CN1771227A - 制造9-顺式视黄酸的方法 - Google Patents
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- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000004519 manufacturing process Methods 0.000 title abstract description 4
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N 9-cis-retinoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 title description 2
- 229960001445 alitretinoin Drugs 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- -1 alkali metal salt Chemical class 0.000 claims abstract description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 238000004821 distillation Methods 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000012452 mother liquor Substances 0.000 claims description 8
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- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 6
- 125000005907 alkyl ester group Chemical group 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- ZFDIRQKJPRINOQ-UHFFFAOYSA-N transbutenic acid ethyl ester Natural products CCOC(=O)C=CC ZFDIRQKJPRINOQ-UHFFFAOYSA-N 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 235000010755 mineral Nutrition 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical group 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 3
- SHGAZHPCJJPHSC-UHFFFAOYSA-N Panrexin Chemical compound OC(=O)C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-UHFFFAOYSA-N 0.000 abstract 2
- VXAWORVMCLXEKH-DUXPYHPUSA-N (e)-3-methyl-4-oxobut-2-enoic acid Chemical compound O=CC(/C)=C/C(O)=O VXAWORVMCLXEKH-DUXPYHPUSA-N 0.000 abstract 1
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
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- 239000000243 solution Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000007127 saponification reaction Methods 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 238000007239 Wittig reaction Methods 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 150000004714 phosphonium salts Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229930002330 retinoic acid Natural products 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229960001727 tretinoin Drugs 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
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- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
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- C07C403/20—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by carboxyl groups or halides, anhydrides, or (thio)esters thereof
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Abstract
描述了一种新的可工业化应用的制造9-(Z)-视黄酸的方法,其特征在于3-甲基-4-氧代巴豆酸的碱金属盐和C15-三苯基鏻盐的转化。9-(Z)-视黄酸是用于治疗多种皮肤病的多用途化合物。
Description
本发明涉及一种新的可工业化应用的制造9-(Z)-视黄酸(9-(Z)-RA)的方法。
9-(Z)-RA是多用途的化合物,如例如WO 99/09969所公开的,这种化合物据称可用于治疗多种皮肤病。
EP-A 0 659739公开了一种制备9-(Z)-RA的方法,其特征在于在碱存在下β-甲酰基巴豆酸烷基酯和C15-三芳基鏻盐的维蒂希反应(Wittig-reaction)以及随后的所形成的视黄酸酯和碱的皂化反应。
这种方法的不利之处在于需要涉及改变溶剂以进行视黄酸酯皂化反应的两个步骤。由于皂化反应需要非常剧烈的温度条件,因此还观察到不必要的异构体的明显生成。
因此,本发明的目的是找到一种制造9-(Z)-RA的改进的替代方法,这种方法没有本领域已知方法的已知的不利方面。
上述目的已通过本发明的方法而实现,所述方法的特征在于如下通式的3-甲基-4-氧代巴豆酸的碱金属盐:
其中M表示钠或钾,和如下通式的C15-三苯基鏻盐的(Z)-异构体在碱存在下的反应:
其中Ph表示苯基,而X表示卤素,在碱存在下的反应。
在一个优选实施方案中,甲基-4-氧代巴豆酸碱金属盐是从3-甲基-4-氧代巴豆酸烷基酯就地制备的,所述3-甲基-4-氧代巴豆酸烷基酯在碱金属氢氧化物存在下被水解,并且不用分离即可用于随后的反应步骤。
但是,当然也可以在使用甲基-4-氧代巴豆酸的碱金属和通式II的C15-三苯基鏻盐的(Z)-异构体反应之前将其分离。
最优选将3-甲基-4-氧代巴豆酸乙酯用氢氧化钾水解来制备甲基-4-氧代巴豆酸的钾盐。
已经发现优选在低级醇存在下,最优选在乙醇中,在-10℃到10℃之间的温度下,理想地在0℃和5℃之间进行水解反应。优选的氢氧化钾是以水溶液形式,例如以50%水溶液形式很便利地使用的。
C15-三苯基鏻盐的(Z)-异构体在母液中是和(E)-异构体一起以异构体混合物形式出现的,所述的母液是在β-胡萝卜素的制备中获得的(Rüegg等,Helv.44,985(1961))。
这种母液通常既包含(Z)-异构体也包含(E)-异构体,两者的比率可以有所变化,但通常为约2∶1。
在本发明的一个优选实施方案中,可以按照如下步骤将C15-三苯基鏻盐的(Z)-异构体从该母液中分离出来:
a)用二氯甲烷萃取母液浓缩液,
b)将有机相置于乙酸乙酯/正丁醇中,
c)蒸馏除去乙酸乙酯/二氯甲烷,
d)用乙酸乙酯替换蒸馏量,
e)结晶出(Z)-异构体且
f)过滤和干燥。
已经发现在步骤b)中,在3%到10%、优选3%到5%的范围内选择乙酸乙酯中的正丁醇含量是有利的。
结晶过程必须是通过用9-(Z)-异构体接种而开始的,这也许是必要的。
优选的通式II的C15-三苯基鏻盐是氯盐。
输送(Z)-异构体以便随后转化成9-(Z)-RA优选以醇溶液形式进行,更优选以乙醇溶液形式进行。
所述方法适宜在-10℃到15℃之间的温度下进行,优选在0℃和5℃之间的温度下进行。超出该范围的温度导致反应变慢或者副产物生成的增加。
反应在低级醇存在下进行是有利的,优选在乙醇中进行。
用于转化成9-(Z)-RA的合适的碱是碱金属氢氧化物。优选使用氢氧化钠或氢氧化钾,最优选水溶液形式的氢氧化钾,例如50%的水溶液。
反应混合物的处理可以通过如下步骤进行:
a)用有机溶剂,优选用二氯甲烷萃取,
b)用合适的无机酸,例如用磷酸,将水相pH调节到约3至4,
c)用二氯甲烷萃取,
d)通过蒸馏除去二氯甲烷并且优选在蒸馏的同时连续引入甲醇,将溶剂换成甲醇,
e)分离从混合物中结晶出来的9-(Z)-RA。
可以通过在低级醇中,优选在异丙醇中进行重结晶,将9-(Z)-RA进一步纯化。
考虑到反应物和产物的敏感性,反应步骤主要在避光和无氧条件下进行,这一点至关重要。
如下实施例将用于说明本发明,而不限制本发明。
实施例
实施例1
a)9-(Z)-C15-三苯基鏻氯化物的分离
取200,0g包含9-(Z)-和9-(E)C15-三苯基鏻氯化物的异构体混合物的油状浓缩液(E-含量18%,Z-含量36%),并且在氩气气氛中,在20到25℃的温度下,和400ml二氯甲烷混合。分离水相,然后在15到25℃下,在5到10分钟内加入1000ml乙酸乙酯。向先前获得的澄清橙-棕色溶液中加入35ml正丁醇。在28到33℃/180到200毫巴下,蒸馏除去乙酸乙酯和二氯甲烷,将蒸馏除去的量用1600ml乙酸乙酯代替。用0.2ml9-(Z)-C15-三苯基鏻氯化物的悬浮液在30到35℃下开始9-(Z)-C15-三苯基鏻氯化物的结晶。然后将悬浮液在30到35℃下再搅拌2到3小时。然后过滤晶体,用400ml乙酸乙酯洗涤,然后在40℃/25毫巴下真空干燥。获得62.06g(基于油状浓缩液为31.0%)白色晶体形式的9-(Z)-C15-三苯基鏻氯化物(Z-异构体含量为93.6%(HPLC))。
b)9-(Z)-视黄酸的制备
在氩气气氛中,将40.4g(278.5mmol)3-甲基-4-氧代巴豆酸乙酯溶解在80ml乙醇中。在20分钟内小心加入30.6g(272.7mmol)50%氢氧化钾的水溶液,并将反应温度保持在0到5℃下。然后在此温度下搅拌混合物直至在HPLC色谱上观察不到该酯。其后,在20分钟内小心加入258.0g9-(Z)-C15-三苯基鏻氯化物的乙醇溶液(含量38.8%,199.5mmol)。在加入过程中,将反应温度保持在0到5℃下。然后在20分钟内小心加入29.8g(265.6mmol)50%的氢氧化钾水溶液,并将反应温度保持在0到5℃下。在此温度下搅拌混合物直至在HPLC色谱上观察不到鏻盐。向所形成的橙色悬浮液中加入900ml去离子水,形成澄清的橙色溶液。将混合物再搅拌10分钟,然后加入400ml去离子水和260ml二氯甲烷,并再搅拌10分钟。分离有机相,水相用总体积为540ml的二氯甲烷萃取三次。分离有机相。用21ml 85%磷酸将水相调节到pH3.5到4.0,并在氩气气氛中在20到30℃下搅拌20分钟。然后用200ml二氯甲烷萃取水相,再将水相用总量为160ml的二氯甲烷萃取两次。过滤合并的有机相。在开始于30℃/250毫巴、终止于40℃/700毫巴的条件下蒸馏除去二氯甲烷,同时加入800ml甲醇,从而实现将溶剂改变为甲醇。在蒸馏过程中9-(Z)-视黄酸开始结晶。然后将悬浮液冷却到0至5℃并搅拌2小时。过滤橙黄色悬浮液,用0到5℃的总量为170ml的甲醇洗涤,并将所获得的晶体在40到50℃/30毫巴下真空干燥过夜。获得10.6g(17.7%)黄色晶体形式的产物,含量为98.5%。
c)9-(Z)-视黄酸的结晶
在氩气气氛中,在约20℃下,将28.0g 9-(Z)-视黄酸置于在1120ml异丙醇中。将悬浮液加热到60至70℃,形成澄清的黄色溶液。通过缓慢冷却到0至5℃,开始出现结晶。然后过滤悬浮液,并用冷异丙醇洗涤,将所得到的晶体在40到50℃/30毫巴下真空干燥过夜。获得24.4g(87.3%)黄色晶体形式的分析纯9-(Z)-视黄酸。
Claims (12)
2、根据权利要求1的方法,其特征在于甲基-4-氧代巴豆酸的碱金属盐是在原位由3-甲基-4-氧代巴豆酸烷基酯制备的,所述3-甲基-4-氧代巴豆酸烷基酯是在碱金属氢氧化物存在下被水解的。
3、根据权利要求2的方法,其特征在于M表示钾,并且甲基-4-氧代巴豆酸的钾盐是在原位由3-甲基-4-氧代巴豆酸乙酯制备的,所述3-甲基-4-氧代巴豆酸乙酯是在氢氧化钾存在下被水解的。
4、根据权利要求1的方法,其特征在于通式II中的X表示氯。
5、根据权利要求1的方法,其特征在于C15-三苯基鏻盐的(Z)-异构体是从用于β-胡萝卜素合成的母液中分离出来的,所述母液包含(Z)-异构体和(E)-异构体的异构体混合物,分离方法包括如下步骤:
a)用二氯甲烷萃取母液浓缩液,
b)将有机相置于乙酸乙酯/正丁醇中,
c)蒸馏除去乙酸乙酯/二氯甲烷,
d)用乙酸乙酯替换蒸馏量,
e)结晶出(Z)-异构体,
f)过滤和干燥。
6、根据权利要求1到5任何一项的方法,其特征在于反应是在-15℃到15℃之间的温度下进行的。
7、根据权利要求1到6任何一项的方法,其特征在于反应是在低级醇存在下进行的。
8、根据权利要求1到7任何一项的方法,其特征在于碱是碱金属氢氧化物。
9、根据权利要求8的方法,其特征在于碱是氢氧化钾。
10、根据权利要求1到9任何一项的方法,其特征在于按照如下步骤处理反应混合物:
a)用二氯甲烷萃取,
b)用合适的无机酸将水相pH调节到约3至4,
c)用二氯甲烷萃取,
d)通过蒸馏除去二氯甲烷并连续引入甲醇将溶剂换成甲醇,
e)分离从混合物中结晶出来的9-(Z)-视黄酸。
11、依照权利要求1到10的方法制备的9-(Z)-视黄酸。
12、如此处所述的本发明。
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WO2012155796A1 (zh) * | 2011-05-13 | 2012-11-22 | 重庆华邦胜凯制药有限公司 | 一种定向合成维甲酸类化合物的方法 |
CN103153936A (zh) * | 2010-10-01 | 2013-06-12 | 帝斯曼知识产权资产管理有限公司 | 改进的培瑞维a酸的合成 |
CN101516841B (zh) * | 2006-09-27 | 2014-01-22 | Dsm精细化学奥地利Nfg两合公司 | 一种改进的9-顺-视黄酸的制备方法 |
CN104583223A (zh) * | 2012-08-17 | 2015-04-29 | 巴斯夫欧洲公司 | 烯属化合物的异构化 |
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US9221854B2 (en) | 2012-08-17 | 2015-12-29 | Basf Se | Isomerization of olefinic compounds |
KR102420818B1 (ko) | 2021-11-29 | 2022-07-14 | (주)아크에이르 | All-trans에서 9-cis Retinoic acid로의 광 이성질화 전환 반응 장치 및 이를 이용한 이성질체 전환방법 |
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DE1068710B (de) * | 1958-08-06 | 1959-11-12 | Badische Anilin- &. Soda-Fabrik Aktiengesellschaft, Ludwigshafen/Rhein | Verfahren zur Herstellung von Verbindungen der beta-Ionylidenäthyliden-Reihe |
DE4344148A1 (de) * | 1993-12-23 | 1995-08-24 | Basf Ag | Verfahren zur Herstellung von 9-(Z)-Retinsäure |
EP0908179A1 (en) | 1997-08-23 | 1999-04-14 | Werner Bollag | Treatment of cell-mediated immune diseases |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101516841B (zh) * | 2006-09-27 | 2014-01-22 | Dsm精细化学奥地利Nfg两合公司 | 一种改进的9-顺-视黄酸的制备方法 |
CN103153936A (zh) * | 2010-10-01 | 2013-06-12 | 帝斯曼知识产权资产管理有限公司 | 改进的培瑞维a酸的合成 |
US9296677B2 (en) | 2010-10-01 | 2016-03-29 | Dsm Ip Assets B.V. | Synthesis of peretinoin |
WO2012155796A1 (zh) * | 2011-05-13 | 2012-11-22 | 重庆华邦胜凯制药有限公司 | 一种定向合成维甲酸类化合物的方法 |
US8835680B1 (en) | 2011-05-13 | 2014-09-16 | Chongqing Huabangshengkai Pharm. Co., Ltd. | Stereospecific synthesis process for tretinoin compounds |
CN104583223A (zh) * | 2012-08-17 | 2015-04-29 | 巴斯夫欧洲公司 | 烯属化合物的异构化 |
CN104583223B (zh) * | 2012-08-17 | 2017-04-12 | 巴斯夫欧洲公司 | 烯属化合物的异构化 |
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WO2004089887A1 (en) | 2004-10-21 |
EP1615879B1 (en) | 2014-01-29 |
TWI293951B (en) | 2008-03-01 |
KR100743278B1 (ko) | 2007-07-26 |
JP4563997B2 (ja) | 2010-10-20 |
ES2449494T3 (es) | 2014-03-20 |
JP2006522757A (ja) | 2006-10-05 |
KR20050121258A (ko) | 2005-12-26 |
PL1615879T3 (pl) | 2015-02-27 |
CA2520018A1 (en) | 2004-10-21 |
TW200510295A (en) | 2005-03-16 |
IL170829A (en) | 2011-12-29 |
CA2520018C (en) | 2011-01-04 |
US20040235951A1 (en) | 2004-11-25 |
US7015353B2 (en) | 2006-03-21 |
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MXPA05010771A (es) | 2005-12-12 |
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