Preparation process of vitamin D3 key intermediate 7-p-toluenesulfonylepide-3-cholesteryl ester

Abstract

The invention relates to the technical field of vitamin intermediates, and particularly discloses a preparation process of a vitamin D3 key intermediate 7-p-toluenesulfonyl epide-3-cholesteryl ester. The invention relates to a preparation process of a vitamin D3 key intermediate 7-p-toluenesulfonylepide-3-cholesteryl ester, which comprises the following steps: reaction: adding 7-keto-3-cholesteryl ester, p-toluenesulfonhydrazide and concentrated hydrochloric acid into methanol, heating to 45-50 DEG C, and carrying out heat preservation reaction for 6.5-7.5 hours; post-treatment: after the reaction is finished, cooling crystallization and suction filtration are performed to obtain a solid, the solid is eluted by using iced methanol, suction drying is performed to obtain a washing solution and a filter cake, and the filter cake is subjected to vacuum drying to constant weight to obtain the product 7-p-toluenesulfonylepide-3-cholesteryl ester. The concentrated hydrochloric acid is used as a catalyst, and the reaction is carried out at 45-50 DEG C for 6.5-7.5 h, so that the reaction is mild, the energy consumption is reduced, and the production efficiency of the 7-p-toluenesulfonylepide-3-cholesteryl ester is improved.

Description

Technical Field

[0001] This application relates to the technical field of vitamin intermediates, and particularly to a preparation process of a key intermediate of vitamin D3, 7-p-toluenesulfonylhydrazone-3-cholesteryl ester. Background Art

[0002] Vitamin D3, also known as cholecalciferol or calciferol, is a type of vitamin D and a fat-soluble vitamin. A large number of studies have shown that vitamin D3 can not only prevent rickets in children, but also reduce the incidence of common cancers, such as breast cancer, colon cancer, lung cancer and other cancers, regulate the development and function of the placenta, and prevent the occurrence of pregnancy complications such as miscarriage, preeclampsia and premature birth. Generally speaking, vitamin D3 is very important for the healthy development of all populations. Therefore, it is imperative to improve the quality of vitamin D3 products and reduce production costs. 7-p-toluenesulfonylhydrazone-3-cholesteryl ester is a key intermediate in the industrial production of vitamin D3. It is usually obtained by carrying out a hydrazonation reaction using p-toluenesulfonylhydrazide and 7-keto-3-cholesteryl ester as raw materials under the catalysis of an amino acid. The amino acid is expensive and a large amount is added, and the reaction period is as long as 18 h, which is not conducive to industrial production. Summary of the Invention

[0003] In order to improve the production efficiency of 7-p-toluenesulfonylhydrazone-3-cholesteryl ester, this application provides a preparation process of a key intermediate of vitamin D3, 7-p-toluenesulfonylhydrazone-3-cholesteryl ester The preparation process of a key intermediate of vitamin D3, 7-p-toluenesulfonylhydrazone-3-cholesteryl ester provided by this application adopts the following technical scheme: A preparation process of a key intermediate of vitamin D3, 7-p-toluenesulfonylhydrazone-3-cholesteryl ester, comprising the following steps: Reaction: Add 7-keto-3-cholesteryl acid ester, p-toluenesulfonylhydrazide and concentrated hydrochloric acid to methanol, heat up to 45-50 °C, and keep the temperature for reaction for 6.5-7.5 h; Post-treatment: After the reaction is completed, cool down for crystallization, carry out suction filtration to obtain a solid, wash the solid with ice methanol, filter dry to obtain a washing liquid and a filter cake, and vacuum-dry the filter cake to constant weight to obtain the product 7-p-toluenesulfonylhydrazone-3-cholesteryl ester.

[0004] By adopting the above technical scheme, using concentrated hydrochloric acid as a catalyst and carrying out the reaction at 45-50 °C for 6.5-7.5 h, the reaction is mild, the energy consumption is reduced, and therefore the production efficiency of 7-p-toluenesulfonylhydrazone-3-cholesteryl ester is improved; and ice methanol is used for washing, and impurities are easily soluble in methanol, so the purity of the obtained product is improved.

[0005] In a specific feasible embodiment, in the reaction step, the weight ratio of the 7-keto-3-cholesteryl ester to the p-toluenesulfonyl hydrazide is 60:34.

[0006] In a specific feasible embodiment, in the reaction step, the volume ratio of the methanol to the concentrated hydrochloric acid is 400:0.3.

[0007] By adopting the above technical solution, the ratios of the 7-keto-3-cholesteryl ester, the p-toluenesulfonyl hydrazide, and the methanol to the concentrated hydrochloric acid are further defined, so that 7-p-toluenesulfonyl-3-cholesteryl ester can be better produced.

[0008] In a specific feasible embodiment, in the post-treatment step, the temperature for cooling crystallization is -5 to 0 °C and the time is 2 h.

[0009] In a specific feasible embodiment, in the post-treatment step, the drying temperature is 50 °C.

[0010] In a specific feasible embodiment, the temperature of the ice methanol is -5 to 0 °C.

[0011] In a specific feasible embodiment, the reaction step is as follows: methanol is added to the washing liquid to obtain a mother liquor, and then 7-keto-3-cholesteryl ester, p-toluenesulfonyl hydrazide, and concentrated hydrochloric acid are added to the mother liquor, and the temperature is raised to 45 - 50 °C, and the reaction is carried out under insulation for 6.5 - 7.5 h.

[0012] In a specific feasible embodiment, in the reaction step, the weight ratio of the 7-keto-3-cholesteryl ester to the p-toluenesulfonyl hydrazide is 60:25.

[0013] In a specific feasible embodiment, in the reaction step, the volume ratio of the mother liquor to the concentrated hydrochloric acid is 400:0.1.

[0014] By adopting the above technical solution, using the washing liquid, adding methanol thereto to prepare a mother liquor, which can be used as a raw material to continue the production and preparation of the next batch of 7-p-toluenesulfonyl-3-cholesteryl ester, thereby reducing the usage amounts of p-toluenesulfonyl hydrazide and concentrated hydrochloric acid and saving costs.

[0015] In a specific feasible embodiment, the 7-keto-3-cholesteryl ester includes one of 7-keto-3-cholesteryl acetate, 7-keto-3-cholesteryl benzoate, and 7-keto-3-cholesteryl pivalate.

[0016] In summary, the present application includes at least one of the following beneficial technical effects: In this application, concentrated hydrochloric acid is used as a catalyst, and the reaction is carried out at 45 - 50 °C for 6.5 - 7.5 h. The reaction is mild, reducing energy consumption, thus improving the production efficiency of 7-p-toluenesulfonyl-3-cholesteryl ester; and ice methanol is used for washing. The impurities are easily soluble in methanol, so the purity of the obtained product is improved. In this application, the ratios of 7-keto-3-cholesteryl ester, p-toluenesulfonylhydrazide, methanol and concentrated hydrochloric acid are further defined, so that 7-p-toluenesulfonyl-3-cholesteryl ester can be better produced. In this application, a washing solution is used. Methanol is added to it to prepare a mother liquor, which can be used as a raw material to continue to produce the next batch of 7-p-toluenesulfonyl-3-cholesteryl ester, thus reducing the usage amounts of p-toluenesulfonylhydrazide and concentrated hydrochloric acid and saving costs. Description of the Drawings

[0017] Figure 1 It is the liquid chromatogram used to reflect the product in Example 6.

[0018] Figure 2 It is the hydrogen spectrum used to reflect the product in Example 6. Detailed Description of the Embodiments

[0019] The following further elaborates on this application with reference to the embodiments.

[0020] All raw materials in the embodiments can be obtained commercially. Among them, 7-keto-3-cholesteryl ester includes but is not limited to one of 7-keto-3-cholesteryl acetate, 7-keto-3-cholesteryl benzoate, 7-keto-3-cholesteryl pivalate. In this application, 7-keto-3-cholesteryl acetate is preferably used.

[0021] Example 1 Example 1 provides a preparation process of a key intermediate of vitamin D3, 7-p-toluenesulfonyl-3-cholesteryl ester, including the following steps: Reaction: In a 500 ml four-necked flask, 400 ml of methanol is added, and then 60 g of 7-keto-3-cholesteryl ester, 34 g of p-toluenesulfonylhydrazide, and 0.3 ml of concentrated hydrochloric acid are added. The temperature is raised to 47.5 °C and the reaction is carried out under insulation for 7 h; the mass concentration of the concentrated hydrochloric acid is 37%; the 7-keto-3-cholesteryl ester is 7-keto-3-cholesteryl acetate; the reaction equation is: ; Post-treatment: After the reaction is completed, the temperature is lowered to -2 °C for crystallization for 2 h, and then suction filtration is carried out to obtain a solid. The solid is washed with 50 ml of ice methanol, suction dried to obtain a washing solution and a filter cake. The filter cake is vacuum dried at 50 °C to constant weight to obtain 75 g of the product 7-p-toluenesulfonyl-3-cholesteryl ester; the temperature of the ice methanol is 0 °C.

[0022] Example 2 Example 2 provides a preparation process for the key intermediate of vitamin D3, 7-p-toluenesulfonylhydrazono-3-cholesteryl ester, which includes the following steps: Reaction: In a 500 ml four-necked flask, put in the washing liquid from Example 1, then add methanol until the liquid in the flask is 400 ml to obtain the mother liquor. Then add 60 g of 7-keto-3-cholesteryl acetate, 25 g of p-toluenesulfonylhydrazide, and 0.1 ml of concentrated hydrochloric acid to the mother liquor, heat up to 47.5 °C, and keep the reaction at this temperature for 7 h; the mass concentration of the concentrated hydrochloric acid is 37%; the 7-keto-3-cholesteryl acid ester is 7-keto-3-cholesteryl acetate; Post-treatment: After the reaction is completed, cool down to -2 °C for crystallization for 2 h, then perform suction filtration to obtain a solid. Wash the solid with 50 ml of ice methanol (the temperature of the ice methanol is 0 °C), filter it dry to obtain the washing liquid and the filter cake. The filter cake is dried under vacuum at 50 °C until constant weight to obtain 77 g of the product 7-p-toluenesulfonylhydrazono-3-cholesteryl ester;

[0023] Example 3 Example 3 provides a preparation process for the key intermediate of vitamin D3, 7-p-toluenesulfonylhydrazono-3-cholesteryl ester, which includes the following steps: Reaction: In a 500 ml four-necked flask, put in the washing liquid from Example 2, then add methanol until the liquid in the flask is 400 ml to obtain the mother liquor. Then add 60 g of 7-keto-3-cholesteryl acetate, 25 g of p-toluenesulfonylhydrazide, and 0.1 ml of concentrated hydrochloric acid to the mother liquor, heat up to 47.5 °C, and keep the reaction at this temperature for 7 h; the mass concentration of the concentrated hydrochloric acid is 37%; the 7-keto-3-cholesteryl acid ester is 7-keto-3-cholesteryl acetate; Post-treatment: After the reaction is completed, cool down to -2 °C for crystallization for 2 h, then perform suction filtration to obtain a solid. Wash the solid with 50 ml of ice methanol (the temperature of the ice methanol is 0 °C), filter it dry to obtain the washing liquid and the filter cake. The filter cake is dried under vacuum at 50 °C until constant weight to obtain 78.8 g of the product 7-p-toluenesulfonylhydrazono-3-cholesteryl ester;

[0024] Example 4 Example 4 provides a preparation process for the key intermediate of vitamin D3, 7-p-toluenesulfonylhydrazono-3-cholesteryl ester, which includes the following steps: Reaction: In a 500 ml four-necked flask, put in the washing liquid from Example 3, then add methanol until the liquid in the flask is 400 ml to obtain the mother liquor. Then add 60 g of 7-keto-3-cholesteryl acetate, 25 g of p-toluenesulfonylhydrazide, and 0.1 ml of concentrated hydrochloric acid to the mother liquor, heat up to 47.5 °C, and keep the reaction at this temperature for 7 h; the mass concentration of the concentrated hydrochloric acid is 37%; the 7-keto-3-cholesteryl acid ester is 7-keto-3-cholesteryl acetate; Post-treatment: After the reaction was completed, the temperature was lowered to -2°C for crystallization for 2 h, followed by suction filtration to obtain a solid. The solid was rinsed with 50 ml of ice-cold methanol, and then suction dried to obtain a washing solution and a filter cake. The filter cake was vacuum dried at 50°C to a constant weight to obtain 80.6 g of the product 7-p-toluenesulfonylguanidino-3-cholesteryl ester; the temperature of the ice-cold methanol was 0°C.

[0025] Example 5 Example 5 provides a preparation process for the key intermediate 7-p-toluenesulfonylguanidino-3-cholesteryl ester of vitamin D3, comprising the following steps: Reaction: In a 500-ml four-necked flask, the washing solution from Example 4 was charged, and then methanol was added until the volume of the liquid in the flask was 400 ml to obtain a mother liquor. Then, 60 g of 7-keto-3-cholesteryl ester, 25 g of p-toluenesulfonylhydrazide, and 0.1 ml of concentrated hydrochloric acid were added to the mother liquor, and the temperature was raised to 47.5°C and the reaction was carried out under insulation for 7 h; the mass concentration of the concentrated hydrochloric acid was 37%; the 7-keto-3-cholesteryl ester was 7-keto-3-cholesteryl acetate; Post-treatment: After the reaction was completed, the temperature was lowered to -2°C for crystallization for 2 h, followed by suction filtration to obtain a solid. The solid was rinsed with 50 ml of ice-cold methanol, and then suction dried to obtain a washing solution and a filter cake. The filter cake was vacuum dried at 50°C to a constant weight to obtain 83 g of the product 7-p-toluenesulfonylguanidino-3-cholesteryl ester; the temperature of the ice-cold methanol was 0°C.

[0026] Example 6 Example 6 provides a preparation process for the key intermediate 7-p-toluenesulfonylguanidino-3-cholesteryl ester of vitamin D3, comprising the following steps: Reaction: In a 500-ml four-necked flask, the washing solution from Example 5 was charged, and then methanol was added until the volume of the liquid in the flask was 400 ml to obtain a mother liquor. Then, 60 g of 7-keto-3-cholesteryl ester, 25 g of p-toluenesulfonylhydrazide, and 0.1 ml of concentrated hydrochloric acid were added to the mother liquor, and the temperature was raised to 47.5°C and the reaction was carried out under insulation for 7 h; the mass concentration of the concentrated hydrochloric acid was 37%; the 7-keto-3-cholesteryl ester was 7-keto-3-cholesteryl acetate; Post-treatment: After the reaction was completed, the temperature was lowered to -2°C for crystallization for 2 h, followed by suction filtration to obtain a solid. The solid was rinsed with 50 ml of ice-cold methanol, and then suction dried to obtain a washing solution and a filter cake. The filter cake was vacuum dried at 50°C to a constant weight to obtain 87.3 g of the product 7-p-toluenesulfonylguanidino-3-cholesteryl ester; the liquid chromatogram of the product was referred to Figure 1 , and the hydrogen spectrum was referred to Figure 2 ; the temperature of the ice-cold methanol was 0°C.

[0027] Example 7 Example 7 provides a preparation process for the key intermediate 7-p-toluenesulfonylguanidino-3-cholesteryl ester of vitamin D3, comprising the following steps: Reaction: In a 500 ml four-necked flask, 400 ml of methanol was charged, and then 60 g of 7-keto-3-cholesteryl ester, 34 g of p-toluenesulfonyl hydrazide, and 0.3 ml of concentrated hydrochloric acid were added. The temperature was raised to 45 °C and the reaction was carried out under insulation for 7.5 h; the mass concentration of the concentrated hydrochloric acid was 37%; the 7-keto-3-cholesteryl ester was 7-keto-3-cholesteryl acetate; Post-treatment: After the reaction was completed, the temperature was lowered to -2 °C for crystallization for 2 h, and then suction filtration was carried out to obtain a solid. The solid was washed with 50 ml of ice-cold methanol, and then suction-dried to obtain a washing solution and a filter cake. The filter cake was vacuum-dried at 50 °C to constant weight to obtain the product 7-p-toluenesulfonyl-3-cholesteryl ester; the temperature of the ice-cold methanol was 0 °C.

[0028] Example 8 Example 8 provides a preparation process for the key intermediate 7-p-toluenesulfonyl-3-cholesteryl ester of vitamin D3, which includes the following steps: Reaction: In a 500 ml four-necked flask, 400 ml of methanol was charged, and then 60 g of 7-keto-3-cholesteryl ester, 34 g of p-toluenesulfonyl hydrazide, and 0.3 ml of concentrated hydrochloric acid were added. The temperature was raised to 50 °C and the reaction was carried out under insulation for 6.5 h; the mass concentration of the concentrated hydrochloric acid was 37%; the 7-keto-3-cholesteryl ester was 7-keto-3-cholesteryl acetate; Post-treatment: After the reaction was completed, the temperature was lowered to -2 °C for crystallization for 2 h, and then suction filtration was carried out to obtain a solid. The solid was washed with 50 ml of ice-cold methanol, and then suction-dried to obtain a washing solution and a filter cake. The filter cake was vacuum-dried at 50 °C to constant weight to obtain the product 7-p-toluenesulfonyl-3-cholesteryl ester; the temperature of the ice-cold methanol was 0 °C.

[0029] Comparative Example 1 Comparative Example 1 provides a preparation method for 7-p-toluenesulfonyl-3-cholesteryl ester, which includes the following steps: In a 1000 mL reaction flask, 50 g of 7-keto-3-cholesteryl acetate, 22 g of p-toluenesulfonyl hydrazide, 10 g of taurine, 300 mL of methanol, 100 mL of cyclohexane, and 20 mL of water were added in sequence. The reaction was carried out at 50 °C for 18 h. After detection by high performance liquid chromatography, the reaction was stopped when the residual amount of the 7-keto-3-cholesteryl acetate raw material was 0.1%. Then, the reaction mixture was cooled to -5 °C for crystallization for 4 hours, filtered while it was cold, and the filter cake was washed with cold water. The filter cake was vacuum-dried at 50 °C to constant weight to obtain 67 g of the product 7-p-toluenesulfonyl-3-cholesteryl ester.

[0030] Yield: Calculate the weight yield and theoretical yield of the product 7-p-toluenesulfonyl-3-cholesteryl ester in each example and comparative example.

[0031] Table 1 Performance test results of the product

[0032] Combined with Example 1, Example 7, Example 8 and Comparative Example 1, the yields of the products in Example 1, Example 7 and Example 8 are relatively high. It can be seen that by using the method in the present application, concentrated hydrochloric acid is used as a catalyst and the reaction is carried out at 45-50 °C for 6.5-7.5 h. The reaction is mild, the energy consumption is reduced, so the production efficiency of 7-p-toluenesulfonylguanidine-3-cholesteryl ester is improved, and the yield of the product is also improved.

[0033] Combined with Examples 1-6, the yields of the products in Examples 2-6 are also relatively high. It can be seen that for the washing liquid after each leaching of the solid, methanol can be added to form a mother liquor as a raw material to continue the production of 7-p-toluenesulfonylguanidine-3-cholesteryl ester, thereby reducing the usage amounts of the raw materials p-toluenesulfonylhydrazide and concentrated hydrochloric acid and saving costs.

[0034] This specific embodiment is only an interpretation of the present application and is not a limitation to the present application. Those skilled in the art can make modifications without creative contributions to this embodiment after reading this specification, but as long as it is within the scope of the claims of the present application, it is protected by the patent law.

Claims

1. A process for preparing 7-toluenesulfonylamine-3-cholesterol ester, a key intermediate of vitamin D3, characterized in that: The following steps are involved: Reaction: Add 7-keto-3-cholesterol ester, p-toluenesulfonyl hydrazide and concentrated hydrochloric acid to methanol, raise the temperature to 45-50°C, and keep the temperature for 6.5-7.5 hours; Post-treatment: After the reaction is completed, cool and crystallize, filter to obtain a solid, rinse the solid with ice methanol, dry to obtain a washing liquid and a filter cake, and vacuum dry the filter cake to constant weight to obtain the product 7-toluenesulfonylamine-3-cholesterol ester.

2. The process for preparing a vitamin D3 key intermediate 7-toluenesulfonylamine-3-cholesterol ester according to claim 1, characterized in that: In the reaction step, the weight ratio of the 7-keto-3-cholesterol ester to the p-toluenesulfonyl hydrazide is 60:

34.

3. The process for preparing 7-toluenesulfonylamine-3-cholesterol ester, a key intermediate of vitamin D3, according to claim 1, characterized in that: In the reaction step, the volume ratio of the methanol to the concentrated hydrochloric acid is 400:0.

3.

4. The process for preparing 7-toluenesulfonylamine-3-cholesterol ester, a key intermediate of vitamin D3, according to claim 1, characterized in that: In the post-treatment step, the temperature of the cooling crystallization is -5-0°C and the time is 2h.

5. The process for preparing 7-toluenesulfonylamine-3-cholesterol ester, a key intermediate of vitamin D3, according to claim 1, characterized in that: In the post-treatment step, the drying temperature is 50°C.

6. The process for preparing 7-toluenesulfonylamine-3-cholesterol ester, a key intermediate of vitamin D3, according to claim 1, characterized in that: The temperature of the ice methanol is -5-0°C.

7. The process for preparing a key intermediate of vitamin D3, 7-toluenesulfonylamine-3-cholesterol ester, according to claim 1, characterized in that: The reaction steps are: adding methanol to the washing liquid to obtain a mother liquor, then adding 7-keto-3-cholesterol ester, p-toluenesulfonyl hydrazide and concentrated hydrochloric acid to the mother liquor, heating to 45-50° C., and keeping the temperature for reaction for 6.5-7.5 hours.

8. The process for preparing 7-toluenesulfonylamine-3-cholesterol ester, a key intermediate of vitamin D3, according to claim 7, characterized in that: In the reaction step, the weight ratio of the 7-keto-3-cholesterol ester to the p-toluenesulfonyl hydrazide is 60:

25.

9. The process for preparing 7-toluenesulfonylamine-3-cholesterol ester, a key intermediate of vitamin D3, according to claim 8, characterized in that: In the reaction step, the volume ratio of the mother liquor to the concentrated hydrochloric acid is 400:0.

1.

10. The process for preparing 7-toluenesulfonylamine-3-cholesterol ester, a key intermediate of vitamin D3, according to claim 1, characterized in that: The 7-keto-3-cholesterol ester includes one of 7-keto-3-cholesterol acetate, 7-keto-3-cholesterol benzoate and 7-keto-3-cholesterol pivalate.

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