CN102617481A - Preparation method of rosuvastatin calcium - Google Patents

Preparation method of rosuvastatin calcium Download PDF

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CN102617481A
CN102617481A CN201210069448XA CN201210069448A CN102617481A CN 102617481 A CN102617481 A CN 102617481A CN 201210069448X A CN201210069448X A CN 201210069448XA CN 201210069448 A CN201210069448 A CN 201210069448A CN 102617481 A CN102617481 A CN 102617481A
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林开朝
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湖南欧亚生物有限公司
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Abstract

The invention discloses a preparation method of rosuvastatin calcium. The method comprises the following steps of: synthesizing an important intermediate, i.e., [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-mesyl amino)pyrimidine-5-radical]methanol (compound IV); and preparing the rosuvastatin calcium (compound I). The method has the advantages of readily available raw materials, high stereoselectivity, high yield and suitability for industrial production.

Description

一种瑞舒伐他汀钙的制备方法 One kind of preparation statin rosuvastatin calcium

技术领域 FIELD

[0001] 本发明属于药物化学技术领域,具体涉及ー种瑞舒伐他汀钙的制备方法。 [0001] The present invention belongs to the technical field of pharmaceutical chemistry, specifically relates to a method of preparing ー species statin rosuvastatin calcium.

背景技术 Background technique

[0002]瑞舒伐他汀I丐(Rosuvastatin calcium),化学名为( + )- (3R,5S)-7_【4_ (4_ 氟苯基)-6-异丙基-2- (N-甲基-N-甲磺酰基氨基)嘧啶-5-基】-3,5- ニ羟基-6 (E)-庚烯酸I丐,是日本盐野义(大阪Shionogi公司)研制开发,1998年4月转让给英国AstraZeneca公司,2003年8月被美国FDA批准上市。 [0002] Rosuvastatin I Hack (Rosuvastatin calcium), chemical name (+) - (3R, 5S) -7_ [4_ (4_ fluorophenyl) -6-isopropyl -2- (N- methyl -N- methylsulfonyl) pyrimidine-5-yl] -3,5-Ni-hydroxy -6 (E) - heptenoic acid I Hack, Japan Shionogi (Shionogi company, Osaka) developed, April 1998 transfer to the British company AstraZeneca, it was approved in August 2003 listed on the US FDA. 瑞舒伐他汀钙可降低升高的LDL-胆固醇、总胆固醇、甘油三酸酯和ApoB,増加HDL-胆固醇。 Rosuvastatin calcium may reduce elevated LDL- cholesterol, total cholesterol, triglycerides and ApoB, to increase in HDL- cholesterol. 从已有的临床验证结果和同类产品的比较两方面来看,瑞舒伐他汀钙具有高效、低度、副作用小等优点,被称为“超级他汀”,是迄今为止最强效的降血脂药物,市场前景非常好。 From both existing clinical validation results and comparison of similar product point of view, rosuvastatin calcium with high efficiency, low, side effects, etc., known as "super statin", is by far the most potent cholesterol-lowering drugs, the market prospects are very good.

Figure CN102617481AD00031

[0003] I [0003] I

目前关于瑞舒伐他汀钙的合成方法研究的很多,都是采用母核嘧啶衍生物和支链部分通过Wittig Reaction或者Wittig-Horner Reaction将二者结合起来,然后再脱除保护基,最后水解成盐,得到瑞舒伐他汀钙。 Currently a lot of research rosuvastatin calcium statin synthesis of pyrimidine derivatives are based nucleus and branched moieties or by Wittig Reaction Wittig-Horner Reaction to combine the two, and then removal of the protecting group, and finally hydrolyzed to salt, to obtain rosuvastatin calcium. 概括起来有以下两类: Summed up in the following categories:

第一类方法: The first method:

Figure CN102617481AD00032
Figure CN102617481AD00041

上述两类方法用到的中间体化合物II和化合物4都需要用到共同的一个中间体IV,即【4- (4-氟苯基)-6-异丙基-2- (N-甲基-N-甲磺酰基氨基)嘧啶-5-基】甲醇,而该化合物的合成都是采用下面的方法: The method used in the above two types of intermediate compound 4 and compound II need to use a common intermediate IV, i.e., [4- (4-fluorophenyl) -6-isopropyl -2- (N- methyl -N- methylsulfonyl) pyrimidin-yl] methanol, and this compound is synthesized -5- following method:

Figure CN102617481AD00042

采用的还原剂是而异丁基氢化铝(DIBAl-H)或者ニ氢双(2-甲氧こ氧基)铝酸钠(Red-Al),这两种还原剂价格都比较高,因此使得化合物IV的成本高。 And the reducing agent employed is diisobutylaluminium hydride (DIBAl-H) or Ni hydrogen-bis (2-methoxyethoxy group ko) sodium aluminate (Red-Al), both reducing prices are high, so that compound IV of the high cost.

发明内容[0004] 本发明的目的在于克服现有技术中的不足,提供一种瑞舒伐他汀钙的制备方法。 [0004] The present invention is to overcome the disadvantages of the prior art, provides a method of a statin rosuvastatin calcium.

[0005] 一种瑞舒伐他汀钙的制备方法,包括以下步骤: [0005] A method for preparing statin rosuvastatin calcium, comprising the steps of:

(1)反应瓶中加入化合物V和こ酸丁酷,搅拌下,冷却至10°c,加入硼氢化钠,继续在该温度下搅拌20--40分钟,然后降至0-5°C,慢慢滴加三氟化硼こ醚溶液,滴加完毕后,恢复室温反应5—7小吋,反应结束后,降至5°C,慢慢滴加2mol/l氢氧化钠水溶液,至PH=6_7,继续搅拌20-40分钟,静置,反应液分层,水层再用こ酸丁酯萃取,合并有机层,用饱和食盐水洗涤,最后用无水硫酸钠干燥;过滤,滤液浓缩至干,得到粗品,用甲苯和石油醚重结晶,得到化合物IV ; (1) The reaction flask was added the compound V and ko acid butyl cool, with stirring, cooled to 10 ° c, sodium borohydride, and stirring was continued at this temperature for 20--40 min, then lowered to 0-5 ° C, ko was slowly added dropwise boron trifluoride ether solution, after dropwise addition, reaction was brought to room temperature 5-7 inch small, the completion of the reaction, down to 5 ° C, was slowly added dropwise 2mol / l aqueous sodium hydroxide to PH = 6_7, stirring was continued for 20-40 minutes, allowed to stand, the reaction solution was separated and the aqueous layer was extracted with butyl ko, the organic layers were combined, washed with saturated brine, and finally dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated to dryness to give the crude product, toluene and recrystallized from petroleum ether, to give compound IV;

(2)反应瓶中加入化合物IV、こ酸こ酯和催化剂4-甲氧基-2,2,6,6-四甲基哌啶氧自由基,搅拌下,滴加次氯酸钠水溶液,滴加完毕,室温搅拌1—2小时,反应结束后,过滤,滤液分层,水层再用こ酸こ酯萃取,合并有机层,再用饱和食盐水洗涤,最后用无水硫酸钠干燥;过滤,滤液浓缩至干,残余物用甲苯和こ酸こ酯重结晶,得到化合物II ; (2) The reaction flask was added to compound IV, ko ko acid ester and catalyst 4-methoxy-2,2,6,6-tetramethyl-piperidinyloxy radical, with stirring, was added dropwise aqueous sodium hypochlorite solution addition was complete the mixture was stirred at room temperature for 1-2 hours, after the reaction, was filtered, and the filtrate layers were separated, the aqueous layer was extracted acid ester ko ko then the organic layers were combined, washed with a saturated aqueous sodium chloride solution, finally dried over anhydrous sodium sulfate; filtered and the filtrate concentrated to dryness and the residue was recrystallized from toluene and ko ko acid ester to give compound II;

(3)反应瓶中加入化合物VI、亚磷酸三甲酯和甲苯,回流反应过夜,反应结束后,浓缩除去甲苯和未反应完全的亚磷酸三甲酷,得到化合物III的粗品,可直接投入下步反应;氮气保护下,反应瓶中加入化合物III和无水四氢呋喃,搅拌下,分批加入氢化钠,加料完毕,室温搅拌20—40分钟,然后冷却至5°C,滴加溶有化合物II的四氢呋喃溶液,滴加完毕,回流反应4—6小时,反应结束后,将反应液倾入到冰水中,搅拌10—20分钟,分层,水层再用こ酸こ酯萃取,合并有机层,用饱和食盐水洗涤,最后用无水硫酸钠干燥,过滤,滤液浓缩至干,残余物加入异丙醇重结晶,得到化合物νπ ; (3) The reaction flask was added compound Vl, trimethylphosphite and toluene, the reaction was refluxed overnight. After completion of the reaction, concentrated to remove the toluene and unreacted Trimethylphosphit completely cool, to give the crude compound III can be directly into the next step reaction; under nitrogen, the reaction flask was added compound III and anhydrous tetrahydrofuran, under stirring, was added sodium hydride, addition was complete the mixture was stirred at room temperature for 20-40 minutes, then cooled to 5 ° C, was added dropwise a solution of compound II tetrahydrofuran, dropwise addition, the reaction was refluxed for 4-6 hours. after completion of the reaction, the reaction solution was poured into ice water, stirred for 10-20 minutes, layers were separated, the aqueous layer was extracted acid ester ko ko then the organic layers were combined, was washed with saturated brine, and finally dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness, the residue was recrystallized from isopropanol was added, to give compound νπ;

(4)反应瓶中加入化合物YD和四氢呋喃,搅拌下,滴加4Ν盐酸,滴加完毕,室温搅拌反应2—4小吋,反应结束后,反应液冷却至(TC,慢慢滴加2mol/l氢氧化钠水溶液至PH=6,然后加入ニ氯甲烷萃取,ニ氯甲烷层再用水洗,最后用无水硫酸钠干燥;过滤,滤液浓缩至干,残余物加入异丙醚搅洗,得到固体,得到的固体再用こ醇和水重结晶,得到白色固体,即化合物VDI ; (4) The reaction flask was added compound YD and tetrahydrofuran, with stirring, dropwise 4Ν hydrochloric acid addition was complete, the reaction was stirred at room temperature 2-4 small inch, after the reaction, the reaction solution was cooled to (the TC, was slowly added dropwise 2mol / l sodium hydroxide aqueous solution to PH = 6, then extracted with methylene chloride was added Ni, Ni chloride layer was washed with water, and finally dried over anhydrous sodium sulfate; filtered and the filtrate was concentrated to dryness, the residue was added isopropyl ether and stirred to wash to give the solid obtained solid was then recrystallized from alcohol and water ko, to give a white solid, i.e. a compound of the VDI;

(5)反应瓶中加入化合物VDI和无水こ醇,冷却至5°C,加入氢氧化钠水溶液,保持该温度搅拌反应1-3小时,然后滴加氯化钙的水溶液,滴加完毕,继续搅拌反应过夜,抽滤,滤饼用水洗涤,干燥,即得到化合物I,即瑞舒伐他汀钙。 (5) The reaction flask was added compound VDI and anhydrous alcohol ko, cooled to 5 ° C, was added aqueous sodium hydroxide, maintaining the reaction temperature for 1-3 hours, then aqueous calcium chloride addition was complete, stirring was continued overnight, washed with suction, the filter cake was washed with water, and dried, to obtain compound I, i.e. rosuvastatin calcium.

[0006] 在本发明中,所述的化合物V与硼氢化钠摩尔比为I. 00:1. 50-1. 00:2. 50 ;化合物V与三氟化硼こ醚溶液的摩尔比为1.00:2.00-1.00:3.00。 [0006] In the present invention, the compound V with a molar ratio of sodium borohydride to I. 00: 1 50-1 00: 2 50; molar ratio of compound V with a boron trifluoride ether solution was ko... 1.00: 2.00-1.00: 3.00.

[0007] 在本发明中,所述的化合物IV与催化剂的摩尔比为I. 00:0. 01-1. 00:0. 05,化合物IV与次氯酸钠水溶液的摩尔比为I. 00:3. 00-1. 00:5. 00 ;化合物VI与亚磷酸三甲酯的摩尔比为I. 00:2. 00-1. 00:5. 00 ;化合物II与化合物III的摩尔比为I. 00:1. 00-1. 00:0. 80,化合物III与氢化钠的摩尔比为1.00:1. 10-1.00:1.50 ;化合物νπ与盐酸的摩尔比为 [0007] In the present invention, the molar ratio of compound IV with a catalyst I. 00: 0 01-1 00:... 0 05, molar ratio of compound IV with sodium hypochlorite aqueous solution is I. 00: 3. . 00-100: 500; molar ratio of compound VI with trimethyl phosphite to I. 00: 2 00-100:... 500; molar ratio of compound II to compound III is I. 00 ...: 100-100: 080, the molar ratio of compound III with sodium hydride was 1.00: 1 10-1.00: 1.50; molar ratio of the compound and hydrochloric acid is νπ.

I. 00:3. 00-1. 00:10. 00 ;化合物VDI与氢氧化钠的摩尔比为I. 00:1. 00-1. 00:1. 10 ;化合物VDI与氯化钙的摩尔比为I. 00:0. 50-1. 00:0. 60。 ... I. 00: 3 00-1 00:10 00; and the mole ratio of sodium hydroxide to the compound VDI I. 00: 1 00-1 00:... 1 10; VDI mol of the compound with calcium chloride ratio I. 00: 0 50-1 00:... 0 60. [0008] 一种瑞舒伐他汀钙的制备方法,其制备方法用化学方程式表示为: [0008] A method for preparing statin rosuvastatin calcium, which preparation is represented by the chemical equation:

Figure CN102617481AD00061

本发明还公布了中间体的合成: 手性催化剂(s) -a,α - ニ异丙基ニ甲基叔丁基硅氧基脯氨醇的合成: The present invention also announced synthetic intermediates: -a, chiral catalyst (s) α - Synthesis of Ni Ni isopropyl methyl t-butyl silyloxy prolinol:

Figure CN102617481AD00071

有益效果: Beneficial effects:

本发明有以下有益特点: The present invention has the following advantageous features:

(1)化合物IV的合成,采用硼氢化钠/三氟化硼こ醚溶液体系还原,比现有的还原方法操作简单、条件温和、原料价格便宜; (1) Synthesis of Compound IV, sodium borohydride / boron trifluoride ether solution ko reduction system, a simple, mild conditions, the raw material price is cheaper than the conventional method of reducing operation;

(2)化合物II的合成采用催化剂催化下,用次氯酸钠水溶液做氧化剂,相比现有技术采用的PCC氧化剂(三氧化铬/吡唆)或者吡啶/三氧化硫污染小、操作简单; (2) Synthesis of Compound II catalysis using a catalyst, with an oxidizing agent to make an aqueous solution of sodium hypochlorite, an oxidizing agent as compared to the prior art the PCC used (chromium trioxide / pyridine instigate) or pyridine / sulfur trioxide little pollution, simple operation;

(3)整个过程分离操作简单、适合エ业化生产。 (3) simple operation of the whole separation process, for Ester production industry.

具体实施方式 Detailed ways

[0009] 为了使本发明的技术手段、创作特征、工作流程、使用方法达成目的与功效易于明白了解,下面结合具体实施例,进ー步阐述本发明。 [0009] In order to make the technical means of the present invention, authoring features, workflows, using the method to achieve the purpose and effect readily apparent understanding, the following embodiment with reference to specific embodiments, further illustrate the present invention into ー.

[0010] [0010]

Figure CN102617481AD00072
Figure CN102617481AD00081

化合物V和化合物VI可以直接购买或者參考已有文献报道合成。 Compound V and Compound VI may be directly purchased or synthesized reference has been reported.

[0011] 化合物IV的合成: [0011] Synthesis of Compound IV:

反应瓶中加入762克化合物V (2. OOmol)和こ酸丁酯2500毫升,搅拌下,冷却至10°C,分批加入152克硼氢化钠(4. OOmol ),继续在该温度下搅拌30分钟,然后降至0_5°C,慢慢滴加1434. 8克46%的三氟化硼こ醚溶液(5. OOmol),滴加完毕后,恢复室温反应6小时,反应结束后,降至5°C,慢慢滴加2mol/l氢氧化钠水溶液,至PH=6-7,继续搅拌30分钟,静置,反应液分层,水层再用1200毫升こ酸丁酯萃取,合并有机层,用2000毫升饱和食盐水洗涤,最后用无水硫酸钠干燥;过滤,滤液浓缩至干,得到粗品,用甲苯和石油醚重结晶,得到587. 2克白色固体,即化合物IV,收率:83. 17% (以化合物V计算)。 The reaction flask was added 762 g compound V (2. OOmol) and butyl ko 2500 ml, stirred, cooled to 10 ° C, portionwise 152 g of sodium boron hydride (4. OOmol), stirring was continued at the same temperature for 30 minutes and then reduced 0_5 ° C, was slowly dropwise added 1434.8 g of 46% solution of boron trifluoride ether ko (5. OOmol), after the completion of the dropwise addition, reaction was brought to room temperature for 6 hours. after completion of the reaction, reducing to 5 ° C, was slowly added dropwise 2mol / l aqueous sodium hydroxide to PH = 6-7, stirring continued for 30 minutes, allowed to stand, the reaction solution was separated and the aqueous layer was extracted with butyl ko 1200 ml, combined The organic layer was washed with 2000 ml of saturated brine, and finally dried over anhydrous sodium sulfate; filtered and the filtrate was concentrated to dryness to give the crude product, toluene and recrystallized from petroleum ether to give 587.2 g of white solid, i.e. to compound IV, close rate: 83 17% (V compound calculated).

[0012]熔点:145. 1-146. (TC。 [0012] Melting point:.. 145 1-146 (TC.

[0013] 化合物II的合成: [0013] Synthesis of Compound II:

反应瓶中加入353克化合物IV (I. OOmol ),2000毫升こ酸こ酯和5. 58克催化剂4-甲氧基-2,2,6,6-四甲基哌啶氧自由基(O. 03mol),搅拌下,滴加2980克10%的次氯酸钠水溶液(4. OOmol),滴加完毕,室温搅拌I小吋,反应结束后,过滤,滤液分层,水层再用1000毫升こ酸こ酯萃取,合并有机层,再用饱和食盐水洗涤,最后用无水硫酸钠干燥;过滤,滤液浓缩至干,残余物用甲苯和こ酸こ酯重结晶,得到310. 2克白色固体,即化合物II,收率:88. 38% (以化合物IV计算)。 The reaction flask was added 353 g Compound IV (I. OOmol), 2000 mL ko ko acid ester and 5.58 grams of catalyst 4-methoxy-2,2,6,6-tetramethyl piperidinyloxy free radical (O . 03mol), with stirring, was added dropwise 2980 g of 10% aqueous sodium hypochlorite solution (4. OOmol), completion of the dropwise addition, stirred at room temperature I inch small, after the reaction was filtered, the filtrate was separated and the aqueous layer was 1000 ml ko acid ko acetate, the organic layers were combined, washed with a saturated aqueous sodium chloride solution, finally dried over anhydrous sodium sulfate; filtered and the filtrate was concentrated to dryness, and the residue was recrystallized from toluene and ko ko acid ester, to obtain 310.2 g of white solid, i.e. compound II, yield: 88 38% (calculated as compound IV).

[0014]熔点:186. 3-187. 1°C。 [0014] Melting point:.. 186 3-187 1 ° C.

[0015] 化合物III的合成: [0015] Synthesis of Compound III:

反应瓶中加入322克化合物VI(I. OOmol),372克亚磷酸三甲酯(3. OOmol)和2000毫升甲苯,回流反应过夜,反应结束后,浓缩除去甲苯和未反应完全的亚磷酸三甲酷,得到355. I克化合物III的粗品,可直接投入下步反应; The reaction flask was added 322 g Compound VI (I. OOmol), 372 g of trimethyl phosphate (3. OOmol) and 2,000 ml of toluene, the reaction was refluxed overnight. After completion of the reaction, toluene was completely removed and unreacted concentrated Trimethylphosphit cool to give 355. I g of crude product of compound III can be directly into the next step;

化合物νπ的合成: Synthesis of Compound νπ:

氮气保护下,反应瓶中加入上步制备的355. I克粗品化合物III和1500毫升无水四氢呋喃,搅拌下,分批加入48克60%的氢化钠(I. 20mol),加料完毕,室温搅拌30分钟,然后冷却至5°C,滴加溶有358. O克化合物II (I. 02mol) Under nitrogen, 355. I g of the crude compound III prepared in step a reaction flask, and 1500 ml of anhydrous tetrahydrofuran, under stirring, was added portionwise 48 g of 60% sodium hydride (I. 20mol), the addition was complete the mixture was stirred at room temperature 30 minutes and then cooled to 5 ° C, was added dropwise a solution of 358. O g of compound II (I. 02mol)

的1000毫升四氢呋喃溶液,滴加完毕,回流反应5小时,反应结束后,将反应液倾入到3000毫升冰水中,搅拌15分钟,分层,水层再用1200毫升こ酸こ酯萃取,合并有机层,用饱和食盐水洗涤,最后用无水硫酸钠干燥,过滤,滤液浓缩至干,残余物加入异丙醇重结晶,得到509. 2克类白色固体,即化合物VL收率:88. 25% (以化合物VI计算)。 1000 ml of tetrahydrofuran, dropwise addition, the reaction was refluxed for 5 hours. After completion of the reaction, the reaction solution was poured into 3000 ml of ice water, stirred for 15 minutes, separated and the aqueous layer was 1200 ml ko ko acid ester, and the combined The organic layer was washed with saturated brine, and finally dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness, the residue was recrystallized from isopropyl alcohol was added to give 509.2 grams off-white solid, i.e. compound VL yield: 88. 25% (calculated as compound VI).

[0016]熔点:152. 1-153. (TC。 [0016] Melting point:.. 152 1-153 (TC.

[0017] 化合物VDI的合成: [0017] Synthesis of Compound VDI:

反应瓶中加入288. 5克化合物VIKO. 50mol)和500毫升四氢呋喃,搅拌下,滴加625毫升4N盐酸,滴加完毕,室温搅拌反应3小吋,反应结束后,反应液冷却至0°C,慢慢滴加2mol/l氢氧化钠水溶液至PH=6,然后加入2000毫升ニ氯甲烷萃取,ニ氯甲烷层再用800毫升水洗,最后用无水硫酸钠干燥;过滤,滤液浓缩至干,残余物加入异丙醚搅洗,得到固体,得到的固体再用こ醇和水重结晶,得到255. 4克白色固体,即化合物珊,收率:95. 12% (以化合物νπ计算)。 The reaction flask was added 288.5 g compound VIKO. 50mol) and 500 ml of tetrahydrofuran, with stirring, 625 ml of 4N hydrochloric acid was added dropwise, the addition was complete, the reaction was stirred at room temperature for 3 hours inch, after completion of the reaction, the reaction solution was cooled to 0 ° C was slowly added dropwise 2mol / l aqueous sodium hydroxide to PH = 6, then extracted with methylene chloride is added 2000 ml Ni, Ni chloride layer was 800 ml water, and finally dried over anhydrous sodium sulfate; filtered and the filtrate was concentrated to dryness , stir the residue was added isopropyl ether wash to give a solid, then the resulting solid was recrystallized from aqueous alcohol ko, to give 255.4 g of white solid, compound Shan, yield: 95 12% (calculated νπ compound).

[0018] 化合物I即瑞舒伐他汀钙的制备: [0018] i.e. Compound I statin rosuvastatin calcium prepared:

反应瓶中加入429. 6克化合物VDI(O. 80mol)和300毫升こ醇,冷却至5°C,加入420毫升2. Omol/1的氢氧化钠水溶液,保持该温度搅拌反应2小时,然后滴加溶有45. 3克氯化钙的水溶液250毫升,滴加完毕,继续搅拌反应过夜,抽滤,滤饼用水洗涤,干燥,得到382. I克白色固体,即化合物I,即瑞舒伐他汀钙,收率:95. 43% (以化合物VDI计算)。 The reaction flask was added 429.6 g Compound VDI (O. 80mol) ko alcohol and 300 ml, cooled to 5 ° C, aqueous sodium hydroxide was added 420 ml 2. Omol / 1 is maintained at the temperature for 2 hours, then was added dropwise a solution of 45.3 g of calcium chloride aqueous solution 250 ml, addition was complete, stirring was continued overnight, suction filtered, the filter cake was washed with water, and dried, to obtain 382. I g of a white solid, i.e. compound I, i.e. rosuvastatin atorvastatin calcium, yield: 95 43% (calculated as the VDI compound).

[0019] e. e: 99. 4% . [0019] e e: 99. 4%

HPLC :99. 1% (外标法)。 HPLC:. 99 1% (external standard method).

[0020] 以上显示和描述了本发明的基本原理和主要特征和本发明的优点。 [0020] The above description and the basic principles and features of this invention and the main advantages of the invention. 本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,这些变化和改进都落入要求保护的本发明范围内。 The industry the art will appreciate, the present invention is not limited to the above embodiment, the above-described examples and embodiments described in the specification are only illustrative of the principles of the present invention, without departing from the spirit and scope of the present invention, the present invention will have various changes and improvements, changes and modifications which fall within the scope of the claimed invention. 本发明要求保护范围由所附的权利要求书及其等效物界定。 The scope of the invention as claimed by the appended claims and their equivalents.

Claims (3)

1. 一种瑞舒伐他汀钙的制备方法,其特征在于,包括以下步骤: (1)反应瓶中加入化合物V和乙酸丁酯,搅拌下,冷却至10°c,加入硼氢化钠,继续在该温度下搅拌20--40分钟,然后降至0-5°C,慢慢滴加三氟化硼乙醚溶液,滴加完毕后,恢复室温反应5—7小时,反应结束后,降至5°C,慢慢滴加2mol/l氢氧化钠水溶液,至PH=6_7,继续搅拌20-40分钟,静置,反应液分层,水层再用乙酸丁酯萃取,合并有机层,用饱和食盐水洗涤,最后用无水硫酸钠干燥;过滤,滤液浓缩至干,得到粗品,用甲苯和石油醚重结晶,得到化合物IV ; (2)反应瓶中加入化合物IV、乙酸乙酯和催化剂4-甲氧基-2,2,6,6-四甲基哌啶氧自由基,搅拌下,滴加次氯酸钠水溶液,滴加完毕,室温搅拌1—2小时,反应结束后,过滤,滤液分层,水层再用乙酸乙酯萃取,合并有机层,再用饱和食盐水洗 CLAIMS 1. A method for the preparation of statin rosuvastatin calcium, characterized by comprising the steps of: (1) the reaction flask was added the compound V and butyl acetate, stirred, cooled to 10 ° c, was added sodium boron hydride, continued 20--40 minutes stirring at this temperature was then reduced to 0-5 ° C, was slowly added dropwise boron trifluoride diethyl ether solution, after dropwise addition, reaction was brought to room temperature 5-7 hours. after completion of the reaction, down to 5 ° C, was slowly added dropwise 2mol / l aqueous sodium hydroxide to PH = 6_7, stirring was continued for 20-40 minutes, allowed to stand, the reaction solution was separated and the aqueous layer was extracted with butyl acetate, the organic layers were combined, dried washed with saturated brine, and finally dried over anhydrous sodium sulfate; filtered and the filtrate was concentrated to dryness to give the crude product, toluene and recrystallized from petroleum ether to give compound IV; (2) a reaction flask was added to compound IV, ethyl acetate and the catalyst 4-methoxy-2,2,6,6-tetramethyl-piperidinyloxy radical, with stirring, was added dropwise aqueous sodium hypochlorite solution addition was complete the mixture was stirred at room temperature for 1-2 hours, after the reaction was filtered, the filtrate was divided layer, the aqueous layer extracted with ethyl acetate, the organic layers were combined, washed with saturated brine ,最后用无水硫酸钠干燥;过滤,滤液浓缩至干,残余物用甲苯和乙酸乙酯重结晶,得到化合物II ; (3)反应瓶中加入化合物VI、亚磷酸三甲酯和甲苯,回流反应过夜,反应结束后,浓缩除去甲苯和未反应完全的亚磷酸三甲酯,得到化合物III的粗品,可直接投入下步反应;氮气保护下,反应瓶中加入化合物III和无水四氢呋喃,搅拌下,分批加入氢化钠,加料完毕,室温搅拌20—40分钟,然后冷却至5°C,滴加溶有化合物II的四氢呋喃溶液,滴加完毕,回流反应4—6小时,反应结束后,将反应液倾入到冰水中,搅拌10—20分钟,分层,水层再用乙酸乙酯萃取,合并有机层,用饱和食盐水洗涤,最后用无水硫酸钠干燥,过滤,滤液浓缩至干,残余物加入异丙醇重结晶,得到化合物νπ ; (4)反应瓶中加入化合物YD和四氢呋喃,搅拌下,滴加4Ν盐酸,滴加完毕,室 , And finally dried over anhydrous sodium sulfate; filtered and the filtrate was concentrated to dryness, the residue was recrystallized from toluene and ethyl acetate, to give compound II; (3) The reaction flask was added compound Vl, toluene and trimethyl phosphite, reflux react overnight, after completion of the reaction, concentrated to remove the toluene and unreacted complete trimethyl phosphite, to give a crude product of compound III can be directly into the next step; under nitrogen, the reaction flask was added compound III and anhydrous tetrahydrofuran, stirred next, was added sodium hydride, addition was complete the mixture was stirred at room temperature for 20-40 minutes, then cooled to 5 ° C, a tetrahydrofuran solution was added dropwise a solution of compound II, the addition was complete, the reaction was refluxed for 4-6 hours. after completion of the reaction, the reaction solution was poured into ice water, stirred for 10-20 minutes, separated and the aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, and finally dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness and the residue was recrystallized from isopropanol was added, to give compound νπ; (4) the reaction flask was added compound YD and tetrahydrofuran, with stirring, dropwise 4Ν hydrochloric acid addition was complete, the chamber 温搅拌反应2—4小时,反应结束后,反应液冷却至(TC,慢慢滴加2mol/l氢氧化钠水溶液至PH=6,然后加入二氯甲烷萃取,二氯甲烷层再用水洗,最后用无水硫酸钠干燥;过滤,滤液浓缩至干,残余物加入异丙醚搅洗,得到固体,得到的固体再用乙醇和水重结晶,得到白色固体,即化合物VDI ; (5)反应瓶中加入化合物VDI和无水乙醇,冷却至5°C,加入氢氧化钠水溶液,保持该温度搅拌反应1-3小时,然后滴加氯化钙的水溶液,滴加完毕,继续搅拌反应过夜,抽滤,滤饼用水洗涤,干燥,即得到化合物I,即瑞舒伐他汀钙。 The reaction temperature was stirred for 2-4 hours. After completion of the reaction, the reaction solution was cooled to (the TC, was slowly added dropwise 2mol / l aqueous sodium hydroxide to PH = 6, then extracted with added dichloromethane, the dichloromethane layer washed with water, Finally, dried over anhydrous sodium sulfate; filtered and the filtrate was concentrated to dryness, the residue was added isopropyl ether and stirred to wash to obtain a solid, then the resulting solid was recrystallized from ethanol and water to give a white solid, i.e. compound VDI; (5) reaction flask was added compound VDI and ethanol, cooled to 5 ° C, was added aqueous sodium hydroxide, maintaining the reaction temperature for 1-3 hours, then aqueous calcium chloride addition was complete, stirring was continued overnight, filtered off with suction, the filter cake was washed with water, and dried, to obtain compound I, i.e. rosuvastatin calcium.
2. 一种瑞舒伐他汀钙的制备方法,其特征在于,包括以下步骤:所述的化合物V与硼氢化钠摩尔比为I. 00:1. 50-1. 00:2. 50 ;化合物V与三氟化硼乙醚溶液的摩尔比为I. 00:2. 00-1. 00:3. 00。 A method for the preparation of statin rosuvastatin calcium, characterized by comprising the steps of: a compound V with a molar ratio of sodium boron hydride I. 00: 1 50-1 00:... 2 50; compound V molar ratio of boron trifluoride ether solution was I. 00: 2 00-1 00:... 3 00.
3. 一种瑞舒伐他汀钙的制备方法,其特征在于,包括以下步骤:所述的化合物IV与催化剂的摩尔比为I. 00:0. 01-1. 00:0. 05,化合物IV与次氯酸钠水溶液的摩尔比为I. 00:3. 00-1. 00:5. 00 ;化合物VI与亚磷酸三甲酯的摩尔比为I. 00:2. 00-1. 00:5. 00 ;化合物II与化合物III的摩尔比为I. 00:1. 00-1. 00:0. 80,化合物III与氢化钠的摩尔比为I. 00:1. 10-1. 00:1. 50 ;化合物Vn与盐酸的摩尔比为I. 00:3. 00-1. 00:10. 00 ;化合物VDI与氢氧化钠的摩尔比为I. 00:1. 00-1. 00:1. 10 ;化合物VDI与氯化钙的摩尔比为I. 00:0. 50-1. 00:0. 60。 A method for the preparation of statin rosuvastatin calcium, characterized by comprising the steps of: the molar ratio of compound IV with a catalyst I. 00: 0 01-1 00:... 0 05, Compound IV the molar ratio of sodium hypochlorite aqueous solution is I. 00: 3 00-1 00: 5 00; the molar ratio of compound VI is trimethyl phosphite I. 00:... 2 00-1 00: 5 00... ; molar ratio of compound II to compound III is I. 00: 1 00-1 00: 0 80, molar ratio of compound III with sodium hydride to I. 00: 1 10-1 00: 1 50...... ; molar ratio of the compound and hydrochloric acid is Vn I. 00: 3 00-1 00:10 00; and the mole ratio of sodium hydroxide to the compound VDI I. 00:... 1 00-1 00: 1 10... ; molar ratio of the compound is calcium chloride VDI I. 00: 0 50-1 00: 0 60....
CN201210069448XA 2012-03-16 2012-03-16 Preparation method of rosuvastatin calcium CN102617481A (en)

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