.1 - 2.0:1, such as 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1.0:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2.0:1.

[0054] In some embodiments, the mass ratio of the catalyst to Compound II is 0.2:1.

[0055] In some embodiments, the reaction solvent used in the transfer hydrogenation reaction is selected from any one or more of N,N - dimethylformamide, N,N - dimethylacetamide, dimethyl sulfoxide, acetonitrile, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, ethyl acetate, propyl acetate, dichloromethane, chloroform, methanol, ethanol, propanol, butanol, and water.

[0056] In some embodiments, the reaction solvent used in the transfer hydrogenation reaction is selected from any one or more of N,N - dimethylformamide, N,N - dimethylacetamide, acetonitrile, acetone, dioxane, and methanol.

[0057] In some embodiments, the reaction solvent used in the transfer hydrogenation reaction is selected from N,N - dimethylformamide or N,N - dimethylacetamide.

[0058] In some embodiments, the volume ratio of the reaction solvent used in the transfer hydrogenation reaction to Compound II is 1 - 20:1, such as 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1.

[0059] In certain embodiments, the temperature of the transfer hydrogenation reaction is 0 to 80 °C, such as 0 to 5 °C, 5 to 10 °C, 10 to 15 °C, 15 to 20 °C, 20 to 25 °C, 25 to 30 °C, 30 to 35 °C, 35 to 40 °C, 40 to 45 °C, 45 to 50 °C, 50 to 55 °C, 55 to 60 °C, 60 to 65 °C, 65 to 70 °C, 70 to 75 °C, 75 to 80 °C.

[0060] In certain embodiments, the temperature of the transfer hydrogenation reaction is 0 to 50 °C.

[0061] In certain embodiments, the temperature of the transfer hydrogenation reaction is 25 to 30 °C.

[0062] In certain embodiments, the preparation method further comprises a post-treatment step: after the transfer hydrogenation reaction is completed, the hydrogenation reaction solution is filtered, and an organic solvent is added to the filtrate for crystallization to obtain a crude product of the tibercept intermediate.

[0063] In certain embodiments, the organic solvent used in the post-treatment is selected from any one or more of ethyl acetate, isopropyl acetate, methyl tert-butyl ether, tetrahydrofuran, acetone, acetonitrile, and n-butanol.

[0064] In certain embodiments, a refining step is further included after the post-treatment: the obtained crude product of the tibercept intermediate is slurried with purified water, filtered, the filtrate is taken, and acetone is added after the filtrate is cooled to 0 to 5 °C, and stirred for crystallization to obtain a refined tibercept intermediate.

[0065] Example 1 Palladium-carbon transfer hydrogenation

[0066] The preparation method of the compound of formula I of the tibercept intermediate in this example includes the following steps:

[0067] Add 6 L of N,N-dimethylformamide to the reaction kettle, start stirring, add 1.0 kg (1.93 mol) of the compound of formula II, control the temperature at 20 to 25 °C, add 0.2 kg of 10% palladium-carbon to the reaction kettle, stir and disperse, and displace nitrogen three times. Control the reaction temperature at 20 to 25 °C, and dropwise add 2.24 kg (19.30 mol) of triethylsilane. After adding, keep the temperature for reaction for 5 h; after the reaction is completed, filter the reaction solution by suction, wash the filter cake with N,N-dimethylformamide, and combine the filtrates; add ethyl acetate, stir and crystallize at room temperature, filter by suction, wash the filter cake with ethyl acetate and then filter by suction to obtain a crude product of the compound of formula I.

[0068] At a temperature of 20 - 25 °C, the crude product of the compound of formula I was slurried with purified water, filtered by suction, the filter cake was rinsed with purified water, the filtrates were combined, and after the filtrate was cooled to 0 - 5 °C, 120 L of acetone was added, and the mixture was stirred while maintaining the temperature for crystallization; filtered by suction, the filter cake was rinsed with acetone, filtered, and dried in vacuo to obtain 0.67 kg of a white solid of the intermediate of tibipenem (compound of formula I), with a molar yield of 76.3% and an HPLC purity of 99.93%. See Figure 1 。

[0069] Example 2 Palladium - carbon transfer hydrogenation

[0070] The preparation method of the intermediate of tibipenem ester of formula I in this example comprises the following steps:

[0071] 5 L of N,N - dimethylacetamide was added to a reaction kettle, stirring was started, 1.0 kg (1.93 mol) of the compound of formula II was added, the temperature was controlled at 15 - 20 °C, 2 kg of 10% palladium - carbon was added to the reaction kettle, stirred and dispersed, and nitrogen was displaced three times, the reaction temperature was controlled at 75 - 80 °C, 0.78 kg (9.7 mol) of cyclohexene was added dropwise, and after addition, the mixture was kept at the temperature for reaction for 5 h; after the reaction was completed, the reaction solution was filtered by suction, the filter cake was rinsed with N,N - dimethylacetamide, and the filtrates were combined; ethyl acetate was added, and the mixture was stirred at room temperature for crystallization, filtered by suction, and the filter cake was rinsed with ethyl acetate and then filtered by suction to obtain the crude product of the compound of formula I.

[0072] [[ID=!4]]At a temperature of 15 - 20 °C, the crude product of the compound of formula I was slurried with purified water, filtered by suction, the filter cake was rinsed with purified water, the filtrates were combined, and after the filtrate was cooled to 0 - 5 °C, 120 L of acetone was added, and the mixture was stirred while maintaining the temperature for crystallization; filtered by suction, the filter cake was rinsed with acetone, filtered, and dried in vacuo to obtain 0.68 kg of a white solid of the intermediate of tibipenem (compound of formula I), with a molar yield of 77.4% and an HPLC purity of 99.95%.

[0073] Example 3, Palladium - carbon transfer hydrogenation

[0074] Referring to the preparation method of Example 1, using acetonitrile instead of N,N - dimethylformamide as the reaction solvent, using 7.65 kg (57.9 mol) of tetralin instead of 2.24 kg (19.30 mol) of triethylsilane as the hydrogen source, using 0.5 kg of platinum - carbon instead of 0.2 kg of 10% palladium - carbon, controlling the reaction temperature at 10 - 15 °C, and keeping other conditions unchanged, 0.62 kg of a white solid of the intermediate of tibipenem (compound of formula I) was obtained, with a molar yield of 70.6% and an HPLC purity of 99.94%.

[0075] Example 4, Palladium - carbon transfer hydrogenation

[0076] Referring to the preparation method of Example 1, dioxane was used to replace N,N-dimethylformamide as the reaction solvent, pyrrolidine 3.54 kg (28.9 mol) was used to replace triethylsilane 2.24 kg (19.30 mol) as the hydrogen source, 0.1 kg of palladium oxide was used to replace 0.2 kg of 10% palladium carbon, the reaction temperature was controlled at 60 - 65 °C, and other conditions remained unchanged. 0.65 kg of white solid of the teicoplanin intermediate (Compound of Formula I) was obtained, with a molar yield of 74.0% and an HPLC purity of 99.96%.

[0077] Example 5, Palladium Carbon Transfer Hydrogenation

[0078] Referring to the preparation method of Example 1, acetone was used to replace N,N-dimethylformamide as the reaction solvent, formic acid 1.78 kg (38.6 mol) was used to replace triethylsilane 2.24 kg (19.30 mol) as the hydrogen source, the reaction temperature was controlled at 5 - 10 °C, and other conditions remained unchanged. 0.68 kg of white solid of the teicoplanin intermediate (Compound of Formula I) was obtained, with a molar yield of 77.4% and an HPLC purity of 99.96%.

[0079] Example 6, Palladium Carbon Transfer Hydrogenation

[0080] Referring to the preparation method of Example 1, methanol was used to replace N,N-dimethylformamide as the reaction solvent, ammonium formate 1.46 kg (23.2 mol) was used to replace triethylsilane 2.24 kg (19.30 mol) as the hydrogen source, the reaction temperature was controlled at 35 - 40 °C, and other conditions remained unchanged. 0.66 kg of white solid of the teicoplanin intermediate (Compound of Formula I) was obtained, with a molar yield of 75.1% and an HPLC purity of 99.93%.

[0081] Comparative Example 1, Zinc Powder / Buffered Salt Deprotection

[0082] Add 15.0 L of tetrahydrofuran to the reaction kettle, start stirring, add 1.5 kg (2.89 mol) of Compound of Formula II, control the temperature at 20 - 25 °C, add an aqueous solution of potassium dihydrogen phosphate (30.0 L of purified water and 4.5 kg of potassium dihydrogen phosphate) to the main reaction kettle and stir for 10 min, add 4.5 kg (68.82 mol) of zinc powder in batches. After adding, continue to keep the temperature for reaction for 1 h. After the reaction is completed, filter the reaction solution by suction, wash the filter cake, and combine the filtrates. Extract the filtrate twice with ethyl acetate, collect the aqueous layer; control the temperature at 0 - 5 °C, slowly add 150 L of acetone to the collected aqueous layer, keep the temperature and stir for 30 min, then filter to obtain the crude product of Compound of Formula I. Pulp the crude product with purified water at 20 - 25 °C, filter, and dry in vacuo to obtain 0.75 kg of white solid of the teicoplanin intermediate (Compound of Formula I), with a molar yield of 57.0% and an HPLC purity of 99.84%, see Figure 2 。

[0083] Comparative Example 2: Palladium-carbon hydrogenation under pressure

[0084] Add 500 mL of n-butanol to the reaction kettle, start stirring, add 50.0 g of the compound of Formula II, after stirring and dispersing, add an aqueous solution of sodium bicarbonate (500 mL of purified water and 4.05 g of sodium bicarbonate), then add 10.0 g of 10% palladium-carbon, displace with nitrogen three times, and then displace with hydrogen. React at 20-30 °C for 3 h under a hydrogen pressure of 0.4 MPa. After the reaction is completed, filter by suction, wash the filter cake with 50 mL of purified water, collect the filtrate, adjust the pH to 5.5 with 2M HCl, extract the aqueous layer with 200 mL of n-butanol once, and collect the aqueous layer; cool the aqueous layer to 0-5 °C, slowly add 2500 mL of acetone, crystallize, filter by suction, and dry to obtain 33.3 g of the intermediate of tibolone (the compound of Formula I), with a molar yield of 75.85% and an HPLC purity of 99.76%. See Figure 3 。

[0085] The comparison data of the purity and yield of Example 1 with Comparative Examples 1 and 2 are shown in Table 1.

[0086] Table 1 Comparison of the purity and yield of Example 1 with Comparative Examples 1-2

[0087] Method Feed amount Output Purity Molar yield Example 1 (Transfer hydrogenation) 1000g 670 g (tetrahydrate) 99.93％ 76.3％ Comparative Example 1 (Zinc powder / buffer salt) 1500g 750 g (tetrahydrate) 99.84％ 57.0％ Comparative Example 2 (Palladium on carbon pressurized hydrogenation) 50g 33.3 g (tetrahydrate) 99.76％ 75.85％

[0088] According to Table 1, the purity and yield of transfer hydrogenation are slightly better than those of hydrogenation under pressure. Moreover, compared with hydrogenation under pressure, the reaction conditions required for transfer hydrogenation are milder, no special equipment and site are needed, it is more suitable for industrial production, and the yield and purity of transfer hydrogenation are significantly better than those of the zinc powder / buffer salt deprotection process.

[0089] For those skilled in the art, various corresponding changes and deformations can be made according to the technical solutions and concepts described above, and all these changes and deformations should fall within the protection scope of the claims of the present invention.

Claims

1. A method for preparing a telbipenem pivoxil intermediate, characterized in that, It comprises the following steps: The compound of formula II undergoes a transfer hydrogenation reaction under the action of a catalyst and a hydrogen source to obtain the compound of formula I: wherein, the hydrogen source is not hydrogen.

2. The preparation method according to claim 1, wherein The hydrogen source is selected from any one or more of triethylsilane, trimethylsilane, tribenzylsilane, diphenylmethylsilane, dihydropyridine, cyclohexene, cyclohexadiene, tetrahydronaphthalene, pyrrolidine, formic acid, ammonium formate.

3. The preparation method according to claim 1 or 2, characterized in that, The molar ratio of the hydrogen source to the compound II is 5-30:

1.

4. The preparation method according to claim 1, wherein The catalyst is selected from any one or more of 10% palladium on carbon, platinum on carbon, palladium hydroxide, platinum oxide, palladium oxide.

5. The preparation method according to claim 1 or 4, characterized in that, The mass ratio of the catalyst to the compound II is 0.1-2.0:

1.

6. The preparation method according to claim 1, wherein The solvent used in the transfer hydrogenation reaction is selected from any one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, acetone, butanone, tetrahydrofuran, dioxane, ethyl acetate, propyl acetate, dichloromethane, chloroform, methanol, ethanol, propanol, butanol and water.

7. The preparation method according to claim 6, characterized in that, The volume ratio of the solvent used in the transfer hydrogenation reaction to the compound II is 1-20:

1.

8. The preparation method according to any one of claims 1 to 7, characterized in that, The temperature of the transfer hydrogenation reaction is 0-80 °C.

9. According to the preparation method described in claim 1, characterized in that, It also comprises a post-treatment step: After the transfer hydrogenation reaction is completed, the hydrogenation reaction solution is filtered, and an organic solvent is added to the filtrate for crystallization to obtain a crude product of the temocillin intermediate; Preferably, the organic solvent is selected from any one or more of ethyl acetate, isopropyl acetate, methyl tert-butyl ether, tetrahydrofuran, acetone, acetonitrile, n-butanol.

10. The preparation method according to claim 9, characterized in that, It also comprises a purification step: The obtained crude product is slurried with purified water, filtered, and the filtrate is taken. After the filtrate is cooled to 0-5 °C, a crystallization solvent is added, and crystallization is carried out by stirring to obtain a purified temocillin intermediate; wherein, the crystallization solvent is selected from any one or more of acetone, tetrahydrofuran, acetonitrile, isopropanol and tert-butanol.

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