Preparation method of atorvastatin calcium intermediate

Abstract

The invention relates to a preparation method of an atorvastatin calcium intermediate. The preparation method comprises the following steps: mixing 3-6 parts of acetonitrile, 0.14-0.16 part of concentrated hydrochloric acid and 1.5-1.8 parts of water for later use; mixing 0.13-0.15 part of sodium bicarbonate and 3-5 parts of water for later use; mixing 4.0-5.5 parts of acetonitrile and 1 part of the atorvastatin calcium intermediate I, heating to dissolve the solid, cooling, adding an acetonitrile hydrochloric acid aqueous solution, and reacting for 2-3 hours to obtain a first mixed solution; adding a sodium bicarbonate aqueous solution into the first mixed solution, and then adding 2.5-5 parts of water to obtain a second mixed solution; cooling the second mixed solution to 0-10 DEG C, stirring for 6-10 hours, and then carrying out suction filtration to obtain a crude product of an atorvastatin calcium intermediate II; and adding 6-9 parts of water into the crude product of the atorvastatin calcium intermediate II, stirring for 2-4 hours, then carrying out suction filtration, washing with water, and carrying out vacuum drying to obtain the atorvastatin calcium intermediate II. According to the method, the atorvastatin calcium intermediate can be more sufficiently separated out, and the molar yield reaches 90% or above, so that the production cost is reduced.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug synthesis, in particular to a preparation method of atorvastatin calcium intermediate. BACKGROUND

[0002] Atorvastatin calcium, the trade name is "Lipitor", is a third generation statin developed by Pfizer. (English name: Atorvastatin Calcium), chemical name: (3R, 5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-isopropylpyrrol-1-yl]-3, 5-dihydroxyheptanoate trihydrate. The third generation statin developed by Pfizer, mainly used for the treatment of primary hypercholesterolemia, mixed hyperlipidemia, hyperlipidemia and coronary heart disease.

[0003] The main synthesis route at present is as follows: tert-butyl 2-((4R, 6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylaminocarbonyl<phenylaminocarbamoyl>)-1H-pyrrol-1-yl)ethyl)-2, 2-dimethyl-1, 3-dioxan-4-yl)acetate (hereinafter referred to as atorvastatin calcium intermediate I) is obtained by condensation of tert-butyl 2-[(4R, 6R)-6-(2-aminoethyl)-2, 2-dimethyl-1, 3-dioxan-4-yl]acetate (abbreviation: ATS-9) and 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylvaleramide (abbreviation: M4) as starting materials, then hydrolysis is carried out to obtain (3R, 5R)-tert-butyl 7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylaminocarbonyl<phenylaminocarbamoyl>)-1H-pyrrol-1-yl)-3, 5-dihydroxyheptanoate (hereinafter referred to as atorvastatin calcium intermediate II), and finally calcium acetate is salified to obtain atorvastatin calcium hydrate.

[0004] However, there is a big problem in the above synthesis route: the yield is low in the process of preparing atorvastatin calcium intermediate II from atorvastatin calcium intermediate I, the molar yield is only about 75%, and more than 20% of the product is not precipitated in the mother liquor, so that the commercial production material cost is high, the production efficiency is low, and it is not conducive to commercial production. SUMMARY

[0005] Based on this, the purpose of the present application is to provide a preparation method of atorvastatin calcium intermediate, which can precipitate the product atorvastatin calcium intermediate in the atorvastatin calcium intermediate crystallization system more fully, the molar yield reaches more than 90%, so as to reduce the production cost, and the method is simple to operate and easy to industrial production.

[0006] A preparation method of atorvastatin calcium intermediate, comprising the following steps:

[0007] The atorvastatin calcium intermediate I is 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylaminocarbonyl<phenylaminocarbamoyl>)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid tert-butyl ester, and the atorvastatin calcium intermediate II is (3R,5R)-tert-butyl 7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylaminocarbonyl<phenylaminocarbamoyl>)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate.

[0008] Preparation of acetonitrile hydrochloric acid aqueous solution: 3-6 parts of acetonitrile, 0.14-0.16 parts of concentrated hydrochloric acid and 1.5-1.8 parts of water are mixed for standby;

[0009] Preparation of sodium bicarbonate aqueous solution: 0.13-0.15 parts of sodium bicarbonate and 3-5 parts of water are mixed for standby;

[0010] Reaction: 4.0-5.5 parts of acetonitrile and 1 part of atorvastatin calcium intermediate I are mixed at 20-30℃, and the solid is completely dissolved by heating to 40-60℃, then cooled to 20-25℃, the acetonitrile hydrochloric acid aqueous solution is added, and the reaction is carried out for 2-3 hours to obtain a first mixed solution;

[0011] Crystallization: the sodium bicarbonate aqueous solution is added to the first mixed solution, and then 2.5-5 parts of water is added to obtain a second mixed solution;

[0012] Crystal growth: the second mixed solution is cooled to 0-10℃, and incubated and stirred for 6-10 hours, then filtered or centrifuged to obtain atorvastatin calcium intermediate II crude product;

[0013] Purification: 6-9 parts of water is added to the atorvastatin calcium intermediate II crude product, stirred for 2-4 hours, then filtered, washed with water, and vacuum dried to obtain atorvastatin calcium intermediate II;

[0014] The atorvastatin calcium intermediate I is 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylaminocarbonyl<phenylaminocarbamoyl>)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid tert-butyl ester, and the atorvastatin calcium intermediate II is (3R,5R)-tert-butyl 7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylaminocarbonyl<phenylaminocarbamoyl>)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate.

[0015] The atorvastatin calcium intermediate I is first mixed with acetonitrile, and then completely dissolved after being heated, and then cooled. The atorvastatin calcium intermediate I cannot be precipitated in pure acetonitrile. At this time, the pre-prepared acetonitrile hydrochloric acid aqueous solution is added for reaction. After the reaction, the pre-prepared sodium bicarbonate aqueous solution is added to adjust the pH. Then, water is added to make the product preliminarily precipitate. Then, the product is crystallized by cooling. The stirring is kept during the cooling process to ensure that the concentration of the system is uniform, so that the atorvastatin calcium intermediate II is precipitated. Finally, the high-purity atorvastatin calcium intermediate II is obtained through purification. The final molar yield is more than 90%, and the purity is more than 99%.

[0016] As a preferred solution, in the crystallization step, after the sodium bicarbonate aqueous solution is added to the first mixed solution, the pH is adjusted to 6-8, and then 3-5 parts of water is added. More preferably, the pH is adjusted to 6.8-7.0.

[0017] As a preferred solution, in the reaction step, 4.8 parts of acetonitrile and 1 part of atorvastatin calcium intermediate I are mixed, and the solid is completely dissolved by heating to 45-55℃.

[0018] As a preferred solution, 4 parts of acetonitrile, 0.15 parts of concentrated hydrochloric acid and 1.6 parts of water are mixed to obtain the acetonitrile hydrochloric acid aqueous solution. This ratio is the best ratio.

[0019] As a preferred solution, the mass fraction of the concentrated hydrochloric acid is 36-38%.

[0020] As a preferred solution, 0.14 parts of sodium bicarbonate and 4 parts of water are mixed to obtain the sodium bicarbonate aqueous solution. This ratio is the best ratio.

[0021] As a preferred solution, in the aging step, the stirring time is 6-8 hours.

[0022] As a preferred solution, in the purification step, the stirring time is 2.5 hours.

[0023] As a preferred solution, in the purification step, the product is washed with water for 1-2 times after being suction filtered, and the vacuum drying temperature is 50-65℃. DETAILED DESCRIPTION

[0024] The application will be described more fully below. However, the application can be embodied in many different forms and is not limited to the embodiments described herein. The experimental methods in the following examples or comparative examples are not specified, and are generally carried out according to conventional conditions in the art or according to the conditions recommended by the manufacturer; the raw materials, reagents, etc. used are commercially available raw materials and reagents unless otherwise specified.

[0025] A preparation method of atorvastatin calcium intermediate, comprising the following steps:

[0026] The atorvastatin calcium intermediate I is taken as a basis, and 1 part is used;

[0027] Preparation of acetonitrile hydrochloric acid aqueous solution: 3-6 parts of acetonitrile, 0.14-0.16 parts of concentrated hydrochloric acid and 1.5-1.8 parts of water are mixed and prepared;

[0028] Preparation of sodium bicarbonate aqueous solution: 0.13-0.15 parts of sodium bicarbonate and 3-5 parts of water are mixed, stirred until clear, and prepared;

[0029] Reaction: 4.0-5.5 parts of acetonitrile and 1 part of atorvastatin calcium intermediate I are mixed at room temperature, heated to 40-60 DEG C to completely dissolve the solid, then cooled to room temperature, acetonitrile hydrochloric acid aqueous solution is added, and reacted for 2-3 hours to obtain a first mixed solution;

[0030] Crystallization: sodium bicarbonate aqueous solution is added to the first mixed solution, the pH is adjusted to 6-8, then 2.5-5 parts of water is added to obtain a second mixed solution;

[0031] Crystal growth: the second mixed solution is cooled to 0-10 DEG C, and incubated and stirred for 6-10 hours, then suction filtered to obtain atorvastatin calcium intermediate II crude product;

[0032] Purification: 6-9 parts of water is added to the atorvastatin calcium intermediate II crude product, stirred for 2-4 hours, then suction filtered, washed with water, and dried at 50-65 DEG C under vacuum to obtain atorvastatin calcium intermediate II;

[0033] In the embodiment, the atorvastatin calcium intermediate I is tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylaminocarbonyl<phenylaminocarbamoyl>)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate, and the atorvastatin calcium intermediate II is (3R,5R)-tert-butyl 7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylaminocarbonyl<phenylaminocarbamoyl>)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate.

[0034] In the embodiment, the concentrated hydrochloric acid used is commercially available CP grade concentrated hydrochloric acid, and the mass fraction is about 37%.

[0035] Example 1

[0036] A preparation method of atorvastatin calcium intermediate, comprising the following steps:

[0037] Preparation of acetonitrile hydrochloric acid aqueous solution: 100 g acetonitrile, 3.7 g concentrated hydrochloric acid and 40 g water were added into a reaction bottle and stirred until uniform, ready for use.

[0038] Preparation of sodium bicarbonate aqueous solution: 100 g water was added into a reaction bottle, and then 3.5 g sodium bicarbonate was added and stirred until the solution was clear, ready for use.

[0039] Reaction: 120 g acetonitrile and 25 g atorvastatin calcium intermediate I were added into a 1000 ml reaction bottle at 20°C. The temperature was increased to 50°C until the solid was completely dissolved, and then slowly cooled to 21°C. The acetonitrile hydrochloric acid aqueous solution was added dropwise into the reaction bottle, and after the addition was completed, the reaction was incubated for 3 hours.

[0040] Crystallization: after the reaction was completed, the sodium bicarbonate aqueous solution was added into the reaction system, the pH was adjusted to 7.0, and then 62.5 g water was added dropwise.

[0041] Crystal growth: the temperature was decreased to 0°C, and the incubation was stirred for 8 hours; the atorvastatin calcium intermediate II crude product was obtained by suction filtration,

[0042] Purification: 175 g water was added into the atorvastatin calcium intermediate II crude product, stirred for 2.5 hours, suction filtered, washed once with water, and dried at 60°C under vacuum, finally 21.4 g atorvastatin calcium intermediate II was obtained, the molar yield was 91%, and the purity was 99.34%.

[0043] Example 2

[0044] A preparation method of an atorvastatin calcium intermediate, comprising the following steps:

[0045] Preparation of acetonitrile hydrochloric acid aqueous solution: 100 g acetonitrile, 3.7 g concentrated hydrochloric acid and 40 g water were added into a reaction bottle and stirred until uniform, ready for use.

[0046] Preparation of sodium bicarbonate aqueous solution: 100 g water was added into a reaction bottle, and then 3.5 g sodium bicarbonate was added and stirred until the solution was clear, ready for use.

[0047] Reaction: 120 g acetonitrile and 25 g atorvastatin calcium intermediate I were added into a 1000 ml reaction bottle at 20°C. The temperature was increased to 50°C until the solid was completely dissolved, and then slowly cooled to 21°C. The acetonitrile hydrochloric acid aqueous solution was added dropwise into the reaction bottle, and after the addition was completed, the reaction was incubated for 3 hours.

[0048] Crystallization: after the reaction was completed, the sodium bicarbonate aqueous solution was added into the reaction system, the pH was adjusted to 7.0, and then 62.5 g water was added dropwise.

[0049] Crystal growth: the temperature was decreased to 0°C, and the incubation was stirred for 8 hours; the atorvastatin calcium intermediate II crude product was obtained by suction filtration,

[0050] Purification: 175 g of water was added to the crude atorvastatin calcium intermediate II, stirred for 2 hours, suction filtered, washed with water twice, and dried under vacuum at 65°C. Finally, 21.6 g of atorvastatin calcium intermediate II was obtained with a molar yield of 92% and a purity of 99.42%.

[0051] Example 3

[0052] A method for preparing an atorvastatin calcium intermediate, comprising the following steps:

[0053] Preparation of acetonitrile hydrochloric acid aqueous solution: 100 g of acetonitrile, 3.7 g of concentrated hydrochloric acid and 40 g of water were added to a reaction bottle and stirred until uniform, and then prepared.

[0054] Preparation of sodium bicarbonate aqueous solution: 100 g of water was added to a reaction bottle, and then 3.5 g of sodium bicarbonate was added and stirred until the solution was clear, and then prepared.

[0055] Reaction: 120 g of acetonitrile and 25 g of atorvastatin calcium intermediate I were added to a 1000 ml reaction bottle at 20°C. The temperature was increased to 52°C until the solid was completely dissolved, and then slowly cooled to 25°C. The acetonitrile hydrochloric acid aqueous solution was added dropwise to the reaction bottle, and after the dropwise addition was completed, the reaction was incubated for 2.5 hours.

[0056] Crystallization: after the reaction was completed, the sodium bicarbonate aqueous solution was added to the reaction system, the pH was adjusted to 7.2, and then 125 g of water was added dropwise.

[0057] Crystal growth: the temperature was lowered to 10°C, and incubated for 8 hours with stirring; suction filtration was performed to obtain the crude atorvastatin calcium intermediate II,

[0058] Purification: 175 g of water was added to the crude atorvastatin calcium intermediate II, stirred for 2.5 hours, suction filtered, washed with water twice, and dried under vacuum at 65°C. Finally, 21.8 g of atorvastatin calcium intermediate II was obtained with a molar yield of 93% and a purity of 99.32%.

[0059] The above examples only express several embodiments of the present application, and the description is more specific and detailed, but it cannot be understood as limiting the scope of the patent. For ordinary skilled in the art, without departing from the concept of the present application, a number of modifications and improvements can be made, which are within the scope of the present application.

Claims

1. A process for the preparation of an intermediate of atorvastatin calcium characterized in that, Includes the following steps: Based on the mass of atorvastatin calcium intermediate I, and consisting of 1 part; Preparation of acetonitrile-hydrochloric acid aqueous solution: Mix 3-6 parts acetonitrile, 0.14-0.16 parts concentrated hydrochloric acid and 1.5-1.8 parts water for later use; Preparation of sodium bicarbonate aqueous solution: Mix 0.13-0.15 parts sodium bicarbonate with 3-5 parts water for later use; Reaction: At 20-30℃, 4.0-5.5 parts of acetonitrile and 1 part of atorvastatin calcium intermediate I are mixed, heated to 40-60℃ to completely dissolve the solid, then cooled to 20-25℃, and the acetonitrile hydrochloric acid aqueous solution is added. The reaction is carried out for 2-3 hours to obtain the first mixed solution. Crystallization: Add the sodium bicarbonate aqueous solution to the first mixed solution, and then add 2.5-5 parts of water to obtain the second mixed solution; Crystallization: Cool the second mixed solution to 0-10℃, keep it warm and stir for 6-10 hours, and then filter or centrifuge to obtain crude atorvastatin calcium intermediate II; Purification: Add 6-9 parts of water to the crude atorvastatin calcium intermediate II, stir for 2-4 hours, then filter, wash with water, and vacuum dry to obtain atorvastatin calcium intermediate II; Atorvastatin calcium intermediate I is 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylaminocarbonyl<phenylcarbamoyl>)-1H-pyrrolo-1-yl)ethyl)-2,2-dimethyl-1,3-dioxane-4-yl)tert-butyl acetate, and atorvastatin calcium intermediate II is (3R,5R)-tert-butyl7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylaminocarbonyl<phenylcarbamoyl>)-1H-pyrrolo-1-yl)-3,5-dihydroxyheptanoate.

2. A process for the preparation of atorvastatin calcium intermediate as claimed in claim 1, wherein, In the crystallization step, after adding the sodium bicarbonate aqueous solution to the first mixed solution, the pH is adjusted to 6-8, and then 3-5 parts of water are added.

3. A process for the preparation of atorvastatin calcium intermediate as claimed in claim 1, wherein, In the reaction step, 4.8 parts of acetonitrile and 1 part of atorvastatin calcium intermediate I are mixed and heated to 45-55°C to completely dissolve the solid.

4. A process for the preparation of Atorvastatin calcium intermediate as claimed in claim 1, wherein, Mix 4 parts acetonitrile, 0.15 parts concentrated hydrochloric acid and 1.6 parts water to obtain the acetonitrile hydrochloric acid aqueous solution.

5. A process for the preparation of atorvastatin calcium intermediate as claimed in claim 4 wherein, The concentrated hydrochloric acid has a mass fraction of 36-38%.

6. A process for the preparation of Atorvastatin calcium intermediate substantially as herein described with reference to claim 1. Mix 0.14 parts sodium bicarbonate and 4 parts water to obtain the sodium bicarbonate aqueous solution.

7. A process for the preparation of atorvastatin calcium intermediate as claimed in claim 1, wherein, In the crystal growth step, the temperature holding and stirring time is 6-8 hours.

8. A process for the preparation of atorvastatin calcium intermediate as claimed in claim 1, wherein, In the purification step, the stirring time is 2.5 hours.

9. A process for the preparation of atorvastatin calcium intermediate as claimed in claim 1, wherein, In the purification step, the sample is washed with water 1-2 times after filtration, and the vacuum drying temperature is 50-65℃.