WO2013185309A1 - Rosuvastatine calcique et procédé pour la préparation d'un intermédiaire de celle-ci - Google Patents

Rosuvastatine calcique et procédé pour la préparation d'un intermédiaire de celle-ci 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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English (en)
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/fr
Publication of WO2013185309A1 publication Critical patent/WO2013185309A1/fr

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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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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur de la rosuvastatine calcique et sur un procédé pour la préparation d'un intermédiaire de celle-ci. Plus précisément, l'invention porte sur un composé intermédiaire pour la préparation de rosuvastatine calcique et sur son procédé de préparation. Les structures de l'intermédiaire sont représentées respectivement par une formule (II), une formule (III), une formule (VI) ou une formule (VII) telles que définies dans la description. L'invention porte en outre sur un procédé de préparation de rosuvastatine ou d'un sel de celle-ci. Le procédé est basé sur les cinq composés intermédiaires et sur leur procédé de préparation, il a une mise en œuvre simple et sans danger, il a un faible coût de production et il est approprié pour une production industrielle.
PCT/CN2012/076856 2012-06-13 2012-06-13 Rosuvastatine calcique et procédé pour la préparation d'un intermédiaire de celle-ci WO2013185309A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103864698A (zh) * 2014-02-27 2014-06-18 常州金隆生物医药有限公司 一种制备瑞舒伐他汀钙的工艺方法
CN107698518A (zh) * 2017-06-20 2018-02-16 迪沙药业集团（天津）药物研究有限公司 一种瑞舒伐他汀钙差向异构体杂质的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1527821A (zh) * 2001-07-13 2004-09-08 氨基嘧啶化合物的制备方法
WO2005054207A1 (fr) * 2003-12-04 2005-06-16 Glenmark Pharmaceuticals Limited Procede de preparation de derives de pyrimidine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1527821A (zh) * 2001-07-13 2004-09-08 氨基嘧啶化合物的制备方法
WO2005054207A1 (fr) * 2003-12-04 2005-06-16 Glenmark Pharmaceuticals Limited Procede de preparation de derives de pyrimidine

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103864698A (zh) * 2014-02-27 2014-06-18 常州金隆生物医药有限公司 一种制备瑞舒伐他汀钙的工艺方法
CN107698518A (zh) * 2017-06-20 2018-02-16 迪沙药业集团（天津）药物研究有限公司 一种瑞舒伐他汀钙差向异构体杂质的制备方法

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