CN1547566A - (r)-(-)-2-羟基-2-(2-氯苯基)乙酸的拆分方法 - Google Patents
(r)-(-)-2-羟基-2-(2-氯苯基)乙酸的拆分方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims description 29
- RWOLDZZTBNYTMS-SSDOTTSWSA-N (2r)-2-(2-chlorophenyl)-2-hydroxyacetic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1Cl RWOLDZZTBNYTMS-SSDOTTSWSA-N 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 13
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 230000003287 optical effect Effects 0.000 claims description 9
- UXFQFBNBSPQBJW-UHFFFAOYSA-N 2-amino-2-methylpropane-1,3-diol Chemical compound OCC(N)(C)CO UXFQFBNBSPQBJW-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 230000006340 racemization Effects 0.000 claims description 6
- 239000012452 mother liquor Substances 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 4
- 239000000010 aprotic solvent Substances 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000005194 fractionation Methods 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 2
- 238000010956 selective crystallization Methods 0.000 claims 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 125000006501 nitrophenyl group Chemical group 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 43
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
- 239000000284 extract Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000000463 material Substances 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical class CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- -1 hydroxyl-methyl Chemical group 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002178 crystalline material Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- CJPVPOYTTALCNX-UHFFFAOYSA-N (2-chlorophenyl) acetate Chemical compound CC(=O)OC1=CC=CC=C1Cl CJPVPOYTTALCNX-UHFFFAOYSA-N 0.000 description 1
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- RRNJROHIFSLGRA-JEDNCBNOSA-N acetic acid;(2s)-2,6-diaminohexanoic acid Chemical compound CC(O)=O.NCCCC[C@H](N)C(O)=O RRNJROHIFSLGRA-JEDNCBNOSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 230000002744 anti-aggregatory effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
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- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
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- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- AFLWNOOVIPMXRH-UHFFFAOYSA-N methanol;propan-2-yl acetate;hydrate Chemical compound O.OC.CC(C)OC(C)=O AFLWNOOVIPMXRH-UHFFFAOYSA-N 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 229940020573 plavix Drugs 0.000 description 1
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- 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
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
- C07C215/34—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton and at least one hydroxy group bound to another carbon atom of the carbon skeleton
- C07C215/36—1-Aryl-2-amino-1,3-propane diols
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Abstract
本发明的目的是使用通式(II)的化合物通过拆分相应的外消旋化合物而制备式(I)的(R)－(－)－2－羟基－2－(2－氯苯基)乙酸。
Description
本发明的目的是外消旋的2-羟基-2-(2-氯苯基)乙酸的一种新的拆分方法，使式(I)的(R)-(-)-2-羟基-2-(2-氯苯基)乙酸的制备成为可能。
式(I)的旋光化合物是已知旋光活性trombocyta antiaggregant化合物clopidogrel(Plavix)(WO-99/18110)的一种起始物质。
外消旋的2-羟基-2-(2-氯苯基)乙酸可通过不同的方法获得/Chem.Ber.
37S.3173(1904)，J.Am.Chem.Soc.
55p 2593(1933)，Chem.Ber.92S 1739(1959)/。从文献中(Chirality
7(8)p 652-76(1995)，Bull.Soc.Chim.Fr.(1973)12，Pt2，3330)已经知道几种制备式(I)的旋光化合物的方法，但是从工业的观点看它们存在缺陷，因为它们或者使用昂贵的拆分试剂(生物碱类)，或者应用要求极大量的微生物学方法，并且它们的生产率低。(EP-A610048，EP-A-449648，EP-A-527553)。目的是找到一种比已知方法更有利的化学方法，其对于式(I)的化合物的制备提供一种技术上更简单和更价廉的方法。
我们意外地发现通式(II)的化合物与唯一的一个对映体或外消旋的2-羟基-2-(2-氯苯基)乙酸形成一种难溶解的盐，因此一种对映体可以被选择性地从本拆分方法的反应混合物中去除。
根据本发明，式(I)的化合物产生于与一种通式(II)的化合物形成的它的固体非对映盐或产生于本拆分方法的母液，且它的光学纯度通过选择性重结晶可选择地增加。
根据本发明此方法可优选在一种有机溶剂中进行，例如在甲醇中或一种水和有机溶剂的混合物，例如在水-乙酸乙酯混合物或水-甲醇混合物或乙酸异丙酯-甲醇-水混合物中。
作为通式(II)的一种化合物，(1S，2S)-(+)-1-苯基-2-氨基-1，3-丙烷-二醇、(1R，2r)-treo-(-)-1-(4-硝基苯基)-2-氨基-1，3-丙烷-二醇或L-(+)-赖氨酸是可应用的最佳选择。/Aldrich Cat.No.L-(+)-lizin：16971-4(2000-1)；(1S，2S)-(+)-1-苯基(fenil)-2-氨基-1，3-丙二醇：18654-6(2000-1)；(1R，2r)-treo-(-)-1-(4-硝基苯基)-2-氨基-1，3-丙二醇：A7070-4(2000-1)/。
通式(II)的化合物通常都以根据外消旋酸计数的等克分子率使用。
本拆分方法优选在10℃和30℃之间实施。如此获得的式(I)的粗化合物光学纯度是84-98％。通过使用甲苯或乙酸异丙酯作为溶剂，式(I)的粗化合物在40-100℃重结晶，可得到近乎100％光学纯度的式(I)的化合物。依靠将要重结晶的化合物的一个质量单位，使用该溶剂1.5-10容积单位，优选6-8容积单位。
本发明的另一个目的是与通式(II)的化合物形成的式(I)化合物的盐类。
通过从(S)-(+)-2-羟基-2-(2-氯苯基)乙酸形成的和从通式(I)的一种化合物形成的非对映体盐的分解增加此发明的方法的效率，(S)-(+)-异构体被外消旋且根据本发明将其再次拆分。
此外消旋方法是本发明的另一目的。
这样，起始的外消旋化合物几乎全部能被转化成所需要的对映体。
此外消旋能在碱存在下实施，优选可使用氢氧化钠水溶液或氢氧化钾水溶液。在含水媒介物中使用少量非质子溶剂加速该外消旋方法。优选的非质子溶剂是二甲亚砜、环丁砜、二甲基甲酰胺、六甲替磷酰三胺或N-甲基吡咯烷酮。在0.1-0.5容积单位的非质子溶剂存在下，在反应混合物的沸点进行外消旋化更佳。
本发明更多的细节显示于下面的实施例中，其内容不限制我们的权利要求。
实施例1
通过(1S，2S)-(+)-1-苯基-2-氨基-1，3-丙烷-二醇拆分外消旋的
2-羟基-2-(2-氯苯基)乙酸
(通式(II)的化合物-其中R1是羟基-甲基，R2是苯基，R3是羟基)
将外消旋的2-羟基-2-(2-氯苯基)乙酸(20.0g 107mmol)溶解在60cm3以水饱和的乙酸乙酯中，向其中加入(1S，2S)-(+)-1-苯基-2-氨基-1，3-丙烷-二醇(18.0g 107.5mmol)，然后该混合物在室温下接种由(S)-(+)-2-羟基-2-(2-氯苯基)醋酸盐和(1S，2S)-(+)-1-苯基2-氨基-1，3-丙烷-二醇形成的盐。
在室温下搅拌该混合物3小时，过滤出其沉淀的物质，用乙酸乙酯洗涤，干燥：得到30.7g白色结晶物质。将该物质溶解到50cm3水和15cm3 37％盐酸的混合物中，用甲基-叔丁基-醚提取。提取物在硫酸钠上干燥且蒸发溶剂：得到15.3g富含(S)-(+)-2-羟基-2-(2-氯苯基)乙酸的能按照实施例4被外消旋和在本方法中反复应用的对映体的混合物([α]D 20＝+38°(c＝4，甲醇/，光学纯度为24％)。
浓缩从拆分得到的母液，溶入15cm3水和4.0cm3 37％盐酸的混合物中，用甲基-叔丁基-醚提取。合并的提取物在硫酸钠上干燥并浓缩：得到4.3g(R)-(-)-2-羟基-2-(2-氯苯基)乙酸([α]D 20＝-132.2°(c＝4，甲醇)，光学纯度84.2％。产出物从甲苯中重结晶，60℃过滤，甲苯洗涤。干燥后，得到3.62g(19.4mmol 18.1％)的(R)-(-)-2-羟基-2-(2-氯苯基)乙酸([α]D 20＝-157°(c＝4，甲醇)。
实施例2
通过(1R，2R)-(-)-treo-1-(4-硝基苯基)-2-氨基-1，3-丙烷-二
醇(通式(II)的化合物，其中R
1
是羟基甲基，R
2
是对-硝基苯基，
R
3
是羟基)拆分外消旋的2-羟基-2-(2-氯苯基)乙酸
将外消旋的2-羟基-2-(2-氯苯基)乙酸(20.0g 107mmol)溶解在120g乙酸异丙基酯、16cm3甲醇和2cm3水的混合物中。
向其中加入22.8g(107mmol)(1R，2R)-(-)-treo-1-(4-硝基苯基)-2-氨基-1，3-丙烷-二醇，期间温和加热以帮助溶解。在室温下混合物接种与(R)-(-)-2-羟基-2-(2-氯苯基)乙酸形成的(1R，2R)-(-)-treo-1-(4-硝基苯基)-2-氨基-1，3-丙烷-二醇的盐。反应混合物在室温下搅拌3小时，过滤沉淀的物质，洗涤并干燥，得到13.6g结晶物质(是上面的二醇和(R)-(-)-2-羟基-2-(2-氯苯基)乙酸的盐)。
将该盐溶解在20cm3水中，该溶液以5.7cm3浓盐酸酸化，且以甲基-叔丁基醚提取，将提取物合并、干燥、浓缩并得到5.84g(31.3mmol)粗(R)-(-)-2-羟基-2-(2-氯苯基)乙酸([α]D 20＝-151°(c＝4，甲醇)，其光学纯度为96％。
此粗酸在60℃从41cm3甲苯中重结晶，干燥产物。(R)-(-)-2-羟基-2-(2-氯苯基)乙酸的重量为5.6g(30.0mmol)。产率为28％。([α]D 20＝-157°(c＝4，甲醇)。
浓缩拆分的母液，将其溶解于40cm3水中，用12.3cm337％盐酸酸化，用甲基-叔丁基醚提取，所得到的富含(S)-(+)-2-羟基-2-(2-氯苯基)乙酸的物质，是一种对映体的混合物，为13.8g(73.95mmol)([α]D 20＝+61°(c＝4，甲醇)，光学纯度是39％。本物质是可外消旋的，且其反复应用到本方法中是可能的。
实施例3
通过L-(+)-赖氨酸(通式(II)的化合物，其中R
1
是羧基，
R
2
是3-氨基-丙基，R
3
是氢原子)拆分外消旋的2-羟基-2-(2-氯苯基)
乙酸
将15.64g(107mmol)L-(+)-赖氨酸溶解在60cm3甲醇中，且将20g(107mmol)外消旋的2-羟基-2-(2-氯苯基)乙酸溶解在另外的60cm3甲醇中。将这两个溶液合并，并加热到40-45℃至全部溶解。混合物在40℃以(R)-(-)-2-羟基-2-(2-氯苯基)乙酸的L-(+)-赖氨酸盐接种。混合物在40℃搅拌2小时且在30℃搅拌2小时，然后过滤，沉淀的物质用甲醇洗涤并干燥，如此得到9.44g(R)-(-)-2-羟基-2-(2-氯苯基)乙酸-L-(+)-赖氨酸盐。将得到的干燥的盐溶解在10cm3水中，以5.7cm337％盐酸酸化，用甲基-叔丁基醚提取。将提取物于硫酸钠上干燥并浓缩：得到5.3g(R)-(-)-2-羟基-2-(2-氯苯基)乙酸，([α]D 20＝-153.8°(c＝4，甲醇)，光学纯度为98％。)，将其用甲苯(42cm3)重结晶，60℃过滤并以甲苯覆盖。
干燥后得到5.2g(27.86gmmol)(R)-(-)-2-羟基-2-(2-氯苯基)乙酸。产率：26％[α]D 20＝-157°(c＝4，甲醇)。
浓缩拆分的母液，将其溶解于40cm3水中，用13.2cm3 37％盐酸酸化，用甲基-叔-丁基醚提取。蒸发后，得到13.9g(74.54mmol)富含(S)-(+)-2-羟基-2-(2-氯苯基)乙酸的对映体的混合物，([α]D 20＝+57°(c＝4，甲醇)，本物质是可外消旋的，且其反复应用到本方法中是可能的。
实施例4
外消旋化
将实施例3中获得的13.5g富含(S)-(+)-2-羟基-2-(2-氯苯基)乙酸的对映体的混合物，溶解在24cm3水中，用11.56g(289mmol)氢氧化钠碱化，加入2.4cm3二甲基亚砜且将该混合物于100℃搅拌5小时。
所获得的反应混合物以20cm3水稀释并用24.3cm3 37％盐酸(289mmol)酸化，并以甲基-叔-丁基醚提取。
干燥提取物，以1.5g活性炭澄清，过滤，浓缩并在5℃从17.4cm3甲苯中重结晶，于过滤后以甲苯洗涤。干燥后得到的物质为12.8g(68.6mmol)2-羟基-2-(2-氯苯基)乙酸([α]D 20＝0.0°(c＝4，甲醇).
图1显示式(I)的化合物，图2显示通式(II)的化合物。
Claims (14)
1.制备(R)-(-)-2-羟基-2-(2-氯苯基)乙酸的方法，其特征在于，以一种通式(II)的取代胺拆分外消旋的2-羟基-2-(2-氯苯基)乙酸，式(II)中R1代表羟基-甲基或羧基，R2代表苯基、硝基-苯基或由一个氨基取代的C1-C4烷基，R3代表羟基或氢原子。
2.权利要求1的方法，特征在于，使用被通式(II)覆盖的(1S，2S)-(+)-1-苯基-2-氨基-1，3-丙二醇作为拆分试剂。
3.权利要求1的方法，特征在于，使用被通式(II)覆盖的(1R，2R)-treo-(-)-1-(4-硝基苯基)-2-氨基-1，3-丙二醇作为拆分试剂。
4.权利要求1的方法，特征在于，使用被通式(II)覆盖的L-(+)-赖氨酸作为拆分试剂。
5.权利要求1的方法，特征在于，外消旋的2-羟基-2-(2-氯苯基)乙酸与通式(II)(其中R1、R2或R3的含义如前所述)的一种化合物的盐，形成于一种有机溶剂或在水与一种或一种以上的有机溶剂的混合物中，且从反应混合物得到从一对非对映异构体盐中由于不同的溶解性分离的盐，且从该盐或从拆分的碱性母液中得到式(I)的化合物。
6.权利要求1的方法，特征在于，通过拆分得到的式(I)的粗化合物的光学纯度通过选择性结晶而增加。
7.权利要求6的方法，特征在于，该选择性结晶在甲苯或在乙酸异丙酯中实施。
8.权利要求6的方法，特征在于，通过选择性结晶得到的式(I)的高光学纯度的化合物在+40℃和+100℃之间的温度从溶剂中分离。
9.权利要求1的方法，特征在于，通过拆分得到的(S)-(+)-2-羟基-2-(2-氯苯基)乙酸被外消旋，然后它被返回到拆分过程。
10.权利要求9的方法，特征在于，以碱金属氢氧化物，有利地用氢氧化钠实施消旋。
11.权利要求9的方法，特征在于，在少量非质子溶剂存在下，有利地在二甲基亚砜、环丁砜、二甲基甲酰胺、六甲替磷酰三胺或N-甲基吡咯烷酮存在下，在水中实施消旋。
12.(1S，2S)-(+)-1-苯基-2-氨基-1，3-丙二醇(S)-(+)-2-羟基-2-(2-氯苯基)醋酸盐。
13.(1R，2R)-(-)-treo-1-(4-硝基苯基)-2-氨基-1，3-丙二醇(R)-(-)-2-羟基-2-(2-氯苯基)醋酸盐。
14.(R)-(-)-2-羟基-2-(2-氯苯基)乙酸-L-(+)-赖氨酸盐。
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| CN102336653A (zh) * | 2011-11-08 | 2012-02-01 | 广州辉宏生物医药科技有限公司 | 光学纯手性邻氯扁桃酸的制备方法 |
| CN102516002A (zh) * | 2011-12-09 | 2012-06-27 | 中原工学院 | 一种光学纯α-羟基酸及其衍生物的制备工艺 |
| CN109232220A (zh) * | 2017-09-15 | 2019-01-18 | 上海健康医学院 | 一种新的3-羟基-3苯基丙酸类化合物的化学拆分方法 |
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| CN101253271A (zh) * | 2005-09-02 | 2008-08-27 | 第一精密化学株式会社 | 光学活性α-羟基羧酸的制造方法 |
| EP3401929A1 (en) * | 2017-05-09 | 2018-11-14 | Borealis AG | Cable insulation |
| CN110627808B (zh) * | 2018-06-21 | 2022-04-01 | 江苏同禾药业有限公司 | 一种硫酸氢氯吡格雷拆分母液的回收处理工艺 |
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| EP0306585B1 (en) | 1987-09-10 | 1992-07-22 | International Business Machines Corporation | Data transmission system with a digital alarm facility |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102336653A (zh) * | 2011-11-08 | 2012-02-01 | 广州辉宏生物医药科技有限公司 | 光学纯手性邻氯扁桃酸的制备方法 |
| CN102336653B (zh) * | 2011-11-08 | 2014-04-30 | 广州市金匮贸易有限公司 | 光学纯手性邻氯扁桃酸的制备方法 |
| CN102516002A (zh) * | 2011-12-09 | 2012-06-27 | 中原工学院 | 一种光学纯α-羟基酸及其衍生物的制备工艺 |
| CN109232220A (zh) * | 2017-09-15 | 2019-01-18 | 上海健康医学院 | 一种新的3-羟基-3苯基丙酸类化合物的化学拆分方法 |
| CN109232220B (zh) * | 2017-09-15 | 2021-09-10 | 上海健康医学院 | 一种3-羟基-3-苯基丙酸类化合物的化学拆分方法 |
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| BR0210512A (pt) | 2004-06-22 |
| HUP0401404A2 (hu) | 2004-11-29 |
| CZ305524B6 (cs) | 2015-11-18 |
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| CY1111606T1 (el) | 2015-10-07 |
| HU229402B1 (hu) | 2013-12-30 |
| CZ2004102A3 (cs) | 2004-06-16 |
| CA2450490A1 (en) | 2003-01-03 |
| CN1276907C (zh) | 2006-09-27 |
| PL369004A1 (en) | 2005-04-18 |
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| DK1397335T3 (da) | 2011-02-28 |
| CA2450490C (en) | 2010-04-06 |
| SI1397335T1 (sl) | 2011-03-31 |
| SK15342003A3 (sk) | 2004-06-08 |
| ATE487688T1 (de) | 2010-11-15 |
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