Preparation method of clarithromycin crude product

Abstract

The invention provides a preparation method of a clarithromycin crude product, and relates to the technical field of medicine preparation. According to the method, oxime etherified silanide is taken as a starting material, various methylation reagents are adopted, toluene is taken as a solvent system, tributyl methyl ammonium chloride is taken as a solid-liquid phase transfer catalyst, potassium hydroxide is taken as an acid-binding agent, a methylation reaction is carried out, deprotection is carried out through tetrabutylammonium fluoride, and oxime hydroxyl is reduced through potassium borohydride, so that a clarithromycin crude product is obtained.

Description

Technical Field

[0001] The invention relates to the technical field of drug preparation, and in particular to a method for preparing a crude clarithromycin product. Background Art

[0002] Clarithromycin is an excellent broad-spectrum antibiotic developed by Taisho Pharmaceutical Co., Ltd. of Japan. Clarithromycin is a macrolide antibiotic. Macrolide antibiotics are a class of antibacterial drugs with similar chemical structures and antibacterial effects. Clarithromycin (6-O-methylerythromycin) is a new erythromycin derivative obtained by methylating the upper hydroxyl group of the C-hydroxyl group of erythromycin. After the C-6 hydroxyl group is etherified, the intramolecular cyclization reaction of the erythromycin ring is prevented from being inactivated under acidic conditions, thereby improving the antibacterial activity. It has the advantages of strong antibacterial activity, high bioavailability, wide tissue distribution and long half-life.

[0003] Currently, the most common method for preparing clarithromycin includes the following steps: (a) protecting the oxime hydroxyl group at position 9; (b) protecting the hydroxyl groups at positions 2' and 4"; (c) methylating the hydroxyl group at position 6; (d) removing the protecting groups at positions 2', 4" and 9. In the methylation reaction, common methylating agents such as methyl bromide, dimethyl sulfate, methyl iodide, etc. each have their own advantages and disadvantages: methyl bromide has a good overall reaction effect, but in the methylation reaction, it is easy to lose from the reaction system in the form of gas, and the reaction sustainability is poor; dimethyl sulfate is more stable than methyl bromide, but the reaction effect is average; methyl iodide is a commonly used methylating agent in industry, but it has strong volatility and toxicity. Various methylating agents have their own advantages and disadvantages. Summary of the invention

[0004] The purpose of the present invention is to provide a method for preparing a crude clarithromycin product, which is used to solve the technical problems of the reaction activity, sustainability, stability, safety and other aspects of the common methylation reagents in the prior art, and to provide a new feasible solution for the methylation reaction of clarithromycin.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0006] The present invention provides a method for preparing a crude clarithromycin product, comprising the following steps:

[0007] Step 1), methylating erythromycin oxime etherified silane, toluene and a methylating agent under the action of tributyl methylammonium chloride and potassium hydroxide, followed by quenching and layering to obtain an organic phase, and washing, layering and concentrating the obtained organic phase in sequence to obtain a methylated product;

[0008] Step 2), dissolving the methylated product obtained in step 1) in a deprotection reaction solvent, and then mixing with tetrabutylammonium fluoride to react, and then adding potassium borohydride to reduce, and after quenching, extracting, washing and concentrating the reduced product in sequence to obtain an organic phase, dissolving the obtained organic phase in methanol, and filtering to obtain a crude clarithromycin product;

[0009] The methylating agent includes one or more of methyl bromide, dimethyl sulfate and methyl p-toluenesulfonate.

[0010] Furthermore, in step 1), the mass ratio of the erythromycin oxime etherified silane to toluene is 1:9-11.

[0011] Furthermore, in step 1), the molar ratio of the erythromycin oxime etherified silane, the methylating agent and potassium hydroxide is 1:2.4-2.6:2.8-3.0.

[0012] Furthermore, in step 1), the amount of tributyl methyl ammonium chloride used is 0.5-1.5% of the amount of erythromycin oxime etherified silylated substance.

[0013] Furthermore, in step 1), the reaction temperature of the methylation reaction is 0 to 15° C., and the reaction time of the methylation reaction is 0.5 to 1.5 h.

[0014] Furthermore, in step 2), the deprotection reaction solvent comprises a mixture of methanol and tetrahydrofuran.

[0015] Furthermore, in step 2), the mass ratio of the methylated product, methanol and tetrahydrofuran is 1:1.36-1.4:1.36-1.4;

[0016] The molar ratio of the methylated compound to tetrabutylammonium fluoride is 1:3.5-4.0, and the molar ratio of the methylated compound to potassium borohydride is 1:2.0-2.5.

[0017] Furthermore, in step 2), the reaction temperature is 55-65° C., the reaction time is 1-2 h, and the reduction time is 1-3 h.

[0018] Further, in step 2), the quenching is to add water to the reaction system, and the extraction agent is dichloromethane;

[0019] The mass ratio of the methylated product, water and dichloromethane is 1:3.9-4.1:2.9-3.1.

[0020] Furthermore, in step 2), when the organic phase is dissolved in methanol, the temperature is first raised to 55-60° C. and stirred for 1-1.5 h, and then the temperature is lowered to 0-10° C. and stirred for 0.8-1.5 h;

[0021] The mass ratio of the methylated product to methanol is 1:1.36-1.4.

[0022] Beneficial effects of the present invention:

[0023] 1) In the process of preparing the crude clarithromycin product of the present invention, methyl p-toluenesulfonate is selected as the methylating agent, which enhances the continuity of the reaction and improves the stability during the reaction while maintaining the yield and purity at the same level as the existing process conditions.

[0024] 2) The methylation reagent for preparing the crude clarithromycin of the present invention is low in price, which effectively controls the production cost and is more environmentally friendly.

[0025] 3) The preparation of the crude clarithromycin product according to the present invention is simple and easy to operate, and the selected methylation reagent reduces the safety risks and hidden dangers that may exist in the production process, thereby ensuring the safety of the production process. DETAILED DESCRIPTION

[0026] The present invention provides a method for preparing a crude clarithromycin product, comprising the following steps:

[0027] Step 1), methylating erythromycin oxime etherified silane, toluene and a methylating agent under the action of tributyl methylammonium chloride and potassium hydroxide, followed by quenching and layering to obtain an organic phase, and washing, layering and concentrating the obtained organic phase in sequence to obtain a methylated product;

[0028] Step 2), dissolving the methylated product obtained in step 1) in a deprotection reaction solvent, and then mixing with tetrabutylammonium fluoride to react, and then adding potassium borohydride to reduce, and after quenching, extracting, washing and concentrating the reduced product in sequence to obtain an organic phase, dissolving the obtained organic phase in methanol, and filtering to obtain a crude clarithromycin product;

[0029] The methylating agent includes one or more of methyl bromide, dimethyl sulfate and methyl p-toluenesulfonate.

[0030] In the present invention, the methylating agent is preferably methyl bromide, dimethyl sulfate or methyl p-toluenesulfonate, more preferably methyl bromide or dimethyl sulfate, and more preferably methyl bromide.

[0031] In the present invention, in step 1), the mass ratio of the erythromycin oxime etherified silane to toluene is 1:9-11, preferably 1:10.

[0032] In the present invention, in step 1), the molar ratio of the erythromycin oxime etherified silane, the methylating agent and potassium hydroxide is 1:2.4-2.6:2.8-3.0, preferably 1:2.5:2.9.

[0033] In the present invention, in step 1), the amount of tributyl methyl ammonium chloride used is 0.5-1.5% of the amount of erythromycin oxime etherified silylated substance, preferably 0.8-1.3%, and more preferably 1.0%.

[0034] In the present invention, in step 1), the reaction temperature of the methylation reaction is 0-15°C, preferably 2-13°C, more preferably 8°C, and the reaction time of the methylation reaction is 0.5-1.5h, preferably 0.8-1.3h, more preferably 1h.

[0035] In the present invention, in step 1), the starting temperature of the methylation reaction is preferably <0°C, more preferably <-2°C, and more preferably <-3°C.

[0036] In the present invention, in step 2), after the reduction reaction is quenched by adding water, the layers are separated, the organic phase is washed with saturated brine, the layers are separated, and the organic phase is concentrated until there is no fraction to obtain a methylated product.

[0037] In the present invention, in step 2), the deprotection reaction solvent comprises a mixture of methanol and tetrahydrofuran.

[0038] In the present invention, in step 2), the mass ratio of the methylated product, methanol and tetrahydrofuran is 1:1.36-1.4:1.36-1.4, preferably 1:1.38:1.38;

[0039] The molar ratio of the methylate to tetrabutylammonium fluoride is 1:3.5-4.0, preferably 1:3.6-3.8, and more preferably 1:3.7. The molar ratio of the methylate to potassium borohydride is 1:2.0-2.5, preferably 1:2.2-2.4, and more preferably 1:2.3.

[0040] In the present invention, in step 2), the reaction temperature is 55-65°C, preferably 58-62°C, more preferably 60°C, the reaction time is 1-2h, preferably 1.2-1.8h, more preferably 1.5h, and the reduction time is 1-3h, preferably 1.5-2.5h, more preferably 2h.

[0041] In the present invention, in step 2), the quenching is to add water to the reaction system, and the extraction agent is dichloromethane;

[0042] The mass ratio of the methylated product, water and dichloromethane is 1:3.9-4.1:2.9-3.1, preferably 1:4:3.

[0043] In the present invention, in step 2), when the organic phase is dissolved in methanol, the temperature is first raised to 55-60° C. and stirred for 1-1.5 h, and then the temperature is lowered to 0-10° C. and stirred for 0.8-1.5 h.

[0044] In the present invention, the heating temperature is preferably 56-58°C, more preferably 57°C, the stirring time after heating is preferably 1.3h, the cooling temperature is preferably 3-7°C, more preferably 5°C, and the stirring time after cooling is preferably 1-1.3h, more preferably 1.2h.

[0045] In the present invention, in step 2), the mass ratio of the methylated product to methanol is 1:1.36-1.4, preferably 1:1.38.

[0046] In the present invention, the reaction is carried out in a 500 mL four-necked reaction bottle equipped with a thermometer.

[0047] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0048] Example 1

[0049] 230 mL of toluene and 20 g of erythromycin oxime etherified silane were mixed, stirred at room temperature to dissolve, cooled to -2°C, 10.77 g of methyl bromide-toluene solution (the mass fraction of methyl bromide was 45%), 0.2 g of tributyl methyl ammonium chloride and 3.32 g of potassium hydroxide were added to carry out a methylation reaction with a reaction time of 1 h, and then 3 g of water was added and stirred for 10 min to quench the methylation reaction, the reaction solution was placed in a separatory funnel and allowed to stand for 20 min to separate, the organic phase obtained after separation was mixed and stirred with 100 g of saturated brine for 15 min, allowed to stand for 30 min and separated, and the obtained organic phase was concentrated under reduced pressure to obtain 22.0 g of methylated product;

[0050] The methylated product was mixed with 30.5 g methanol and 30.5 g tetrahydrofuran, and stirred evenly. Then 21.4 g tetrabutylammonium fluoride was added, and the temperature was raised to 65° C. and stirred for 2 h. After cooling to room temperature within 40 min, 3.0 g potassium borohydride was added and reacted for 3 h. 66.0 g dichloromethane and 88.0 g water were added again and stirred for 10 min. The reaction solution was allowed to stand for 25 min and separated to obtain an organic phase. The organic phase was concentrated under reduced pressure and dissolved in 30.5 g methanol. The temperature was raised to 58° C. and stirred for 1.5 h. The temperature was lowered to 5° C. and stirred for 1 h. The product was filtered to obtain 16.57 g crude clarithromycin with a yield of 79.25% and a content of >95%.

[0051] Example 2

[0052] 230 mL of toluene and 20 g of erythromycin oxime etherified silane were mixed, stirred at room temperature until dissolved, cooled to -3°C, 6.43 g of dimethyl sulfate, 0.2 g of tributyl methylammonium chloride and 3.32 g of potassium hydroxide were added to carry out a methylation reaction for 1.5 h, and then 3 g of water was added and stirred for 15 min to quench the methylation reaction, the reaction solution was placed in a separatory funnel and allowed to stand for 35 min to separate, the organic phase obtained after separation was mixed with 100 g of saturated brine and stirred for 15 min, allowed to stand for 25 min and separated, and the obtained organic phase was concentrated under reduced pressure to obtain 20.5 g of methylated product;

[0053] The methylated product was mixed with 28.4 g methanol and 28.4 g tetrahydrofuran, and stirred evenly. Then 22.0 g tetrabutylammonium fluoride was added, and the temperature was raised to 63°C and stirred for 2 h. After cooling to room temperature within 35 min, 3.0 g potassium borohydride was added and reacted for 3 h. 61.5 g dichloromethane and 82.0 g water were added again and stirred for 15 min. The reaction solution was allowed to stand for 30 min and separated to obtain an organic phase. The organic phase was concentrated under reduced pressure and dissolved in 28.4 g methanol. The temperature was raised to 59°C and stirred for 1.5 h. The temperature was lowered to 7°C and stirred for 1 h. The product was filtered to obtain 14.32 g of crude clarithromycin with a yield of 73.52% and a content of >95%.

[0054] Example 3

[0055] 230 mL of toluene and 20 g of erythromycin oxime etherified silane were mixed, stirred at room temperature until dissolved, then cooled to -2°C, 9.51 g of methyl p-toluenesulfonate, 0.2 g of tributyl methylammonium chloride and 3.32 g of potassium hydroxide were added to carry out a methylation reaction for 1.5 h, then 3 g of water was added and stirred for 15 min to quench the methylation reaction, the reaction solution was placed in a separatory funnel and allowed to stand for 30 min to separate, the organic phase obtained after separation was mixed and stirred with 100 g of saturated brine for 20 min, allowed to stand for 30 min and separated, and the obtained organic phase was concentrated under reduced pressure to obtain 22.3 g of methylated product;

[0056] The methylated product was mixed with 30.9 g methanol and 30.9 g tetrahydrofuran, and stirred evenly. Then 22.4 g tetrabutylammonium fluoride was added, and the temperature was raised to 63° C. and stirred for 2 h. After cooling to room temperature within 35 min, 3.2 g potassium borohydride was added and reacted for 3 h. 67.0 g dichloromethane and 89.2 g water were added again and stirred for 15 min. The reaction solution was allowed to stand for 30 min and separated to obtain an organic phase. The organic phase was concentrated under reduced pressure and dissolved in 30.9 g methanol. The temperature was raised to 60° C. and stirred for 1.5 h. The temperature was lowered to 7° C. and stirred for 1 h. The product was filtered to obtain 16.72 g of crude clarithromycin with a yield of 78.93% and a content of >95%.

[0057] From the above examples, it can be seen that the present invention provides a method for preparing a crude clarithromycin product. It can be seen that the use of methyl p-toluenesulfonate as a methylating agent has a reaction activity comparable to that of methyl bromide, a product yield and a purity level similar to that of methyl bromide, and maintains the continuity and stability of the reaction process; compared with dimethyl sulfate, the reaction is more thorough, and the product purity and yield are significantly improved. The present invention has a lower cost for preparing a crude clarithromycin product, is more environmentally friendly, and the safety of the reaction process is further guaranteed.

[0058] The above is only 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 principle 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 a crude clarithromycin product, characterized in that: The following steps are involved: Step 1), methylating erythromycin oxime etherified silane, toluene and a methylating agent under the action of tributyl methylammonium chloride and potassium hydroxide, followed by quenching and layering to obtain an organic phase, and washing, layering and concentrating the obtained organic phase in sequence to obtain a methylated product; Step 2), dissolving the methylated product obtained in step 1) in a deprotection reaction solvent, and then mixing with tetrabutylammonium fluoride to react, and then adding potassium borohydride to reduce, and after quenching, extracting, washing and concentrating the reduced product in sequence to obtain an organic phase, dissolving the obtained organic phase in methanol, and filtering to obtain a crude clarithromycin product; The methylating agent includes one or more of methyl bromide, dimethyl sulfate and methyl p-toluenesulfonate.

2. The method for preparing a crude clarithromycin according to claim 1, characterized in that: In step 1), the mass ratio of the erythromycin oxime etherified silane to toluene is 1:9-11.

3. The method for preparing a crude clarithromycin according to claim 1 or 2, characterized in that: In step 1), the molar ratio of the erythromycin oxime etherified silane, the methylating agent and potassium hydroxide is 1:2.4-2.6:2.8-3.

0.

4. The method for preparing a crude clarithromycin according to claim 3, characterized in that: In step 1), the amount of tributyl methyl ammonium chloride used is 0.5-1.5% of the amount of erythromycin oxime etherified silylated substance.

5. The method for preparing a crude clarithromycin according to claim 1, 2 or 4, characterized in that: In step 1), the reaction temperature of the methylation reaction is 0 to 15° C., and the reaction time of the methylation reaction is 0.5 to 1.5 h.

6. The method for preparing a crude clarithromycin according to claim 5, characterized in that: In step 2), the deprotection reaction solvent comprises a mixture of methanol and tetrahydrofuran.

7. The method for preparing a crude clarithromycin according to claim 6, characterized in that: In step 2), the mass ratio of the methylated product, methanol and tetrahydrofuran is 1:1.36-1.4:1.36-1.4; The molar ratio of the methylated compound to tetrabutylammonium fluoride is 1:3.5-4.0, and the molar ratio of the methylated compound to potassium borohydride is 1:2.0-2.

5.

8. The method for preparing a crude clarithromycin according to claim 1 or 7, characterized in that: In step 2), the reaction temperature is 55-65° C., the reaction time is 1-2 h, and the reduction time is 1-3 h.

9. The method for preparing a crude clarithromycin according to claim 8, characterized in that: In step 2), the quenching is to add water to the reaction system, and the extraction agent is dichloromethane; The mass ratio of the methylated product, water and dichloromethane is 1:3.9-4.1:2.9-3.

1.

10. The method for preparing a crude clarithromycin according to claim 9, characterized in that: In step 2), when the organic phase is dissolved in methanol, the temperature is first raised to 55-60° C. and stirred for 1-1.5 h, and then the temperature is lowered to 0-10° C. and stirred for 0.8-1.5 h; The mass ratio of the methylated product to methanol is 1:1.36-1.4.