CN1051991C - 戊二酸衍生物的制备方法 - Google Patents
戊二酸衍生物的制备方法 Download PDFInfo
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- 238000000034 method Methods 0.000 claims abstract description 26
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- MXJWWBZRSZLYCM-UHFFFAOYSA-N C1(CCCC1)C(=O)O.[Li] Chemical compound C1(CCCC1)C(=O)O.[Li] MXJWWBZRSZLYCM-UHFFFAOYSA-N 0.000 description 1
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- 238000007429 general method Methods 0.000 description 1
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- 238000010438 heat treatment Methods 0.000 description 1
- NEXSMEBSBIABKL-UHFFFAOYSA-N hexamethyldisilane Chemical compound C[Si](C)(C)[Si](C)(C)C NEXSMEBSBIABKL-UHFFFAOYSA-N 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
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- 238000002156 mixing Methods 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
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- 239000001103 potassium chloride Substances 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
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- 229940095064 tartrate Drugs 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/30—Preparation of optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
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- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
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- Lubricants (AREA)
- Peptides Or Proteins (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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Abstract
本发明提供了式(Ⅰ)和(Ⅱ)化合物的基本光学纯的2(S)-立体异构体及其盐,以及它们的制备方法,这些化合物是制备抗血压剂的中间体。
Description
本发明涉及戊二酸衍生物及它们的制备方法。
更明确地讲,本发明涉及2-氨基甲基-3-(1-羧基环戊基)丙酸衍生物的2(S)-立体异构体和其中间体,以及它们的制备方法。
欧洲专利申请89308740.3公开了一系列环烷基取代的戊二酰胺衍生物,它们是抗高血压剂,可用于治疗多种心血管疾病(包括高血压和心力衰竭),特别优选其分子的戊二酰胺部分具有2(S)-构型。这些化合物是从具有所需2(S)-构型的光学纯的前体制备的,而这些前体可通过某些相应的外消旋(即,2(R,S)-)中间体的分步结晶得到。
在本发明的一个方面提供的一些新颖化合物可用作有用的中间体,以制备欧洲专利申请89308740.3中公开的一些优选化合物。新的合成路线和已有的方法相比。具有更重要的工业改进,比如,操作的方便和低成本。
本发明的新化合物可有效地通过一个意料之外的发现制造,即所需的2(S)-戊二酸部分可通过不对称合成的方法,在全过程的比较早的阶段产生。在该过程步骤中产生了基本纯的2(S)-立体异构中间体,而避免了为去掉相应的不需要的2(R)-立体异构体所需的分步结晶阶段。
因此,本发明提供了:a)具有下式的化合物的基本光学纯的2(S)-立体异构体、及其酸加成盐和碱盐,其中,R为C1-C4烷基或-CH2CH2Si(CH3)3,*表示具有(S)-构型的不对称中心;b)具有式(II)的化合物的基本光学纯的2(S)-立体异构体、及其酸加成盐和碱盐,其中R和*如对式(I)所定义;c)制备式(I)化合物的基本光学纯的2(S)-立体异构体及其酸加成盐和碱盐的方法,包括如下步骤:(i)在非质于性溶剂中,在或低于-10℃的温度下,使式(III)化合物与式(IV)盐反应,
其中R如在式(I)中所定义,
其中M1和M2可以相同或不同。选自于Li+,Na+和K+;
(ii)在-10℃或低于该温度下,酸化反应混合物;
然后可任意地把式(I)产物转化成酸加成盐或碱盐;d)式(II)化合物的基本光学纯的2(S)-立体异构体及其酸加成盐或碱盐的制备方法,包括将式(I)化合物的基本光学纯的2(S)-立体异构体及其酸加成盐或碱盐催化氢化;接下来可任意地把式(II)产物转化成其酸加成盐或碱盐。
在上面的式(I)和(III)中,取代基“C6H5”代表苯基。
含有3或4个碳原子的烷基可以是直链的或支链的。
术语“基本光学纯的”含义是,式(I)和(II)化合物及其酸加成盐和碱盐含有低于10%,最好低于5%的2(R)-立体异构体。
合适的式(I)和(II)化合物的酸加成盐的例子包括:盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐或硫酸氢盐、磷酸盐或磷酸氢盐、乙酸盐、马来酸盐、富马酸盐、乳酸盐、酒石酸盐、柠檬酸盐、葡糖酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐和对甲苯磺酸盐。
合适的式(I)和(II)化合物的碱盐的例子包括:碱金属盐、碱土金属盐、三烷基铵盐和N-烷基吗啉盐等。
在上面式(I)、(II)和(III)化合物的定义中,R优选为C1-C4烷基。
R最优选为甲基,乙基或叔丁基。
式(I)和(II)化合物的优选的碱盐是钠盐。
在式(IV)化合物的定义中,M1和M2都优选为Li+。
在本发明的一个方面中提供的化合物可按如下方法制备:1、式(I)化合物的基本光学纯的2(S)-立体异构体通过不对称合成制备,其中,通常,盐(IV)可用至少两个当量的合适强碱使环戊烷羧酸去质子化就地产生,也可以用至少一个当量的合适强碱使合适的环戊烷羧酸盐(如环戊烷羧酸锂、钠或钾盐)去质子化产生。
适合于这些目的强碱的例子有:二异丙基胺基钾、六甲基二硅烷基胺基锂、最好是二异丙基胺基锂。
在优选的方法中,盐(IV)用至少两个当量的二异丙基胺基锂使环戊烷羧酸去质子化就地产生。去质子化反应在惰性气氛下和合适的非质子有机溶剂例如四氢呋喃中进行,温度为从-70℃到室温。然后,使丙烯酸酯(III)与盐(IV)在最初的温度(从-80℃到-10℃,最好是从-70℃到-15℃)下反应,在大约-15℃搅拌一段时间后,通过酸化来停止反应。
酸化反应的进行,最好是将在大约-15℃的反应混合物倒入冰冷却的合适酸的水溶液中。
酸化步骤中可使用任何合适的无机酸或有机酸,例如,盐酸、硫酸、柠檬酸或乙酸。最优选的是盐酸。
然后,式(I)产物可用常规的技术进行分离和纯化,如萃取工艺和/或色谱方法。
该方法出人意料地产生了具有高光学纯度的2(S)-构型的式(I)产物,通常含有低于或等于5%的相应的2(R)-立体异构体。
在典型的方法中,将(S,S)-α,α′-二甲基二苄基胺(VI)加到2-溴甲基丙烯酸酯(V)和碳酸钾在乙腈中的冷的混合物中。将混合物在约60℃加热大约18小时,然后用常规技术分离丙烯酸酯(III)。
2-溴甲基丙烯酸酯(V)或可以买到,或可用一般方法制备。
式(VI)手性助剂可用文献的方法制备,见C.G.Overberger,N.P.Marullo and R.G.Hiskey.J.A.C.S.,83.1374(1961)。2、式(II)化合物的基本光学纯的2(S)-立体异构体,可通过相应的式(I)化合物的基本光学纯的2(S)-立体异构体或其酸加成盐或碱盐的催化氢化来制备。这可通过除去经手性助剂引入的甲基苄基而去掉氨基的取代基,产生更有用的合成中间体(II)。
催化氢化最好用式(I)化合物的适当碱盐形式进行,以减少或避免氨基去保护之后形成内酰胺的可能性。由于这个原因,化合物(II)最好以适当碱盐的形式分离和保存。
在典型的方法中,化合物(I)首先转化成适当的碱盐,如,碱金属盐,碱土金属盐,三烷基铵盐或N-烷基吗啉盐,然后在合适的溶剂(如,C1-C4醇或其水溶液)中,用催化氢化还原。
催化氢化最好是用氢氧化钯-活性炭作催化剂,在室温下和甲醇中,用化合物(I)的钠盐进行。
然后可用常规的技术,分离并纯化式(II)产物的碱盐。如果需要,式(I)和(II)化合物可通过把含有等摩尔量的适当化合物的溶液和一种合适的酸或碱混合在一起,而转化成其酸加成盐或碱盐。该盐可以从溶液中沉淀出来,并可用过滤法收集,或者通过蒸发溶剂来回收。
本发明提供的式(I)和(II)化合物及其酸加成盐或碱盐,可用来制备欧洲专利申请89308740.3中公开的某些优选化合物,举例如下:
(i)把式(I)化合物或其酸加成盐或碱盐转化成适当的戊二酰胺衍生物,用催化氢化脱去氨基的保护基,并使得到的一级氨基与适当的赖氨酸衍生物反应;
(ii)式(II)化合物碱盐的氨基与适当的赖氨酸衍生物反应,然后形成适当的戊二酰胺衍生物。
下列实施例解释发明:
实施例1
(a)2-[(S,S)-α,α'-二甲基二苄基]氨基甲基丙烯酸叔丁酯
在搅拌和冰冷却下,向2-(溴甲基)丙烯酸叔丁酯(29.4g,0.133ml)在乙腈(150ml)中的溶液中,加入无水碳酸钾(22.9g,0.166mol),按着滴加(S,S)-α,α'-二甲基二苄基胺(34.3g,0.152mol)(见C.G.Overberger等人,J.A.C.S.,83 1374(1961))在乙腈(150ml)中的溶液,得到的混合物在60℃搅拌18小时,然后真空蒸发。残留物在乙醚(200ml)和水(100ml)之间分配,分出醚层,水相进一步用乙醚提取(3×200ml)。
合并的乙醚层用水(5×100ml)洗涤,干燥(无水硫酸镁),过滤并真空蒸发,给出淡黄色油状物。用硅胶层折纯化,梯度洗脱剂为0-2%乙酸乙酯在己烷中的溶液。合并和真空蒸发适当的部分,得到所要的产物(40.5g,83%),[α]589-59.3°(c=1,甲醇)。实验值:C,78.63;H,8.58;N,3.59;C24H31NO2理论值:C,78.86;H,8.55;N.3.83%。(b)2(S)-[(S,S)-α,α′-二甲基二苄基]氨基甲基-3-(1-羧基环戊基)丙酸叔丁酯·一水合物
在-30℃和干燥氮气氛下,将正丁基锂己烷溶液(2.5M,34.4ml,0.086mol)滴加到搅拌着的二异丙基胺(8.70g,0.086mol)在干燥四氢呋喃(200ml)中的溶液中,得到的溶液温热至0℃保持15分钟,然后再冷却到-40℃,再滴加环戊烷羧酸(4.68g,0.041mol)在干燥四氢呋喃(65ml)中的溶液。反应混合物在室温搅拌2小时,然后冷却至-70℃。向含有该双负离子的混合物中滴加部分(a)的产物(15.0g,0.041mol)在干燥四氢呋喃(35ml)中的溶液,反应温度在-70℃保持30分钟,然后温热至-15℃,并在-15℃保持2小时。
在搅拌和冰冷却下,将得到的淡黄色溶液倒入1M盐酸(200ml)和乙醚(200ml)的混合物中。分出醚相,水相继续用乙醚(3×200ml)提取。合并的醚相依次用饱和碳酸氢钠水溶液(5×100ml),水(2×200ml)和饱和盐水(2×200ml)洗涤,然后干燥(无水硫酸镁)。过滤并真空蒸发,得到黄色油状物,经硅胶层析纯化,用0-25%乙酸乙酯的己烷溶液梯度洗脱。合并并真空蒸发适当的部分,给出所要的产物(16.3g,80%),[α]589-19.9°(c=1,甲醇)。实验值:C,72.62;H,8.48;N,2.79;C30H41NO4·H2O的理论值:C,72.40;H,8.71;N,2.81%。1H-NMR(300MHz)表明,就所要求的2(S)-立体异构体而论,产物的光学纯度大约为95%。(c)2(S)-氨基甲基-3-(1-羧基环戊基)丙酸叔丁酯·钠盐·半水合物
部分(b)中产物(10.0g,0.020mol)在乙醇(100ml)中的溶液,用氢氧化钠水溶液(1M,19.9ml)处理,得到的溶液在高真空和室温下蒸发。得到的胶状物溶于乙醇(150ml),在60p.s.i.(414kPa)压力和室温下,用20%氢氧化钯-活性炭(1.0g)催化氢化18小时。通过一个由专买的纤维基过滤助剂构成的垫,过滤除去催化剂.在高真空和室温下蒸发滤液。残留溶剂用二氯甲烷(3×50ml)经共沸除去,得到所要的产物,呈白色腊状固体(5.79g,95%),[α]589-3.0°(c=1,甲醇)。实验值:C,55.81;H,8.28;N,4.34;C14H24NO4Na·0.5H2O理论值:C,55.61;H,8.33;N,4.63%。
实施例22(S)-[(S,S)-α,α′-二甲基二苄基]氨基甲基-3-(1-羧基环戊基)丙酸乙酯(a)2-[(S,S)-α,α′-二甲基二苄基]氨基甲基丙烯酸乙酯
该合成按实施例1(a)的方法进行,使用2-(溴甲基)丙烯酸乙酯(10.0g,0.052mol)在乙腈(60ml)中的溶液,无水碳酸钾(8.9g,O.065mol)和(S,S)-α,α'-二甲基二苄基胺(12.8g,0.057mol)在乙腈(40ml)中的溶液。
得到的油状物粗品用硅胶柱层析纯化,用0-10%乙酸乙酯的己烷溶液梯度洗脱,经合并和蒸发适当部分的洗脱液之后,得到所要的产物(16.8g,96%),[α] 589-62.5°(c=1,甲醇)。实验值:C,78.25;H,8.10;N,4.29;C22H27NO2的理论值:C,78.30;H,8.07;N,4.15%。(b)2(S)-[(S,S)-α,α′-二甲基二苄基]氨基甲基-3-(1-羧基环戊基)丙酸乙酯
该合成按实施例1(b)的方法进行,使用正丁基锂己烷溶液(2.5M,17.4ml,0.0435mol),二异丙基胺(4.4g,0.0435mol)在干燥四氢呋喃(100ml)中的溶液,环戊烷羧酸(2.41g,0.021mol)在干燥四氢呋喃(35ml)中的溶液,及部分(a)的产物(7.0g,0.021mol)在干燥四氢呋喃(15ml)中的溶液。
得到的胶状物粗品经硅胶层析纯化,用0-10%乙酸乙酯的己烷溶液梯度洗脱,在合并并蒸发适当的洗脱液之后,得到所要产物(4.9g,52%),[α]589-13.2°(c=1,甲醇)。实验值:C,74.16;H,8.18;N,3.27;C28H37NO4理论值:C,74.47;H,8.26;N,3.10%。1H-NHR(300MHz)表明,就所要求的2(S)-立体异构体而言,产物的光学纯度大约为95%。
实施例32-(S)[(S,S)-α,α′-二甲基二苄基]氨基甲基-3-(1-羧基环戊基)丙酸甲酯(a)2-[(S,S)-α,α'-二甲基二苄基]氨基甲基丙烯酸甲酯
该合成按实施例1(a)的方法进行,使用2-(溴甲基)丙烯酸甲酯(5.8g,0.032mol)在乙腈(40ml)中的溶液,无水碳酸钾(5.52g,0.040mol)和(S,S)-α,α'-二甲基二苄基胺(8.1g,0.036mol)在乙腈(40ml)中的溶液。
得到的油状物粗品经硅胶层析纯化,用0-10%乙酸乙酯的己烷溶液梯度洗脱,在合并及蒸发适当的洗脱部分之后,得到所要产物(9.7g,94%),[α] 589-69.7°(c=1,甲醇)。实验值:C,78.19;H,8.00;N,4.45;C21H25NO2理论值:C,77.99;H,7.91;N,4.33%。(b)2(S)-[(S,S)-α,α'-二甲基二苄基]氨基甲基-3-(1-羧基环戊基)丙酸甲酯
该合成按实施例1(b)的方法进行,使用正丁基锂己烷溶液(2.5M,17.4ml,0.0435mol),二异丙基胺(4.4g,0.0435mol)在干燥四氢呋喃(100ml)中的溶液,环戊烷羧酸(2.41g,0.021mol)在干燥四氢呋喃(35ml)中的溶液及部分(a)的产物(6.79g,0.021mol)在干燥四氢呋喃(15ml)中的溶液。
得到的油状物粗品经硅胶层析纯化,用0-30%乙酸乙酯的己烷溶液梯度洗脱,在合并及蒸发适当的洗脱部分之后,得到所要产物(7.77g,84%),[α]589-10.8°(c=1,甲醇)。实验值:C,73.61;H,8.01;N,3.21;C27H35NO4理论值:C,74.12;H,8.06;N,3.20%。1H-NMR(300MHz)表明,就所要求的2(S)-立体异构体而言,产物的光学纯度大约为95%。
Claims (7)
2.根据权利要求1所要求的方法,其中M1和M2都是Li+。
3.根据权利要求2所要求的方法,其中式(IV)盐是用二异丙基胺基锂使环戊烷羧酸去质子化而产生的,非质子性有机溶剂是四氢呋喃。
4.根据权利要求1所要求的方法,其中R是C1-C4烷基。
5.根据权利要求1所要求的方法,其中式(I)化合物的盐是指酸加成盐或碱盐。
6.根据权利要求5所要求的方法,其中所述盐是碱盐。
7.根据权利要求1所要求的方法,其中式(I)化合物及其酸加成盐和碱盐含有少于5%的2(R)-立体异构体。
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