CN100582073C - 制备5-羟基-3-氧-己酸衍生物的新方法 - Google Patents
制备5-羟基-3-氧-己酸衍生物的新方法 Download PDFInfo
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- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/716—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
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Abstract
本发明涉及一种制备光学活性5-羟基-3-氧-己酸衍生物或其互变异构体的新方法,所述5-羟基-3-氧-己酸衍生物或其互变异构体可用作制备抑制素,如阿托伐他汀和瑞舒伐他汀的中间体。(S)-4-卤代-3-羟基丁腈与卤代乙酸的布勒斯反应被用作提供所述产品的主要反应,其能使副产物形成最小化,并具有优良的产率。
Description
技术领域
本发明涉及一种新的制备具有光学活性的5-羟基-3-氧-己酸衍生物或其互变异构体的方法,该衍生物具有下式(1)
其中
R代表氢,饱和-C1-C4-烃基,或不饱和-C2-C4烃基,以及X代表卤素,例如Br,Cl,I等,该衍生物是一种用于制备已知作为高胆固醇血症和高脂血症的治疗剂的抑制素例如阿托伐他汀,瑞舒伐他汀(rosuvastatin)的有用的中间体。
背景技术
在已经存在的用于制备上述式(1)化合物的方法中,一种光学活性的3-羟基酯化合物与经在低温(-78℃)处理二异丙基酰胺锂(LDA)或六甲基二硅叠氮化锂(LHMDS)生成的乙酸叔丁酯烯醇化锂起反应,生成式(1)化合物(见:美国专利5,278,313)。最近,通过在克莱森缩合前添加格氏试剂,与上述相类似的一个反应也得以实现。该条件允许反应在5℃进行(见:欧洲专利公开No.1104750)。
但是,上述过程中都使用了过量的六甲基二硅叠氮化锂或二异丙基酰胺锂,这在工业生产中存在一些问题。而且,即使在极低的温度下,前面的合成路线也会同时生成大量不希望得到的副产物,使合成路线复杂化(见:Tetrahedron Lett,2002,43,2679-2682)。后一方法与前面的相比,其产率相当低。后一方法唯一的优点是反应可以在5℃下进行。
发明内容
本发明人针对上述方法中存在的问题进行了大量的研究工作。因此,发明人研究了一种制备式(1)化合物的新方法,即使用有机酸或其衍生物原位活化的锌金属来催化(S)-4-卤代-3-羟基丁腈和α-卤代乙酸或α-卤代乙酸酯的布勒斯反应。在这条新的路线中形成副产物的量很少,并且所有的反应可以在室温附近或更高的温度下进行。
因此,本发明提供了一种制备上述所定义的式(1)化合物或其互变异构体的有效的方法,即在布勒斯反应中使用有机酸或其衍生物原位活化的锌金属。
完成本发明的最佳模式
本发明涉及一种制备式(1)化合物或其互变异构体的方法:
其中
R代表氢,饱和C1-C4-烃基,或不饱和C2-C4烃基,以及X代表卤素,例如Br,Cl,I等,该方法包括以下步骤:
1)下式(2)的(S)-4-卤代-3-羟基丁腈衍生物
其中
X的定义如前所述,并且
P代表氢或羟基保护基团,与如下式(3)所示的α-卤代乙酸或α-卤代乙酸酯反应:
YCH2CO2R(3)
其中,
R的定义如前所述,并且
Y代表Br或I,该反应在有机溶剂中于被有机酸或其衍生物活化的锌金属存在下进行,并且
2)在酸水溶液存在下,步骤1)的产物被水解。
在上述方法中,有机溶剂优选是选自四氢呋喃、苯、甲苯和醚中的一种或几种溶剂。
式(1)化合物的互变异构体是指下式(1a)的烯醇式形式化合物:
但是,按本发明的方法所得到的主要产物为式(1)化合物。
本发明的关键之处在于,当使用被有机酸或其衍生物激活的锌金属时,式(2)的腈官能团与式(3)的α-卤代乙酸或α-卤代乙酸酯进行布勒斯反应生成式(1)的β-酮酯基团。该反应机理可描述如反应流程图1所示:
反应流程图1
在本发明之方法中,向搅拌下的锌金属有机溶剂悬浮液中加入催化量的有机酸或其衍生物,混合液边回流边搅拌以活化锌金属。然后向混合液中缓慢加入式(2)的腈化合物和式(3)的α-卤代乙酸或α-卤代乙酸酯化合物,以制备式(4)的烯胺中间体。反应完成后,将整个混合物用酸水溶液进行水解,以生成所需的式(1)化合物。其各自的反应条件将在后面详细阐述。
式(2)中的P基团代表氢或羟基保护基团。羟基保护基团包括SiRR1R2,其中R的定义如前面所述,R1和R2分别代表氢、饱和C1-C6-烃基,不饱和C2-C6烃基,或者C6-C12芳香基团,以及乙氧基乙基和四氢吡喃基。SiRR1R2基团优选包括三甲基甲硅烷基(TMS),三乙基甲硅烷基(TES),叔丁基二甲基甲硅烷基(TBDMS)和叔丁基二苯基甲硅烷基(TBDPS)。在纯度和产率方面,三甲基甲硅烷基是最优的羟基保护基团。
反应溶剂可以使用四氢呋喃、苯、甲苯和醚。其中在纯度和产率方面,四氢呋喃是最佳选择。
式(3)的α-卤代乙酸或α-卤代乙酸酯化合物在0.5至2.0小时内逐滴加入,当加入时间在1.0至1.5小时之间时,纯度和产率最令人满意。优选使用相当于式(2)化合物1.0至3.0当量的式(3)化合物。尤其使用R取代基为饱和C1-C4-烃基的式(3)化合物为佳。在各种卤代乙酸烷基酯中,卤代乙酸异丙酯要好于卤代乙酸甲酯或乙酯,并且在产率方面,卤代乙酸叔丁酯要好于卤代乙酸异丙酯。
优选使用相当于式(2)化合物1.0至3.0当量的锌金属。锌金属通常在20至120℃的温度范围内边与溶剂搅拌边进行回流。优选使用锌屑或锌粉。
至于活化锌金属的有机酸或其衍生物,优选使用相当于式(2)化合物0.001至0.1当量的R3CO2H,R3SO3H,R3CO2TMS,R3SO3TMS,或者(R3SO2)2NH,其中R3代表氢,饱和C1-C6-烃基,不饱和C2-C6烃基,卤素取代的饱和C1-C6-烃基,卤素取代的不饱和C2-C6烃基,C6-C12芳香基团或卤素取代的C6-C12芳香基团。
盐酸水溶液或硫酸水溶液可被用于水解反应步骤,而盐酸更合适。考虑纯度和产率因素,优选将反应溶液的pH值调至3到4之间。在0至5℃的温度范围内逐滴加入酸水溶液,优选在该温度下边搅拌边水解。
本发明之方法比以前的方法具有如下优点:1)副产物生成最少,2)所有的反应在室温或更高温度下进行,3)通过使用有机酸介导的活化作用,使各种试剂、α-卤代乙酸或α-卤代乙酸酯和锌的使用量最少。
所有这些改进应该有效地完成该方法,并且增进产品的质量和产率。
本发明将用以下实施例来做进一步解释。
实施例
实施例1:(S)-6-氯-5-羟基-3-氧-己酸叔丁酯的制备
将锌屑(690mg),四氢呋喃(4.0ml)和甲烷磺酸(10mg)加入反应容器中,并将混合液边回流边搅拌。在1小时内向混合液中加入(S)-4-氯-3-三甲基硅烷基氧丁腈(1.00克),接着加入溴代乙酸叔丁酯(2.04克)。混合液回流搅拌30分钟,然后冷却至0℃。逐滴加入3N的盐酸水溶液直至反应溶液的酸度值为pH4,然后将反应溶液搅拌3小时。反应结束后,减压蒸干四氢呋喃,残渣用乙酸乙酯提取后经硅胶柱层析纯化(洗脱液:乙酸乙酯/正己烷=1/3,v/v)得到目标化合物,产率为87%(1.07克)。
1H-NMR(400MHz,CDCl3)δ
烯醇型(7%):12.40(bs,1H),5.01(s,1H),4.19(m,1H),3.61(m,2H),2.88(m,2H),2.54(m,1H),2.49(bs,1H),2.47(m,1H),1.49(s,9H).
酮型(93%):4.32(m,1H),3.62(m,2H),3.42(s,2H),3.00(bd,1H),2.88(m,2H),1.48(s,9H).
质谱(ESI,m/z):497(2M+Na+2),495(2M+Na),261(M+Na+2),259(M+Na).
Claims (16)
2.权利要求1所述的方法,其中式(2)(S)-4-卤代-3-羟基丁腈衍生物中的P代表氢,或者代表SiRR1R2,其中R的定义如权利要求1所述,并且R1和R2各代表氢、饱和C1-C6-烃基、不饱和C2-C6烃基,或者C6-C12芳香基团,或者代表乙氧基乙基或四氢吡喃基。
3.权利要求2所述的方法,其中P代表三甲基甲硅烷基,三乙基甲硅烷基,叔丁基二甲基甲硅烷基或叔丁基二苯基甲硅烷基。
4.权利要求3所述的方法,其中P代表三甲基甲硅烷基。
5.权利要求1所述的方法,其中有机溶剂是选自苯,甲苯和醚中的一种或几种溶剂。
6.权利要求5所述的方法,其中有机溶剂是四氢呋喃。
7.权利要求1所述的方法,其中式(3)α-卤代乙酸或α-卤代乙酸酯化合物中的R代表饱和C1-C4-烃基。
8.权利要求7所述的方法,其中R代表叔丁基。
9.权利要求1或7所述的方法,其中式(3)α-卤代乙酸或α-卤代乙酸酯化合物的用量相当于式(2)化合物的1.0至3.0倍当量。
10.权利要求1所述的方法,其中锌金属的用量相当于式(2)化合物的1.0至3.0倍当量。
11.权利要求10所述的方法,其中锌金属为锌屑或锌粉。
12.权利要求1所述的方法,其中有机酸或其衍生物选自R3CO2H,R3SO3H,R3CO2TMS,R3SO3TMS,以及(R3SO2)2NH,其中R3代表氢,饱和C1-C6-烃基,不饱和C2-C6烃基,卤素取代的饱和C1-C6-烃基,卤素取代的不饱和C2-C6烃基,C6-C12芳香基团或卤素取代的C6-C12芳香基团。
13.权利要求12所述的方法,其中有机酸或其衍生物的用量相当于式(2)化合物的0.001至0.1倍当量。
14.权利要求1所述的方法,其中酸水溶液为盐酸或硫酸水溶液。
15.权利要求1所述的方法,其中所加酸水溶液的量应使pH值调至3到4。
16.权利要求15所述的方法,其中酸水溶液应在0至5℃的温度范围内逐滴加入。
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US7732546B2 (en) * | 2007-10-03 | 2010-06-08 | Bausch & Lomb Incorporated | Use of silylated sulfonate monomers to improve contact lens wettability |
KR101076680B1 (ko) * | 2007-11-01 | 2011-10-26 | 한미홀딩스 주식회사 | (6r)-3-헥실-4-히드록시-6-운데실-5,6-다이히드로피란-2-온의 제조방법 및 이에 사용되는 중간체 |
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US5594153A (en) * | 1992-03-27 | 1997-01-14 | E. R. Squibb & Sons, Inc. | Process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-COA reductase inhibitors |
US6340767B1 (en) * | 1999-06-04 | 2002-01-22 | Kaneka Corporation | Processes for the preparation of 5-hydroxy-3-oxopentanoic acid derivatives |
US6399339B1 (en) * | 1998-12-14 | 2002-06-04 | Forschungszentrum Julich Gmbh | Method for the enantioselective reduction of 3,5-dioxocarboxylic acids, their salts and their esters |
EP1024139B1 (en) * | 1998-08-05 | 2004-05-12 | Kaneka Corporation | Process for the preparation of optically active 2-(6-(hydroxymethyl)-1,3-dioxan-4-yl) acetic acid derivatives |
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US5594153A (en) * | 1992-03-27 | 1997-01-14 | E. R. Squibb & Sons, Inc. | Process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-COA reductase inhibitors |
EP1024139B1 (en) * | 1998-08-05 | 2004-05-12 | Kaneka Corporation | Process for the preparation of optically active 2-(6-(hydroxymethyl)-1,3-dioxan-4-yl) acetic acid derivatives |
US6399339B1 (en) * | 1998-12-14 | 2002-06-04 | Forschungszentrum Julich Gmbh | Method for the enantioselective reduction of 3,5-dioxocarboxylic acids, their salts and their esters |
US6340767B1 (en) * | 1999-06-04 | 2002-01-22 | Kaneka Corporation | Processes for the preparation of 5-hydroxy-3-oxopentanoic acid derivatives |
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JP2006513245A (ja) | 2006-04-20 |
DE60328717D1 (de) | 2009-09-17 |
CA2512630A1 (en) | 2004-07-29 |
EP1583730A4 (en) | 2006-08-09 |
IL169191A0 (en) | 2009-02-11 |
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US7081546B2 (en) | 2006-07-25 |
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