CN1196793C - 二羟基酯及其衍生物的制备方法 - Google Patents
二羟基酯及其衍生物的制备方法 Download PDFInfo
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- CN1196793C CN1196793C CNB018124895A CN01812489A CN1196793C CN 1196793 C CN1196793 C CN 1196793C CN B018124895 A CNB018124895 A CN B018124895A CN 01812489 A CN01812489 A CN 01812489A CN 1196793 C CN1196793 C CN 1196793C
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- formula
- compound
- alkyl
- lipase
- vinyl
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- 150000001875 compounds Chemical class 0.000 claims abstract description 57
- 230000032050 esterification Effects 0.000 claims abstract description 11
- 238000005886 esterification reaction Methods 0.000 claims abstract description 11
- 238000011916 stereoselective reduction Methods 0.000 claims abstract description 7
- 108090001060 Lipase Proteins 0.000 claims description 23
- 239000004367 Lipase Substances 0.000 claims description 23
- 102000004882 Lipase Human genes 0.000 claims description 23
- 235000019421 lipase Nutrition 0.000 claims description 23
- 210000004027 cell Anatomy 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 17
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 7
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
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- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 4
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- XFNHABJTGIHGPN-SFYZADRCSA-N tert-butyl (3r,5s)-3,5,6-trihydroxyhexanoate Chemical compound CC(C)(C)OC(=O)C[C@H](O)C[C@H](O)CO XFNHABJTGIHGPN-SFYZADRCSA-N 0.000 description 1
- IHXJKEHRLMXFTC-UHFFFAOYSA-N tert-butyl 6-acetyloxy-3,5-dihydroxyhexanoate Chemical compound CC(=O)OCC(O)CC(O)CC(=O)OC(C)(C)C IHXJKEHRLMXFTC-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- PTMFUWGXPRYYMC-UHFFFAOYSA-N triethylazanium;formate Chemical compound OC=O.CCN(CC)CC PTMFUWGXPRYYMC-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 238000013022 venting Methods 0.000 description 1
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Abstract
本发明提供制备式(1)化合物的方法,其中R和R′代表未取代的或取代的烃基并且X代表烃基连接基。该方法包括立体选择性还原二羟基酮前体中的酮基,然后选择性酯化伯羟基或选择性酯化二羟基酮前体的伯羟基,然后立体选择性还原酮基。
Description
本发明涉及立体选择性制备二羟基酯及其衍生物的方法。
一方面,本发明提供制备式(1)化合物的方法
式1
该方法包括
a)、立体选择性还原式(2)化合物
式2
产生式(3)化合物,和
式3
b)、在式R″-O-COR′化合物和脂肪酶或水解酶存在下酯化式(3)化合物,由此形成式(1)化合物;或者
c)、在式R″-O-COR′化合物和脂肪酶或水解酶存在下酯化式(2)化合物,由此形成式(4)化合物,和
式4
d)、立体选择性还原式(4)化合物,产生式(1)化合物;
其中
X代表未取代的或取代的烃基连接基,
R和R″各独立地代表未取代的或取代的烃基,并且
R′代表未取代的或取代的烃基,优选未取代的或取代的烷基。
由X、R、R′或R″表示的烃基可以被一个或多个取代基取代,并且可以是全取代的,例如全卤代。取代基的实例包括:卤素,特别是氟和氯;烷氧基,如C1-4烷氧基;和氧代。
优选地,X代表式-(CH2)n-,其中n为1-4,并且最优选X代表式-CH2-。
R″可以是烷基,如C1-6烷基;或烷基羰基,如C1-6烷基羰基(例如CH3(C=O)-或CF3(C=O)-基);最优选R″为乙烯基或异丙烯基。
优选地,R代表C1-6烷基,它可以是直链或支链的,并且可以是由1个或多个取代基取代的。最优选地,R代表叔丁基。
R′可代表取代的烷基,通常为C1-6烷基,如CF3-或CF3CH2-基,但优选未取代的C1-6烷基,并且尤其最优选甲基。
优选地,利用化学或微生物还原方法如氢化、转移氢化、金属氢化物还原或脱氢酶立体选择性还原式(2)或(4)化合物。适宜的氢化方法的实例如Helv.Chim.Acta 69,803,1986中所描述的方法(引入本文供参考),包括使用溶剂如甲醇、乙醇、叔丁醇、二甲基甲酰胺、叔丁基甲醚、甲苯或己烷,使用0.01-10%(w/w)的催化剂,如在异种支撑物如碳、铝、硅石上的铂、钯或铑,和使用1-10巴的分子氢。或者可以使用同种的氢化催化剂如EP0583171中所描述的那些(引入本文供参考)。
适宜的化学转移氢化方法的实例包括在Zassinovich,Mestroni andGladiali,Chem.Rev.1992,92,1051中所描述的那些方法(引入本文供参考)或由Fuji等人在J.Am.Chem.Soc.118,2521,1996中所描述的那些方法(引入本文供参考)。优选地,化学转移氢化方法利用过渡金属如钌或铑手性配位体络合物,特别是手性二胺配位的中性芳香钌络合物。优选地,所述化学转移氢化方法使用酸特别是甲酸盐如甲酸三乙基铵作为氢源。
可使用金属氢化物试剂,如Tet.1993,1997,Tet.Asymm.1990,1,307(引入本文供参考)或J.Am.Chem.Soc.1998,110,3560(引入本文供参考)中所描述的那些。
适宜的微生物还原的实例包括将式(2)或式(4)化合物与具有微生物特性的生物体接触,所述微生物选自白僵菌属优选蚕白僵菌、毕赤氏酵母属优选红橡胶树毕赤氏酵母或巴斯德毕赤氏酵母、喜海藻糖毕赤氏酵母、甲虫毕赤氏酵母或膜醭毕赤氏酵母、念珠菌属优选土生假丝酵母、马铃薯假丝酵母、季也蒙氏假丝酵母、迪丹氏假丝酵母或弗里德氏假丝酵母、克鲁维氏酵母属优选果蝇克鲁维氏酵母或有孢圆酵母属优选Torulaspora hansenii。所述还原可通过将式(2)或(4)化合物与由上述微生物提取的酶接触实现。最优选地,将式(2)或(4)化合物与选自红橡胶毕赤氏酵母、巴斯德毕赤氏酵母、季也蒙氏假丝酵母、卡尔斯伯糖酵母(Saccharomyces carisbergensis)、喜海藻糖毕赤氏酵母、果蝇克鲁维氏酵母和Torulaspora hansenii的微生物或上述微生物的提取物接触。
优选地,本发明包括利用上述微生物,优选红橡胶毕赤氏酵母、巴斯德毕赤氏酵母、季也蒙氏假丝酵母、卡尔斯伯糖酵母(Saccharomycescarisbergensis)、喜海藻糖毕赤氏酵母、果蝇克鲁维氏酵母和Torulaspora hansenii的全细胞或提取物选择性还原式(2)化合物来制备式(3)化合物。
最优选地,利用微生物的全细胞进行本发明,因为这样避免了分离所需要的酶和提供反应辅因子的需要。
可使用任一种上述微生物,但在很多实例中,发现使用红橡胶毕赤氏酵母的酶或全细胞可获得高转化率和高选择性。
通常,辅因子NAD(P)H(烟酰胺腺嘌呤二核苷酸或烟酰胺腺嘌呤二核苷酸磷酸)和再生辅因子,例如葡萄糖和葡萄糖脱氢酶的系统与酶一起使用以便驱动反应。适宜的辅因子和还原机构存在于全细胞中,优选使用在营养培养基中的全细胞,所述营养培养基中优选地包含适宜的碳源,所述碳源可包括下列一种或多种:糖如麦芽糖、蔗糖或者优选葡萄糖,多元醇如丙三醇或山梨糖醇,枸橼酸或低级醇如甲醇或乙醇。
如果打算让全细胞在反应过程中生长,那么培养基中应该包含氮和磷源以及微量元素。这些可以是培养生物体时通常使用的那些。
可通过将式(2)或(4)化合物加到在能够支持生长并含有生长生物体的培养基中或加到活细胞在包含碳源但缺少一种或多种生长必需营养物的培养基中所形成的悬浮液中进行本方法。也可以使用死细胞,前提条件是存在必需的酶和辅因子,如果需要,可将它们加到所述死细胞中。
如果需要,所述细胞可固定在一载体上,然后,优选地在上述适宜的碳源存在下,将该载体与式(2)或(4)化合物接触。
适宜的pH为3.5-9,例如4-9,优选至多6.5并且更优选至多5.5。非常适宜的pH为4-5。本方法可适宜地在10-50℃,优选20-40℃并且更优选25-35℃的温度下进行。如果上述生物体的活的全细胞存在,那么优选在需氧条件下进行所述方法。在上述pH和温度下使用在标准温度和压力下测定时相当于每分钟每份量培养基通入0.01-1.0份量空气的充气速度是适宜的,但应该理解,考虑周到的变更是可能的。在生物体生长过程中如果将方法分开进行,可使用类似的pH、温度和充气条件。
按照已知的方法,通过离心解体细胞的悬浮液并分离澄清的溶液与碎片,以及通过离子交换色谱法,用离子强度递增的液体洗脱柱子分离所需要的酶与溶液和/或通过加入离子物质,例如硫酸铵选择性沉淀来分离提纯的酶。如果需要,可重复所述操作以便提高纯度。
特别优选微生物还原式(2)或(4)化合物,并且该方法构成本发明第二方面。
在式(2)或(3)化合物酯化中,优选用另一酯进行酯基转移,所述另一酯至少与醇等摩尔量并且适宜地为乙烯基酯(在后-反应中不涉及副产品乙醛)。或者,可使用酸酐如乙酸酐或三氟乙酸酐或酯如乙酸乙酯或氟化酯如三氟乙酸乙酯。优选在20-75℃,更优选25-50℃的温度下,在含有低于1%(w/w)水的有机溶剂如乙腈、乙酸乙酯、四氢呋喃、叔丁基甲基醚、甲苯、丁酮、戊酮或己酮中进行区域专一性酯化。优选地,所述酯是具有2-8个碳原子的低级链烷酸的酯或其取代的衍生物。可以不使用或使用惰性环境,例如可让氮气流通过溶液。
所述酶可以以酶或包含它们的全细胞形式提供。优选固定它们以便促进它们与产物的分离,如果需要,可再使用。
优选的酶包括脂肪酶如猪胰腺脂肪酶,Candida cylindracea脂肪酶,荧光假单胞菌脂肪酶,Candida antarctica fraction B如以Chirazyme L2为商标销售的那些,由Humicola lanuginosa获得的脂肪酶,例如以Lipolase为商标销售的那些或由假单孢杆菌属获得的脂肪酶,例如以SAM II为商标销售的那些并且更优选由Candida antarctica获得的脂肪酶,例如以Chirazyme为商标销售的那些。
其中R′为CH3,R为未取代的或取代的烃基,X为-(CH2)n-并且n为1-4的式(1)化合物构成本发明第三方面。优选地,R为叔丁基并且最优选地,X为-CH2-。
式(1)化合物是制备药用化合物有用的中间体。通常,将它们与1,3-二羟基部分的保护基如2,2-二甲氧基丙烷反应形成丙酮化合物(如合成1998,1713所述)。然后,可通过在水溶液或含有足以支持水解量水的有机溶液中用弱碱性醇溶液,例如K2CO3溶液(如US5,278,313所述)或脂肪酶处理选择性除去R′-(C=)-基,形成式(5)化合物:
式5
制备式(5)化合物的方法构成本发明第四方面。
实施例1
制备(3R,5S)3,5,6-三羟基己酸叔丁酯
在搅拌下,向250ml圆底烧瓶中加入20ml乙腈、0.405g(0.662mmol)二-μ-氯双[(对-异丙基甲苯)氯钌(II)]和0.492g(1.34mmol)(1S,2S)-(+)-N-(4-甲苯磺酰基)-1,2-二苯基乙二胺。该溶液通过以喷射形式通入氮,然后保持小流量进行脱氧。将26g(0.119mol)光学纯(5S)-3-酮基-5,6--二羟基己酸叔丁酯在15ml乙腈中的脱氧溶液加到反应容器中并将该溶液在室温下搅拌20分钟。然后用10分钟的时间加入65ml蒸馏的甲酸和三乙胺5∶2(mol/mol)的混合物中并将该反应混合物在室温下搅拌48小时。缓慢地向该溶液中加入80ml二氯甲烷和120ml饱和碳酸氢钠溶液。将70g氯化铵加到水层中并分离有机层。水层用90ml乙酸乙酯洗涤三次以上,合并有机相,用硫酸钠干燥并除去溶剂得到21.1g主要含(3R,5S)3,5,6-三羟基己酸叔丁基酯的粗品油状物。通过13CNMR测定的非对映异构体的比例为5.2∶1(3R∶5S)∶(3S∶5R)。该物质用作下一步反应的粗品,但可通过柱色谱层析纯化。
制备(3R,5S)6-乙酰氧基-3,5-二羟基-己酸叔丁基酯
在搅拌下,向1L的圆底烧瓶中加入700ml四氢呋喃和70.7g(0.32mol)(3R,5S)--3,5,6-三羟基-己酸叔丁基酯,41ml(0.46mol)乙烯基乙酸酯和6.3g支撑脂肪酶Chirazyme L2TM。在室温下搅拌3小时后,通过筛选作用除去脂肪酶并通过真空蒸馏除去挥发物。粗品油状物的量为78.7g,所测定的主要成分为(3R,5S)-6-乙酰氧基-3,5-二羟基-己酸叔丁基酯。该物质直接用于下一步中。
制备(4R,6S)-6-[(乙酰氧基)甲基]-2,2-二甲基-1,3-二恶烷-4-乙酸1,1-二甲基乙酯
在搅拌下,向1L的圆底烧瓶中加入78.7g(3R,5S)叔丁基6-乙酰氧基-3,5-二羟基-己酸酯,800ml 2,2-二甲氧基丙烷和5.7g对甲苯磺酸。35分钟后,将反应物浓缩至其体积的一半并加入300ml二氯甲烷和300ml1M碳酸氢钠。分离有机层,水层用150ml乙酸乙酯洗涤三次以上。合并有机相,用硫酸钠干燥并通过真空蒸馏除去挥发物,得到92g粗品油状物。该粗品首先通过短闪式硅胶柱,用己烷洗脱,然后用己烷∶乙酸乙酯85∶15(v/v)洗脱,然后将该物质在己烷中结晶3次得到22.17g(4R,6S)-6-[(乙酰氧基)甲基]-2,2-二甲基-1,3-二恶烷-4-乙酸1,1-二甲基乙酯,通过手性GC测定该物质为99.9%de。
制备(4R,6S)-6-[(羟基)甲基]-2,2-二甲基-1,3-二恶烷-4-乙酸1,1-二甲基乙酯
在搅拌下,向500ml的圆底烧瓶中加入22.17g(3R,6S)-6-[(乙酰氧基)甲基]-2,2-二甲基-1,3-二恶烷-4-乙酸1,1-二甲基乙酯,250ml甲醇和5.05g粉碎的碳酸钾。将该反应搅拌35分钟直至水解结束,然后通过过筛除去碳酸钾,浓缩反应物并加入150ml 5%(w/w)的盐水和150ml甲苯。分离有机层,水层用250ml甲苯洗涤两次以上。合并有机相,用15%(w/w)的盐水洗涤三次并通过真空蒸馏除去溶剂,得到17.78g澄清的油状物,经测定该油状物为>99%的(4R,6S)-6-[(羟基)甲基]-2,2-二甲基-1,3-二恶烷-4-乙酸1,1-二甲基乙酯。
实施例2
制备(5S)-6-乙酰氧基-5-羟基-3-酮己酸叔丁基酯
在搅拌下,向250ml圆底烧瓶中加入2.32g(0.0106mol)(5S)5,6-二羟基-3-酮己酸叔丁基酯、40ml四氢呋喃、0.98ml(0.0106mol)乙酸乙烯基酯和0.22g支撑脂肪酶Chirazyme L2TM。20分钟后,通过筛选作用除去脂肪酶并通过真空蒸馏除去挥发物,得到2.96g粗品油状物,通过NMR确定为(5S)-6-乙酰氧基-5-羟基-3-酮己酸叔丁基酯。
实施例3
制备(3R,5S)-3,5,6-三羟基己酸叔丁基酯
在Braun Biostat Q多-发酵罐系统中,红橡胶毕赤氏酵母NCYCR230(按照1995年5月18日布达佩斯条约中有关食品的内容保存)在下列培养基中生长(每升含):葡萄糖,40g;MgSO4,1.2g;K2SO4,0.21g;KH2PO4,0.69g;H3PO4(浓的),1ml;酵母菌提取物(Oxoid),2g;FeSO4·7H2O,0.05g;止泡剂(EEA 142 Foammaster),微量元素溶液,1ml(该溶液每升包含CuSO4·5H2O,0.02g;MnSO4·4H2O,0.1g;ZnSO4·7H2O,0.1g;CaCO3,1.8g)。
4个发酵罐中的每个发酵罐中加入250ml培养基并通过高压灭菌法灭菌。用7摩尔氢氧化铵溶液调至pH4.5,温度设定在28℃下,气流设定在300ml/分钟,搅拌速度设定在1200rpm。将发酵罐与琼脂平皿(2%琼脂,其中除葡萄糖浓度为20g/升外包含上述相同培养基)中采集的细胞一起培养。在发酵罐中生长22小时后,通过加入(5S)叔丁基3-酮基-5,6-二羟基己酸酯开始生物还原反应;其中两个发酵罐各加入3.75ml而另外两个发酵罐各加入5m。
反应再继续78小时直至底物100%转化。在该过程中,培养基中以1-3g葡萄糖/升培养基/小时的速度加入50%葡萄糖溶液以便保持细胞生存力和提供还原力来源。通过离心除去细胞终止反应。向回收的不含细胞上清液中加入氯化钠至最终浓度20%w/v,混合物用等体积的乙腈提取三次。所收集的乙腈提取液用无水硫酸钠干燥,在旋转蒸发器(水浴温度45℃)中减压除去溶剂得到粘性淡黄色油状物。各反应所得到产物确定为(3R,5S)-3,5,6-三羟基己酸叔丁基酯并且各样品中非对映异构体过量显示于下表。
实验 | 非对映异构体过量(%) |
1 | 99.6 |
2 | 99.6 |
3 | 99.4 |
4 | 99.6 |
实施例4
制备(3R,5S)-3,5,6-三羟基己酸叔丁基酯
在Braun Biostat Q多-发酵罐系统中,红橡胶毕赤氏酵母NCYCR230(按照1995年5月18日布达佩斯条约中有关食品的内容保存)在下列培养基中生长(每升含):葡萄糖,20g;硫酸铵,10g;酵母菌提取物(Oxoid),2g;MgSO4·7H2O,1.2g;KH2PO4,0.69g;K2SO4,0.21g;FeSO4·7H2O,0.05g;H3PO4(浓的),1ml;EEA 142“foammaster”止泡剂,0.5ml;微量元素溶液,1ml(该溶液每升包含Ca(CH3CO2)2,2.85g;ZnSO4·7H2O,0.1g;MnSO4·H2O,0.075g;CuSO4·5H2O,0.02g;硫酸(浓的),1ml)。
一个发酵罐中加入250ml培养基并通过高压灭菌法灭菌。用2摩尔氢氧化钠溶液调至pH5.0。温度设定在28℃下,气流设定在250ml/分钟,搅拌速度设定在1200rpm。将发酵罐与2.5ml毕赤氏酵母属angusta NCYC R320琼脂平皿中采集细胞的灭菌去离子水悬浮液一起培养。生长17小时后,通过加入6.36g(5S)-3-酮基-5,6-二羟基己酸叔丁基酯的水溶液开始生物还原。同时以2g葡萄糖/升/小时的速度向发酵罐中加入葡萄糖。
反应再继续78小时直至达到底物96%转化点。通过HPLC检测起始物质和产物(Hichrom S5 CN-250A柱,温度35℃,流动相:TFA水溶液(0.1%)∶乙腈95∶5,流速1ml/分钟,注射体积5ml,折光率检测器)。
通过在4000×g下离心20分钟除去细胞终止反应。所回收的不含细胞的上清液用2M NaOH调至pH7.5。将MgSO4·1.6H2O(按无水物计算为15%w/v)溶解在不含下表的上清液中,所得到的溶液用等体积的2-戊酮提取2次。收集溶剂相,在45℃旋转蒸发器中减压除去溶剂得到粘性橙色油状物。该油状物再溶解在50ml无水蒸馏的2-戊酮中并再通过旋转蒸发除去溶剂得到叔丁基3,5,6-三羟基己酸酯(5.08g,80%分离收率)。如下测定非对映异构体过量;通过在过量三氟乙酸酐中,在室温下反应至少10分钟得到叔丁基3,5,6-三羟基己酸酯(30mg)样品,在氮气流下减压除去过量酸酐,所得到的残余油状物用二氯甲烷(1ml)稀释。样品在140℃(等温的)下用Chiralcel Dex CB柱(25米)分析。在14.4分钟(3R,5S非对映异构体)和15.7分钟(3S,5S非对映异构体)洗脱非对映异构体。通过该方法测定的样品非对映异构体过量为99.7%。
Claims (19)
2、权利要求1的方法,其中X代表-CH2-基。
3、权利要求1的方法,其中R″代表乙烯基或异丙烯基。
4、权利要求1的方法,其中R′代表甲基。
5、权利要求1-4中任何一项的方法,其中通过与选自白僵菌属、毕赤氏酵母属、假丝酵母属、克鲁维氏酵母属或有孢圆酵母属的具有微生物特性的生物体或由上述生物体提取的酶接触还原式(2)或(4)化合物。
6、权利要求5的方法,其中通过与选自红橡胶毕赤氏酵母、巴斯德毕赤氏酵母、季也蒙氏假丝酵母、卡尔斯伯糖酵母、喜海藻糖毕赤氏酵母、果蝇克鲁维氏酵母和Torulaspora hansenii的生物体或由上述生物体提取的酶接触将式(2)或(4)化合物还原。
7、权利要求5的方法,其中使用全细胞。
8、权利要求5的方法,其中在pH4-5下还原式(2)或(4)化合物。
9、权利要求1-4中任何一项的方法,其中在选自猪胰腺脂肪酶、Candida cylindracea脂肪酶、荧光假单胞菌脂肪酶、Candidaantarctica fraction B和由Humicola lanuginosa获得的脂肪酶存在下将式(2)或(4)化合物酯化。
10、权利要求1-4中任何一项的方法,其中式R″-O-CO R′化合物为乙酸乙烯酯。
11、一种制备式(5)化合物的方法
式5
该方法包括:
a)、按照权利要求1-10中任何一项的方法制备式(1)化合物;
b)、将式(1)化合物与2,2-二甲氧基丙烷反应,形成丙酮化合物;和
c)、除去R′-(C=O)-基;
其中
X代表-(CH2)n-并且n为1-4,
R代表直链或支链的C1-6烷基;
R″代表C1-6烷基、C1-6烷基羰基、乙烯基或异丙烯基,和
R′代表C1-6烷基。
12、权利要求11的方法,其中通过用碱性醇溶液处理除去R′-(C=O)-。
14、权利要求13的化合物,其中R为叔丁基并且X为-CH2-。
15、一种制备式(1)化合物的方法,
式1
该方法包括在式R″-O-COR′化合物和脂肪酶或水解酶存在下酯化式(3)化合物,形成式(1)化合物,
式3
其中
X代表-(CH2)n-并且n为1-4,
R代表直链或支链的C1-6烷基;
R″代表C1-6烷基、C1-6烷基羰基、乙烯基或异丙烯基,和
R′代表C1-6烷基。
17、权利要求15或16的方法,其中R′为CH3,R为叔丁基并且X为-CH2-。
18、权利要求15或16的方法,其中R″为乙烯基或异丙烯基。
19、权利要求15或16的方法,其中所述酶选自猪胰腺脂肪酶、Candida cylindracea脂肪酶、荧光假单胞菌脂肪酶、Candidaantarctica fraction B和由Humicola lanuginosa获得的脂肪酶。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101624609B (zh) * | 2009-07-31 | 2013-04-17 | 浙江九洲药业股份有限公司 | 酶催化制备(s)-3-取代戊二酸单酯类化合物的方法 |
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