CN1625546A - O-去甲文拉法辛的制备方法 - Google Patents
O-去甲文拉法辛的制备方法 Download PDFInfo
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- CN1625546A CN1625546A CNA028242386A CN02824238A CN1625546A CN 1625546 A CN1625546 A CN 1625546A CN A028242386 A CNA028242386 A CN A028242386A CN 02824238 A CN02824238 A CN 02824238A CN 1625546 A CN1625546 A CN 1625546A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Abstract
本发明提供一种用硫醇盐阴离子将文拉法辛去甲基化以制备O-去甲文拉法辛的有效方法。
Description
本发明涉及制备O-去甲文拉法辛的方法。
发明背景
O-去甲文拉法辛是文拉法辛的主要代谢物。在美国专利4,535,186中描述了制备O-去甲文拉法辛的方法。该方法使用苄基保护基团,导致产率较低。
在WO00/59851中也描述了一种制备O-去甲文拉法辛的方法,其中文拉法辛在THF中与二苯基磷化物(通过向0℃下的二苯基膦/THF中加入正丁基锂/THF产生)在回流下反应过夜。据报道产率为73.8%。另外,此方法包含的萃取步骤要用大量的溶剂。
本发明提供了一种在时间和材料方面都具有高效率的制备O-去甲文拉法辛的方法。
发明内容
根据本发明,提供了一种制备O-去甲文拉法辛的方法,该方法包括如方案1所示的式I化合物去甲基化形成式II化合物的步骤。
式1 式II
方案I
如方案1中所述,起始物文拉法辛(式1)被去甲基化。文拉法辛可以按照本领域已知的方法,例如美国专利4,535,186中所述方法制备。
根据本发明,去甲基化是用高分子量的烷烃、芳烃或芳烷基硫醇盐阴离子,例如直链或支链的有8-20个碳原子的烷烃硫醇盐阴离子,有6-10个碳原子的单环或双环芳烃硫醇盐阴离子,或有7-12个碳原子的单环或双环芳烷基阴离子,在质子溶剂或非质子溶剂存在下进行的。任选地,可以存在一种碱,例如含有1-6个碳原子的直链或支链烷基的醇盐,以便产生硫醇盐阴离子。
优选该脂族硫醇有10-20个碳原子,最优选该脂族硫醇是十二烷硫醇。芳族硫醇优选是苯硫醇。芳烷基硫醇盐阴离子优选是α-甲苯硫醇或萘甲硫醇。
如果存在,所述醇盐优选是低级醇盐,例如1-6个碳原的低级醇盐(如甲醇盐、乙醇盐等),例如甲醇钠。
溶剂优选是含羟基或含醚溶剂或其混合物,更优选是一种醇、乙二醇或乙二醇的醚。乙二醇的醚包括但不限于乙二醇单乙醚、三乙二醇二甲醚和聚乙二醇。优选该溶剂是一种惰性、极性、高沸点的乙二醇的醚,例如聚乙二醇,最优选是PEG 400(分子量约为380-420的聚乙二醇)。
反应在约150℃-220℃的温度下进行,反应温度更优选为约170-220℃,最优选为约180-200℃。反应一般可以进行到最好是留下的文拉法辛不超过1%。在本发明的某些情形,反应在约2-5小时内完成,更优选在约2-3.5小时内完成。
硫醇盐阴离子可以分别制备或原位制备。在本发明的一些优选的实施方案中,将文拉法辛碱溶解在含有十二烷硫醇的聚乙二醇400和甲醇钠的甲醇溶液中,将温度升至约180-200℃,同时搅拌约2-3.5小时。在本发明的其它优选的实施方案中,文拉法辛碱被溶在含十二烷硫醇盐的聚乙二醇中并在约180-200℃下搅拌约2-3.5小时。
该方法可以方便地在硫醇盐摩尔量过剩下进行,优选硫醇盐与文拉法辛的摩尔比最高达约3.0∶1,例如,从约1.05∶1到约2.8∶1,优选为约1.15∶1至约2.5∶1。
随后反应混合物可冷却至约65-75℃,可以加入作为稀释剂的醇,然后用适当的中和剂如盐酸中和至等电点(约pH 9.5~10.0)。该醇介质还可能在开始中和时促进产物的结晶。
优选醇含有1-6个碳原卫的直链或支链烷基,例如甲醇、乙醇、异丙醇、丁醇等,及它们的混合物。在本发明的一些优选实施方案中,该醇是异丙醇。
本发明的产率大于约75%,一般为约85%至90%以上。
以下实施例用于示例说明,但不意味着是对本发明的限制。
实施例1
将十二烷硫醇(122g)、文拉法辛(111g)、甲醇钠(30%,90g)和PEG 400的甲醇溶液加热至190℃。将甲醇馏出,溶液在190℃搅拌2小时,随后降温,加入2-丙醇(450g),用盐酸将pH调节至9.5。抽气过滤收集沉淀,滤饼用2-丙醇、甲苯、2-丙醇和水洗。湿的O-去甲文拉法辛在真空下干燥。产量:87g。
1H-NMR:(Gemini 200,Varian,200MHz)(DMSO-d6)δ=9.11(s,br,1H;OH),6.98(d,br,J=8.4,2H;arom.),6.65(d,br,J=8.4,2H;arom.),5.32(s,br,1H;OH),3.00(dd,J=12.3和8.5,1H),2.73(dd,J=8.5和6.3,1H),2.36(dd,J=12.3和6.3,1H),2.15(s,6H,2xMe),1.7-0.8(m,10H,c-hex).
实施例2
向PEG 400(25g)中加入文拉法辛(5.6g)和苯硫醇钠盐(6.9g)。将反应混合物在160℃加热5小时,然后降温,加水(60g)。用H3PO4将pH调节至3.5。用庚烷(25g)萃取除去有机副产物。然后用氨水将水层的pH调节至9.5。抽气过滤收集沉淀物,重新在水(100g)中浆化,抽气过滤并真空干燥。
产量:1g。
1H-NMR:(Gemini 200,Varian,200MHz)(DMSO-d6)δ=9.11(s,br,1H;OH),6.98(d,br,J=8.4,2H;arom.),6.65(d,br,J=8.4,2H;arom.),5.32(s,br,1H;OH),3.00(dd,J=12.3和8.5,1H),2.73(dd,J=8.5和6.3,1H),2.36(dd,J=12.3和6.3,1H),2.15(s,6H,2xMe),1.7-0.8(m,10H,c-hex).
实施例3
将十二烷硫醇(69g)、文拉法辛(55g)和乙醇钠的乙醇溶液(21%,82g)装入压力容器。升温至150℃,将反应混合物搅拌2天,然后降温,将溶液过滤。用盐酸将滤液的pH调节至9.5。抽气过滤收集晶体。滤饼用乙醇洗,真空干燥。
产量:42g。
1H-NMR:(Gemini 200,Varian,200MHz)(DMSO-d6)δ=9.11(s,br,1H;OH),6.98(d,br,J=8.4,2H;arom.),6.65(d,br,J=8.4,2H;arom.),5.32(s,br,1H;OH),3.00(dd,J=12.3和8.5,1H),2.73(dd,J=8.5和6.3,1H),2.36(dd,J=12.3和6.3,1H),2.15(s,6H,2xMe),1.7-0.8(m,10H,c-hex).
实施例4
步骤a-试剂十二烷硫醇钠的形成
将十二烷硫醇(246g)和甲醇钠/甲醇(30%,216g)装入旋转蒸发仪中。抽真空,利用最高达90℃的浴温将溶剂去净。不经进一步纯化,将剩下的十二烷硫醇钠(272g)直接用于下一步骤。
步骤b-去甲基化
将十二烷硫醇钠(272g)、文拉法辛(256g)和PEG 400(185g)的混合物在190℃搅拌3小时。然后降低温度,加入2-丙醇(915g),用盐酸调节pH至9.5。抽气过滤收集沉淀,滤饼用2-丙醇和水洗。湿的O-去甲文拉法辛在真空下干燥。产率:200g。
1H-NMR:(Gemini 200,Varian,200MHz)(DMSO-d6)δ=9.11(s,br,1H;OH),6.98(d,br,J=8.4,2H;arom.),6.65(d,br,J=8.4,2H;arom.),5.32(s,br,1H;OH),3.00(dd,J=12.3和8.5,1H),2.73(dd,J=8.5和6.3,1H),2.36(dd,J=12.3和6.3,1H),2.15(s,6H,2xMe),1.7-0.8(m,10H,c-hex).
Claims (21)
1.一种制备O-去甲文拉法辛的方法,该方法包括用高分子量的烷烃、芳基烷基或芳烃硫醇盐阴离子在含羟基或含醚溶剂或其混合物中将文拉法辛去甲基化。
2.权利要求1的方法,该方法在醇、乙二醇、乙二醇的醚或其混合物中进行。
3.权利要求1的方法,其中的溶剂是乙二醇单乙醚、三乙二醇、二甲醚或聚乙二醇。
4.权利要求1的方法,其中溶剂是聚乙二醇400。
5.权利要求1至4中任一项的方法,其中反应在约150-220℃下进行。
6.权利要求1至4中任一项的方法,其中反应是在约170℃-220℃下进行。
7.权利要求1至4中任一项的方法,其中反应是在约180℃-200℃下进行。
8.权利要求1至8中任一项的方法,其中反应进行约2-5小时。
9.权利要求1至8中任一项的方法,其中硫醇盐阴离子是有8-20个碳原子的直链或支链烷烃硫醇盐阴离子。
10.权利要求9的方法,其中烷烃硫醇盐阴离子是十二烷硫醇盐。
11.权利要求1-8中任一项的方法,其中硫醇是有6-10个碳原子的芳烃硫醇盐阴离子。
12.权利要求11的方法,其中芳烃硫醇盐阴离子是苯硫醇盐。
13.权利要求1-12中任一项的方法,其中硫醇盐阴离子是在醇盐存在下产生的。
14.权利要求13的方法,其中醇盐是甲醇盐。
15.权利要求1-14中任一项的方法,该方法在硫醇盐:文拉法辛化学计量比过量最高达约30∶1的情况下进行。
16.权利要求1-14中任一项的方法,其中硫醇盐:文拉法辛的摩尔比为约1.15∶1至约2.5∶1。
17.权利要求1-16中任一项的方法,其中还包括在含有1-6个碳原子的直链或支链烷基的醇存在下,将产物中和至等电点。
18.权利要求18的方法,其中的醇是异丙醇。
19.权利要求18或19的方法,其中反应混合物在加醇之前先冷却到约65-75℃。
20.权利要求18-20中任一项的方法,其中等电点是从约pH9.5到约pH10。
21.一种制备O-去甲文拉法辛的方法,该方法包括,在甲醇钠/甲醇的存在下,在约180-200℃下用十二烷基硫醇盐和聚乙二醇400将文拉法辛去甲基化约2-5小时,并在异丙醇存在下将产物中和至约pH9.5。
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US33495301P | 2001-12-04 | 2001-12-04 | |
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CN1319934C CN1319934C (zh) | 2007-06-06 |
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US (4) | US6689912B2 (zh) |
EP (1) | EP1451143B9 (zh) |
JP (1) | JP4342312B2 (zh) |
KR (1) | KR100939650B1 (zh) |
CN (1) | CN1319934C (zh) |
AR (1) | AR037622A1 (zh) |
AT (1) | ATE403641T1 (zh) |
AU (1) | AU2002357049B2 (zh) |
BR (1) | BR0214701A (zh) |
CA (1) | CA2466779C (zh) |
CO (1) | CO5580816A2 (zh) |
DE (1) | DE60228118D1 (zh) |
DK (1) | DK1451143T3 (zh) |
EC (1) | ECSP045135A (zh) |
ES (1) | ES2311647T4 (zh) |
HK (1) | HK1065778A1 (zh) |
HU (1) | HUP0402269A3 (zh) |
IL (3) | IL162253A0 (zh) |
MX (1) | MXPA04005309A (zh) |
NO (1) | NO20042680L (zh) |
NZ (1) | NZ533316A (zh) |
PL (1) | PL369299A1 (zh) |
PT (1) | PT1451143E (zh) |
RU (1) | RU2317286C2 (zh) |
SI (1) | SI1451143T1 (zh) |
TW (1) | TWI260982B (zh) |
UA (1) | UA80543C2 (zh) |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102164886A (zh) * | 2008-07-30 | 2011-08-24 | 基因里克斯(英国)有限公司 | 用于制备o-去甲文拉法辛的方法 |
CN109665966A (zh) * | 2018-11-01 | 2019-04-23 | 山东蒲济医药科技有限公司 | 一种琥珀酸去甲文拉法辛化合物的制备方法 |
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