WO2013185309A1 - Rosuvastatin calcium and method for preparing intermediate thereof - Google Patents

Rosuvastatin calcium and method for preparing intermediate thereof Download PDF

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Publication number
WO2013185309A1
WO2013185309A1 PCT/CN2012/076856 CN2012076856W WO2013185309A1 WO 2013185309 A1 WO2013185309 A1 WO 2013185309A1 CN 2012076856 W CN2012076856 W CN 2012076856W WO 2013185309 A1 WO2013185309 A1 WO 2013185309A1
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formula
compound
preparation
rosuvastatin
reaction
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PCT/CN2012/076856
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French (fr)
Chinese (zh)
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李金亮
赵楠
熊毅
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上海迪赛诺药业有限公司
上海迪赛诺化学制药有限公司
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Priority to PCT/CN2012/076856 priority Critical patent/WO2013185309A1/en
Publication of WO2013185309A1 publication Critical patent/WO2013185309A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing rosuvastatin calcium and an intermediate thereof. Background technique
  • Rosuvastatin Calcium was developed by Japan Yanyeyi Co., Ltd., chemical name: [S-[R,S-CE]]]-7-[4-(4-fluorophenyl)-6 -Isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl]-3,5-dihydroxy-hept-6-enoate (acid and calcium are as follows:
  • Rosuvastatin calcium is a new generation of single-enantiomers of a new synthetic statin lipid regulating agent, belonging to the HMG-CoA reductase inhibitor, which lowers elevated low-density cholesterol, total cholesterol, triglycerides and The concentration of the prostaglandin B increases the concentration of high-density cholesterol. It can be used as a combination therapy for primary hypercholesterolemia and mixed lipodystrophy and homozygous familial hypercholesterolemia. It is called superstatin.
  • the method uses p-fluorobenzaldehyde as a raw material, and it takes 13 steps to obtain rosuvastatin calcium. Further, the side chain compound 10 is very expensive to be commercially available; if it is synthesized by itself, it is difficult to obtain a side chain compound 10 having high optical purity. In addition, post-treatment of multi-step reactions in this route requires column chromatography, which is not suitable for industrial applications.
  • the side chain compound 20 used in the method i.e., the compound of the formula V used in the present invention
  • a conventional preparation method e.g., Tetrahedron: Asymmetry, 18 (20), 2454-2461, 2007.
  • Chain compound 20 can be obtained by a conventional preparation method (e.g., Tetrahedron: Asymmetry, 18 (20), 2454-2461, 2007).
  • the Wittig reaction conditions in the sixth step are harsh (for example, the reaction temperature is -75 °C, which requires cryogenic equipment), and the post-treatment is extremely cumbersome, so it is not suitable for industrial applications.
  • This method also uses the side chain compound 20, although the temperature of the Wittig reaction is increased (-25 to -40 ° C can be used), but refrigeration equipment is still required, and a large amount of 2, 2, 6 is required in the reaction. 6-tetramethylpiperidine (the molar amount is 4-5 times that of the reaction substrate), and n-butyllithium, and the transportation, storage, use and post-treatment of n-butyllithium are dangerous and therefore neither Suitable for industrial applications.
  • One object of the present invention is to provide a method for preparing rosuvastatin calcium which is low in production cost, mild in condition, simple in operation, safe and effective.
  • Another object of the present invention is to provide a class of intermediates of rosuvastatin calcium which are simple to prepare and low in production cost and a process for preparing the same.
  • the intermediate compound represented by the formula A is an intermediate represented by the formula II, an intermediate represented by the formula III, an intermediate represented by the formula IV, or an intermediate represented by the formula VI.
  • a process for the preparation of an intermediate of formula II which comprises the steps of: reacting a compound of formula I with methanesulfonyl chloride in a CM halogenated hydrocarbon solvent to form a compound of formula II.
  • a process for the preparation of an intermediate of the formula in which comprises the steps of: subjecting a compound of formula II to reduction in the presence of a reducing agent in an inert solvent to form a compound of formula III.
  • the reducing agent is selected from the group consisting of diisobutylaluminum hydride, lithium tetrahydrogenate, Sodium hydride, potassium borohydride, or a combination thereof; more preferably diisobutylaluminum hydride.
  • the compound of formula II is prepared according to the process of the second aspect of the invention.
  • a process for the preparation of an intermediate of formula IV which comprises the steps of:
  • the compound of the formula III is subjected to a bromination reaction in the presence of a brominating reagent to form a compound of the formula IV.
  • the molar ratio of the compound of formula III to the brominating agent is 1: 0.5 to 5 (more preferably 1: 0.6'.
  • the compound of formula III is according to the third aspect of the invention.
  • a process for the preparation of an intermediate of formula VI which comprises the steps of: reacting a compound of formula IV with triphenylphosphine in an inert solvent, without treatment Directly reacting with the compound of formula V to form a compound of VI.
  • the molar ratio of the compound of the formula IV to the triphenylphosphine, the compound of the formula V is 1: 1-2: 1 to 2; more preferably 1: 1 to 1 ⁇ 2: 1 ⁇ 1 to 1 ⁇ 5 .
  • the reaction with the compound of formula V is carried out in the presence of a base; preferably, the base is selected from the group consisting of potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, Sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate, trimethylamine, triethylamine, pyridine, piperidine, morpholine, or a combination thereof; more preferably potassium carbonate, triethylamine or sodium hydroxide.
  • the base is selected from the group consisting of potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, Sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate, trimethylamine, triethylamine, pyridine, piperidine, morpholine, or a combination thereof; more preferably potassium carbonate, triethylamine or sodium hydroxide.
  • the compound of formula IV is prepared according to the process of the fourth aspect of the invention.
  • a process for the preparation of an intermediate of formula VII which comprises the steps of: deprotecting a compound of formula VI under acidic conditions in an inert solvent to form a compound of formula VII.
  • the acid is selected from the group consisting of sulfuric acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, formic acid, acetic acid, or a combination thereof; preferably hydrochloric acid or sulfuric acid; more preferably Aqueous hydrochloric acid or aqueous sulfuric acid.
  • the compound of the formula VI is produced according to the preparation method of the fifth aspect of the invention.
  • a method for preparing rosuvastatin is provided, which comprises the steps of:
  • the c 2 -8 ester solvent comprises a c 4 -6 acetate solvent, preferably comprising: ethyl acetate, isopropyl acetate, n-butyl acetate, or a combination thereof; More preferably, it is n-butyl acetate.
  • the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, or a combination thereof; lithium hydroxide is preferred.
  • the compound of formula VII is prepared according to the preparation method of the sixth aspect of the invention.
  • a salt forming step is further included: salting rosuvastatin to form a rosuvastatin salt.
  • the rosuvastatin salt is rosuvastatin calcium. It is to be understood that within the scope of the present invention, the various technical features of the present invention and the technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here. detailed description
  • a series of novel intermediates for the preparation of rosuvastatin or its calcium salt including: a compound of formula II, a compound of formula III, a compound of formula IV, formula VI a compound or a compound of formula VII.
  • the preparation method of the rosuvastatin or the calcium salt thereof according to the invention is based on the above intermediate compound, the raw material is cheap, easy to obtain, safe, and the reaction condition is mild, and no special freezing or cryogenic equipment is required, so the operation is simple and safe. , low production cost, suitable for industrial production and other advantages.
  • ⁇ 4 halohydrocarbon solvent means a halogenated anthracene hydrocarbon having 1 to 4 carbon atoms, such as (but not limited to, haloformamidine (e.g., methylene chloride, trichloromethane, etc.) ), halogenated acetamidine, etc.
  • haloformamidine e.g., methylene chloride, trichloromethane, etc.
  • C 2 -8 ester solvent as used in the present invention means an ester having 2 to 8 carbon atoms, such as (but not limited to, formates such as methyl formate, ethyl formate, etc.), acetates (such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, etc.)
  • formates such as methyl formate, ethyl formate, etc.
  • acetates Such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, etc.
  • the invention provides an intermediate compound for preparing rosuvastatin calcium represented by formula II, and the structure is as follows:
  • the compound of the formula II used in the present invention can be obtained by a conventional method in the art, or can be preferably obtained by the following steps: in a ⁇ 4 halogenated hydrocarbon solvent (e.g., may be selected from the group consisting of dichloromethane, trichloromethane, or In a combination, etc., the compound of the formula I is reacted with methanesulfonyl chloride for a certain period of time (eg 2-8 hours or 3-5 hours) at a certain temperature (eg -5 to 30 ° C, preferably 0 to 25 ° C). a certain period of time (eg 2-8 hours or 3-5 hours) at a certain temperature (eg -5 to 30 ° C, preferably 0 to 25 ° C). ,
  • the present invention provides an intermediate compound for preparing rosuvastatin calcium represented by Formula III, which has the structure shown below:
  • the compound of the formula III used in the present invention can be obtained by a conventional method in the art, or can be preferably obtained by the following steps: in an inert solvent at a certain temperature (e.g., -15 to 0 ° C, preferably -10 to 5 ° C).
  • the compound of formula II is subjected to a reduction reaction for a period of time (e.g., 1-8 hours or 1-4 hours) in the presence of a reducing agent to form a compound of formula III.
  • the reducing agent may be selected from the group consisting of, but not limited to, diisobutylaluminum hydride, lithium tetrahydrogenate, sodium borohydride, potassium borohydride, or a combination thereof; preferably diisobutyl Aluminum hydride.
  • the inert solvent may be selected from the group consisting of, but not limited to, tetrahydrofuran, 1,4-dioxane, diethyl ether, toluene, xylene or a combination thereof; more preferably toluene or tetrahydrofuran.
  • the compound of the formula II can be obtained by a conventional method or can be obtained by the method for producing a compound of the formula II according to the present invention.
  • Intermediate shown in formula IV
  • the invention provides an intermediate compound for preparing rosuvastatin calcium represented by formula IV, and the structure is as follows
  • the compound of the formula IV used in the present invention can be obtained by a conventional method in the art, or can be preferably obtained by the following steps: in the d ⁇ 4 halogenated hydrocarbon solvent (e.g., may be selected from the group consisting of: methylene chloride, trichloromethane) In a hydrazine, or a combination thereof, bromination of a compound of formula III in the presence of a brominating reagent such as PBr 3 at a temperature (eg, 10-40 ° C, preferably 20-30 ° C) For example, a compound of formula IV is formed.
  • a halogenated hydrocarbon solvent e.g., may be selected from the group consisting of: methylene chloride, trichloromethane
  • a hydrazine or a combination thereof
  • bromination of a compound of formula III in the presence of a brominating reagent such as PBr 3 at a temperature (eg, 10-40 ° C, preferably 20-30
  • the molar ratio of the compound of formula III to the brominating reagent is 1: 0.5 to 5 (more preferably 1: 0.6 ⁇ ) 2).
  • the compound of the formula III can be obtained by a conventional method or can be obtained by the method for producing a compound of the formula III according to the present invention.
  • Intermediate represented by formula VI
  • the present invention provides an intermediate compound for the preparation of rosuvastatin calcium of the formula V, which has the structure shown below:
  • the intermediate of formula VI can be prepared by methods commonly used in the art, and the present invention provides a preferred method of preparing a compound of formula VI, comprising the steps of:
  • the compound of the formula IV is reacted with triphenylphosphine for a period of time (e.g., 1-10 hours, preferably 1-5 hours) in an inert solvent at a temperature (e.g., 10 to 30 ° C, preferably 20 to 28 ° C). ), without treatment, directly with the compound of formula V.
  • the inert solvent may be selected from the group consisting of, but not limited to, tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N-dimethylformamide, chloroform, or Combination; preferably tetrahydrofuran, dioxane, dimethyl sulfoxide, or a combination thereof.
  • the compound of the formula IV can be obtained by a conventional method or can be obtained by the preparation method of the compound of the formula IV according to the present invention.
  • reaction with the compound of formula V is carried out at a certain temperature (e.g., 40 to 70 ° C, preferably
  • the reaction is carried out at 50 to 65 ° C; and/or in the presence of a base, the base may be selected from the group consisting of (but not limited to, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, sodium hydroxide) , potassium hydroxide, lithium hydroxide, acetic acid Sodium, trimethylamine, triethylamine, pyridine, piperidine, morpholine, or a combination thereof; more preferably potassium carbonate, triethylamine or sodium hydroxide.
  • the base may be selected from the group consisting of (but not limited to, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, sodium hydroxide) , potassium hydroxide, lithium hydroxide, acetic acid Sodium, trimethylamine, triethylamine, pyridine, piperidine, morpholine, or a combination thereof; more preferably potassium carbonate, triethylamine or sodium hydroxide.
  • the molar ratio of the compound of the formula IV to the triphenylphosphine, the compound of the formula V is 1 : 1-2: 1 to 2; preferably 1 : 1 ⁇ 2: 1 ⁇ 1 to 1 ⁇ 5.
  • the present invention provides an intermediate compound of the formula VII for preparing rosuvastatin calcium, the structure of which is as follows:
  • the intermediate of formula VII can be prepared according to the methods commonly used in the art.
  • the present invention provides a preferred process for the preparation of a compound of formula VII, comprising the steps of: in an inert solvent at a temperature (e.g., 10-30 ° C; preferably The compound of formula VI of the present invention is subjected to a deprotection reaction under acidic conditions for a period of time (e.g., 2 to 10 hours, preferably 3 to 6 hours) at 20 to 28 ° C to form a compound of formula VII.
  • the inert solvent may be selected from the group consisting of, but not limited to, tetrahydrofuran, dioxane, acetonitrile, toluene, or a combination thereof; preferably acetonitrile, dioxane, or a combination thereof.
  • the acid may be selected from the group consisting of, but not limited to, sulfuric acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, formic acid, acetic acid, or a combination thereof; Hydrochloric acid or sulfuric acid; more preferably aqueous hydrochloric acid or aqueous sulfuric acid having a concentration of less than 2N.
  • the compound of the formula VI can be obtained by a conventional method or can be obtained by the method for producing a compound of the formula VI according to the present invention.
  • the invention provides a preparation method of rosuvastatin, comprising the steps of:
  • the c 2 -8 ester solvent is a c 2 -8 acetate solvent, for example, selected from the group consisting of (but not limited to, ethyl acetate, isopropyl acetate, n-butyl acetate) Or a combination thereof; preferably n-butyl acetate.
  • the compound of the formula VII can be obtained according to the preparation method of the compound of the formula VII according to the present invention.
  • the base may be selected from the group consisting of, but not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, or a combination thereof; lithium hydroxide is preferred.
  • the present invention further comprises the step of salting it, preferably by reacting rosuvastatin under alkaline conditions to form a rosuvastatin salt.
  • the base comprises a calcium-containing base (e.g., calcium hydroxide) or a calcium-free base (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, or a combination thereof).
  • a calcium-containing base e.g., calcium hydroxide
  • a calcium-free base e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, or a combination thereof.
  • the rosuvastatin salt is rosuvastatin calcium.
  • the rosuvastatin calcium salt can be obtained as follows:
  • the method comprises the steps of: reacting rosuvastatin with a calcium-containing base such as calcium hydroxide to form rosuvastatin calcium; or
  • the method includes the steps of:
  • rosuvastatin is reacted with a calcium-free base to form a reaction mixture comprising rosuvastatin calcium-free salts;
  • the calcium-free base may be selected from the group consisting of, but not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, or a combination thereof; lithium hydroxide is preferred.
  • the calcium source is preferably an inorganic calcium salt
  • the inorganic calcium salt refers to an inorganic compound containing calcium ions, which may be selected from the group consisting of (but not limited to): calcium chloride, bromination Calcium, calcium acetate, or a combination thereof; calcium chloride is preferred.
  • the present invention mainly has the following advantages:
  • the preparation method of the above five intermediate compounds is also provided.
  • the raw materials or reagents used in the reaction are cheap and easy to obtain and safe, the reaction conditions are mild, and no special freezing or cryogenic equipment is required. Simple, safe, low production cost, suitable for industrial production.
  • a method for preparing rosuvastatin or a calcium salt thereof which is based on the above five intermediates and a preparation method thereof, which is advantageous for shortening the synthetic route, avoiding the use of special equipment (such as cryogenic equipment) and danger Reagents (such as n-butyl lithium) significantly reduce the production cost of rosuvastatin calcium, improve production safety, and are very suitable for industrial production.
  • special equipment such as cryogenic equipment
  • danger Reagents such as n-butyl lithium
  • the invention will be further elucidated below in conjunction with specific implementations. It should be understood that these embodiments are for illustrative purposes only. The invention is not intended to limit the scope of the invention.
  • the experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.
  • the starting materials or reagents used in the present invention are obtained by conventional methods or are commercially available unless otherwise specified.
  • the starting compound of formula I can be prepared by reference to CN101376647A.
  • the side chain V compound can be prepared by referring to Tetrahedron: Asymmetry, 18(20), 2454-2461, 2007.
  • Example 1
  • a compound of formula I (29.0 g, 0.10 mol), 300 ml of dichloromethane, and triethylamine (12. 2 g,
  • the compound of the formula I (15.0 g, 0.052 mol), 150 ml of dichloromethane, pyridine (4.7 g, 0.059 mol) was added to the reaction flask, and the temperature was lowered to 0 ° C, and methylsulfonyl chloride (8.6 g, 0. 073mol). The reaction was allowed to rise to room temperature for 4 hours. After the reaction was completed, 300 ml of water was added and stirred for 15 minutes.
  • a compound of the formula II (18.4 g, 0.050 mol) and 200 ml of toluene were added to the reaction flask, and the temperature was lowered to -10 ° C. 60 ml of a 2 mol/L lithium tetrahydrogen aluminum toluene solution was slowly added dropwise, and the reaction was continued for 3 hours. After completion of the reaction, the reaction mixture was slowly poured into a 0.2 N diluted hydrochloric acid solution and stirred for 15 minutes.
  • a compound of the formula VI (18.6 g, 0.033 mol) and 200 ml of acetonitrile were added to the reaction flask, and 40 ml of 1N diluted hydrochloric acid was added dropwise at room temperature for 5 hours. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure to yield 17.2 g of crude compound of formula VI.
  • a compound of the formula VII (14.4 g, 0.027 mol) and 100 ml of acetonitrile were added to the reaction flask, and 30 ml of 0.5 N sodium hydroxide was added thereto at room temperature, and the mixture was reacted at room temperature for 5 hours. After completion of the reaction, it was neutralized to pH 7.0 with 0.5 N hydrochloric acid. Evaporate the acetonitrile, cool to 0-5 ° C, slowly add 56 ml of 0.5 mol/L calcium chloride, filter, and wash the filter cake with cold water. Drying gave 11.4 g of a white solid. The yield was 85.7%, and the HPLC purity was 99.6%.

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Abstract

The present invention relates to rosuvastatin calcium and a method for preparing an intermediate thereof. Specifically, disclosed are an intermediate compound for preparing rosuvastatin calcium and a preparation method thereof. Structures of the intermediate are shown respectively by a formula II, a formula III, a formula VI or a formula VII in the specification. Further disclosed is a preparation method of rosuvastatin or a salt thereof. The method is based on the five intermediate compounds and preparation method thereof, is simple and safe in operation, has low production cost, and is suitable for industrial production.

Description

瑞舒伐他汀钙及其中间体的制备方法  Preparation method of rosuvastatin calcium and intermediate thereof
技术领域  Technical field
本发明属于药物合成技术领域， 具体涉及瑞舒伐他汀钙及其中间体的制备方 法。 背景技术  The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing rosuvastatin calcium and an intermediate thereof. Background technique
瑞舒伐他汀钙 (Rosuvastatin Calcium)由日本盐野义公司研制开发， 化学名为： [S-[R，S-CE)]]-7-[4-(4-氟基苯基) -6-异丙基 -2- [甲基（甲磺酰基)胺基] -嘧啶 -5-基] -3，5- 二羟基-庚 -6-烯酸钙 (酸与钙离 如下：  Rosuvastatin Calcium was developed by Japan Yanyeyi Co., Ltd., chemical name: [S-[R,S-CE]]]-7-[4-(4-fluorophenyl)-6 -Isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl]-3,5-dihydroxy-hept-6-enoate (acid and calcium are as follows:
Figure imgf000002_0001
Figure imgf000002_0001
瑞舒伐他汀钙是全合成的单一对映异构体的新一代他汀类血脂调节药， 属于 HMG-CoA还原酶抑制剂， 可降低升高的低密度胆固醇， 总胆固醇， 甘油三酯和脱 辅基蛋白 B浓度， 同时升高高密度胆固醇的浓度。 可用于原发性高胆固醇血症和 混合型脂肪代谢障碍症及纯合家族型高胆固醇血症的综合治疗，被称为超级他汀。  Rosuvastatin calcium is a new generation of single-enantiomers of a new synthetic statin lipid regulating agent, belonging to the HMG-CoA reductase inhibitor, which lowers elevated low-density cholesterol, total cholesterol, triglycerides and The concentration of the prostaglandin B increases the concentration of high-density cholesterol. It can be used as a combination therapy for primary hypercholesterolemia and mixed lipodystrophy and homozygous familial hypercholesterolemia. It is called superstatin.
目前， 关于瑞舒伐他汀钙的合成方法有很多种， 其中：  At present, there are many methods for synthesizing rosuvastatin calcium, among which:
方法  Method
Figure imgf000002_0002
Figure imgf000002_0002
Figure imgf000003_0001
Figure imgf000003_0001
该方法以对氟苯甲醛为原料， 需经过 13步反应才能得到瑞舒伐他丁钙。 且侧 链化合物 10市售价格十分昂贵； 若自行合成， 很难得到高光学纯度的侧链化合物 10。 此外， 该路线中多步反应的后处理均需要柱层析， 不适合工业化应用。  The method uses p-fluorobenzaldehyde as a raw material, and it takes 13 steps to obtain rosuvastatin calcium. Further, the side chain compound 10 is very expensive to be commercially available; if it is synthesized by itself, it is difficult to obtain a side chain compound 10 having high optical purity. In addition, post-treatment of multi-step reactions in this route requires column chromatography, which is not suitable for industrial applications.
方法  Method
Figure imgf000003_0002
Figure imgf000003_0002
Figure imgf000004_0001
Figure imgf000004_0002
Figure imgf000004_0001
Figure imgf000004_0002
Figure imgf000004_0003
该方法所用的侧链化合物 20 (即本发明所用的式 V化合物） ， 虽然可通过现 有的制备方法 (如 Tetrahedron: Asymmetry, 18(20), 2454-2461 , 2007)制得高纯度的 侧链化合物 20。然而该路线中，第六步的 Wittig反应条件苛刻 (如反应温度为 -75 °C， 需要深冷设备)， 且后处理极其繁琐， 因此也不适合工业化应用。
Figure imgf000004_0003
The side chain compound 20 used in the method (i.e., the compound of the formula V used in the present invention) can be obtained by a conventional preparation method (e.g., Tetrahedron: Asymmetry, 18 (20), 2454-2461, 2007). Chain compound 20. However, in this route, the Wittig reaction conditions in the sixth step are harsh (for example, the reaction temperature is -75 °C, which requires cryogenic equipment), and the post-treatment is extremely cumbersome, so it is not suitable for industrial applications.
方  Square
Figure imgf000004_0004
Figure imgf000004_0004
Figure imgf000005_0001
Figure imgf000005_0001
该方法同样使用了侧链化合物 20， 虽然 Wittig反应的温度有所提升高 (可采用 -25〜- 40°C)，但是仍然需要冷冻设备，且反应中还需要大量的 2，2，6，6-四甲基哌啶 (其 摩尔量是该反应底物的 4-5倍)， 以及正丁基锂， 而正丁基锂的运输、 保存、 使用 和后处理都很危险， 因此也不适合工业化应用。  This method also uses the side chain compound 20, although the temperature of the Wittig reaction is increased (-25 to -40 ° C can be used), but refrigeration equipment is still required, and a large amount of 2, 2, 6 is required in the reaction. 6-tetramethylpiperidine (the molar amount is 4-5 times that of the reaction substrate), and n-butyllithium, and the transportation, storage, use and post-treatment of n-butyllithium are dangerous and therefore neither Suitable for industrial applications.
因此， 仍然需要研发一种生产成本低、 条件温和、 操作简便， 安全有效的瑞 舒伐他汀钙的制备方法。 发明内容  Therefore, there is still a need to develop a preparation method of rosuvastatin calcium which is low in production cost, mild in condition, simple in operation, safe and effective. Summary of the invention
本发明一个目的是提供一种生产成本低、 条件温和、 操作简便， 安全有效的 瑞舒伐他汀钙的制备方法。  SUMMARY OF THE INVENTION One object of the present invention is to provide a method for preparing rosuvastatin calcium which is low in production cost, mild in condition, simple in operation, safe and effective.
本发明另一个目的是提供一类制备简便、 生产成本低的瑞舒伐他汀钙的中间 体及其制备方法。  Another object of the present invention is to provide a class of intermediates of rosuvastatin calcium which are simple to prepare and low in production cost and a process for preparing the same.
Figure imgf000005_0002
在另一优选例中， 所述的式 A所示的中间体化合物为式 II所示的中间体、 式 III 所示的中间体、 式 IV所示的中间体、 式 VI所示的中间体或式 VII所示的中间体：
Figure imgf000005_0002
In another preferred embodiment, the intermediate compound represented by the formula A is an intermediate represented by the formula II, an intermediate represented by the formula III, an intermediate represented by the formula IV, or an intermediate represented by the formula VI. Or an intermediate of formula VII:
Figure imgf000006_0001
Figure imgf000006_0001
VI 、 VI I 。  VI, VI I.
在本发明第二方面中， 提供了式 II所示中间体的制备方法， 它包括步骤： 在 CM卤代烃类溶剂中， 将 I化合物与甲磺酰氯进行反应， 从而形成式 II化合物。  In a second aspect of the invention, there is provided a process for the preparation of an intermediate of formula II which comprises the steps of: reacting a compound of formula I with methanesulfonyl chloride in a CM halogenated hydrocarbon solvent to form a compound of formula II.
Figure imgf000006_0002
Figure imgf000006_0002
I II  I II
在本发明第三方面中， 提供了式 in所示中间体的制备方法， 它包括步骤： 在 惰性溶剂中， 在还原剂的存在下， 将式 II化合物进行还原反应， 从而形成式 III化 合物。  In a third aspect of the invention, there is provided a process for the preparation of an intermediate of the formula in which comprises the steps of: subjecting a compound of formula II to reduction in the presence of a reducing agent in an inert solvent to form a compound of formula III.
Figure imgf000006_0003
Figure imgf000006_0003
II III  II III
在另一优选例中， 所述的还原剂选自下组： 二异丁基氢化铝、 四氢铝锂、 氢化钠、 硼氢化钾、 或其组合； 更优选二异丁基氢化铝。 In another preferred embodiment, the reducing agent is selected from the group consisting of diisobutylaluminum hydride, lithium tetrahydrogenate, Sodium hydride, potassium borohydride, or a combination thereof; more preferably diisobutylaluminum hydride.
在另一优选例中， 所述的式 II化合物按本发明第二方面所述的制备方法制得。 在本发明第四方面中， 提供了式 IV所示中间体的制备方法， 它包括步骤： 在 In another preferred embodiment, the compound of formula II is prepared according to the process of the second aspect of the invention. In a fourth aspect of the invention, there is provided a process for the preparation of an intermediate of formula IV, which comprises the steps of:
CM卤代烃类溶剂中， 在溴化试剂的存在下， 将式 III化合物进行溴化反应， 从而 形成式 IV化合物。 In the CM halogenated hydrocarbon solvent, the compound of the formula III is subjected to a bromination reaction in the presence of a brominating reagent to form a compound of the formula IV.
Figure imgf000007_0001
Figure imgf000007_0001
III IV  III IV
在另一优选例中， 式 III化合物和溴化试剂摩尔比为 1 : 0.5〜5(更优选 1 : 0.6' 在另一优选例中，所述的式 III化合物按本发明第三方面所述的制备方法制得。 在本发明第五方面中， 提供了式 VI所示中间体的制备方法， 它包括步骤： 在 惰性溶剂中， 将式 IV化合物与三苯基膦进行反应， 不经处理， 直接与式 V化合物 继续进行 成 VI化合物。  In another preferred embodiment, the molar ratio of the compound of formula III to the brominating agent is 1: 0.5 to 5 (more preferably 1: 0.6'. In another preferred embodiment, the compound of formula III is according to the third aspect of the invention. In a fifth aspect of the invention, there is provided a process for the preparation of an intermediate of formula VI which comprises the steps of: reacting a compound of formula IV with triphenylphosphine in an inert solvent, without treatment Directly reacting with the compound of formula V to form a compound of VI.
Figure imgf000007_0002
Figure imgf000007_0002
IV VI  IV VI
在另一优选例中， 式 IV化合物与三苯基膦、 式 V化合物的摩尔比为 1 : 1-2： 1〜2； 更优选 1 : 1〜1 ·2 : 1 · 1〜1 ·5。  In another preferred embodiment, the molar ratio of the compound of the formula IV to the triphenylphosphine, the compound of the formula V is 1: 1-2: 1 to 2; more preferably 1: 1 to 1 · 2: 1 · 1 to 1 · 5 .
在另一优选例中， 所述的与式 V化合物的反应是在碱存在下进行； 较佳地， 所述的碱选自下组： 碳酸钾、 碳酸氢钠、 碳酸氢钾、 碳酸钠、 氢氧化钠、 氢氧化 钾、 氢氧化锂、 醋酸钠、 三甲胺、 三乙胺、 吡啶、 哌啶、 吗啉、 或其组合； 更佳 地为碳酸钾、 三乙胺或氢氧化钠。  In another preferred embodiment, the reaction with the compound of formula V is carried out in the presence of a base; preferably, the base is selected from the group consisting of potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, Sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate, trimethylamine, triethylamine, pyridine, piperidine, morpholine, or a combination thereof; more preferably potassium carbonate, triethylamine or sodium hydroxide.
在另一优选例中，所述的式 IV化合物按本发明第四方面所述的制备方法制得。 在本发明第六方面中， 提供了式 VII所示的中间体的制备方法， 它包括步骤： 于惰性溶剂中， 将式 VI化合物在酸性条件下进行脱保护反应， 从而形成式 VII化合 In another preferred embodiment, the compound of formula IV is prepared according to the process of the fourth aspect of the invention. In a sixth aspect of the invention, there is provided a process for the preparation of an intermediate of formula VII, which comprises the steps of: deprotecting a compound of formula VI under acidic conditions in an inert solvent to form a compound of formula VII.
Figure imgf000008_0001
在另一优选例中， 所述的酸选自下组： 硫酸、 盐酸、 氢溴酸、 氢氟酸、 氢碘 酸、 磷酸、 甲酸、 醋酸、 或其组合； 优选盐酸或硫酸； 更优选为盐酸水溶液或硫 酸水溶液。
Figure imgf000008_0001
In another preferred embodiment, the acid is selected from the group consisting of sulfuric acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, formic acid, acetic acid, or a combination thereof; preferably hydrochloric acid or sulfuric acid; more preferably Aqueous hydrochloric acid or aqueous sulfuric acid.
在另一优选例中，所述的式 VI化合物按本发明第五方面所述的制备方法制得。 在本发明第七方面中， 提供了一种瑞舒伐他汀的制备方法， 它包括步骤： In another preferred embodiment, the compound of the formula VI is produced according to the preparation method of the fifth aspect of the invention. In a seventh aspect of the invention, a method for preparing rosuvastatin is provided, which comprises the steps of:
(a) 在 C2〜8酯类溶剂中， 将式 VII化合物与 N-甲基甲磺酰胺进行反应， 从而形 成式 VIII化 (a) reacting a compound of the formula VII with N-methylmethanesulfonamide in a C 2 -8 ester solvent to form a formula VIII
Figure imgf000008_0002
Figure imgf000008_0002
VII VIII  VII VIII
(b) 在碱 汀。  (b) in the base.
Figure imgf000008_0003
Figure imgf000008_0003
VIII  VIII
在另一优选例中， 所述的 c2〜8酯类溶剂包括 c4〜6乙酸酯类溶剂， 较佳地包括: 乙酸乙酯、 乙酸异丙酯、 乙酸正丁酯、 或其组合； 更佳地为乙酸正丁酯。 In another preferred embodiment, the c 2 -8 ester solvent comprises a c 4 -6 acetate solvent, preferably comprising: ethyl acetate, isopropyl acetate, n-butyl acetate, or a combination thereof; More preferably, it is n-butyl acetate.
在另一优选例中， 在步骤 (b)中， 所述的碱选自下组： 氢氧化钠、 氢氧化钾、 氢氧化锂、 或其组合； 优选氢氧化锂。  In another preferred embodiment, in the step (b), the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, or a combination thereof; lithium hydroxide is preferred.
在另一优选例中， 所述的式 VII化合物按本发明第六方面所述的制备方法制 在另一优选例中， 所述步骤之后， 还包括成盐步骤： 将瑞舒伐他汀成盐， 从 而形成瑞舒伐他汀盐。 In another preferred embodiment, the compound of formula VII is prepared according to the preparation method of the sixth aspect of the invention. In another preferred embodiment, after the step, a salt forming step is further included: salting rosuvastatin to form a rosuvastatin salt.
在另一优选例中， 所述的瑞舒伐他汀盐为瑞舒伐他汀钙。 应理解， 在本发明范围内中， 本发明的上述各技术特征和在下文 (如实施例) 中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。 限于篇幅， 在此不再一一累述。 具体实施方式  In another preferred embodiment, the rosuvastatin salt is rosuvastatin calcium. It is to be understood that within the scope of the present invention, the various technical features of the present invention and the technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here. detailed description
本发明人通过长期而深入的研究， 意外地发现了一系列结构新颖、 用于制备 瑞舒伐他汀或其钙盐的中间体， 包括： 式 II化合物、 式 III化合物、 式 IV化合物、 式 VI化合物或式 VII化合物。本发明所述的瑞舒伐他汀或其钙盐的制备方法， 基于 上述中间体化合物， 原料便宜易得、 安全， 且反应条件温和， 无需特殊的冷冻或 深冷设备， 故具有操作简便， 安全， 生产成本低， 适合工业化生产等优点。 在此 基础上， 发明人完成了本发明。 术语  Through long-term and intensive research, the inventors have unexpectedly discovered a series of novel intermediates for the preparation of rosuvastatin or its calcium salt, including: a compound of formula II, a compound of formula III, a compound of formula IV, formula VI a compound or a compound of formula VII. The preparation method of the rosuvastatin or the calcium salt thereof according to the invention is based on the above intermediate compound, the raw material is cheap, easy to obtain, safe, and the reaction condition is mild, and no special freezing or cryogenic equipment is required, so the operation is simple and safe. , low production cost, suitable for industrial production and other advantages. On this basis, the inventors completed the present invention. the term
如本发明所用的 " ~4卤代烃类溶剂" 是指含 1〜4个碳原子的卤代垸烃， 例 如 (但不限于 卤代甲垸 (如二氯甲垸、 三氯甲垸等)、 卤代乙垸等。 The "~ 4 halohydrocarbon solvent" as used in the present invention means a halogenated anthracene hydrocarbon having 1 to 4 carbon atoms, such as (but not limited to, haloformamidine (e.g., methylene chloride, trichloromethane, etc.) ), halogenated acetamidine, etc.
如本发明所用的" C2〜8酯类溶剂"是指含 2〜8个碳原子的酯，例如 (但不限于 甲酸酯类 (如甲酸甲酯、 甲酸乙酯等)， 乙酸酯类 (如乙酸甲酯、 乙酸乙酯、 乙酸丙 酯、 乙酸丁酯等)。 式 II所示的中间体 The "C 2 -8 ester solvent" as used in the present invention means an ester having 2 to 8 carbon atoms, such as (but not limited to, formates such as methyl formate, ethyl formate, etc.), acetates ( Such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, etc.) Intermediates of formula II
本发明提供了一种式 II所示的制备瑞舒伐他汀钙的中间体化合物， 结构如下 所示：
Figure imgf000010_0001
The invention provides an intermediate compound for preparing rosuvastatin calcium represented by formula II, and the structure is as follows:
Figure imgf000010_0001
II  II
本发明所用的式 II化合物可以按本领域常规方法制得， 也可优选通过如下步 骤制得： 在 ~4卤代烃类溶剂 (如可选自二氯甲垸、 三氯甲垸、 或其组合等)中， 于 一定温度 (如 -5〜30°C， 优选 0〜25°C)下， 将式 I化合物与甲磺酰氯进行反应一段时 间 (如 2-8小时或 3-5小时）， The compound of the formula II used in the present invention can be obtained by a conventional method in the art, or can be preferably obtained by the following steps: in a ~ 4 halogenated hydrocarbon solvent (e.g., may be selected from the group consisting of dichloromethane, trichloromethane, or In a combination, etc., the compound of the formula I is reacted with methanesulfonyl chloride for a certain period of time (eg 2-8 hours or 3-5 hours) at a certain temperature (eg -5 to 30 ° C, preferably 0 to 25 ° C). ,
Figure imgf000010_0002
Figure imgf000010_0002
式 III所示的中间体 Intermediate shown in formula III
本发明提供了一种式 III所示的制备瑞舒伐他汀钙的中间体化合物， 结构如下 所示：  The present invention provides an intermediate compound for preparing rosuvastatin calcium represented by Formula III, which has the structure shown below:
Figure imgf000010_0003
本发明所用的式 III化合物可以按本领域常规方法制得， 也可优选通过如下步 骤制得： 在惰性溶剂中， 于一定温度 (如 -15〜0°C， 优选 -10〜- 5°C)下， 在还原剂 的存在下， 将式 II化合物进行还原反应一段时间 (如 1-8小时或 1-4小时）， 从而形成 式 III化合物。
Figure imgf000011_0001
在另一优选例中， 所述的还原剂可选自下组 (但不限于 二异丁基氢化铝、 四氢铝锂、 硼氢化钠、 硼氢化钾、 或其组合； 优选二异丁基氢化铝。
Figure imgf000010_0003
The compound of the formula III used in the present invention can be obtained by a conventional method in the art, or can be preferably obtained by the following steps: in an inert solvent at a certain temperature (e.g., -15 to 0 ° C, preferably -10 to 5 ° C). The compound of formula II is subjected to a reduction reaction for a period of time (e.g., 1-8 hours or 1-4 hours) in the presence of a reducing agent to form a compound of formula III.
Figure imgf000011_0001
In another preferred embodiment, the reducing agent may be selected from the group consisting of, but not limited to, diisobutylaluminum hydride, lithium tetrahydrogenate, sodium borohydride, potassium borohydride, or a combination thereof; preferably diisobutyl Aluminum hydride.
在另一优选例中， 所述的惰性溶剂可选自下组 (但不限于 四氢呋喃、 1，4- 二氧六环、 ***、 甲苯、 二甲苯或其组合； 更优选甲苯或四氢呋喃。  In another preferred embodiment, the inert solvent may be selected from the group consisting of, but not limited to, tetrahydrofuran, 1,4-dioxane, diethyl ether, toluene, xylene or a combination thereof; more preferably toluene or tetrahydrofuran.
所述的式 II化合物可按常规方法制得， 也可按本发明所述的式 II化合物制备方 法得到。 式 IV所示的中间体  The compound of the formula II can be obtained by a conventional method or can be obtained by the method for producing a compound of the formula II according to the present invention. Intermediate shown in formula IV
发明提供了一种式 IV所示的制备瑞舒伐他汀钙的中间体化合物， 结构如下  The invention provides an intermediate compound for preparing rosuvastatin calcium represented by formula IV, and the structure is as follows
Figure imgf000011_0002
本发明所用的式 IV化合物可以按本领域常规方法制得， 也可优选通过如下步 骤制得： 在 d~4卤代烃类溶剂 (如可选自下组： 二氯甲垸、 三氯甲垸、 或其组合等) 中， 于一定温度 (如 10-40 °C， 优选 20-30°C)下， 在溴化试剂 (如 PBr3)存在下， 将式 III化合物进行溴化反应 (如 形成式 IV化合物。
Figure imgf000011_0002
The compound of the formula IV used in the present invention can be obtained by a conventional method in the art, or can be preferably obtained by the following steps: in the d~ 4 halogenated hydrocarbon solvent (e.g., may be selected from the group consisting of: methylene chloride, trichloromethane) In a hydrazine, or a combination thereof, bromination of a compound of formula III in the presence of a brominating reagent such as PBr 3 at a temperature (eg, 10-40 ° C, preferably 20-30 ° C) For example, a compound of formula IV is formed.
Figure imgf000011_0003
Figure imgf000011_0003
在另一优选例中， 式 III化合物和溴化试剂摩尔比为 1 : 0.5〜5(更优选 1 : 0.6〜 2)。 In another preferred embodiment, the molar ratio of the compound of formula III to the brominating reagent is 1: 0.5 to 5 (more preferably 1: 0.6~) 2).
所述的式 III化合物可按常规方法制得， 也可按本发明所述的式 III化合物制备 方法得到。 式 VI所示的中间体  The compound of the formula III can be obtained by a conventional method or can be obtained by the method for producing a compound of the formula III according to the present invention. Intermediate represented by formula VI
本发明提供了一种式 V所示的制备瑞舒伐他汀钙的中间体化合物， 结构如下 所示：  The present invention provides an intermediate compound for the preparation of rosuvastatin calcium of the formula V, which has the structure shown below:
Figure imgf000012_0001
Figure imgf000012_0001
VI  VI
式 VI所示中间体可按本领域常用方法制得， 本发明提供了一种优选的式 VI化 合物的制备方法， 包括步骤：  The intermediate of formula VI can be prepared by methods commonly used in the art, and the present invention provides a preferred method of preparing a compound of formula VI, comprising the steps of:
在惰性溶剂中， 于一定温度 (如 10〜30°C， 优选 20〜28°C)下， 将式 IV化合物 与三苯基膦进行反应一段时间 (如 1-10小时， 优选 1-5小时)， 不经处理， 直接与式 V 化合物继 合物。  The compound of the formula IV is reacted with triphenylphosphine for a period of time (e.g., 1-10 hours, preferably 1-5 hours) in an inert solvent at a temperature (e.g., 10 to 30 ° C, preferably 20 to 28 ° C). ), without treatment, directly with the compound of formula V.
Figure imgf000012_0002
Figure imgf000012_0002
在另一优选例中， 所述的惰性溶剂可选自下组 (但不限于 四氢呋喃、 二氧 六环、 二甲亚砜， N，N-二甲基甲酰胺、 二氯甲垸、 或其组合； 优选四氢呋喃、 二 氧六环、 二甲亚砜、 或其组合。  In another preferred embodiment, the inert solvent may be selected from the group consisting of, but not limited to, tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N-dimethylformamide, chloroform, or Combination; preferably tetrahydrofuran, dioxane, dimethyl sulfoxide, or a combination thereof.
所述的式 IV化合物可按常规方法制得， 也可按本发明所述的式 IV化合物制备 方法得到。  The compound of the formula IV can be obtained by a conventional method or can be obtained by the preparation method of the compound of the formula IV according to the present invention.
在另一优选例中， 所述的与式 V化合物的反应在一定温度 (如 40〜70°C， 优选 In another preferred embodiment, the reaction with the compound of formula V is carried out at a certain temperature (e.g., 40 to 70 ° C, preferably
50〜65 °C)下进行； 和 /或是在碱存在下进行的， 所述的碱可选自下组 (但不限于 碳酸钾、 碳酸氢钠、 碳酸氢钾、 碳酸钠、 氢氧化钠、 氢氧化钾、 氢氧化锂、 醋酸 钠、 三甲胺、 三乙胺、 吡啶、 哌啶、 吗啉、 或其组合； 更优选为碳酸钾、 三乙胺 或氢氧化钠。 The reaction is carried out at 50 to 65 ° C; and/or in the presence of a base, the base may be selected from the group consisting of (but not limited to, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, sodium hydroxide) , potassium hydroxide, lithium hydroxide, acetic acid Sodium, trimethylamine, triethylamine, pyridine, piperidine, morpholine, or a combination thereof; more preferably potassium carbonate, triethylamine or sodium hydroxide.
在另一优选例中， 式 IV化合物与三苯基膦、 式 V化合物的摩尔比为 1 : 1-2： 1〜2； 优选 1 : 1 ·2: 1 ·1〜1 ·5。 式 VII所示的中间体  In another preferred embodiment, the molar ratio of the compound of the formula IV to the triphenylphosphine, the compound of the formula V is 1 : 1-2: 1 to 2; preferably 1 : 1 · 2: 1 · 1 to 1 · 5. Intermediate represented by formula VII
本发明提供了一种式 VII所示的制备瑞舒伐他汀钙的中间体化合物，结构如下 所示：  The present invention provides an intermediate compound of the formula VII for preparing rosuvastatin calcium, the structure of which is as follows:
Figure imgf000013_0001
Figure imgf000013_0001
VII  VII
式 VII所示中间体可按本领域常用方法制得， 本发明提供了一种优选的式 VII 化合物的制备方法，包括步骤：于惰性溶剂中，于一定温度 (如 10-30°C ;优选 20-28°C) 下， 将本发明所述的式 VI化合物在酸性条件下进行脱保护反应一段时间 (如 2-10小 时， 优选 3-6小时 ， 从而形成式 VII化合物。  The intermediate of formula VII can be prepared according to the methods commonly used in the art. The present invention provides a preferred process for the preparation of a compound of formula VII, comprising the steps of: in an inert solvent at a temperature (e.g., 10-30 ° C; preferably The compound of formula VI of the present invention is subjected to a deprotection reaction under acidic conditions for a period of time (e.g., 2 to 10 hours, preferably 3 to 6 hours) at 20 to 28 ° C to form a compound of formula VII.
Figure imgf000013_0002
Figure imgf000013_0002
在另一优选例中， 所述的惰性溶剂可选自下组 (但不限于 四氢呋喃、 二氧 六环、 乙腈、 甲苯、 或其组合； 优选乙腈、 二氧六环、 或其组合。  In another preferred embodiment, the inert solvent may be selected from the group consisting of, but not limited to, tetrahydrofuran, dioxane, acetonitrile, toluene, or a combination thereof; preferably acetonitrile, dioxane, or a combination thereof.
在另一优选例中， 所述的酸可选自下组 (但不限于 硫酸、 盐酸、 氢溴酸、 氢氟酸、 氢碘酸、 磷酸、 甲酸、 醋酸、 或其组合； 较佳地为盐酸或硫酸； 更佳地 为浓度小于 2N的盐酸水溶液或硫酸水溶液。  In another preferred embodiment, the acid may be selected from the group consisting of, but not limited to, sulfuric acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, formic acid, acetic acid, or a combination thereof; Hydrochloric acid or sulfuric acid; more preferably aqueous hydrochloric acid or aqueous sulfuric acid having a concentration of less than 2N.
所述的式 VI化合物可按常规方法制得， 也可按本发明所述的式 VI化合物的制 备方法制得。 瑞舒伐他汀的制备方法 The compound of the formula VI can be obtained by a conventional method or can be obtained by the method for producing a compound of the formula VI according to the present invention. Preparation method of rosuvastatin
本发明提供了一种瑞舒伐他汀的制备方法， 包括步骤：  The invention provides a preparation method of rosuvastatin, comprising the steps of:
(a) 在 C2〜8酯类溶剂中， 于一定温度 (如 40〜160°C， 优选 100〜130°C)下， 将 式 VII化合物与 N-甲基甲磺酰胺进行反应一段时间 (如 2〜8小时， 优选 3〜5小时)， 从 而形成式 V (a) reacting a compound of the formula VII with N-methylmethanesulfonamide in a C 2 to 8 ester solvent at a temperature (for example, 40 to 160 ° C, preferably 100 to 130 ° C) for a period of time ( For example, 2 to 8 hours, preferably 3 to 5 hours), thereby forming the formula V
Figure imgf000014_0001
Figure imgf000014_0001
VII VIII  VII VIII
在另一优选例中， 所述的 c2〜8酯类溶剂为 c2〜8的乙酸酯类溶剂， 例如选自下 组 (但不限于 乙酸乙酯、 乙酸异丙酯、 乙酸正丁酯、 或其组合； 优选乙酸正丁 酯。 In another preferred embodiment, the c 2 -8 ester solvent is a c 2 -8 acetate solvent, for example, selected from the group consisting of (but not limited to, ethyl acetate, isopropyl acetate, n-butyl acetate) Or a combination thereof; preferably n-butyl acetate.
在另一优选例中， 所述的式 VII化合物可按本发明所述的式 VII化合物制备方 法得到。  In another preferred embodiment, the compound of the formula VII can be obtained according to the preparation method of the compound of the formula VII according to the present invention.
(b) 在碱 进行水解 从而形成瑞舒伐他汀。 (b) Hydrolysis in the base to form rosuvastatin.
Figure imgf000014_0002
Figure imgf000014_0002
VIII  VIII
在另一优选例中， 所述的碱可选自下组 (但不限于）： 氢氧化钠、 氢氧化钾. 氢氧化锂、 或其组合； 优选氢氧化锂。 瑞舒伐他汀盐的制备方法  In another preferred embodiment, the base may be selected from the group consisting of, but not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, or a combination thereof; lithium hydroxide is preferred. Preparation method of rosuvastatin salt
在按本发明所述的方法制得瑞舒伐他汀后， 本发明还包括将其成盐的步骤， 优选地， 将瑞舒伐他汀在碱性条件下反应， 从而形成瑞舒伐他汀盐。  After the preparation of rosuvastatin according to the method of the present invention, the present invention further comprises the step of salting it, preferably by reacting rosuvastatin under alkaline conditions to form a rosuvastatin salt.
在另一优选例中， 所述的碱包括含钙的碱 (如氢氧化钙)或不含钙的碱 (如氢氧 化钠、 氢氧化钾、 氢氧化锂、 或其组合)。  In another preferred embodiment, the base comprises a calcium-containing base (e.g., calcium hydroxide) or a calcium-free base (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, or a combination thereof).
在另一优选例中， 所述的瑞舒伐他汀盐为瑞舒伐他汀钙。 在另一优选例中， 所述的瑞舒伐他汀钙盐可按如下方法制得： In another preferred embodiment, the rosuvastatin salt is rosuvastatin calcium. In another preferred embodiment, the rosuvastatin calcium salt can be obtained as follows:
所述方法包括步骤： 将瑞舒伐他汀和含钙的碱 (如氢氧化钙)反应， 从而形成 瑞舒伐他汀钙； 或  The method comprises the steps of: reacting rosuvastatin with a calcium-containing base such as calcium hydroxide to form rosuvastatin calcium; or
所述方法包括步骤：  The method includes the steps of:
首先， 将瑞舒伐他汀和不含钙的碱反应， 从而形成含瑞舒伐他汀不含钙的盐 的反应混合物；  First, rosuvastatin is reacted with a calcium-free base to form a reaction mixture comprising rosuvastatin calcium-free salts;
然后， 在 钙。  Then, in calcium.
Figure imgf000015_0001
Figure imgf000015_0001
瑞舒伐他汀 瑞舒伐他汀钙  Rosuvastatin rosuvastatin calcium
在另一优选例中， 所述的不含钙的碱可选自下组 (但不限于 氢氧化钠、 氢 氧化钾、 氢氧化锂、 或其组合； 优选氢氧化锂。  In another preferred embodiment, the calcium-free base may be selected from the group consisting of, but not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, or a combination thereof; lithium hydroxide is preferred.
在另一优选例中， 所述的钙源优选为无机钙盐， 所述的无机钙盐是指含有钙 离子的无机化合物， 可选自下组 (但不限于)： 氯化钙、 溴化钙、 醋酸钙、 或其组 合； 优选氯化钙。 与现有技术相比， 本发明主要具有以下优点：  In another preferred embodiment, the calcium source is preferably an inorganic calcium salt, and the inorganic calcium salt refers to an inorganic compound containing calcium ions, which may be selected from the group consisting of (but not limited to): calcium chloride, bromination Calcium, calcium acetate, or a combination thereof; calcium chloride is preferred. Compared with the prior art, the present invention mainly has the following advantages:
1. 提供了五个结构新颖的用于制备瑞舒伐他汀钙的中间体化合物， 包括式 II 化合物、 式 III化合物、 式 IV化合物、 式 VI化合物和式 VII化合物。  1. Five novel intermediate compounds for the preparation of rosuvastatin calcium are provided, including a compound of formula II, a compound of formula III, a compound of formula IV, a compound of formula VI and a compound of formula VII.
2. 还提供了上述五个中间体化合物的制备方法， 其中式 VI化合物的制备过程 中， 反应所用原料或试剂均便宜易得且安全， 反应条件温和， 无需特殊的冷冻或 深冷设备， 操作简便， 安全， 生产成本低， 适合工业化生产。  2. The preparation method of the above five intermediate compounds is also provided. In the preparation process of the compound of the formula VI, the raw materials or reagents used in the reaction are cheap and easy to obtain and safe, the reaction conditions are mild, and no special freezing or cryogenic equipment is required. Simple, safe, low production cost, suitable for industrial production.
3. 还提供了一种瑞舒伐他汀或其钙盐的制备方法， 该方法基于上述五种中间 体及其制备方法， 有利于缩短合成路线， 避免使用特殊设备 (如深冷设备)和危险 试剂 (如正丁基锂)， 显著降低瑞舒伐他汀钙的生产成本， 提高了生产安全性， 非 常适合工业化生产。 下面结合具体实施， 进一步阐述本发明。 应理解， 这些实施例仅用于说明本 发明而不用于限制本发明的范围。 下列实施例中未注明具体条件的实验方法， 通 常按照常规条件， 或按照制造厂商所建议的条件。 除非另外说明， 否则百分比和 份数按重量计算。 3. There is also provided a method for preparing rosuvastatin or a calcium salt thereof, which is based on the above five intermediates and a preparation method thereof, which is advantageous for shortening the synthetic route, avoiding the use of special equipment (such as cryogenic equipment) and danger Reagents (such as n-butyl lithium) significantly reduce the production cost of rosuvastatin calcium, improve production safety, and are very suitable for industrial production. The invention will be further elucidated below in conjunction with specific implementations. It should be understood that these embodiments are for illustrative purposes only. The invention is not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.
本发明所用的原料或试剂， 若无特别说明， 均按常规方法制得或市售可得。 优选地， 原料式 I化合物可参考 CN101376647A制备得到。 侧链式 V化合物可参考 Tetrahedron: Asymmetry, 18(20), 2454-2461 , 2007制备得到。 实施例 1  The starting materials or reagents used in the present invention are obtained by conventional methods or are commercially available unless otherwise specified. Preferably, the starting compound of formula I can be prepared by reference to CN101376647A. The side chain V compound can be prepared by referring to Tetrahedron: Asymmetry, 18(20), 2454-2461, 2007. Example 1
1.1 式 II化合物的制备  1.1 Preparation of the compound of formula II
在反应瓶中加入式 I化合物 (29.0g， 0.10mol)、二氯甲垸 300ml、三乙胺（ 12.2g， A compound of formula I (29.0 g, 0.10 mol), 300 ml of dichloromethane, and triethylamine (12. 2 g,
0.12mol) ， 降温至 0°C， 缓慢滴加入甲基磺酰氯 （12.5g， O. l lmol) 。 加完升至室 温反应 4小时。 反应完， 加入 300ml水， 搅拌 15分钟。 分层， 有机层依次用饱和氯 化铵溶液、 饱和食盐水各洗涤一次，无水 MgSO4干燥， 减压浓缩至干得到白色固体 35.0g, 收率为 94·9%。 MS ( ESI) m/z: ( M+H) =369.4。 0.12 mol), the temperature was lowered to 0 ° C, and methylsulfonyl chloride (12.5 g, 0.1 mol) was slowly added dropwise. The reaction was allowed to rise to room temperature for 4 hours. After the reaction was completed, 300 ml of water was added and stirred for 15 minutes. Separation, the organic layer was washed with saturated ammonium chloride solution was washed with saturated saline water each time, dried over anhydrous MgSO 4, and concentrated to dryness under reduced pressure to give a white solid 35.0 g, yield 94 · 9%. MS (ESI) m/z: (M+H) = 369.4.
1.2 式 III化合物的制备 1.2 Preparation of the compound of formula III
在反应瓶中加入式 II化合物 （35.0g， 0.095mol) 、 甲苯 350ml， 降温至 -10°C， 缓慢滴加 2mol/L的二异丁基氢化铝 （DIBA1-H) 的甲苯溶液 95ml， 滴完继续反应 3 小时。 反应完， 将反应混合液缓慢倒入 0.2N稀盐酸溶液中， 搅拌 15分钟。 分层， 有机层依次用饱和碳酸氢钠溶液、 水、 饱和食盐水各洗涤一次， 无水 MgSO4干燥， 减压浓缩至干得到白色固体 29.6g， 收率 91.6%。 MS ( ESI) m/z: ( M+H) =341.4。 Add the compound of formula II (35.0g, 0.095mol), 350ml of toluene to the reaction flask, cool down to -10 °C, slowly add 2ml / L of diisobutylaluminum hydride (DIBA1-H) toluene solution 95ml, drop Continue to react for 3 hours. After completion of the reaction, the reaction mixture was slowly poured into a 0.2 N diluted hydrochloric acid solution and stirred for 15 minutes. Separation, the organic layer was washed with saturated sodium bicarbonate solution, water, and washed once each with saturated brine, dried over anhydrous MgSO 4, and concentrated to dryness under reduced pressure to give 29.6 g of a white solid, 91.6% yield. MS (ESI) m/z: (M+H) = 341.4.
1.3 式 IV化合物的制备 1.3 Preparation of compounds of formula IV
在反应瓶中， 加入式 III化合物 （29.6g， 0.087mol) 、 二氯甲垸 200ml， 在室 温下滴加 PBr3 ( 14.1g， 0.052mol) ， 滴完再搅拌反应 1小时。 反应完， 倒入冰水中， 分层， 有机相用水洗， 无水 MgSO4干燥， 减压浓缩至干得到白色固体 33. lg， 收率 94.7%。 MS ( ESI) m/z: ( M+H) =404.3。 In the reaction flask, a compound of the formula III (29.6 g, 0.087 mol) and 200 ml of dichloromethane were added, and PBr 3 (1,1 g, 0.052 mol) was added dropwise at room temperature, and the reaction was further stirred for 1 hour. After the reaction, poured into ice water, separated and the organic phase was washed with water, dried over anhydrous MgSO 4, and concentrated to dryness under reduced pressure to give a white solid 33. lg, 94.7% yield. MS (ESI) m/z: (M+H) = 404.3.
1.4 式 VI化合物的制备 1.4 Preparation of compound of formula VI
在反应瓶中加入式 IV化合物（33. lg， 0.082mol)、三苯基磷（21.5g， 0.082mol)、 二甲基亚砜 300ml，室温下反应 2小时。反应完，加入式 V化合物（25.8g， O. lOmol)， 无水碳酸钾 （13.5g， 0.098mol) ， 升温至 60°C反应 6-8小时。 反应完， 将反应混合 物冷却至室温， 倒入水中， 搅拌 10分钟， 分层， 有机相用饱和食盐水洗， 减压浓 缩至干。粗品用 50%的乙醇 -水重结晶得到标题化合物 38.2g，收率 82.3%。 MS ( ESI) m/z: ( M+H) =565.7。 A compound of the formula IV (33. lg, 0.082 mol), triphenylphosphine (21.5 g, 0.082 mol) and 300 ml of dimethyl sulfoxide were added to the reaction flask, and the mixture was reacted at room temperature for 2 hours. After the reaction, a compound of the formula V (25.8 g, 0.1 mol) was added. Anhydrous potassium carbonate (13.5 g, 0.098 mol) was heated to 60 ° C for 6-8 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, poured into water, and stirred for 10 minutes, and the mixture was evaporated. The crude product was recrystallized from 50% ethanol-water toiel MS (ESI) m/z: (M+H) = 565.7.
1.5 式 VII化合物的制备 1.5 Preparation of a compound of formula VII
在反应瓶中加入式 VI化合物 （38.4g， 0.068mol) 、 二氧六环 400ml， 室温下 滴加 0.5N的稀硫酸 70ml， 反应 5小时。 反应完， 减压浓缩至干得到式 VII化合物粗 品 36.5g， 直接投下一步反应。  A compound of the formula VI (38.4 g, 0.068 mol) and 400 ml of dioxane were added to the reaction flask, and 70 ml of 0.5 N dilute sulfuric acid was added dropwise at room temperature for 5 hours. After completion of the reaction, the mixture was concentrated to dryness to dryness to give 36.5 g of crude compound of formula VII.
1.6式 VIII化合物的制备 Preparation of a compound of formula VIII
在反应瓶中加入上一步得到的式 VII化合物粗品 36.5g、 乙酸正丁酯 300ml、 N- 甲基甲磺酰胺 （7.4g， 0.068mol) ， 回流反应 4小时。 反应完， 加入 300ml水， 搅 拌 15分钟。 分层， 有机层无水 MgSO4干燥， 减压浓缩至原体积的一半， 滴加入正 己垸， 析出固体。 过滤， 得到白色固体 27.0g， 收率 73.8%， HPLC纯度 99.3%。 MS ( ESI) m/z: ( M+H) =538.6。 36.5 g of the crude compound of the formula VII obtained in the previous step, 300 ml of n-butyl acetate, and N-methylmethanesulfonamide (7.4 g, 0.068 mol) were added to the reaction mixture, and the mixture was refluxed for 4 hours. After the reaction was completed, 300 ml of water was added and stirred for 15 minutes. The layers were separated, and the organic layer was dried over anhydrous MgSO 4 and evaporated. Filtration gave 27.0 g of a white solid, yield 73.8%, HPLC purity 99.3%. MS (ESI) m/z: (M+H) = 538.6.
1.7瑞舒伐他汀钙的制备 Preparation of 1.7 rosuvastatin calcium
在反应瓶中加入式 VII化合物 （26.8g， 0.050mol) 、 甲醇 200ml， 室温下加入 1N氢氧化钠 52.5ml， 室温反应 5小时。反应完， 用 1N盐酸中和至 pH 7.0。蒸去甲醇， 降温至 15-20°C， 缓慢滴加 0.5mol/L的氯化钙 110ml, 过滤， 冷水洗涤滤饼。 干燥得 到白色固体 22.0g。收率 87.9%， HPLC纯度 99.7%。 MS ( ESI) m/z: ( M+H) =482.1。 实施例 2  A compound of the formula VII (26.8 g, 0.050 mol) and methanol (200 ml) were added to a reaction flask, and 52.5 ml of 1N sodium hydroxide was added thereto at room temperature, and the mixture was reacted at room temperature for 5 hours. After completion of the reaction, it was neutralized to pH 7.0 with 1N hydrochloric acid. The methanol was distilled off, the temperature was lowered to 15-20 ° C, and 110 ml of 0.5 mol/L calcium chloride was slowly added dropwise, filtered, and the filter cake was washed with cold water. Drying gave 22.0 g of a white solid. The yield was 87.9%, and the HPLC purity was 99.7%. MS (ESI) m/z: (M+H) = 4821. Example 2
2.1 式 II化合物的制备  2.1 Preparation of the compound of formula II
在反应瓶中加入式 I化合物（15.0g， 0.052mol)、二氯甲垸 150ml、 吡啶（4.7g， 0.059mol) ， 降温至 0°C， 缓慢滴加入甲基磺酰氯 （8.6g， 0. 073mol) 。 加完升至 室温反应 4小时。 反应完， 加入 300ml水， 搅拌 15分钟。 分层， 有机层依次用饱和 氯化铵溶液、 饱和食盐水各洗涤一次，无水 MgSO4干燥， 减压浓缩至干得到白色固 体 18.4g， 收率为 96·7%。 MS ( ESI) m/z: ( M+H) =369.4。 2.2 式 III化合物的制备 The compound of the formula I (15.0 g, 0.052 mol), 150 ml of dichloromethane, pyridine (4.7 g, 0.059 mol) was added to the reaction flask, and the temperature was lowered to 0 ° C, and methylsulfonyl chloride (8.6 g, 0. 073mol). The reaction was allowed to rise to room temperature for 4 hours. After the reaction was completed, 300 ml of water was added and stirred for 15 minutes. Separation, the organic layer was washed with saturated ammonium chloride solution was washed with saturated saline water each time, dried over anhydrous MgSO 4, and concentrated to dryness under reduced pressure to give 18.4 g of a white solid, a yield of 96 · 7%. MS (ESI) m/z: (M+H) = 369.4. 2.2 Preparation of a compound of formula III
在反应瓶中加入式 II化合物 （18.4g， 0.050mol) 、 甲苯 200ml， 降温至 -10°C， 缓慢滴加 2mol/L的四氢铝锂的甲苯溶液 60ml， 滴完继续反应 3小时。 反应完， 将反 应混合液缓慢倒入 0.2N稀盐酸溶液中， 搅拌 15分钟。 分层， 有机层依次用饱和碳 酸氢钠溶液、 水、 饱和食盐水各洗涤一次， 无水 MgSO4干燥， 减压浓缩至干得到 白色固体 15.4g， 收率 90·4%。 MS ( ESI) m/z: ( M+H) =341.4。 A compound of the formula II (18.4 g, 0.050 mol) and 200 ml of toluene were added to the reaction flask, and the temperature was lowered to -10 ° C. 60 ml of a 2 mol/L lithium tetrahydrogen aluminum toluene solution was slowly added dropwise, and the reaction was continued for 3 hours. After completion of the reaction, the reaction mixture was slowly poured into a 0.2 N diluted hydrochloric acid solution and stirred for 15 minutes. Separation, the organic layer was washed with saturated sodium bicarbonate solution, water, and washed once each with saturated brine, dried over anhydrous MgSO 4, and concentrated to dryness under reduced pressure to give 15.4 g of a white solid, a yield of 90 3.4%. MS (ESI) m/z: (M+H) = 341.4.
2.3 式 IV合物的制备 2.3 Preparation of formula IV
在反应瓶中， 加入式 III化合物 （15.4g， 0.045mol) 、 二氯甲垸 100ml, 在室 温下滴加 PBr3 ( 13.5g, 0.050mol) ， 滴完再搅拌反应 1小时。 反应完， 倒入冰水中， 分层， 有机相用水洗， 无水 MgSO4干燥， 减压浓缩至干得到白色固体 14.1g， 收率 91.8%。 MS ( ESI) m/z: ( M+H) =404.3。 In the reaction flask, a compound of the formula III (15.4 g, 0.045 mol) and 100 ml of dichloromethane were added, and PBr 3 ( 13.5 g, 0.050 mol) was added dropwise at room temperature, and the reaction was further stirred for 1 hour. After the reaction, poured into ice water, separated and the organic phase was washed with water, dried over anhydrous MgSO 4, and concentrated to dryness under reduced pressure to give a white solid 14.1 g, yield 91.8%. MS (ESI) m/z: (M+H) = 404.3.
2.4 式 VI化合物的制备 2.4 Preparation of compound of formula VI
在反应瓶中加入式 IV化合物（14.1g， 0.041mol)、三苯基磷（16.3g， 0.062mol)、 二氧六环 150ml， 室温下反应 2小时。反应完， 加入式 V化合物（12.9g， 0.050mol)、 三乙胺 （10.2g， O. lOmol) ， 升温至 60°C反应 6-8小时。 反应完， 将反应混合物冷 却至室温， 倒入水中， 搅拌 10分钟， 分层， 有机相用饱和食盐水洗， 减压浓缩至 干。 粗品用 50%的乙醇 -水重结晶得到标题化合物 18.3g， 收率 78.9%。 MS ( ESI) m/z: ( M+H) =565.7。  A compound of the formula IV (14.1 g, 0.041 mol), triphenylphosphine (16.3 g, 0.062 mol) and 150 ml of dioxane were added to the reaction flask, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, a compound of the formula V (12.9 g, 0.050 mol), triethylamine (10.2 g, 0.1 mol) was added, and the mixture was heated to 60 ° C for 6-8 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, poured into water, stirred for 10 minutes, and the layers were separated. The crude product was recrystallized from 50% ethyl alcohol-water toield of the title compound 18.3 g. MS (ESI) m/z: (M+H) = 565.7.
2.5 式 VII化合物的制备 2.5 Preparation of a compound of formula VII
在反应瓶中加入式 VI化合物 （18.6g， 0.033mol) 、 乙腈 200ml， 室温下滴加 1N的稀盐酸 40ml， 反应 5小时。 反应完， 减压浓缩至干得到式 VI化合物粗品 17.2g， 直接投下一步反应。  A compound of the formula VI (18.6 g, 0.033 mol) and 200 ml of acetonitrile were added to the reaction flask, and 40 ml of 1N diluted hydrochloric acid was added dropwise at room temperature for 5 hours. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure to yield 17.2 g of crude compound of formula VI.
2.6式 VIII化合物的制备 Preparation of 2.6 compound of formula VIII
在反应瓶中加入上一步得到的式 VII化合物粗品 17.2g、 乙酸正丁酯 150ml、 N- 甲基甲磺酰胺 （7.1g， 0.065mol) ， 回流反应 4小时。 反应完， 加入 150ml水， 搅 拌 15分钟。 分层， 有机层无水 MgSO4干燥， 减压浓缩至原体积的一半， 滴加入正 己垸， 析出固体。 过滤， 得到白色固体 14.4g， 收率 81.3%， HPLC纯度 99.1%。 MS ( ESI) m/z: ( M+H) =538.6。 17.2 g of the crude compound of the formula VII obtained in the previous step, 150 ml of n-butyl acetate and N-methylmethanesulfonamide (7.1 g, 0.065 mol) were added to the reaction flask, and the mixture was refluxed for 4 hours. After completion of the reaction, 150 ml of water was added and stirred for 15 minutes. The layers were separated, and the organic layer was dried over anhydrous MgSO 4 and evaporated. Filtration gave 14.4 g of a white solid, yield 81.3%, HPLC purity 99.1%. MS (ESI) m/z: (M+H) = 538.6.
2.7瑞舒伐他汀钙的制备 Preparation of 2.7 rosuvastatin calcium
在反应瓶中加入式 VII化合物 （14.4g， 0.027mol) 、 乙腈 100ml, 室温下加入 0.5N氢氧化钠 30ml， 室温反应 5小时。 反应完， 用 0.5N盐酸中和至 pH 7.0。 蒸去乙 腈， 降温至 0-5°C， 缓慢滴加 O.5mol/L的氯化钙 56ml， 过滤， 冷水洗涤滤饼。 干燥 得到白色固体 11.4g。收率 85.7%， HPLC纯度 99.6%。 MS ( ESI ) m/z： ( M+H ) =482· 1。 在本发明提及的所有文献都在本申请中引用作为参考， 就如同每一篇文献被 单独引用作为参考那样。 此外应理解， 在阅读了本发明的上述讲授内容之后， 本 领域技术人员可以对本发明作各种改动或修改， 这些等价形式同样落于本申请所 附权利要求书所限定的范围。  A compound of the formula VII (14.4 g, 0.027 mol) and 100 ml of acetonitrile were added to the reaction flask, and 30 ml of 0.5 N sodium hydroxide was added thereto at room temperature, and the mixture was reacted at room temperature for 5 hours. After completion of the reaction, it was neutralized to pH 7.0 with 0.5 N hydrochloric acid. Evaporate the acetonitrile, cool to 0-5 ° C, slowly add 56 ml of 0.5 mol/L calcium chloride, filter, and wash the filter cake with cold water. Drying gave 11.4 g of a white solid. The yield was 85.7%, and the HPLC purity was 99.6%. MS (ESI) m/z: (M+H) = 482. All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the the In addition, it is to be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.

Claims

权 利 要 求 Rights request
1、 一种结构如式 A所示的中间 1, a structure as shown in the middle of the formula A
其中， R为 COOCH3、 CH2OH、 CH
Figure imgf000020_0001
Wherein R is COOCH 3 , CH 2 OH, CH
Figure imgf000020_0001
2、 式 II所示中间体的制备方法， 其特征在于， 包括步骤： 在 ~4卤代烃类溶 剂中， 将式 I化合物与甲 物。 2. A process for the preparation of an intermediate of formula II, which comprises the steps of: reacting a compound of formula I with an onyx in a ~ 4 halogenated hydrocarbon solvent.
3、 式 III所示中间体的制备方法， 其特征在于， 包括步骤： 在惰性溶剂中， 在 还原剂的存在下， 将式 II化 III化合物。 3. A process for the preparation of an intermediate of formula III, which comprises the steps of: formulating a compound of formula II in an inert solvent in the presence of a reducing agent.
Figure imgf000020_0003
Figure imgf000020_0003
II III  II III
4、 式 IV所示中间体的制备方法， 其特征在于， 包括步骤： 在 ~4卤代烃类溶 剂中， 在溴化试剂的存在下， 将式 III化合物进行溴化反应， 从而形成式 IV化合物。
Figure imgf000021_0001
4. A process for the preparation of an intermediate of the formula IV, which comprises the steps of: brominating a compound of the formula III in the presence of a brominating reagent in a ~ 4 halogenated hydrocarbon solvent to form the formula IV Compound.
Figure imgf000021_0001
5、 式 VI所示中间体的制备方法， 其特征在于， 包括步骤： 在惰性溶剂中， 将 式 IV化合物与三苯基膦进行反应， 不经处理， 直接与式 V化合物继续进行反应， 从而形成 VI化合物。 5. A process for the preparation of an intermediate of the formula VI, which comprises the steps of: reacting a compound of the formula IV with triphenylphosphine in an inert solvent, and continuing the reaction with the compound of the formula V without treatment, thereby A VI compound is formed.
Figure imgf000021_0002
Figure imgf000021_0002
6、 式 VII所示的中间体的制备方法， 其特征在于， 包括步骤： 于惰性溶剂中， VI化合物在酸性条件下进行脱保护反应， 从而形成式 VII化合物。  A process for the preparation of an intermediate of the formula VII, which comprises the steps of: deprotecting a VI compound under acidic conditions in an inert solvent to form a compound of the formula VII.
Figure imgf000021_0003
Figure imgf000021_0003
VI I VI II  VI I VI II
(b) 在碱性条件下， 将式 VIII化合物进行水解反应， 从而形成瑞舒伐他汀。
Figure imgf000022_0001
(b) subjecting a compound of formula VIII to a hydrolysis reaction under basic conditions to form rosuvastatin.
Figure imgf000022_0001
VII I  VII I
8、 如权利要求 7所述的制备方法， 其特征在于， 所述步骤之后， 还包括成盐 步骤： 将瑞舒伐他汀成盐， 从而形成瑞舒伐他汀盐。  8. The preparation method according to claim 7, wherein after the step, a salt forming step is further included: the rosuvastatin is salted to form a rosuvastatin salt.
9、 如权利要求 8所述的制备方法， 其特征在于， 所述的瑞舒伐他汀盐为瑞舒 伐他汀钙。  9. The method according to claim 8, wherein the rosuvastatin salt is rosuvastatin calcium.
PCT/CN2012/076856 2012-06-13 2012-06-13 Rosuvastatin calcium and method for preparing intermediate thereof WO2013185309A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103864698A (en) * 2014-02-27 2014-06-18 常州金隆生物医药有限公司 Method for preparing rosuvastatin calcium
CN107698518A (en) * 2017-06-20 2018-02-16 迪沙药业集团（天津）药物研究有限公司 A kind of preparation method of rosuvastain calcium epimer impurity

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1527821A (en) * 2001-07-13 2004-09-08 Preparation of aminopyrimidine compounds
WO2005054207A1 (en) * 2003-12-04 2005-06-16 Glenmark Pharmaceuticals Limited Process for the preparation of pyrimidine derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1527821A (en) * 2001-07-13 2004-09-08 Preparation of aminopyrimidine compounds
WO2005054207A1 (en) * 2003-12-04 2005-06-16 Glenmark Pharmaceuticals Limited Process for the preparation of pyrimidine derivatives

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103864698A (en) * 2014-02-27 2014-06-18 常州金隆生物医药有限公司 Method for preparing rosuvastatin calcium
CN107698518A (en) * 2017-06-20 2018-02-16 迪沙药业集团（天津）药物研究有限公司 A kind of preparation method of rosuvastain calcium epimer impurity

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