CN100430405C - Processes for preparing calcium salt forms of statins - Google Patents

Processes for preparing calcium salt forms of statins Download PDF

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CN100430405C
CN100430405C CN 02815999 CN02815999A CN100430405C CN 100430405 C CN100430405 C CN 100430405C CN 02815999 CN02815999 CN 02815999 CN 02815999 A CN02815999 A CN 02815999A CN 100430405 C CN100430405 C CN 100430405C
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statin
salt
atorvastatin
mixture
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R·里多尔-哈达斯
R·里斯茨-里伦
V·尼达姆-希尔德希姆
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特瓦制药工业有限公司
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    • C07D239/28Heterocyclic 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
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    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D309/28Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30Oxygen atoms, e.g. delta-lactones
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

本发明提供了一种使用氢氧化钙从他汀的酯衍生物或受护的酯衍生物制备他汀钙盐的方法。 The present invention provides a process for the preparation of statin from an ester derivative or protected ester derivatives by calcium hydroxide statin calcium. 所述酯或受护酯衍生物与氢氧化钙接触而形成钙盐。 The patron ester or ester derivative with calcium hydroxide formed in contact with a calcium salt. 优选的他汀是罗苏伐他汀、匹伐他汀和阿托伐他汀、辛伐他汀和洛伐他汀。 A preferred statin is rosuvastatin, pitavastatin and atorvastatin, simvastatin and lovastatin. 在以受护他汀酯衍生物为原料的方法中,保护基在与氢氧化钙接触成盐期间水解,或者与酸催化剂接触后与氢氧化钙接触。 In the method of the patron to statin ester derivative as a raw material, a protecting group into contact with calcium hydroxide, after contact with the calcium hydroxide to the hydrolyzed during salt, or in contact with an acid catalyst.

Description

制备他汀类的钾盐形式的方法 The method of preparation of potassium salt forms of the statin

相关申请的相互参照 Cross Reference to Related Applications

本申请要求2001年8月16日提出的临时申请60/312,812号以及2001年10月24日提出的美国专利申请序号10/037,412号(其要求了2000年11月16日提出的临时申请60/249,319号的权益)的权益, 所有这些申请均通过引用并入本文。 Provisional Application No. 60 This application claims the 2001 August 16, submitted pursuant to 312,812 and the 2001 October 24 raised US Patent Application Serial / / 10 037,412 (which claims provisional application 60, 2000 November 16 presented / number of equity interests 249,319), all of which applications are incorporated herein by reference.

发明领域 Field of the Invention

本发.明涉及制备钩盐形式的他汀类的方法。 The present method invention relates to a statin preparation hooks salt form. 发明背景 BACKGROUND OF THE INVENTION

称为他汀的一类药物是目前对于降低具有心血管病危险的患者血流中低密度脂蛋白(LDL)颗粒浓度的治疗上最有效的药物,因此他汀类可用于治疗高胆固醇血症、高脂蛋白血症和动脉粥样硬化。 A class of drugs called statins are currently on (LDL) particle concentration in the treatment of the most effective drugs for reducing blood flow in patients with a risk of cardiovascular disease in low-density lipoprotein, and therefore statins for the treatment of hypercholesterolemia, high hyperlipoproteinemia and atherosclerosis. 血流中高的LDL水平与堵塞血流并可导致血管破裂和促使血栓形成的冠状损害(coronary lesions)的形成有关。 High levels of LDL in the bloodstream and can lead to clogged blood vessels rupture and promote thrombosis formation of coronary damage (coronary lesions) concerned. 参见Goodman和Gilman的"the Pharmacological Basis of Therapeutics", 879页(笫9版,1996)。 See Goodman and Gilman's "the Pharmacological Basis of Therapeutics", 879 pages (sleeping mat version 9, 1996).

他汀类通过竟争性抑制3-羟基-3-曱基-戊二酰辅酶A ("HMG-CoA")还原酶来抑制人体中胆固醇的生物合成。 Statins suppress hydroxy-3-yl Yue by competitive nature - glutaryl coenzyme A ( "HMG-CoA") reductase inhibiting the biosynthesis of cholesterol in humans. HMG-CoA还原酶催化HMG向甲羟戊酸的转化,而这是胆固醇生物合成中的决速步骤。 Reductase catalyzes the conversion HMG HMG-CoA to mevalonate conversion, which is the cholesterol biosynthesis rate-determining step. 减少胆固醇的产生引起血流中LDL受体数目的增加和相应LDL浓度的降低。 Decreased production and increased cholesterol causes a corresponding decrease in the number of LDL receptors LDL concentrations in the blood. 血流中LDL水平的降低减轻了冠状动脉疾病的危险。 Reduce the level of LDL in the bloodstream reduces the risk of coronary artery disease. 参见JAMA 1984, 251,351-74。 See JAMA 1984, 251,351-74.

目前可用的他汀类包括洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、西立伐他汀和阿托伐他汀。 Currently available statins include lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin and atorvastatin statins. 洛伐他汀(/>开于美国专利4,231,938)和辛伐他汀(ZOCOR;公开于美国专利4,444,784和WO00/53566)以内酯形式给药。 Lovastatin (/> opening in U.S. Patent 4,231,938) and simvastatin (ZOCOR; disclosed in U.S. Patent No. 4,444,784 and WO00 / 53566) administered in the lactone form. 吸收后,内酯环在肝内通过化学水解或酶法水解打开,并产生活性羟酸。 After absorption, the lactone ring by chemical hydrolysis or enzymatic hydrolysis is opened in the liver, and the active hydroxy acid is generated. 普伐他汀(PRAVACHOL;公开于美闺专利4,346,227号)作为钠盐给药。 Pravastatin (PRAVACHOL; disclosed in U.S. Patent No. 4,346,227 Gui) is administered as the sodium salt. 氟伐他汀(LESCOL;公开于美国专利4,739,073号)和西立伐他汀(公开于美国专利5,006,530和5,177,080号) 也以钠盐形式给药,其完全是合成化合物,结构上与含一个六氢萘环的这种类型的真菌产物部分不同。 Fluvastatin (LESCOL; disclosed in U.S. Patent No. 4,739,073) and West cerivastatin (disclosed in U.S. Pat. Nos. 5,006,530 and No. 5,177,080) may also be administered in the form of sodium salt, completely synthetic compounds containing a hexahydronaphthalene structure different product fractions fungi of this type of ring. 阿托伐他汀和两种新的"超级他汀(superstatin)"罗苏伐他汀和匹伐他汀以钧盐形式给药。 Atorvastatin and two new "super statin (superstatin)" rosuvastatin and pitavastatin administered in the form of a salt Jun. 这些他汀的结构式如下: These statins structural formula is as follows:

M他汀辛伐他汀W他汀 M W statin statin simvastatin

ft伐他汀西立伐他汀 ft fluvastatin, cerivastatin Tingxi

阿M他汀罗苏伐他汀匹伐他汀 He Tingluo Su M A atorvastatin pitavastatin

阿托伐他汀是[R-(R、I^)]-2-(4-氟苯基)-P,S-二羟基-5-(l-甲基乙 Atorvastatin is [R- (R, I ^)] - 2- (4- fluorophenyl) -P, S- dihydroxy -5- (l- methylethyl

基)-3-苯基4-[(苯基氨基)羰基]-lH-吡咯-l-庚酸的通用化学名。 Yl) -3-phenyl-4 - [(phenylamino) carbonyl] -l- lH-pyrrolo common chemical name of heptanoic acid. 阿托 Alto

伐他汀游离酸易于内酯化。 Atorvastatin free acid lactone of easy. 阿托伐他汀内酯的系统化学名为(2R-反)- The system atorvastatin lactone chemical name (2R- trans) -

5-(4-氟苯基)-2-(1-甲基乙基)^,4-二苯基-1-[2-四氢斗羟基-6-氧代-211- 5- (4-fluorophenyl) -2- (1-methylethyl) ^, 4-diphenyl-1- [2-hydroxy-6-oxo-tetrahydro-arm -211-

吡喃-2-基]乙基]-lH-吡咯-3-曱酰胺。 Pyran-2-yl] ethyl] Yue lH-pyrrole-3 carboxamide. 阿托伐他汀和其相应的外消旋内酯公开于美国专利4,681,893。 Atorvastatin and its corresponding racemic lactone are disclosed in U.S. Patent No. 4,681,893.

所迷内酯形式^^开于美国专利5,273,995号。 The lactone form ^^ fan opening in U.S. Patent No. 5,273,995. 在'995专利的实施例4和5中,所迷内酯如下制备:将(RH-[2-(4-氟苯基)-5-(l-甲基乙基)-3-苯基-4-[(苯基^J0絲HH-吡咯-l-基】-5-羟基-3-氧代-l-庚酸1,1-二曱基乙酯溶解于四氢呋喃和三乙基曱硼烷中,接着加入叔丁基曱酸。冷却后,加入曱醇并接着加入硼氢化钠。将混合物倒入到水/ 过氧化氢/水混合物中。加入三氯甲烷并将混合物进行分配.有机层经硫酸4美干燥、过滤、并蒸发掉溶剂。将产物溶解于四氢呋喃和甲醇中并加入到氢氧化钠溶液中。将混合物浓缩除去有机溶刑,加入到水中并用乙醚萃取。水层用盐酸酸化并用乙酸乙酯萃取,有机层经无水硫酸镁干燥、过滤并蒸发掉溶剂。将残渣溶解于曱苯中并浓缩。将产物从乙酸乙酯和己烷重结晶而产生内酯。 In the '995 patent in Examples 4 and 5, the fan lactone prepared as follows: (RH- [2- (4- fluorophenyl) -5- (l- methylethyl) -3-phenyl - 4 - [(phenyl-pyrrolidin ^ J0 wire HH- yl} -l- hydroxy-3-oxo-heptanoic acid 1,1-Yue -l- yl ethyl ester was dissolved in tetrahydrofuran and triethyl borane Yue followed by addition of t-butyl Yue acid. after cooling, Yue alcohol and followed by the addition of sodium borohydride. the mixture was poured into water / hydrogen peroxide / water mixture was added chloroform and the mixture was partitioned. the organic layer was US 4 dried over sulfate, filtered, and the solvent was evaporated. the product was dissolved in tetrahydrofuran and methanol and added to a solution of sodium hydroxide. the mixture was concentrated to remove the organic solvent sentence, added to water and extracted with ether. the aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. the residue was dissolved in benzene Yue and concentrated. the product was recrystallized from ethyl acetate and hexane to produce the lactone.

所述内酯也可按照公开于美国专利5,003,080号中的方法制备。 The lactone can also be prepared according to the method disclosed in the U.S. Patent No. 5,003,080. 例如,在实施例2方法A中,将顺-2-(4-氟苯J0-P,5-二羟基-5-(l-曱基乙基)-3-苯基-4-(苯基氨基)絲-lH-吡咯-l-庚酸甲酵用氢氧化钠处理,并在用水稀释和分离后,将剩余层用己烷和乙酸乙酯.洗涤并接着用浓盐酸溶液洗涤。分离后,上层用盐酸洗涤并浓缩.将残渣溶解于甲苯中。 For example, in Example 2, Method A, the cis-2- (4-fluorophenyl J0-P, 5- dihydroxy -5- (l- Yue-yl) -3-phenyl-4- (phenyl amino) -l- wire -lH- pyrrole-heptanoic acid a fermentation treatment with sodium hydroxide, and after dilution with water and separation, the remaining layer was washed with hexane and ethyl acetate, washed and then washed with a solution of concentrated hydrochloric acid. after separating , the upper layer was washed with hydrochloric acid and the residue was dissolved in toluene and concentrated.

正如'080专利中所公开的那样,内酯也可通过(±)-顺-6-(2-^ 乙基)-2,2-二甲基-l,3-二嚼烷-4-乙酸(实施例2,方法B); (士)-(2a,4a,6a) 或(±)-(200,邻,6卩)-6-(2-絲乙基)-2-苯基-1,3-二嗨烷-4-乙酸(实施例2, 方法C); (土)-顺-9-(2-氨基乙基)-6,10-二氧杂螺[4.5]癸烷-7-乙酸(实施例2,方法D); (±)-顺-(4-(2-狄乙基)-1,5-二氧杂螺[5.5]十一烷-2-乙酸(实施例2,方法E);或(土)-(2a,4a,6a)或(土)-(2a,4!3,6p)-6-(2-氩基乙基)-2-曱基-l,3-二囉烷-4-乙酸(实施例2,方法F或G)与(士)-4-氟-a-[2-甲基-1 -氧代丙基]个氧代-N,p-二苯基苯丁酰胺在二曱基亚砜中混合来 As the '080 patent disclosed above, it can also be a lactone (±) - cis -6- (2 ^ ethyl) -2,2-dimethyl -l, 3- two chewing-4-acetic acid (Example 2, method B); (Shi) - (2a, 4a, 6a) or (±) - (200, o, 6 Jie) -6- (2-wire) -2-phenyl-1 , Hi-4-3-acetic acid (Example 2, method C Example); (soil) - cis -9- (2-aminoethyl) -6,10-dioxaspiro [4.5] decane -7 - acetic acid (Example 2, method D Example); (±) - cis - (4- (2-Di-ethyl) -1,5-dioxaspiro [5.5] undecane-2-acetic acid (Example 2 , method E); or (earth) - (2a, 4a, 6a) or (soil) - (2a, 4 3,6p) -6- (2- argon-yl) -2-Yue-yl -l,! La-4-3-acetic acid (Example 2, method F or G) was reacted with (persons) -4-fluoro -a- [2- methyl-1 - oxopropyl] oxo -N, p - butyramide diphenylbenzene in diethyl sulfoxide mixing Yue

制备。 preparation. 加热后,将溶液倒入到乙醚和饱和氯化铵水溶液的混合物中。 After heating, the solution was poured into a mixture of ether and aqueous saturated ammonium chloride. 分离后,有机层用水和氢氧化钠洗涂,水层用稀盐酸酸化并用乙酸乙酯萃取,向其中加入盐酸并将溶液浓缩。 After separation, the organic layer was washed with water and sodium hydroxide wash coating, the aqueous layer was acidified with dilute hydrochloric acid and extracted with ethyl acetate, and the solution was concentrated hydrochloric acid was added thereto. 将残渣溶解于曱苯中。 The residue was dissolved in benzene Yue.

按照'080专利,另一种制备内酯的方法包括将(土)-顺-l,l-二甲基乙基-6-(2-絲乙基)-2,2-二曱基-1,3-二嗯烷~4-乙酸酯(实施例2,方法H); (±)-(201,401,600或(±)-(200,4|3,6|3)-1,1-二甲基-6-(2-氨基乙基)-2-苯基-1,3-二嚼烷~4-乙酸酯(实施例2,方法I);或(土)-顺-l,l-二甲基乙基-(4-(2-氨基乙基)-1,5-二氧杂螺[5.5]十一烷-2-乙酸酯(实施例2,方法J)与(士)-4-氟-01-[2-曱基-l-氧代丙基]个氧代-N,(3-二苯基苯丁酰胺在庚烷:甲苯(9:1)中混合,加热后,将溶液倒入到四氢呋喃和氯化铵水溶液的混合物中。分离后,有机层用盐水洗涤,接着加入盐酸。搅拌后,将氢氧化钠加入到有机层中。通过加入水和己烷的混合物停止反应。分离后,水层用稀盐酸酸化,用乙酸乙酯萃取并浓缩。将残渣溶解于曱苯中。 Accordance with the '080 patent, another method includes preparing lactone (soil) - cis -l, l- dimethylethyl 6- (2-wire-ethyl) -2,2-dimethyl-1 Yue , 3-dioxane ~ ah 4-acetate (Example 2, method H Example); (±) - (201,401,600, or (±) - (200,4 | 3,6 | 3) -1,1- dimethyl-6- (2-aminoethyl) -2-phenyl-1,3-dioxane chewing ~ 4-acetate (Example 2, the I method); or (earth) - cis -l, l- dimethylethyl - (4- (2-aminoethyl) -1,5-dioxaspiro [5.5] undecane-2-acetate (Example 2, method J) and (Shi ) -4-fluoro -01- [2- yl Yue -l- oxopropyl] oxo -N, (3- diphenylbenzene butyramide heptane: 1: toluene (9) were mixed and heated after the solution was poured into a mixture of tetrahydrofuran and aqueous ammonium chloride. after separation, the organic layer was washed with brine, followed by addition of hydrochloric acid. after stirring, sodium hydroxide is added to the organic layer. the mixture was added by water and hexane after the reaction was stopped. separated and the aqueous layer was acidified with dilute hydrochloric acid and extracted with ethyl acetate and concentrated. the residue was dissolved in benzene Yue.

所迷内酯或游离酸可用于制备药学上可接受的钧盐[11-(1^,11*)】-2-(4-氟苯基)-P,S-二羟基-5-(1-曱基乙基)-3-苯基4-[(苯基氨基)羰基]-1H-p比咯-l-庚酸钙盐(2:l)三水合物。 The fan may be a free acid or lactone used to prepare pharmaceutically acceptable salts Jun [11- (1 ^, 11 *)] - 2- (4-fluorophenyl) -P, S--dihydroxy-5- (1 - Yue-yl-ethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1H-p -l- pyrrole-heptanoic acid calcium salt (2: l) trihydrate. 在动物模型中,阿托伐他汀钧盐显示出通过抑制肝中HMG-CoA还原酶和胆固醇合成降低血浆胆固醇和脂蛋白水平。 In animal models, atorvastatin salt Jun showed the liver by inhibiting HMG-CoA reductase and cholesterol synthesis lowering plasma cholesterol and lipoprotein levels. 阿托伐他汀以半钩盐三7jc合物形式由PFIZER以LIPITOR的商品名以10、 20、 40和80 mg片剂推向巿场。 Atorvastatin semi hook salt thereof in the form of three 7jc trade name LIPITOR 10, 20, 40 and 80 mg tablets of the market into PFIZER. 阿托伐他汀半钙盐具有下面结构: Atorvastatin hemi calcium salt has the following structure:

<formula>formula see original document page 9</formula>所述半钓盐/>开于美国专利5,273,995号,所述专利指出钙盐可通过用氯化钙与钠盐换位而从盐水溶液中结晶并经从5:3的乙酸乙酯和己烷混合物中重结晶进一步纯化来获得。 <Formula> formula see original document page 9 </ formula> the fishing half salt /> disclosed in U.S. Patent No. 5,273,995, the patent teaches that the calcium salt can be crystallized from an aqueous salt solution with calcium chloride and sodium transposition and by the 5: 3 mixture of ethyl acetate and hexane to obtain further purified by recrystallization.

美国专利5,298,627号也公开了制备半钾盐的方法。 U.S. Patent No. 5,298,627 also discloses a process for preparing a half potassium salt. 在该专利的实施例l中,将(4R-顺H-[2-[6-[2-(二苯基綠)-2-氧代乙基]-2,2-二甲基-l,3-二螺烷-4-基]乙基]-5-(4-氟苯基)-2-(1-曱基乙基)^,4-二苯基-m-吡咯-3-甲酰胺溶解于甲醇中并与盐酸反应形成[11-(11*,11*)】-5-(4-氟苯基)-卩,5-二羟基-2-(1-曱基乙基)-1^凡4-三苯基-3-[(苯基#^)絲〗-1H-吡咯-l-庚酰胺,其与甲醇和氢氧化钠混合。将滤液用叔丁基曱基酯洗涤,水层用含水盐酸酸化并用叔丁基曱基酯萃取而形成[R-(R,R"〗-2-(4-氟苯基)-(3,S-二羟基-5-(l-曱基乙基)-3-苯基4-[(苯基^J0 In this embodiment patent l, the (4R- cis H- [2- [6- [2- (diphenyl green) -2-oxoethyl] -2,2-dimethyl -l, 3-spiro-4-yl] ethyl] -5- (4-fluorophenyl) -2- (1-ethyl Yue-yl) ^, 4-phenyl-pyrrole-3-carboxamide -m- dissolved and formed [11- (11 *, 11 *)] the reaction with hydrochloric acid in methanol - 5- (4-fluorophenyl) - Jie, 5-hydroxy-2- (1-Yue-yl-ethyl) -1 Where a ^ 4-tris-phenyl-3 - [(# ^ phenyl) -1H- pyrrole-wire〗 -l- enantholactam, mixed with methanol and the filtrate was washed with sodium t-butyl ester Yue, water. Yue layer tert-butyl ester formed was extracted with [R- (R, R "〗 acidified with aqueous hydrochloric acid and - 2- (4-fluorophenyl) - (3, S- dihydroxy -5- (l- yl Yue ethyl) -3-phenyl-4 - [(phenyl ^ J0

羰基]-m-吡咯-i-庚酸的钠盐。 Carbonyl] -m-heptanoic acid sodium salt-pyrrolo -i-. 通过加入乙酸辆水溶液将钠盐转化成 Aqueous vehicle by adding acetic acid converted to the sodium salt

半钙盐。 Hemi-calcium salt.

在一种类似方法中,(4R-顺)-6-(2-氨基乙基)-2,2-二甲基-N,N-二(苯基曱基)-l,3-二嗯烷斗乙,被转化成[R-(R、R"]-5-(4-氟苯基)-p,S-二羟基-2-(1-甲基乙基M-苯基-3-[(苯基氨基)羰基]-N,N-二(苯基甲基)-1H-吡咯-l-庚酰胺,其进一步被转化成半钙盐(实施例2); (4R-顺)-6-(2-氨基乙基)-N,N-二乙基-2,2-二曱基-1,3-二喊烷4-乙酰胺被转化成[R-(11*,11*)]-^^二乙基-5-(4-氟苯基)-(3,8-二羟基-2-(1-甲基乙基>4-苯基-3-[(苯基氨基)g]-lH-吡咯-l-庚酰胺,其进一步被转化成半钙盐(实施例3); (411-顺)-6-(2-#^乙基)-]^丁基-1^2,2-三甲基-1,3-二嗨烷-4-乙酰胺被转化成[R-(R、R"]-N-丁基-5-(4-氟苯基)-P,S-二羟基-N-甲基-2-(l-曱基乙基M-苯基-3-[(苯基氨基)羰基】-lH-吡咯-l-庚酰胺,其进一步被转化成半4^盐(实施例4);(収-顺)-6-p-氨基乙基)-N-(l,l-二甲基乙基)-2,2-二曱基-N-(苯基甲基)-1,3-二嗨烷4-乙酰胺被转化成[R-(R、R"]-N-(l,l-(二曱 In an analogous manner, (4R- cis) -6- (2-aminoethyl) -2,2-dimethyl -N, N- (phenyl Yue-yl) -l, 3- dioxane two ah bucket b, is converted to [R- (R, R "] - 5- (4- fluorophenyl) -p, S- dihydroxy-2- (1-methylethyl M- phenyl-3- [ (phenylamino) carbonyl] -N, N- bis (phenylmethyl) -l- lH-pyrrole-heptanoic acid amide, which is further converted to the hemicalcium salt (Example 2); (4R- cis) -6 - (2-aminoethyl) -N, N- Yue-diethyl-2,2-dioxane-1,3-4- call acetamide is converted to [R- (11 *, 11 *)] - ^^ diethyl-5- (4-fluorophenyl) - (3,8-dihydroxy-2- (1-methylethyl> 4-phenyl-3 - [(phenylamino) G] -lH- pyrrole -l- heptanamide which is further converted to the hemicalcium salt (Example 3); (411- cis) -6- (2 - ethyl ^ #) -] ^ 2 ^ butyl-1, 2-trimethyl-1,3-Hi-4-acetamide is converted to [R- (R, R "] - N- butyl-5- (4-fluorophenyl) -P, S- dihydroxy -N- methyl -2- (l- ethyl Yue M- phenyl-3 - [(phenylamino) carbonyl] -lH- pyrrole -l- heptanamide which is further converted to a semi ^ 4 salt (Example 4); (yield - cis) -6-p- aminoethyl) -N- (l, l- dimethylethyl) -2,2-Yue-yl -N- (phenylmethyl yl) -1,3-dioxane Hi 4- acetamide is converted to [R- (R, R "] - N- (l, l- (two Yue 基乙基)-5-(4-氟苯基)-p,S-二羟基-2-(l-甲基乙基M-苯基-3-[(苯基氨基)羰基]-N-(苯基曱基)-lH-败咯-l-庚酰胺,其进一步被转化成半钙盐(实施例5);以及(4R-顺)-l-[[6-(2-氨基乙基)-2,2-二曱基-1,3-二碟烷-4-基】-乙酰基]哌啶被转化成[11-(11*)11*)]-1-[3,5-二羟基-7-氧代-7-(l-哌啶基)庚基】-5-(4-氟苯基-2-(l-曱基乙基)-N-4-联苯基-lH-吡咯-3-甲酰胺,其进一步被转化成半钓盐(实施例6)。 Ethyl-yl) -5- (4-fluorophenyl) -p, S- dihydroxy -2- (l- methylethyl M- phenyl-3 - [(phenylamino) carbonyl] -N- ( Yue-yl-phenyl) -l- lH slightly lost heptanamide which is further converted to the hemicalcium salt (Example 5); and (4R- cis) -l - [[6- (2- aminoethyl) Yue-1,3-dimethyl-4-yl] Singles - acetyl] piperidine is converted to [11- (11 *) 11 *)] - 1- [3,5-bis hydroxy-7-oxo -7- (l-piperidinyl) heptyl] -5- (4-fluorophenyl -2- (l- Yue-yl-ethyl) -N-4- biphenylyl -lH- pyrrole-3-carboxamide which is further converted to a semi fishing salt (Example 6).

罗苏伐他汀是[8-[11*,3*-(£)]】-7-[4-(4-氟苯基)-6-(1-甲基乙基)-2-[曱基(曱基磺酰基)氨基]-5-嘧啶基]-3,5-二羟基-6-庚烯酸的常规化学名。 Rosuvastatin is [8- [11 *, 3 * - (£)]] --7- [4- (4-fluorophenyl) -6- (1-methylethyl) -2- [Yue-yl (Yue-ylsulfonyl) amino] -5-pyrimidinyl] conventional chemical name 3,5-dihydroxy-6-heptenoic acid of. 罗苏伐他汀正在以CRESTOR的商品名(含罗苏伐他汀锔)推向市场的审批过程中,罗苏伐他汀、其钙盐(2:1)及其内酯形式在美国专利5,260,440号中公开并要求得到专利保护。 The approval process is to rosuvastatin CRESTOR trade name (including rosuvastatin curium) to market in rosuvastatin, its calcium salt (2: 1) and its lactone form in US Patent No. 5,260,440 discloses and claims for patent protection. '440专利的方法通过在回流下使4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基氨基)-5-嘧啶甲搭与(3R)-3-(叔丁基二甲基甲硅烷氧基)-5-氧代-6-三苯基正膦亚基(phosphoranylidene)己酸曱酯在乙腈中反应制备罗苏,伐他汀,然后用氟化氢解离曱硅烷基,It^用NaBH4还原来获得罗苏伐他汀的甲酯。 '440 patent method by reacting at reflux 4- (4-fluorophenyl) -6-isopropyl -2- (N- methyl -N- methylsulfonyl) -5-pyrimidinecarboxylic acid and ride ( 3R) -3- (tert-butyldimethylsilyloxy) -5-oxo-6-ylidene triphenylphosphorane (phosphoranylidene) Yue hexanoic acid ester in acetonitrile was prepared rosuvastatin, atorvastatin, Yue then dissociated silyl group with hydrogen fluoride, It ^ with NaBH4 obtained by reduction of the methyl ester of rosuvastatin.

然后将所述酯在室温下用氢氧化钠在乙醇中水解,随后去除乙醇并加入醚而获得罗苏伐他汀的钠盐,然,用一个多步骤方法将钠盐转变成钙盐。 The ester is then hydrolyzed with sodium hydroxide in ethanol at room temperature, followed by removal of ethanol and addition of ether to obtain the sodium salt of rosuvastatin, however, use a multi-step process is converted into the calcium salt. 将钠盐溶解于水中并保持在氮气气氛下,然后将氯化钩加入到溶液中,得到罗苏伐他汀钩(2:1)的沉淀。 The sodium salt was dissolved in water and maintained under a nitrogen atmosphere, and then the hook chloride was added to the solution, to give rosuvastatin hook (2: 1) precipitate. 所以,'44Q专利的方法通过钠盐中间体制备罗苏伐他汀钩, Therefore, 'prepared by the method of the patent 44Q rosuvastatin sodium salt of Intermediate hook,

美国专利6,316,460号公开了一种罗苏伐他汀的药用组合物,所迷药用组令物包含罗苏伐他汀或其盐和多价三元磷酸盐.所迷'460 专利并未公开任何制备罗苏伐他汀的钙盐的方法。 U.S. Patent No. 6,316,460 discloses a rosuvastatin pharmaceutical composition, so that the group comprises drugged with rosuvastatin or a salt thereof and a polyvalent three yuan phosphate. The fans' 460 patent does not disclose any the method of rosuvastatin calcium salt of preparation.

匹伐他汀是(E)-3,5-二羟基-7-[4'-(4"-氟苯基)-2'-环丙基-喹啉-3'-基]-庚-6-烯酸的通用化学名。匹伐他汀、其钙盐(2:1)和其内酯公开于三个相关的美国专利5,011,930、 5,856,336和5,872,130号中。 Pitavastatin is (E) -3,5- dihydroxy-7- [4 '- (4' - fluorophenyl) -2'-cyclopropyl - quinolin-3'-yl] - hept-6 common chemical name pitavastatin acid, its calcium salt (2: 1) and its lactone are disclosed in three related U.S. Patent No. 5,011,930, No. 5,872,130 and 5,856,336.

所述'930专利按照实施例1制备匹伐他汀乙酯,首先通过使2-M-4'-氟二苯酮与异丁酰乙酸乙酯反应制备4<4'-氟苯基)-2'-(1'-环丙基)喹啉-3'-基羧酸酯,再转化成4-(4'-氟苯基)-3-雍曱基-2-(l'-环丙基) 壹啉,其再转化成44'-氟苯基-2-(1'-环丙基)-喹啉-3'-基甲醛,其再转化成3-(3'-乙氧基-l'-羟基-2'-丙烯基M-(4'-氟苯基)-2-(l'-环丙基)喹啉,其再转化成(E)-3-[4'-(4"-氟苯基)-2'-(l-环丙基)-喹啉-3'-基]丙烯醛,其再转化成(E)-7-[4-(4"-氟苯基-2'-(r-环丙基;Hir啉-3'-基)]-5-羟基-3-氧代庚-6-烯酸乙酯,其再转化成(E)-3,5-二羟基-7-[4'-(4"-氟苯基)-2'-(l"-环丙基)-##-3'-基】-庚-6-烯酸乙酯。 The '930 patent was prepared according to Example 1 pitavastatin ethyl ester by first making 2-M-4'- fluoro-benzophenone reaction with ethyl isobutyryl Preparation 4 4'-fluorophenyl <) -2 '- 4- (4'-fluorophenyl) (1'-cyclopropyl) quinolin-3'-yl-carboxylate, reconverted -3- Yong Yue-yl -2- (l'- cyclopropyl) One morpholine, which reconverted 44'--fluorophenyl-2- (1'-cyclopropyl) - quinolin-3'-yl carbaldehyde reconverted 3- (3'-ethoxy -l'- hydroxy-2'-propenyl M- (4'- fluorophenyl) -2- (l'- cyclopropyl) quinoline, which is then converted to (E) -3- [4 '- (4 "- fluoro phenyl) -2 '- (l- cyclopropyl) - quinolin-3'-yl] acrolein, which is then converted to (E) -7- [4- (4 "- fluorophenyl -2' (R- cyclopropyl; the Hir-3'-yl)] - 5-hydroxy-3-oxo-hept-6-enoic acid ethyl ester, which is then converted to (E) -3,5- dihydroxy-7 - [4 '- (4' - fluorophenyl) -2 '- (l "- cyclopropyl) - ## - 3'-yl] - hept-6-enoate.

按照实施例2,通过使用氢氧化钠水溶液将得到的酯一一(E)-3,5-二羟基-7-[4'-(4"-氟苯基)-2'-(l"-环丙基)-喹啉-3'-基】-庚-6-烯酸乙酯转化成钠盐。 2 in accordance with, by using an aqueous sodium hydroxide solution of the resultant ester (E) -3,5- dihydroxy-7- [Example eleven 4 '- (4' - fluorophenyl) -2 '- (l "- cyclopropyl) - quinolin-3'-yl] - hept-6-enoic acid ester is converted to the sodium salt. 将化合物溶解于乙醇中,向其中加入氢氧化钠水溶液。 The compound was dissolved in ethanol, and thereto is added aqueous sodium hydroxide. 搅拌得到的混合物并减压除去乙醇。 The mixture was stirred and ethanol was removed under reduced pressure. 加入水后,将混合物再用醚萃取。 After adding water, the mixture was extracted with ether. 然后将水层冻干获得终产物,或者将水层用稀盐酸溶液弱酸化。 The aqueous layer was then lyophilized to obtain the final product, or the aqueous layer was weakly acidified with dilute hydrochloric acid solution. 然后用醚萃取酸化的水层。 The aqueous layer was acidified and then extracted with ether. 萃取后,将醚层经硫酸镁干燥,然后减压除去醚获得钠盐。 After extraction, the ether layer was dried over magnesium sulfate, and then the ether was removed under reduced pressure to obtain a sodium salt. 所迷'930专利和其相关专利并未/^开任何化合物钙盐的制备。 The fans' 930 patent and its related patents No / ^ Preparation of calcium salt of any compound open.

这些专利如下制备内酯:将制备的钠盐溶解于无水曱苯中,回流溶液并减压除去甲苯。 These patents are as follows lactone: The sodium salt obtained was dissolved in anhydrous Yue benzene, toluene was removed under reduced pressure and the solution was refluxed. 然后将粗制固体从二异丙醚中重结晶获得内酯[4'-(4"-氟苯基)-2'-(1"-曱基乙基)喹啉-3'-基乙炔基H-羟基-3,4,5,6-四氢-2H-吡喃-2-酮。 The crude solid was then recrystallized from diisopropyl ether to obtain the lactone [4 '- (4' - fluorophenyl) -2 '- (1 "- Yue-yl ethyl) quinolin-3'-ylethynyl H- hydroxy-3,4,5,6-tetrahydro -2H- pyran-2-one. 在氮气气氛下用4G/碳进一步还原所述内酯, Further reduction of the lactone with the 4G / carbon under a nitrogen atmosphere,

.美国专利6,335,449号改善了制备匹伐他汀的现有技术方法,其通过使醛喹啉与氛曱基磷酸二乙酯反应来获得合成匹伐他汀用的腈中间体。 . U.S. Patent No. 6,335,449 to improve a prior art method of preparing pitavastatin, which is obtained pitavastatin nitrile intermediate synthetic statins by using an aldehyde quinoline with diethyl reaction atmosphere Yue phosphoric acid. 美国专利6,335,449并未/>开如何制备匹伐他汀的钩盐或其它盐。 US Patent No. 6,335,449 does not /> On how to prepare pitavastatin hook salt or other salts.

辛伐他汀是化合物丁酸2,2-二甲基-l,2,3,7,8,8a-六氢-3,7-二甲基-8-[2-(四氢4-羟基-6-氧代-2H-吡喃-2-基)-乙基萘酯[1S*-[la,3a,7b,8b(2S、4S),-8ab]】的通用化学名称。 Simvastatin is butanoic acid compound 2,2-dimethyl -l, 2,3,7,8,8a- hexahydro-3,7-dimethyl-8- [2- (tetrahydro-4-hydroxy - 6-oxo -2H- pyran-2-yl) - naphthalen-ethyl ester [1S * - [la, 3a, 7b, 8b (2S, 4S), - 8ab]] generic chemical name. (CAS注册号79902-63-9)。 (CAS Registry No. 79902-63-9). 辛伐他汀^ ZOCOR的名称推向市场,并且公开于美国专利4,444,784和6,002,021以及WO00/53566号.这些参考资料公开了内酯和开环形式的辛伐他汀的制备。 ^ ZOCOR simvastatin name market, and are disclosed in U.S. Patent No. 6,002,021 and 4,444,784 and WO00 / 53566. These references disclose preparing the lactone and open-ring form of simvastatin.

这些参考资料中,只有WO00/53566 />开了开环形式辛伐他汀钩盐的制备.在一典型的实施例中,WOOO/53566的方法用氢氧化钠水解辛伐他汀的内酯,接着加入钩源如乙酸钩水合物。 These references, only WO00 / 53566 /> open ring-opening hook salts prepared form simvastatin. In an exemplary embodiment, the method of WOOO / 53566 of simvastatin lactone hydrolysis with sodium hydroxide, followed by hook hook acetic acid was added as a hydrate source.

制备他汀诸如阿托伐他汀、匹伐他汀、罗苏伐他汀和辛伐他汀的钙盐的上述现有技术方法均未公开如何制备钩盐或者通过钠盐中间体制备钙盐。 Preparing statins such as atorvastatin, pitavastatin, calcium salts of the above-described prior art methods rosuvastatin and simvastatin no disclosure of how to make the hook or by the sodium salt intermediates prepared calcium salts. 此外, 一些方法高度敏感并且不能始终重复,对于大规模生产而言,具有不合需要的过滤和干燥步骤.因此需要有可容易重复和适合大规模生产的方法以比现有技术方法更少的步骤荻得稳定产物。 In addition, some methods are highly sensitive and can not always be repeated, for large scale production, the filtration and drying steps having undesirable. There is a need and a method suitable for mass production easily repeatable with step less than the prior art methods Di to obtain a stable product.

本发明简述 Description of the present invention

本发明提供了一种制备具有下式的他汀鈣盐的新方法: The present invention provides a method of preparing the new calcium salt of formula statin having:

与足量的氢氧化钩反应, 其中R,为C广Cg烷基, Is reacted with a sufficient amount of hydroxide hook, wherein R, is a C wide Cg alkyl,

R2、 R3和R4各独立地代表氢、或者相同或不同的可水解保护基, R2, R3 and R4 each independently represents hydrogen or the same or different hydrolyzable protecting group,

或者&和R3与其各自连接的氧原子一起形成可7jC解环状保护基。 Solutions 7jC forming a cyclic protective group, or together with R3 and & respective oxygen atom attached thereto. 所述反应可在有或没有相转移催化剂的存在下进行。 The reaction may be with or without the presence of a phase transfer catalyst. 优选的相 Preferred phase

式中R代表有机基团, 该方法包括使选自下面的他汀的酯l汴生物: Wherein R represents an organic group, which comprises reacting the statin selected from esters of l Bian organisms:

OR2 OR3 O转移催化剂是季铵盐诸如四丁基溴化铵(TBAB)和三乙基爷基氯化铵(TEBA)。 OR2 OR3 O transfer catalyst is a quaternary ammonium salt such as tetrabutylammonium bromide (TBAB) and triethyl ammonium chloride Ye (TEBA). 所ii^应优选加热来促进转化。 Ii ^ The heating should preferably promote the conversion.

优选的他汀为阿托伐他汀、罗苏伐他汀、匹伐他汀和辛伐他汀。 A preferred statin is atorvastatin, rosuvastatin, pitavastatin and simvastatin.

在优选的实施方案中,R2、 Rs和R4为氢。 In a preferred embodiment, R2, Rs and R4 are hydrogen. 各R;z、 R3或R4也可以是 Each R; z, R3 and R4 may be

相同或不同的保护基,其可通过使用氢氧化4丐与酯基即-COOR,的水解一步水解,或通过使用酸催化剂水解后进行酯基-COOR,的水解. 优选的保护基是甲硅烷基诸如三烷基甲硅烷基(其可通过氢氧化钙水解)和丙酮化合物(其可通过酸催化剂水解),丙酮化合物形成环状可水解保护基即二瞎烷。 The same or different protecting groups, which may hydroxide 4 Hack ester group -COOR by using i.e., the hydrolysis step hydrolysis, or acid hydrolysis using a catalyst by ester group -COOR after hydrolysis. Preferred protecting groups are silyl group such as a trialkylsilyl group (which may be hydrolyzed by calcium hydroxide) and acetonide (which can be hydrolyzed by an acid catalyst), may form a cyclic acetonide protecting group that is hydrolyzable alkoxy two blind.

在另一方面,本发明提供了一种制备具有下式的他汀的钩盐的方法: In another aspect, the present invention provides a method of preparing the formula hook statin salt having:

OH OH O OH OH O

式中R代表有机基团, 该方法包括下述步骤: Wherein R represents an organic group, the method comprising the steps of:

将氢氧化钙和如上所述的他汀的酯衍生物加入到水和C广C4醇的混合物中,加热混合物,沉淀出他汀的钩盐并分离钩盐。 Calcium hydroxide as described above and the statin ester derivative is added to the mixture wide C4 alcohols and C in water, heating the mixture, precipitated statins hook hooks salt and isolating the salt.

本发明详述 Detailed Description of the invention

形成酯是人们熟悉的保护羧酸基和遮蔽其酸质子的方法。 Forming esters are familiar protecting group and masking its carboxylic acid proton methods. 参见Green, TW; Wuts, PGM Protective Groups in Organic Synthesis第三版,第5章(John Wiley & Sons: New York 1999) ("Greene & Wuts"). 人们也通常知道作为酯被保护的羧酸可通过用强碱水解酯来脱保护。 See, Green, TW; Wuts, PGM Protective Groups in Organic Synthesis Third Edition, chapter 5 (John Wiley & Sons: New York 1999). ( "Greene & Wuts") It is also commonly known as the carboxylic acid ester can be protected by hydrolysis of the ester with a strong base to deprotection. 参见上述文献377-378页。 See the above-mentioned document pages 377-378.

氢氧化钠是一种具有6.37的解离常数(pKb = -0.80)的强碱,参见化学和物理手册81版845页(CRC出版社:Boca Raton 2000-01), 其作为被酯保护的羧酸的脱保护试剂的用途在本领域已有人说明。 Sodium hydroxide is a strong base solution having a dissociation constant of 6.37 (pKb = -0.80), see Handbook of Physics and Chemistry Edition 81 845 (CRC Press: Boca Raton 2000-01), as the protected carboxy ester use of an acid deprotecting reagent in the art it has been described. 参见所述Green & Wuts笫377页。 See the Green & Wuts 377 Zi. 具有3.74 x 10-3 (pK^2.43)的第一解离常数和4.0xl(T2 (pK^1.40)的第二解离常数的氢氧化钙(Ca(OH)2)是比氢氧化钠弱得多的碱。参见63版的化学和物理手册D-170 (CRC出版社:Boca raton 1983)。有机合成领域中在人们熟悉的官能团转换概要中氢氧化钙并未列在用于水解酯的试剂之中。参见第2版LarockR.C.的Comprehensive Organic Transformations,腈、羧酸和衍生物部分,9.17节的1959-1968 页(Wiley-VCH: New York 1999)。在已知的关于保护和脱保护有机官能团的参考文献中,并未描述其作为被酯保护的羧酸的通用脱保护试剂的应用。参见所述Greene & Wuts的377-379页。事实上,美国专利5,273,995号提醒反对使用过量氢氧化钠来制备钠盐以防止在以后将氯化钩加入到钠盐溶液中时形成氬氧化钾。其似乎没有认识到酯保护形式的他汀诸如阿托伐他汀可直接转化成各自的半钙盐诸如阿托伐他汀半钙盐,没有首 Solutions of the first 3.74 x 10-3 (pK ^ 2.43) and having a dissociation constant 4.0xl second solution (T2 (pK ^ 1.40) the dissociation constant of calcium hydroxide (Ca (OH) 2) is weaker than sodium see much Chemistry and Physics Handbook base plate 63 D-170 (CRC Press: Boca raton 1983).. in the art of organic synthesis familiar outline of functional group transformation of calcium hydroxide is not listed for the hydrolysis of an ester . 2nd ed. see reagent among the LarockR.C Comprehensive Organic Transformations, nitriles, carboxylic acids and derivatives, section 9.17 of page 1959-1968 (Wiley-VCH: New York 1999) and on the protection of the known. deprotecting organic functional group references, which are not described in general use as the carboxylic acid deprotecting agent protected ester. the see Greene & Wuts, page 377-379. in fact, U.S. Patent No. 5,273,995 to remind prepared against sodium hydroxide as argon to prevent the formation after the hook when sodium chloride was added to an excess of sodium hydroxide solution. it does not appear to recognize the protected form of the statin ester such as atorvastatin can be converted directly to the respective the hemi-calcium salt such as calcium salt of atorvastatin and a half, not the first 用强碱象氬氧化钠处理酯来使其水解, 然后通过使钠盐与钙盐诸如氯化钙或乙酸辆接触来置换钠离子。此中所用的术语"酯衍生物"是指用通过碳键合到羟基氧原子的取代基置换开环或二羟基酸形式他汀中羧酸基的羟基质子而荻得的化合物.这种酯衍生物包括例如键合到所缘羧酸的幾基氧的取代基为C广CV烷基的化合物。用于转化的酯衍生物可以是含各种酯的衍生物的混合物。例如曱酯衍生物可加入到乙醇中,使一些曱酯转变成乙酯。所迷他汀的酯衍生物可通过本领域人们熟悉的方法制务或可购置。所述醋衍生物也包括他汀的内酯或闭环形式。所述内酯形式是一种环酯,其中他汀的酯基并入到环中。酯衍生物的混合物也包括开环和闭环形式他汀的混合物。本发明涉及具有下面通式的他汀:<formula>formula see original document page 15</formula>其中一个有机基团R连 With a strong base such as sodium hydroxide treatment argon hydrolyzed esters, and then by replacing sodium ions with a calcium salt such as calcium chloride or sodium acetate contacting vehicles. As used herein, the term "ester derivative" refers to a carbon by a a hydroxyl group bonded to an oxygen atom replaced with a substituent hydroxyl proton ring opening or dihydroxy carboxylic acid form of the statin group and a compound obtained Di such ester derivatives include, for example, is bonded to the edge of the carboxylic acid groups of several oxygen compound C CV wide alkyl substituents. the ester derivatives used for the conversion can be a mixture containing various ester derivatives. Yue e.g. ester derivative may be added to ethanol to make some Yue into ethyl acetate. the fan statin ester derivative may be prepared by the process of service or purchase familiar in the art. the derivative also includes the lactone or vinegar closed form of statins. the lactone form is a cyclic ester, wherein the statin ester group is incorporated into the mixture of cyclic ester derivatives also includes a mixture of open and closed loop form of the present invention is directed to statins having the general formula statin:.. <formula> formula see original document page 15 </ formula> wherein one of the organic the radicals R attached 到二羟基-戊酸基上。这些他汀包括例如普伐他汀、氟伐他汀、西立伐他汀、阿托伐他汀、罗苏伐他汀、匹伐他汀、洛伐他汀和辛伐他汀。其中优选阿托伐他汀、罗苏伐他汀、 匹伐他汀和辛伐他汀。R是指键合到二羟基戊^的有机基团。 根据他汀的种类,所述R基团可以是:普伐他汀:1,2,6,7,8,8a-六氪-6-羟基-2-曱基-8-(2-曱基-l-氧代丁氧基)-l-萘乙基。 The dihydroxy -. These valeric acid group include, for example statins pravastatin, fluvastatin, statin cerivastatin, atorvastatin, rosuvastatin, pitavastatin, lovastatin and simvastatin are preferred . atorvastatin, rosuvastatin, pitavastatin and simvastatin .R means bonded to the dihydroxy-pentyl ^ organic group according to the type of statin, the R radical can be: pravastatin: 1,2,6,7,8,8a- six Yue krypton hydroxy-2-8- (2-oxo Yue -L-yl-butoxy) -L-naphthylethyl. 氟伐他汀:3-(4-氟苯基)-l-(l-甲基乙基)-lH-吲咮-2-基]-乙烯基。 Fluvastatin: 3- (4-fluorophenyl) -l- (l- methylethyl) NEB lH-indazol-2-yl] - vinyl. 西立伐他汀:4-(4-氟苯基》5-甲氧基甲基)-2,6-二(1-甲基乙基)-3-吡啶-乙烯基。 West cerivastatin: 4- (4-Fluorophenyl "5- methoxymethyl) -2,6-bis (1-methylethyl) -3-pyridine - vinyl. 阿托伐他汀:2-(4-氟苯基)-5-(1-甲基乙基)-3-苯基4-[(苯基^J0 皿]-lH-吡咯乙基。罗苏伐他汀:[4-(4-氟苯基)-6-(1-甲基乙基)-2-[曱基(甲基磺酰基) 細-5陽嘧錄]-乙烯基。匹伐他汀:[4'-(4"-氟苯基)-2'-环丙基-全啉-3'-基]乙烯基。所述R基也可以是开环形式,即辛伐他汀或洛伐他汀的二羟基酸。这些开环形式也具有二羟基戊酸基。此中所用的术语辛伐他汀和洛伐他汀包括内酯形式和开环形式。当所述他汀为辛伐他汀或洛伐他汀时,所迷R基团为;辛伐他汀:1,2,6,7,8,8a-六氯-2,6-二曱基-8-(2,2-二甲基-l-氧代丁輔-l-萘乙基'洛伐他汀:1,2,6,7,8,8a-六氬-2,6-二曱基-8-(2-曱基-l-氧代丁氧基)-l-萘乙基,种种他汀的钙盐可通过本发明的方法制备,结合到二羟基戊酸基或相应的内酯的有机基团定义了身为他汀的化合物,即抑制3-羟基-3-甲基戊二酰辅酶A("HMG-CoA")还原酶的化合物。参见例 Atorvastatin: 2- (4-fluorophenyl) -5- (1-methylethyl) -3-phenyl-4 - [(phenyl ^ J0 dish] ethyl-lH-pyrrolo rosuvastatin statins: [4- (4-fluorophenyl) -6- (1-methylethyl) -2- [Yue-yl (methylsulfonyl) -5 fine male pyrimidin record] - vinyl pitavastatin: [4 '- (4' - fluorophenyl) -2'-cyclopropyl - full-3'-yl] vinyl the R group may also be in the form of an open loop, i.e. lovastatin or simvastatin dihydroxy acid. the ring-opened dihydroxy acid form also has a group. as used herein the terms simvastatin and lovastatin include lactone and open-ring form form when the statin is simvastatin or lovastatin when the R group is lost; simvastatin: 1,2,6,7,8,8a- hexachloro-2,6-Yue-8- (2,2-dimethyl -l- oxo oxobutyric auxiliary -l- naphthylethyl 'lovastatin: 1,2,6,7,8,8a- six argon-2,6-Yue-8- (2-oxo-butyl -l- yl Yue oxy) -L-naphthylethyl, various statin calcium salts may be prepared by the method of the present invention, coupled to the dihydroxy acid corresponding to a lactone group or an organic group as defined statin compound, which inhibits 3 - compound reductase hydroxy-3-coenzyme a ( "HMG-CoA") see Example. WO00/53566。因此,不应将R理解为限于键合到此中所公开或例举的他汀的二羟基戊酸基或相应内酯的有机基团。这些他汀的钓盐的所有水合物、溶剂合物和非水合物及其其它多晶型、晶体或无定形物均在本发明的范围内。本发明通过使用阿托伐他汀半钙的制备作为例子说明这些他汀的钙盐的制备。就阿托伐他汀半钾的制备在某些方面不同于另一种他汀的制备而言,本领域技术人员会理解阿托伐他汀只是被用作说明;可容易地修改制备阿托伐他汀半钙的各个方面来制备其它他汀, 而其仍在本发明的宗旨和范围内。本发明提供了一种制备他汀半钙盐的方法,该方法通过使下式的他汀酯矛汙生物:(式中R代表有机基团,R!为CVQ烷基)与足量的氢氧化钙接触,将所述酯衍生物转变成具有下式OH OH O的相应半钙盐.此中所用的术语"足量"是指氢氧化钙的基本上能将 WO00 / 53566. Thus, R should not be construed as limited to this bonding disclosed or exemplified statin dihydroxy acid corresponding to a lactone group or an organic group. All of these hydrates fishing statin salts, solvates and hydrates thereof, and other non-polymorphic, crystalline or amorphous substance of the present invention are within the scope of the present invention is prepared by statins atorvastatin hemi-calcium was prepared using the calcium salt of these statins explained as an example. statins atorvastatin prepared on potassium half in some respects from another preparation of statins, those skilled in the art will appreciate that atorvastatin is used as just described; may be readily modified half atorvastatin prepared various aspects of calcium to the preparation of other statins, while it is still within the spirit and scope of the invention. the present invention provides a process for preparing a statin hemi-calcium salt, by reacting the statin ester of formula spear fouling organisms :( formula R represents an organic group, R! CVQ is an alkyl group) into contact with a sufficient amount of calcium hydroxide, to convert the ester derivative to the corresponding hemi-calcium salt having the formula OH OH O's. as used herein, the term "foot amount "refers to calcium hydroxide can substantially 迷酯衍生物转变成相应半钙盐的量。此中所用的术语"基本上转化"是指将大于约50%(摩尔)、优选大于约70%(摩尔),更优选大于约90%(摩尔)的他汀酯衍生物转化成半钓盐的这样一个量。最优选将大于约95%的他汀酯衍生物转变成相应的半钩盐。本方法一个令人惊异的优点是氢氧化钩起到了两种作用。它起到了作为用于酯水解的碱性催化剂的作用和提供形成半钩盐所需辆离子的作用。本发明另一明显的实际优点是氢氧化钙的量并不需要如用于与本发明不同的其它方法中的氩氣化钠和氯化钩/乙酸钩的量那样小心控制,所迷其它方法涉及用NaOH水解酯衍生物并接着用4丐离子置换钠离子的连续过程。 Fans ester derivative into the corresponding hemi-calcium salt in an amount. As used herein, the term "substantially transformation" refers to greater than (mole) to about 50%, preferably greater than (mole) to about 70%, more preferably greater than about 90% ( mol) of the statin ester derivative he converted into a half amount of such salts fishing most preferably greater than about 95% of the statin ester derivative is converted to the corresponding half-hook salt advantage of this method is that a surprising hooked hydroxide to two effects. it plays a role as a basic catalyst for ester hydrolysis, and is formed to provide the desired effect vehicle ions half hook salts. another significant practical advantage of the present invention, the amount of calcium hydroxide is not required, such as argon gas and an amount of sodium chloride hook / hook acid with other methods of the present invention, as different from the carefully controlled, the fans other methods involve continuous replacement of sodium ions and then with NaOH hydrolysis of the ester derivative of 4 ion cai process. 所述他汀酯衍生物可以纯形式或以与其它他汀酯4汙生物的混合物形式提供。 The statin ester derivative may be provided in a pure form or with other statin ester 4 mixture of fouling organisms. 将任选以与其它他汀酯衍生物的混合物形式的他汀酯衍生物优选溶解或悬浮于包括(VC4醇和水的混合溶剂中。优选的醇是乙醇和异丙醇("IPA"),优选的溶剂混合物为在乙醇或IPA中包含约5-15 %水,更优选含约10%水和约卯。/o乙醇(v/v)或IPA。他汀酯衍生物是否溶解于混合溶剂中取决于各种因素如C广Q醇的选择、水的比例、温度和他汀酯衍生物的纯度。然后将氢氧化钓悬浮于溶剂中,保持碱水解反应混合物直到他汀酯衍生物消耗完毕。他汀酯衍生物的消耗可通过任何常规的方法诸如TLC、 HPLC和NMR监测。 他汀酯衍生物消耗后,通过常规方法从所述碱水解反应混合物回收他汀半钙。对于阿托伐他汀半钙盐来说,不需要加入另一种钾源来提供Ca2+离子。按照实施碱水解方法的优选步骤,所述他汀酯衍生物以足以提供约10毫摩尔/升混合溶剂到约1摩尔/升混合溶剂的量加 He, optionally in admixture with other statin ester derivative dissolved or suspended in comprising (VC4 mixed solvent of alcohol and water. Preferred alcohols are ethanol and isopropyl alcohol ( "IPA") preferred statin ester derivative, preferably the solvent mixture comprises from about 5-15% water in ethanol or IPA, and more preferably from about 10% water, and about d ./o ethanol (v / v) or IPA. statin ester derivative depends on whether each dissolved in a mixed solvent a variety of factors such as the C wide Q alcohols selection, the proportion of water, temperature and his purity statin ester derivative is then hydroxide fishing suspended in a solvent, to maintain alkaline hydrolysis reaction mixture until the statin ester derivative was consumed. statin ester derivative consumption may be such as TLC, HPLC and NMR monitored by any conventional method. after consumption of the statin ester derivative, the reaction solution by a conventional method from a mixture of the alkali recovered statin hemi-calcium. for atorvastatin hemi-calcium salt is not another need to be added to provide a source of potassium ions Ca2 +. according to a preferred embodiment of steps of the method of alkaline hydrolysis, the statin ester derivative is sufficient to provide about 10 mmol / liter to a mixed solvent of about 1 mole / liter of mixed solvent is added an amount of 入。相对于酯衍生物来说,优选使用约1到约6当量的氩氧化钩。 更优选使用约l到约2当量。氢氧化钙只是微溶于C广Q醇:水混合漆剂中,并且只有小比例可以适合于在任一时间以溶液形式催化水解。为了加速碱水解,可加入相转移催化剂来提高氢氧化钾的溶解性。相转移催化剂为本领域人们所熟悉,包括例如四正丁基溴化铵("TBAB")、卡基三乙基氯化铵("TEBA")、四正丁基氯化铵、四正丁基碘化铵、四乙基氯化铵、 苄基三丁基氯化铵、苄基三丁基溴化铵、苄基三乙基溴化铵、四曱基氯化铵和聚乙二醇。 一种最优选的相转移催化剂是TBAB。使用时, 相转移催化剂应以相应于他汀酯衍生物亚化学计量的量使用,优选以相应于他汀酯衍生物约0.05-0.25当量、更优选约0.1当量的量使用。可将所迷混合物加热到最高至混合溶剂的回流温度以加速反应。优选的温度范围是 With respect to the ester derivative is preferably about 1 to about 6 equivalents of an argon hook oxide more preferably from about l to about 2 equivalents of calcium hydroxide is only sparingly soluble in alcohols wide C Q:... Of water are mixed in a varnish and only a small proportion may be adapted to catalyze the hydrolysis at any one time in the form of a solution. to accelerate the base hydrolysis, a phase transfer catalyst may be added to improve the solubility of potassium hydroxide phase transfer catalyst known to those familiar, including, for example, tetra-n butylammonium bromide ( "TBAB"), the card triethylammonium chloride ( "TEBA"), tetra-n-butylammonium chloride, tetra-n-butylammonium iodide, tetraethylammonium chloride, benzyl tributyl ammonium chloride, benzyl tributyl ammonium bromide, benzyl triethyl ammonium bromide, tetra Yue ammonium chloride and polyethylene glycol. a most preferred phase transfer catalyst is TBAB. when using the phase transfer catalyst should be present in an amount corresponding to statin ester derivative substoichiometric used, preferably corresponding to statin ester derivatives about 0.05-0.25 equivalents, more preferably an amount of about 0.1 equivalents to use. the fans can mixture was heated to a maximum to the reflux temperature of the solvent mixture to accelerate the reaction. the preferred temperature range is 约4(V70TC的高温。在消耗他汀酯衍生物后,从碱水解反应混合物回收他汀半钩或其溶剂合物。作为回收他汀半钙的一部分,优选将反应混合物过滤以去除过量悬浮的氢氧化钙。优选将反应混合物趁热过滤以防止他汀半钙沉淀在氬氧化钾滤饼上。过滤除去悬浮的氢氧化钓后,可通过沉淀从滤液回收他汀半钾. 按照一种优选的回收技术,通过緩慢加入水使他汀半钩从滤液沉淀。 将基本上等于滤液体积的水用约1小时时间加入。优选水的緩慢加入也在高温如约40-65'C的温度下进行。通过緩慢加入水沉淀他汀半钙得到结晶形式的他汀半钩并防止了胶状沉淀物的形成。或者,他汀半钾可通过任何常规方法回收。 About 4 (V70TC high temperature. After consumption of the statin ester derivative, the reaction from the alkaline hydrolysis mixture recovered statin half hook or a solvate thereof. As part of recovering the statin hemi-calcium, the reaction mixture is preferably filtered to remove excess suspended hydroxide calcium. the reaction mixture is preferably filtered hot to prevent precipitation of statin hemi-calcium hydroxide in the cake argon. after filtration to remove suspended fishing hydroxide, potassium can be recovered from the filtrate statins half precipitate. according to a preferred recovery technique, by slow addition of water to the filtrate from the hook half statins precipitate. the filtrate is substantially equal to the volume of water was added over about 1 hour. water was slowly added preferably also at elevated temperature such as a temperature of about 40-65'C by slow addition of water the precipitate obtained statin hemi-calcium crystalline form of statin and prevents the formation of half-hook gummy precipitate. Alternatively, the potassium can be recovered statin half by any conventional method. 在所需的纯化步骤后,回收的他汀半钙可用作配制药品的活性成分。 After the desired purification steps, the recovered statin hemi-calcium may be used as the drug active ingredient is formulated. 他汀半钙的过滤特性和纯度可通过加热到足以使全部沉淀溶解的温度来将所述结晶产物重新溶解于含水醇反应混合物中形成透明溶液而加以进一步改善。 He filtering characteristics and purity of the statin hemi-calcium may be sufficient to cause all the precipitate was dissolved by heating to a temperature of the crystalline product redissolved in aqueous alcohol to be further improved and the clear solution to form a reaction mixture. 所迷溶液优选用几个小时緩慢冷却并优选保持在环境温度下直到不再观察到结晶形成。 The solution is preferably cooled slowly for several hours with fans and preferably maintained until no crystal formation was observed at ambient temperature. 过滤和干燥以及任何其它任选的纯化步骤后,他汀半钙或其溶剂合物可用作_药品的活性成分。 After filtration and drying, and any further optional purification steps, the statin hemi-calcium or a solvate thereof used as active ingredients of drugs _. '如上所迷,他汀有时通过中间体制备,其中戊酸二醇基(开环形式)的一个或两个羟基或内酯(闭环形式)的羟基经可水解保护基保护,羧基经酯衍生物保护。 'As fans, sometimes by statin preparation of intermediates wherein a pentanoic acid diol group (open-ring form) or two hydroxyl groups or lactone (closed loop) a hydroxyl group protected by hydrolysable protecting group, carboxyl group, ester derivatives protection. 例如,通过引用并入本文的美国专利5,260,440号在罗苏伐他汀的合成时使用曱硅烷基保护基。 For example, herein incorporated by reference U.S. Patent No. 5,260,440, using Yue silyl protecting group during synthesis of rosuvastatin. 通过引用并入本文的美国专利6,002,021和4,444,784号在辛伐他汀合成时使用曱硅烷基保护基。 Yue using silyl protecting group 6,002,021 and No. 4,444,784 incorporated herein simvastatin synthesized by reference U.S. Pat. 通过引用并入本文的Brower, PL等人在Tet. Lett. 1992, 33, 2279-82的文章和Baumann, K丄.等人在Tet. Lett. 1992, 33,2283-2284的文章通过具有丙嗣化合物保护基,即112和113与各自相连的氧原子一起形成可水解环状保护基的二嚼烷中间体制备阿托伐他汀。 Incorporated by reference herein Brower, PL et al., Tet. Lett. 1992, 33, 2279-82 articles and Baumann, K Shang et al Tet. Lett. 1992, 33,2283-2284 article by having a prop Si compound protective group, i.e., 112 and two chewing pyrrolidine intermediate prepared hydrolyzable cyclic protecting group may be formed together with the oxygen atom attached to the respective 113 atorvastatin. 这些在此中称为"被保护的他汀酯衍生物"的化合物可按照本发明转化成相应的半钙盐。 The compounds referred to herein, "protected statin ester derivatives" may be converted to the corresponding hemi-calcium salt according to the present invention. 因此,在另一实施方案中,本发明涉及一种制备具有下式的他汀的钙盐的方法:(式中R代表有机基团),该方法包括使选自下面的酯衍生物:与足量的氢氧化钙接触,其中R!为CVQ烷基,R2、 R3和R4各独立地代表氢或者相同或不同的可水解保护基,或者R2和R3与它们各自相连的氧原子一起形成可水解环状保护基,所用的保护基优选可在酸性或碱性条件下水解。 Thus, in another embodiment, the present invention relates to a method :( R represents an organic group in the formula) having the formula of the calcium salt of a statin preparation, which comprises reacting ester derivative selected from: and foot together form a contact with an amount of calcium hydroxide, wherein R & lt! CVQ is an alkyl group, R2, R3 and R4 each independently represents hydrogen or the same or different hydrolyzable protecting group, oxygen atom, or R2 and R3 may be connected to their respective hydrolyzable cyclic protecting group, the protecting group used is preferably hydrolyzable under acidic or basic conditions. 按照本发明实施方案的优选保护基R2、 R3 和R4包括例如曱硅烷基(更优选三烷基甲硅烷基和烷基二芳基曱硅烷基,最优选叔丁基二曱基曱硅烷基)和环状保护基(从而R2和R3形成例如二嚼烷)。 According to a preferred protecting groups R2, R3 and R4 embodiments of the present invention include, for example, Yue silyl group (more preferably a trialkylsilyl group and alkyl diaryl Yue silyl group, most preferably tert-Yue Yue silyl group) and cyclic protecting group (R2 and R3 are formed so that two chewing e.g. dioxane). 通过引用并入本文的美国专利6,294,680号公开了用于他汀合成特别是辛伐他汀合成的另外的保护基。 Incorporated herein by reference, U.S. Patent No. 6,294,680 discloses additional protecting groups used in the synthesis of statins especially simvastatin synthesized. 所公开的环状保护基包括二嗨烷、环状硫酸酯、环状磷酸酯或亚硼烷基(borylidene),这些保护基任选被烷基和芳基取代。 Cyclic protecting groups disclosed include bis Hi dioxane, a cyclic sulfate, a cyclic phosphate or a boron group (borylidene), these protecting groups is optionally substituted alkyl and aryl. 其它保护基包括通过引用并入本文的W095/13283中公开的硼酸,并如在通过引用并入本文的美国专利5,159,104号中公开的那样用乙酸酐酯化,通过引用并入本文的美国专利6,100,407号公开了另外的保护基。 Other protecting groups include boronic acid incorporated herein by reference W095 / 13283 are disclosed as above and esterified with acetic anhydride, incorporated herein by reference U.S. Patent No. incorporated herein by reference U.S. Patent Publication No. 5,159,104 to 6,100,407 No. discloses additional protecting groups. 在这些参考文献中公开的保护棊可按照本发明使用。 Protection Qi disclosed in these references may be used according to the present invention. 现已出乎意料地发现曱硅烷基可被水解并且可通过与氢氧化锔接触去除。 Yue has now surprisingly been found that the silane groups may be hydrolyzed and can be removed by contact with curium hydroxide. 所以,曱硅烷基的使用可允许在相同溶剂中以一步去除保护基和将酯转化成钙盐。 Therefore, using silane groups Yue step may allow removal of the protecting group in the same solvent and the ester is converted into the calcium salt. 使用氢氧化钙不需要将曱硅烷保护基用例如卤化氢诸如氟化氢酸解以除去保护基的单独步骤(如美国专利5,260,440和美国专利4,444,784号的方法的需要)。 Use of calcium hydroxide is not necessary to Yue silane protecting group such as a halide such as hydrogen fluoride acid hydrolysis step to remove the protective group alone (e.g., U.S. Patent No. 5,260,440, the need for a method and U.S. Patent No. 4,444,784). 因此,本发明方法适用于具有可通过氢氧化钙水解的甲硅烷基或其它保护基R2、 R3 和114的他汀施。 Thus, the method of the present invention is applicable to calcium hydroxide by hydrolyzable silyl group or other protecting group R2, R3 and 114 of statin administration. 例如可使用/〉开于美国专利5,260,440号中的受护罗苏伐他汀,并有将酮还原来获得作为R2的氢的修改,也可使用公开于美国专利4,444,784号和6,002,021号中的甲硅烷基保护的辛伐他汀。 May be used, for example, /> disclosed in U.S. Patent No. 5,260,440, the patron rosuvastatin, and have obtained the original one further modification of R2 as hydrogen, may also be used is disclosed in U.S. Patent No. 4,444,784 and No. 6,002,021 to the silyl-protected simvastatin. 一些保护基在酸性条件下得到最佳水解。 Some preferred protecting group hydrolyzed under acidic conditions. 因此,在受护他汀酯衍生物与氢氧化钩接触前,加入酸催化剂水解保护基。 Thus, the patron before statin ester derivative with calcium hydroxide in contact with the hook, acid catalyst hydrolyzable protective group. 这种酸催化剂的例子包括乙酸、三氟乙酸、对甲苯黄色、溴化锌和氢氯酸或其它卣氢酸,优选乙酸和盐酸。 Examples of such acid catalysts include acetic acid, trifluoroacetic acid, p yellow, zinc bromide and hydrochloric acid or other hydrogen wine container, preferably acetic acid and hydrochloric acid. 然后将得到的二醇酯通过与氩氧化钓接触转变成钙盐.所述方法也可以一罐法进行。 The resulting glycol ester argon oxidized by contact with a calcium salt into fishing. The method may be carried out one-pot process. 如上所述形成二醇酯,然后使其在相同罐中与氢氧化锅反应形成阿托伐他汀半钩而没有改变溶剂。 Glycol esters formed as described above, and then to form a pot hydroxide in the same pot is reacted with atorvastatin half-hook without changing the solvent. 一种优选的溶剂是水和cvc4醇的混合物,优选为乙醇。 A preferred solvent is a mixture of water and cvc4 alcohol, preferably ethanol. 所迷反应的优选pH是低于约3 ,更优选低于约1 。 Preferably the pH of the reaction fans is less than about 3, more preferably less than about 1. 一种用酸催化剂去除的优选保护基是丙鲷化物,即二醇形成环状可水解保护基的化合物即二嚼烷。 Preferably one kind of the protective group is removed with an acid catalyst prop bream thereof, i.e., hydrolyzable compound of a cyclic diol protecting group i.e. two chewing dioxane. 优选通过例如减压蒸发去除在丙酮化物与酸催化剂反应时形成的丙酮。 Preferably by evaporation under reduced pressure and acetone formed during the reaction is removed with an acid catalyst e.g. acetonide. 使用酸催化剂的一罐法示例说明如下:<formula>formula see original document page 22</formula> 阿托伐他汀半钙盐药用组合物可制备成可供经口、肠胃外、直肠、皮下、颊或鼻给药的药剂,适合经口给药的剂型包括片剂、浓缩丸或包衣丸、糖衣九、小嚢、石更胶嚢或明胶胶嚢、含片、糖浆和悬浮液。 Example pot method using an acid catalyst is described as follows: <formula> formula see original document page 22 </ formula> Atorvastatin hemi-calcium salt may be prepared as pharmaceutical compositions for oral, parenteral, rectal, subcutaneous, buccal or nasal administration of the agent, dosage forms suitable for oral administration include tablets, pill or coated pills, dragees nine, small Nang, stone or more gelatin Nang Nang gum, lozenges, syrups, and suspensions. 适合的肠胃外给药的剂型包括水溶液或非水溶液或乳浊液,适合直肠给药的剂型包括具亲水或疏水栽体的栓剂。 Suitable for parenteral administration include aqueous or non-aqueous solutions or emulsions, suitable for rectal administration include suppositories with hydrophilic or hydrophobic plant body. 对于局部给药的剂型来说,本发明提供了本领域人们熟悉的适合的经皮投送系统,对于经鼻投送来说,本发明提供了本领域人们熟悉的适合的气溶胶投送系统。 For topical administration the dosage form, the present invention provides the art familiar Suitable transdermal delivery systems for delivery via the nose is, the present invention provides the art familiar suitable aerosol delivery systems . 本发明的药用组合物包含他汀半钙,特别是阿托伐他汀半钙、 罗苏伐他汀半钙、匹伐他汀半钩、辛伐他汀半锏和洛伐他汀半钩。 The pharmaceutical composition of the present invention comprise a statin hemi-calcium, particularly atorvastatin hemicalcium, rosuvastatin hemicalcium, pitavastatin half hook, lovastatin and simvastatin semi mace half hook. 除了活性成分外,本发明的药用组合物可包含一种或多种赋形剂。 Addition to the active ingredient, the pharmaceutical compositions of the invention may comprise one or more excipients. 赋形剂及其用量的选择可由制剂师基于经验并参考标准程序和该领域参考文献容易地确定。 Excipients and their amounts can be selected by the formulator and based on the experience in the art with reference to standard procedures and reference readily determined. 通过引用并入本文的美国专利6,316,460号和最新版的美国药学会的药剂赋形剂手册可用作指南。 Which is incorporated herein by reference, US Patent Nos. 6,316,460 and pharmaceutical excipients latest edition of the Manual of the American Pharmaceutical Association serves as a guide. LIPITOR® (阿托伐他汀半钙)和其它药剂的剂型和配制也可用作指南。 LIPITOR® (atorvastatin hemi-calcium) and other pharmaceutical dosage forms and formulations can be used as guidelines. 实施例通则除非另加说明,试剂购之即用.通过相应二酮和相应的手性胺之间的缩合反应形成吡咯环制备[11-(11*,11*)]-2-(4-氟苯基){,5-二嗨烷-S-(l-甲基乙基)-3-苯基-4-[(苯基氨基)羰基]-lH-吡咯-l-叔丁基庚酸酯(二喊烷2, R!-叔丁基)。 Examples General Unless otherwise specified, reagents were prepared with the pyrrole ring that is formed by a condensation reaction between the corresponding diketone and the corresponding chiral amine [11- (11 *, 11 *)] - 2- (4- fluorophenyl) {, 5-hi dioxane -S- (l- methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -l- tert-butyl lH-pyrrolo heptanoate ( two call dioxane 2, R -! t-butyl). 也可通过已知方法制备。 It may also be prepared by known methods. 参见Brower, PL 等人在Tet. Lett. 1992, 33, 2279-82; Baumann, K丄等人在Tet. Lett. 1992, 33, 2283-84中的所迷。 See Brower, PL et al., Tet Lett 1992, 33, 2279-82;... Baumann, K Shang et al. 1992, 33, 2283-84 in the fan in Tet Lett.. 下面的HPLC务ff用于测定在实施例中报告的酸水解中获得的混合物的组成:Waters Spherisorb S3 ODS1 (7.6 xlOO mm), 70:30乙腈:水,0.6 mL/min, 20 pL样品,紫外光检测Y=254,实施例1由二嗯烷醋衍生物制备阿托伐他汀钙在配有磁力搅拌器的烧瓶中,将[R-(R、R"]-2"(4-氟苯基)-P,S-二喊烷-5-(1-曱基乙基)-3-苯基-4-[(苯基氨基)羰基]-lH-吡咯-l-叔丁基庚酸酯(2.0 g)悬浮于80。/。乙酸7jc溶液(50 mL)中。将混合物在环境温度下搅拌约20小时直到获得透明溶液。将透明溶液蒸发至干并通过与曱苯(3 x 50 mL)共沸蒸馏除去痕量乙酸而获得粉末。将上面获得的粉末(200 mg, 0.32><10-3摩尔)溶解于乙醇(8 mL) 中,向其中加入含四丁基溴化斷IO mg)的氢氧化钙饱和溶液(8 mL)。 Ff traffic HPLC the following composition for the acid hydrolysis mixture obtained in Example reports the measured: Waters Spherisorb S3 ODS1 (7.6 xlOO mm), 70:30 acetonitrile: water, 0.6 mL / min, 20 pL sample, ultraviolet photodetector Y = 254, Example 1 was prepared from two ah vinegar dioxane derivative of atorvastatin calcium in a flask equipped with a magnetic stirrer, the [R- (R, R "] - 2" (4- fluorophenyl yl) -P, S- two call dioxane-5- (1-ethyl-Yue-yl) -3-phenyl-4 - [(phenylamino) carbonyl] -l- tert-butyl lH-pyrrolo heptanoate (2.0 g) was suspended in 80./. 7jc acetic acid solution (50 mL) the mixture was stirred at ambient temperature for about 20 hours until a clear solution. the clear solution was evaporated to dryness and by Yue benzene (3 x 50 mL) were azeotropic distillation to remove traces of acetic acid to obtain a powder. the powder (200 mg, 0.32> <10-3 moles) obtained above was dissolved in ethanol (8 mL), to which was added tetrabutyl-containing off IO mg) of A saturated solution of calcium hydroxide (8 mL). 搅拌所述混合物并在约45'C的温度下加热约24小时。 The mixture was stirred and heated at a temperature of about 45'C for about 24 hours. 再另外加入氢氧化钙的饱和溶液(4 mL)。 Still further added a saturated solution of calcium hydroxide (4 mL). 在环境温度下搅拌约20分钟后,反应完成。 After stirring for about 20 minutes at ambient temperature, the reaction was complete. 获得产物的纯度通过HPLC分析。 The purity of the obtained product was analyzed by HPLC. 真空过滤白色沉淀物并在约65 'C的温度下干燥约18小时。 The white precipitate was vacuum filtered and dried at a 'temperature of from about 65 C for about 18 hours. 千燥后,获得77%收率的阿托伐他汀钙盐(142 mg)。 1000 after drying, to obtain 77% yield of atorvastatin calcium salt (142 mg). 实施例2从二嗨烷酯衍生物制备阿托伐他汀4丐在配有磁力搅拌器的烧瓶中,将[R-(R、R"]-2-(4-氟苯基)-p,S-二嗨烷-5-(l-甲基乙基)-3-苯基-4-[(苯基氨基)羰基】-lH-吡咯-l-叔丁基庚酸酯(IO.O g, 15.29x10-3 mmoi)悬浮于80。/。乙酸水溶液(150 mL)中。 将混合物在环境温度下搅拌过夜直到荻得透明溶液。将透明溶液蒸发至干并通过与曱苯(3 x 100 mL)共沸蒸馏除去痕量乙酸而获得含甲苯的油状产物。将油状产物置于乙醇(IOO mL)和水(20 mL)的混合物中。加入氬氧化锔(5.5当量,6.22 g, 84,0 x 10'3 mmol)和5 % (w/w 二嚼烷酯衍生物) 四丁基溴化铵(0.46 g)的混合物。将混合物加热到约45匸的温度约3 小时直到反应完成。趁热将混合物真空过滤除去过量氢氧化45。然后将混合物冷却到环境温度,之后在搅拌下加入水(200 mL)。在环境温度下搅拌约20分钟后,反应完成。得到的产物的纯度通过HPLC 分析。将 Example 2 was prepared from diethyl Hi alkyl ester derivative of atorvastatin Hack 4 equipped with a magnetic stirrer flask, [R- (R, R "] - 2- (4- fluorophenyl) -p, S- dioxide Hi dioxane -5- (l- methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -lH- pyrrole-tert-butyl heptanoate -l- (IO.O g, 15.29 x10-3 mmoi) was suspended in 80./. aqueous acetic acid (150 mL) in. the mixture was stirred at ambient temperature overnight until a clear solution was obtained Di. the clear solution was evaporated to dryness and by Yue benzene (3 x 100 mL) traces of acetic acid removed by azeotropic distillation to obtain an oily product containing toluene. the oily product was placed in a mixture of ethanol (IOO mL) and water (20 mL) in added argon curium oxide (5.5 eq, 6.22 g, 84,0 x 10'3 mmol) and 5% (w / w mixture of two tetrabutylammonium bromide (0.46 g) of the chewing alkyl ester derivative). the mixture is heated to a temperature of about 45 Xi for about 3 hours until the reaction was complete. hot the mixture was removed by vacuum filtration 45. the mixture was then cooled to ambient temperature, water was added under stirring, after (200 mL). after stirring at ambient temperature for about 20 minutes, the reaction was complete. the purity of the obtained product was analyzed by HPLC excess hydroxide .will 白色沉淀物真空过滤并在约65'C的温度下干燥约18小时。 干燥后,获得84 %收率的阿托伐他汀4丐盐(7.44 g)。实施例3由二嚼烷酯衍生物制备阿托伐他汀内酯在配有磁力搅拌器的烧瓶中,在催化量的水存在下,将[R-(R、R"]-2-(4-氟苯基)誦(3,S-二嗯烷-5-(l-甲基乙基)-3-苯基斗[(苯基^J^) g]-lH-吡咯-l-叔丁基庚酸酯(0.5 g, 0.76X10-3 mmol)溶解于1:1三氟乙酸:四氢呋喃的混合物(4 mL)中。将反应混合物在环境温度下搅拌约24小时。将获得的溶液蒸发并通过与乙醚(3x10 mL)共沸蒸馏除去痕量三氟乙酸.获得白色固体(0.3 g)。基于HPLC分析,所述白色固体是比率分别为40:60的阿托伐他汀和阿托伐他汀内酯的混合物。实施例4由二嚼烷酯衍生物制备阿托伐他汀内酯在配有磁力搅拌器的烧瓶中,将[R-(R、R"]-2-(4-氟苯基)-M-二嗨烷-5-(l-曱基乙基)-3-苯基-4-[(苯基氨基)羰基]-lH-吡咯-l-叔丁基庚酸酯(0.2 g, The white precipitate was filtered and vacuum dried at a temperature of about 65'C for about 18 hours. After drying, 84% yield of 4 Hack atorvastatin salt (7.44 g). Example 3 alkyl ester derivative by two chewing embodiment preparation of atorvastatin lactone in a flask equipped with a magnetic stirrer, in the presence of a catalytic amount of water, the [R- (R, R "] - 2- (4- fluorophenyl) chant (3, S - two ah dioxane -5- (l- methylethyl) -3-phenyl bucket [(phenyl ^ J ^) g] -lH- pyrrolo -l- tert-butyl heptanoate (0.5 g, 0.76X10-3 1 trifluoroacetic acid:: a mixture (4 mL) in tetrahydrofuran and the reaction mixture was stirred at ambient temperature for about 24 hours, the obtained solution was evaporated and traces removed by azeotropic distillation with diethyl ether (3x10 mL) mmol) 1 was dissolved in. the amount of trifluoroacetic acid was obtained as a white solid (0.3 g). based on HPLC analysis, the white solid is the ratio of 40:60, respectively atorvastatin and atorvastatin lactone in a mixture of statins. Example 4 by two alkoxy chewing preparation of an ester derivative of atorvastatin lactone in a flask equipped with a magnetic stirrer, the [R- (R, R "] - 2- (4- fluorophenyl) -M- two Hi-5 ( Yue l- yl) -3-phenyl-4 - [(phenylamino) carbonyl] -l- tert-butyl lH-pyrrolo heptanoate (0.2 g, 0,30 x 10-3 mmol)和溴化锌(3.5当量,1.07 x 10-3摩尔)溶解于二氯甲烷(5 mL)中。将反应混合物在环境温度下搅拌约24小时。 加入水(30 mL)并将混合物搅拌约3小时。 0,30 x 10-3 mmol) and zinc bromide (3.5 equiv., 1.07 x 10-3 mol) was dissolved in dichloromethane (5 mL) the reaction mixture was stirred at ambient temperature for about 24 hours. Water was added ( 30 mL) and the mixture was stirred for about 3 hours. 水层用二氯甲烷(3 x 10 mL) 萃取,而有机层用硫酸钠干燥并过滤。 (3 x 10 mL) the aqueous layer was extracted with dichloromethane, the organic layer was dried over sodium sulfate and filtered. 然后将有机层减压蒸发得到形成的产物(150 mg)。 The organic layer was evaporated under reduced pressure to give the product formed (150 mg). 基于HPLC分析,得到的产物为是比率分别为57:43的阿托伐他汀和阿托伐他汀内酯的混合物。 Based on HPLC analysis, the product obtained is the ratio of 57:43, respectively atorvastatin and atorvastatin lactone in a mixture of statins. 实施例5由二鹏烷酯衍生物制备阿托伐他汀内酯在配有磁力搅拌器的烧瓶中,将[R-(R^J^)]-2-(4-氟苯基)-P,S-二嗨烷-5-(1-甲基乙基)-3-苯基-4-[(苯基絲)羰基]-lH-吡咯小叔丁基庚酸酯(0.2 g)悬浮于90%乙酸水溶液(4 mL)中。 Example 5 was prepared from two Peng alkyl ester derivative of atorvastatin lactone in a flask equipped with a magnetic stirrer, the [R- (R ^ J ^)] - 2- (4- fluorophenyl) -P , S- two Hi-5 (1-methylethyl) -3-phenyl-4 - [(phenylmethyl based wires) carbonyl] butyl lH-pyrrolo brother-heptanoate (0.2 g) was suspended in 90% aqueous solution (4 mL) in acetic acid. 将该混合物在约50'C 温度下搅拌约5天。 The mixture was stirred at a temperature of from about 50'C to about 5 days. 将得到的溶液蒸发至干并通过与曱苯(3 x 15 mL) 共沸蒸馏除去痕量乙酸得到一种粉末。 The resulting solution was evaporated to dryness and by Yue benzene (3 x 15 mL) to remove traces of acetic acid by azeotropic distillation to obtain a powder. 基于HPLC分析,得到的产物是比率分别为54:46的阿托伐他汀和阿托伐他汀内酯的混合物。 Based on HPLC analysis, the resulting product is a 54:46 mixture of atorvastatin and atorvastatin lactone in the ratio, respectively. 实施例6由二瞎烷酯衍生物制备阿托伐他汀内酯在配有磁力搅拌器的烧瓶中,将盐酸(l mL)和[R-(R、R"]-2-(4-氟苯基)-|3,5-二嗨烷-5-(1-甲基乙基)-3-苯基-4-[(苯基^J0羰基]-lH-吡咯-1-叔丁基庚酸酯(0.2 g)的3%水溶液溶解于甲醇(2 mL)中。将混合物在约IIO'C的温度下搅拌约4小时,然后在环境温度下搅拌过夜。 将得到的溶液蒸发至干获得一种粉末。基于HPLC分析,该粉末是比率分别为54:46的阿托伐他汀和阿托伐他汀内酯的混合物。25实施例7由酯4汙生物制备罗苏伐他汀钙在配有磁力搅拌器的烧瓶中,将7-[4-(4-氟苯基)-6-异丙基-2-(N-曱基-N-曱基磺酰基M)嘧啶-5-基]-(3民5S)-二羟基-(E)-6-庚酸甲酯溶解于乙醇中,并向其中加入含5。/。(占酯衍生物的重量比率)四丁基溴化铵的氢氧化钩饱和溶液。将混合物搅拌并在约45'C的温度下加热约24小时。再加入氢氧化钓饱和溶液。在环境温度下搅 Example 6 was prepared from two blind alkyl ester derivative of atorvastatin lactone in a flask equipped with a magnetic stirrer, a hydrochloric acid (l mL) and [R- (R, R "] - 2- (4- fluoro phenyl) - | 3,5- two Hi-5 (1-methylethyl) -3-phenyl-4 - [(phenyl ^ J0 carbonyl] lH-pyrrole-l-tert-butyl heptanoate (0.2 g) was dissolved in 3% aqueous solution of methanol (2 mL) the mixture was stirred at a temperature of about IIO'C about 4 hours and then stirred overnight at ambient temperature. the resulting solution was evaporated to dryness to obtain a powder based on HPLC analysis, the powder is a ratio of 54:46, respectively atorvastatin and atorvastatin lactone mixture stirred .25 Example 7 was prepared from 4 fouling organisms rosuvastatin calcium carbonate equipped with a magnetic 's flask, a 7- [4- (4-fluorophenyl) -6-isopropyl -2- (N- Yue Yue-ylsulfonyl group -N- M) pyrimidin-5-yl] - (3 China 5S) - dihydroxy -. (E) -6- heptanoate was dissolved in ethanol, and thereto is added 5 ./ containing (by weight ratio of the ester derivative) tetrabutyl ammonium bromide, hydroxide hook saturated solution. the mixture was stirred and heated at a temperature of about 45'C for about 24 hours was added a saturated solution of hydroxide fishing. stirring at ambient temperature 拌约20分钟后,反应完成,得到罗苏伐他汀钙。实施例8由酯4汙生物制备罗苏伐他汀钙在配有磁力搅拌器的烧瓶中,将7-[4-(4-氟苯基)-6-异丙基-2-(N-曱基-N-曱基磺酰基絲)嘧啶-5-基]-(3R,SS)-二羟基-(E)-6-庚烯酸甲酯置于乙醇和水的混合物中。向其中加入氢氧化4丐和5%(占酯衍生物的重量比率)四丁基溴化铵的混合物。将混合物在约45。C的温度下加热约3小时直到反应完成。将混合物趁热真空过滤除去过量氢氧化4丐。然后将混合物冷却至室温,之后在搅拌的同时加入水。在环境温度下搅拌约20分钟后,反应完成,得到罗苏伐他汀钙。实施例9由酯衍生物制备匹伐他汀钙在配有磁力搅拌器的烧瓶中,将(E)-3,5-二幾基-7-[4'-(4"-氟苯基)-2'-环丙基-喹啉-3'-基]-庚-6-烯酸乙酯溶解于乙醇中,并向其中加入含5%(占酯衍生物的重量比率)四丁基溴化铵的氢氧化钙饱和溶液。将混 After stirred for about 20 minutes, the reaction was complete, to give rosuvastatin calcium. Example 8 was prepared from 4 fouling organisms rosuvastatin calcium carbonate in a flask equipped with a magnetic stirrer, a 7- [4- (4-fluoro phenyl) -6-isopropyl -2- (N- -N- Yue Yue sulfonyl group based wires) pyrimidin-5-yl] - (3R, SS) - dihydroxy - (E) -6- heptene acid methyl ester was placed in a mixture of ethanol and water. to this mixture was added tetrabutylammonium bromide 4 hack hydroxide and 5% (by weight ratio of the ester derivatives). the mixture at a temperature of from about 45.C for about 3 hours until the reaction was complete. the mixture was vacuum filtered hot to remove excess 4 hack hydroxide. the mixture was then cooled to room temperature, then water was added while stirring. after stirring at ambient temperature for about 20 minutes, the reaction was complete, to give . rosuvastatin calcium prepared in Example 9 from the ester derivative of pitavastatin calcium in a flask equipped with a magnetic stirrer, a (E) -3,5- several two-7- [4 '- (4 " - fluorophenyl) -2'-cyclopropyl - quinolin-3'-yl] - hept-6-enoate is dissolved in ethanol, and thereto is added 5% (by weight ratio of the ester derivative ) of tetrabutylammonium bromide in saturated calcium hydroxide solution. the mixture 物搅拌并在约45'C的温度下加热约24小时。再加入氢氧化钩饱和溶液。在环境温度下搅拌约20分钟后,反应完成,得到匹4戈他汀辆。由酯衍生物制备匹伐他汀钙在配有磁力搅拌器的烧瓶中,将问-3,5-二羟基-7-[4'-(4"-氟苯基)-2'-环丙基-喹啉-3'-基]-庚-6-烯酸乙酯置于乙醇和水的混合物中。 向其中加入氢氧化钩和5%(占酯衍生物的重量比率)四丁基溴化铵的混合物。 Was stirred and heated at a temperature of about 45'C for about 24 hours was added a saturated solution of hook hydroxide. After stirring at ambient temperature for about 20 minutes, the reaction was complete, to give horses 4 Ge statin vehicle. Pivoxil derivative prepared from atorvastatin calcium in a flask equipped with a magnetic stirrer, a Q -3,5-dihydroxy-7- [4 '- (4' - fluorophenyl) -2'-cyclopropyl - quinoline-3 ' - yl] --6-enoate was placed in a mixture of ethanol and water was added thereto hook hydroxide and 5% (by weight ratio of the ester derivative) tetrabutyl ammonium bromide mixture. 将混合物在约45'C的温度下加热约3小时直到反应完成。 The mixture was heated for about 3 hours until the reaction was complete at a temperature of about 45'C. 将混合物趁热真空过滤除去过量氢氧化钩。 The mixture was vacuum filtered hot to remove excess hydroxide hook. 将混合物冷却到环境温度,然后在搅拌下加入水。 The mixture was cooled to ambient temperature, water was then added with stirring. 在环境温度下搅拌约20分钟后,反应完成,得到匹伐他汀4丐。 After stirring at ambient temperature for about 20 minutes, the reaction was complete, to give 4 pitavastatin hack. 这样参照具体优选的实施方案描述本发明并用实施例示例说明后,本领域技术人员可知道各种并不背离如专利说明书中所公开的本发明宗旨和范围的如上所述和示例的对本发明的修改。 Thus described the present invention with reference to particular preferred embodiments and with the embodiment described exemplary embodiments, those skilled in the art may be aware of the various not departing from the spirit and scope of the invention as disclosed in the patent specification and the examples of the present invention as described above modify. 所述实施例用于帮助理解本发明,但并不拟也不应以任何方式看作限制本发明的范围。 The examples are intended to aid in understanding the invention but are not intended and should not be regarded in any way limit the scope of the present invention. 所述实施例并不包括常规方法的描述,这种方法为本领域技术人员所熟悉并公开于各种文献中。 The embodiments do not include descriptions of conventional methods, such methods familiar to the skilled artisan and disclosed in various documents. 所有此中所述的参考文献全文并入本文。 All references recited herein are incorporated herein by reference.

Claims (41)

1.一种制备具有下式的他汀的钙盐的方法: 式中R代表有机基团, 该方法包括使选自下面的他汀的酯衍生物和与足量的氢氧化钙反应, 其中R1为C1-C8烷基,R2、R3和R4各独立地代表氢、或者相同或不同的可水解保护基,或者R2和R3与其各自相连的氧原子一起形成可水解环状保护基。 A method for preparing a calcium salt of the statin of formula: wherein R represents an organic group, which comprises reacting the statin selected from ester derivatives and reaction with a sufficient amount of calcium hydroxide, wherein R1 is C1-C8 alkyl, R2, R3 and R4 each independently represents hydrogen or the same or different hydrolyzable protecting group, or R2 and R3 are each an oxygen atom attached thereto form a hydrolyzable cyclic protecting group.
2. 权利要求l的方法,其中R为选自普伐他汀、氟伐他汀、西立伐他汀、阿托伐他汀、罗苏伐他汀、匹伐他汀、辛伐他汀和洛伐他汀的他汀的有机基团。 L 2. The method of claim, wherein R is selected from pravastatin, fluvastatin, statin cerivastatin, atorvastatin, rosuvastatin, pitavastatin, simvastatin and lovastatin statins organic group.
3. 权利要求2的方法,其中所述他汀选自阿托伐他汀、罗苏伐他汀、匹伐他汀和辛伐他汀。 The method of claim 2, wherein the statin is selected from atorvastatin, rosuvastatin, pitavastatin and simvastatin.
4. 权利要求3的方法, The method of claim 3,
5. 权利要求3的方法, 5. The method as claimed in claim 3,
6. 权利要求3的方法, 6. The method as claimed in claim 3,
7. 权利要求3的方法, 7. The method as claimed in claim 3,
8. 权利要求1的方法:其中所述他汀为罗苏伐他汀。 The method of claim 1: wherein said statin is rosuvastatin. 其中所述他汀为匹伐他汀。 Wherein the statin is pitavastatin. 其中所述他汀为辛伐他汀。 Wherein the statin is simvastatin. 其中所述他汀为阿托伐他汀。 Wherein the statin is atorvastatin. 其中所述方法在水和C!-C4醇的混合物中进行。 Wherein said method is performed in a mixture of water and C!-C4 alcohol.
9. 权利要求l的方法,其中所述接触在升高的温度下进行。 9. The method of claim L, wherein said contacting is carried out at an elevated temperature.
10. 权利要求1的方法,其中所述接触在相转移催化剂的存在下进行。 10. The method of claim 1, wherein said contacting is carried out in the presence of a phase transfer catalyst.
11. 权利要求l的方法,还包括回收他汀的钓盐的步骤。 L 11. The method of claim, further comprising the step of statins fishing salt recovered.
12. 权利要求l的方法,其中R2和R3均为氬。 The method of claim 12. l, wherein R2 and R3 are both argon.
13. 权利要求l的方法,其中R4为氢。 13. l The method of claim, wherein R4 is hydrogen.
14. 权利要求l的方法,其中R2或R3中至少一个为三烷基曱硅烷基保护基。 14. l The method of claim, wherein at least one of R2 or R3 is a trialkyl silyl protecting group Yue.
15. 权利要求1的方法,其中R4为三烷基曱硅烷基保护基。 15. The method of claim 1, wherein R4 is a trialkyl silyl protecting group Yue.
16. 权利要求1的方法,还包括使酯衍生物与酸催化剂接触以水解保护基的预备步骤,其中所述酯衍生物具有至少一个保护基。 16. The method of claim 1, further comprising ester derivatives with an acid catalyst to hydrolyze the protecting group preliminary step, wherein the ester derivative has at least one protective group.
17. 权利要求16的方法,其中所述酯衍生物具有下式: 17. The method of claim 16, wherein the ester derivative has the following formula:
18. 权利要求17的方法,其中R为阿托伐他汀的有机基团。 18. The method of claim 17, wherein R is an organic atorvastatin group.
19. 权利要求l的方法,其中所制备的他汀盐是罗苏伐他汀钙盐, 该方法包括使7-[4-(4-氟苯基)-6-异丙基-2-(N-曱基-N-甲基磺酰基氨基) 嘧啶-5-基]-(3R, 5S)-二羟基-(E)-6-庚烯酸的d-Cg酯与足量的氢氧化钙接触。 19. l The method of claim, wherein the statin salt prepared is the calcium salt of rosuvastatin, which comprises reacting 7- [4- (4-fluorophenyl) -6-isopropyl -2- (N- Yue group -N- methylsulfonyl) pyrimidine-5-yl] - (3R, 5S) - dihydroxy - (E) -6- d-Cg ester heptenoic acid with a sufficient amount of calcium hydroxide in contact.
20. 权利要求l的方法,其中所制备的他汀盐是罗苏伐他汀钙盐, 该方法包括使内酯形式的罗苏伐他汀与足量的氬氧化4丐接触。 20. The method as claimed in claim l, wherein the salt is prepared statin rosuvastatin calcium salt, which comprises reacting a lactone form of rosuvastatin with a sufficient amount of Hack Ar 4 in contact oxide.
21. 权利要求1的方法,其中所制备的他汀盐是匹伐他汀钙盐, 该方法包括使@)-3,5-二羟基-7-[4'-(4"-氟苯基)-2'-(1"-环丙基)-喹啉-3'-基]-庚-6-烯酸的CrQ酯与足量的氬氧化钩接触。 21. The method of claim 1, wherein the salt is prepared statins pitavastatin calcium salt, which comprises reacting @) - 3,5-dihydroxy-7- [4 '- (4' - fluorophenyl) - 2 '- (1 "- cyclopropyl) - quinolin-3'-yl] - hept-6-enoic acid ester with a sufficient amount of CrQ argon oxidation hook contacts.
22. 权利要求1的方法,其中所制备的他汀盐是匹伐他汀钩盐, 该方法包括^使内酯形式的匹伐他汀与足量的氢氧化钩接触。 22. The method of claim 1, wherein the salt is prepared statins hook pitavastatin salt thereof, which comprises ^ lactone form of pitavastatin with a sufficient amount of hydroxide hook contacts.
23.权利要求l的方法,其中所制备的他汀的钙盐具有下式:其中R代表有机基团, 该方法包括下面步骤:a)向水和CrC4醇的混合物中加入氩氧化钓和选自下面的他汀的酯衍生物:其中为d-Cs烷基,R2、 R3和R4各独立地代表氢、或者相同或不同的可水解保护基,或者R2和R3与其各自相连的氧原子一起形成可水解环状保护基;b) 加热所述混合物;c) 沉淀他汀的钓盐;和d) 分离钙盐。 23. A method as claimed in claim l, wherein the calcium salt of a statin having the formula was prepared: wherein R represents an organic group, the method comprising the following steps: a) oxidation of argon was added to the mixture of fish and water and is selected from CrC4 alcohol statin ester derivative of the following: where is d-Cs-alkyl, R2, R3 and R4 each independently represents hydrogen or the same or different hydrolyzable protecting group, or R2 and R3 are each an oxygen atom attached thereto may together form a hydrolyzable cyclic protecting group; b) heating the mixture; c) statins fishing precipitated salt thereof; and d) separating the calcium salt.
24. 权利要求23的方法,其中R为选自普伐他汀、氟伐他汀、 西立伐他汀、阿托伐他汀、罗苏伐他汀、匹伐他汀、辛伐他汀和洛伐他汀的他汀的有机基团。 24. The method of claim 23, wherein R is selected from pravastatin, fluvastatin, statin cerivastatin, atorvastatin, rosuvastatin, pitavastatin, simvastatin and lovastatin statins organic group.
25. 权利要求24的方法,其中所述他汀选自阿托伐他汀、罗苏伐他汀、匹伐他汀和辛伐他汀。 25. The method of claim 24, wherein the statin is selected from atorvastatin, rosuvastatin, pitavastatin and simvastatin.
26. 权利要求25的方法,其中所述他汀为罗苏伐他汀。 26. The method of claim 25, wherein the statin is rosuvastatin.
27. 权利要求25的方法,其中所述他汀为匹伐他汀。 27. The method of claim 25, wherein the statin is pitavastatin.
28. 权利要求25的方法,其中所述他汀为辛伐他汀。 28. The method of claim 25, wherein the statin is simvastatin. OH OH 0.OR2 OR3 O OH OH 0.OR2 OR3 O
29. 权利要求25的方法,其中所述他汀为阿托伐他汀。 29. The method of claim 25, wherein the statin is atorvastatin.
30. 权利要求23的方法,其中R2和Rs均为氢。 30. The method of claim 23, wherein R2 and Rs are both hydrogen.
31. 权利要求23的方法,其中R4为氢。 31. The method of claim 23, wherein R4 is hydrogen.
32. 权利要求23的方法,其中R2或R3中至少一个为三烷基曱硅烷基保护基。 32. The method of claim 23, wherein at least one of R2 or R3 is a trialkyl silyl protecting group Yue.
33. 权利要求23的方法,其中R4为三烷基甲硅烷基保护基。 33. The method of claim 23, wherein R4 is a trialkylsilyl protecting group.
34. 权利要求23的方法,还包括使酯衍生物与酸催化剂接触以水解保护基的预备步骤,其中所述酯衍生物具有至少一个保护基。 34. The method of claim 23, further comprising the ester derivative with an acid catalyst to hydrolyze the protecting group preliminary step, wherein the ester derivative has at least one protective group.
35. 权利要求34的方法,其中所述酯衍生物具有下式: 35. The method of claim 34, wherein the ester derivative has the following formula:
36. 权利要求35的方法,其中R为阿托伐他汀的有机基团。 36. The method of claim 35, wherein R is an organic atorvastatin group.
37. 权利要求23的方法,其中所述水和醇的混合物是体积比为5 %至20 %的水和醇的混合物。 37. The method of claim 23, wherein the mixture of water and an alcohol are by volume mixture of 5-20% of water and alcohol.
38. 权利要求23的方法,还包括向步骤a)的混合物中加入相转移催化剂。 38. The method of claim 23, further comprising the mixture of step a) in phase transfer catalyst.
39. 权利要求23的方法,其中将所述混合物从4(TC加热到7(TC。 39. The method of claim 23, wherein the mixture is from 4 (TC heated to 7 (TC.
40. 权利要求23的方法,还包括在步骤(b)和(c)之间的过滤步骤。 40. The method of claim 23, further comprising a filtering step between steps (b) and (c) is.
41. 权利要求23的方法,其中所述沉淀通过加入水来进行。 41. The method of claim 23, wherein the precipitation is carried out by addition of water.
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CN105111173B (en) * 2015-06-26 2017-06-23 上海应用技术学院 The fluorine-containing statin derivatives and their use
CN105017231B (en) * 2015-06-26 2018-01-26 上海应用技术学院 Multi statin-substituted indoles and their use fluorine-containing modifications

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