CN1371362A - 异维甲酸的制备方法 - Google Patents
异维甲酸的制备方法 Download PDFInfo
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- C07C403/00—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
- 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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- 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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- C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
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Abstract
本发明涉及以单步制备维A酸的13-顺式异构体(通称异维甲酸)的方法。
Description
技术领域
本发明涉及单步制备维A酸的13-顺式异构体、通称异维甲酸的方法。
背景技术
异维甲酸(13-顺式视黄酸)属于维生素A(视黄醇)相关化合物家族。它抑制皮脂腺的功能和角质化,并用于治疗皮肤疾病如痤疮。它对非常严重的和囊结化的(nodulocytic)痤疮的防治非常有效,并能预防疤痕的形成。最近,还评估了异维甲酸用于某些癌性病症的可能性。
从结构上,异维甲酸是个高度共轭的分子,由一个被取代的环己烯部分和带有一个末端羧基的9个碳的多烯烃侧链构成。侧链中的所有双键中仅有一个双键(C-13双键)是反式的,此双键是这个多烯烃侧链的立体特异性结构,这一结构在最近30年来给合成有机化学家提出了挑战。已方便地使用市售且易于得到的β-紫罗酮用于异维甲酸的环己烯部分的构建。下面总结了现有的合成多烯烃侧链的结构的方法。
通常,采用汇集方法,该方法涉及合适的C15(由β-紫罗酮合成)和C5合成子的立体特异性偶联。(但是,还已描述了一个从β-紫罗酮开始的7步的线性程序;J Org.Chem.,54,2620-2628,1989)。例如,Patternden和Weedon,J.Chem.Soc.(C),1984-97(1968)已公开了一种制备13-顺式视黄酸的方法,使C15-三芳基磷鎓盐(Wittig盐)与C5-丁烯羟酸内酯在乙醚中反应,制得13-顺式视黄酸的异构体混合物(C-11双键的顺式和反式异构体),产率为66-75%;所需的11-反式-13-顺式异构体仅占约36%,剩余的是相应的11,13-二顺式异构体。极难使11-顺式双键在13-顺式双键的存在下实现选择性异构化。大量的努力用于在11,13-二顺式视黄酸中选择性异构化11-顺式双键(没有使13-顺式双键异构化)。这种方法包括使用碘(J.Chem.Soc.(C),1982,1968)、过渡金属催化剂(美国专利No.4556518)或光敏剂如藻红B、玫瑰红等(美国专利No.5424465)进行光异构化。这些方法受下述限制所困并且因为各种原因而不适合用于异维甲酸的商业生产。例如,在漫射光下使用碘进行选择性异构化方法很难在不影响13-顺式双键的情况下实现。这导致在由此方法制得的异维甲酸中产生了作为主要杂质的全反式视黄酸(维甲酸)。虽然在美国专利No.5424465中描述了光敏化剂的使用提高了C11-顺式双键的光异构化的选择性,但是,它没有提供在该方法中维甲酸形成的程度的数据。
美国专利No.4556518中所述的钯催化剂的使用可能潜在地导致所需的异维甲酸受痕量的过渡金属的污染,从而产生稳定性问题。另外,该方法的后处理涉及费事的抽提步骤。
美国专利No.4916250描述了一种方法,该方法涉及膦酸酯(作为一个C15合成子)的使用,从β-紫罗酮开始在几个步骤中首先产生此膦酸酯。然后使该膦酸酯与5-羟基-4-甲基-2-(5H)-呋喃酮(C5合成子)反应,得到异维甲酸。虽然此方法没有涉及烦琐的光异构化步骤,但是因为包括大量的步骤,因此在商业生产规模上是不经济的。
Cainelli等人,Gazz.Chim.Ital,103,117-125(1973)报道了异维甲酸的合成,使3,3-二甲基丙烯酸钠的二烯醇盐(dienolate)(C5-合成子)在-78℃与β-芷香亚基乙醛(C15合成子)反应12小时,得到羟酸中间物。将该羟酸中间物转化成中间物内酯,接着用碱处理,从而得到异维甲酸。这个方法受到下述限制:需要两种不同的碱(氢化钠和二异丙基氨化锂),此外,二烯醇盐的产生需要维持长时间的低温(-78℃),这在商业规模上将需要非常高的能量成本。此外,如该文所述的采用制备性的高效液体色谱纯化中间物内酯在商业上也是行不通的。
发明内容
本发明的一个目的是解决与现有技术相关的问题,并提供在一个单一步骤内(C15和C5合成子的立体特异性偶联)使用便于在商业规模上进行操作的条件有效合成高纯度异维甲酸的方法。
本发明的另一目的是提供一种方法,该方法提供异维甲酸的同时控制维甲酸的水平小于0.1%。各药典中都描述了在异维甲酸中含这种的杂质的界限是1-2%。
本发明涉及单步制备异维甲酸的方法,该方法包括在合适的溶剂中,将式I的3,3-二甲基丙烯酸甲酯的二烯醇盐与式II的β-芷香亚基乙醛,(i)在-60℃到-80℃缩合1-2小时,(ii)在25-45℃缩合1-24小时,接着用酸性水溶液进行后处理,得到异维甲酸:通过未分离的式III的中间物内酯的形成进行缩合反应:
内酯化导致甲醇盐离子的释放,这又使该内酯开环,从而得到异维甲酸(羧酸盐);较高的温度(25-45℃)与较长的反应时间促进甲醇盐与内酯的反应。使用酸性水溶液进行后处理,由此由β-芷香亚基乙醛开始在一个单一步骤内制得异维甲酸。
通常,上述式I的3,3-二甲基丙烯酸甲酯的二烯醇盐与上述式II的β-芷香亚基乙醛的最初的缩合反应在-60℃到-80℃下进行1-2小时。较佳的是,反应温度为-65℃到-75℃。随后将温度升至25-45℃,较佳是升至30-40℃,并维持该温度1-24小时,并且监控该反应的进程。合适的溶剂包括四氢呋喃、1,4-二噁烷、己烷、二异丙醚、六甲基磷酰胺、四甲基脲和它们的混合物。四氢呋喃是优选的溶剂。
使用酸性水溶液进行后处理涉及使用无机酸调节pH以及用有机溶剂进行抽提。酸可包括盐酸、硫酸和磷酸。优选硫酸。可使用任何有机溶剂进行抽提,并且这些溶剂对于本领域的普通技术人员来说是周知的,它们包括不与水混溶的溶剂,如氯仿、二氯甲烷、1,2-二氯乙烷、己烷、甲苯、乙酸乙酯等。
通过下面的示范性实施例将会明白本发明的其它特征,这些实施例是阐述性的,而非限制本发明的范围。
发明的详细描述
实施例1
在氮气气氛中,将正丁基锂在己烷中的溶液(321ml,15%)加到二异丙基胺(48.6g,0.48摩尔)在-30℃的四氢呋喃(1000ml)中的溶液中,搅拌所得混合物1小时。然后将该反应混合物冷却至-72℃,加入3,3-二甲基丙烯酸甲酯(55g,0.48摩尔)。继续在-65℃到-75℃搅拌30分钟。将β-芷香亚基乙醛(100g,0.458摩尔,9-反式异构体含量:80%)溶液加到所得混合物中,-65℃到-75℃搅拌该反应混合物1小时。然后将该反应混合物温热至40℃,并在此温度搅拌3小时。真空去除溶剂,用水(700ml)和甲醇(300ml)稀释反应混合物。然后加入活性炭(4g),回流该混合物30分钟。在hyflo上过滤该多相混合物,用甲醇(300ml)和水(150ml)洗涤该hyflo床。然后用己烷萃取该甲醇性水溶液层(2×500ml),用10%硫酸酸化,使pH为2.8±0.5。然后用二氯甲烷萃取出所需的产物(2×500ml)。用水洗涤合并的二氯甲烷层(2×300ml),真空浓缩,得到所需的异维甲酸。从甲醇(200ml)中结晶,得到HPLC纯度在99%以上的异维甲酸(44g);HPLC测定表明维甲酸的含量少于0.1%。
实施例2
在氮气气氛中,将正丁基锂在己烷(20ml,15%)中的溶液加到二异丙基胺(2.7g,0.027摩尔)在-74℃的二异丙醚(10ml)中的溶液中,搅拌所得反应混合物0.5小时。在-74℃将3,3-二甲基丙烯酸甲酯(2.51g,0.022摩尔)加到此混合物中。在-70℃±2℃继续搅拌30分钟,然后将该混合物加到β-芷香亚基乙醛(5g,0.022摩尔,9-反式异构体含量:80%)在-74℃二异丙醚(20ml)的溶液中。在-72℃±2℃搅拌所得混合物1小时,然后慢慢温热至室温。环境温度下搅拌该反应混合物过夜,按实施例1的方法进行后处理,得到1.03g的纯异维甲酸。
虽然本发明以特殊的实施例进行描述,但是,本领域熟练的技术人员将会明白某些修改和等同内容,这些修改和等同内容将包括在本发明的范围之内。
Claims (10)
2.如权利要求1所述的方法,其特征在于,所述溶剂选自四氢呋喃、1,4-二噁烷、己烷、二异丙醚、六甲基磷酰胺、四甲基脲和它们的混合物。
3.如权利要求2所述的方法,其特征在于,所述溶剂是四氢呋喃。
4.如权利要求1所述的方法,其特征在于,所述使用酸性水溶液进行的后处理用水和无机酸进行。
5.如权利要求4所述的方法,其特征在于,所述无机酸选自盐酸、硫酸和磷酸。
6.如权利要求1所述的方法,其特征在于,所述使用酸性水溶液进行后处理的步骤包括使用有机溶剂萃取。
7.如权利要求6所述的方法,其特征在于,所述有机溶剂不与水混溶。
8.如权利要求7所述的方法,其特征在于,所述有机溶剂选自氯仿、二氯甲烷、1,2-二氯乙烷、己烷、甲苯和乙酸乙酯。
9.如权利要求1所述的方法,其特征在于,原位产生了式III的中间物内酯:
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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IN1037DE1999 IN190846B (zh) | 1999-07-30 | 1999-07-30 | |
IN1037/DEL/99 | 1999-07-30 | ||
US09/467,201 US6441226B1 (en) | 1999-07-30 | 1999-12-20 | Process for the preparation of isotretinoin |
US09/467,201 | 1999-12-20 |
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CN1371362A true CN1371362A (zh) | 2002-09-25 |
CN1167679C CN1167679C (zh) | 2004-09-22 |
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CNB008119988A Expired - Fee Related CN1167679C (zh) | 1999-07-30 | 2000-07-24 | 异维甲酸的制备方法 |
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EP (1) | EP1204637B1 (zh) |
JP (1) | JP2003506349A (zh) |
CN (1) | CN1167679C (zh) |
AP (1) | AP2002002414A0 (zh) |
AT (1) | ATE293596T1 (zh) |
AU (1) | AU778584B2 (zh) |
BG (1) | BG106369A (zh) |
BR (1) | BR0012866A (zh) |
CA (1) | CA2380026A1 (zh) |
DE (1) | DE60019611T2 (zh) |
EA (1) | EA004651B1 (zh) |
EE (1) | EE200200053A (zh) |
ES (1) | ES2240117T3 (zh) |
HK (1) | HK1046901B (zh) |
HR (1) | HRP20020098A2 (zh) |
HU (1) | HUP0202230A3 (zh) |
IL (1) | IL147918A0 (zh) |
MX (1) | MXPA02001107A (zh) |
OA (1) | OA12002A (zh) |
PL (1) | PL353491A1 (zh) |
PT (1) | PT1204637E (zh) |
SK (1) | SK1612002A3 (zh) |
TR (1) | TR200200455T2 (zh) |
WO (1) | WO2001009089A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN104447459A (zh) * | 2014-11-28 | 2015-03-25 | 重庆华邦制药有限公司 | 异维a酸的新晶型及其制备方法与应用 |
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US2951853A (en) * | 1957-06-08 | 1960-09-06 | Sumitomo Chemical Co | Method for preparing polyenecarboxylic acid derivatives |
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- 2000-07-24 ES ES00944156T patent/ES2240117T3/es not_active Expired - Lifetime
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- 2000-07-24 JP JP2001514293A patent/JP2003506349A/ja active Pending
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- 2000-07-24 MX MXPA02001107A patent/MXPA02001107A/es active IP Right Grant
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- 2000-07-24 EA EA200200110A patent/EA004651B1/ru not_active IP Right Cessation
- 2000-07-24 CN CNB008119988A patent/CN1167679C/zh not_active Expired - Fee Related
- 2000-07-24 HU HU0202230A patent/HUP0202230A3/hu unknown
- 2000-07-24 PL PL00353491A patent/PL353491A1/xx not_active Application Discontinuation
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- 2000-07-24 OA OA1200200035A patent/OA12002A/en unknown
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN104447459A (zh) * | 2014-11-28 | 2015-03-25 | 重庆华邦制药有限公司 | 异维a酸的新晶型及其制备方法与应用 |
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Publication number | Publication date |
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BG106369A (bg) | 2002-08-30 |
ATE293596T1 (de) | 2005-05-15 |
HRP20020098A2 (en) | 2003-12-31 |
CA2380026A1 (en) | 2001-02-08 |
IL147918A0 (en) | 2002-08-14 |
WO2001009089A1 (en) | 2001-02-08 |
PT1204637E (pt) | 2005-08-31 |
OA12002A (en) | 2006-04-18 |
EE200200053A (et) | 2003-04-15 |
DE60019611T2 (de) | 2006-03-02 |
MXPA02001107A (es) | 2002-08-20 |
JP2003506349A (ja) | 2003-02-18 |
HK1046901A1 (en) | 2003-01-30 |
AP2002002414A0 (en) | 2002-03-31 |
BR0012866A (pt) | 2002-07-09 |
TR200200455T2 (tr) | 2002-07-22 |
ES2240117T3 (es) | 2005-10-16 |
HUP0202230A2 (hu) | 2002-11-28 |
EP1204637B1 (en) | 2005-04-20 |
EA200200110A1 (ru) | 2002-08-29 |
EP1204637A1 (en) | 2002-05-15 |
CN1167679C (zh) | 2004-09-22 |
HUP0202230A3 (en) | 2004-03-01 |
DE60019611D1 (de) | 2005-05-25 |
PL353491A1 (en) | 2003-11-17 |
AU5838800A (en) | 2001-02-19 |
SK1612002A3 (en) | 2002-06-04 |
AU778584B2 (en) | 2004-12-09 |
EA004651B1 (ru) | 2004-06-24 |
HK1046901B (zh) | 2005-09-23 |
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