CN1444579A - 用作镇咳药的2,2-二取代的1,3-二氧环戊烷 - Google Patents

用作镇咳药的2,2-二取代的1,3-二氧环戊烷 Download PDF

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CN1444579A
CN1444579A CN01813457A CN01813457A CN1444579A CN 1444579 A CN1444579 A CN 1444579A CN 01813457 A CN01813457 A CN 01813457A CN 01813457 A CN01813457 A CN 01813457A CN 1444579 A CN1444579 A CN 1444579A
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M·阿莱格蒂
M·C·切斯塔
R·柯蒂
L·尼可里尼
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Abstract

本发明叙述了(±)3-(4-苯基-1-哌嗪基)-1,2-丙二醇环缩醛类、它们光学拆分法、以及其用作制备(-)3-(4-苯基-1-哌嗪基)-1,2-丙二醇(左羟丙哌嗪)及其盐类的中间体。

Description

用作镇咳药的2,2-二取代的1,3-二氧环戊烷
技术领域
本发明涉及(±)3-(4-苯基-1-哌嗪基)-1,2-丙二醇环缩醛类、它们的光学拆分法以及其用作为制备(-)3-(4-苯基-1-哌嗪基)-1,2-丙二醇(左羟丙哌嗪)及其盐类的中间体。
发明内容
更准确地说,本发明涉及以一般式(1)表示的(±)2,2-取代的1,3-二氧环戊烷:
Figure A0181345700031
式中:
每个Ra和Rb可以相同或不同,表示氢、C1-C6烷基、苯基,或
Ra和Rb与它们连接的碳原子一起形成可选择性取代的4至7个原子数的碳环。
在以一般式(1)表示的本发明的化合物中,Ra和Rb优选为含有少于6个碳原子的烷基。Ra和Rb优选相同;Ra和Rb更优选为甲基或乙基或者,与它们连接的碳原子一起形成含有5至6个碳原子的环。
本发明还涉及以一般式(1)表示的2,2-取代的1,3-二氧环戊烷的纯对映体一价盐,其含有药学上可接受的手性酸,如L-苹果酸、D-酒石酸和L-酒石酸、D-扁桃酸和L-扁桃酸、L-樟脑磺酸和D-樟脑磺酸。
本发明特别优选的化合物是:
(±)1,2-亚环戊基-3-(4-苯基-哌嗪-1-基)-丙-1,2-二醇;
(±)1,2-亚环己基-3-(4-苯基哌嗪-1-基)-丙-1,2-二醇;
(±)1,2-(2-亚丙基)-3-(4-苯基-哌嗪-1-基)-丙-1,2-二醇;
(±)1,2-(3-亚戊基)-3-(4-苯基-哌嗪-1-基)-丙-1,2-二醇;
S(-)-1,2-亚环己基-3-(4-苯基哌嗪-1-基)-丙-1,2-二醇L-酒石酸盐;
S(-)-1,2-亚环戊基-3-(4-苯基哌嗪-1-基)-丙-1,2-二醇L-酒石酸盐。
以一般式(1)表示的本发明的化合物是以苯基哌嗪与以一般式(2)表示的(±)1,2-甘油基-二氧环戊烷反应而制成:
Figure A0181345700041
式中:X选自由氯、溴、碘及适当磺酯(R-SO3-)组成的组,其中R选自由C1-C3烷基(优选为甲基)、三氟甲基、苯基、对甲苯基及对甲氧苯基组成的组。
以一般式(2)表示的二氧环戊烷为已知化合物和/或可按已知方法制备。
以一般式(2)(X=R-SO3-)表示的磺酯是用酸酐或用一般式(3)表示的烷基和/或芳基磺酰氯与以一般式(4)表示的(±)2,2-取代的1,3-二氧环戊烷-4-甲醇经酯化作用而制备:
                        R-SO3H    (3)式中:Ra和Rb的定义同上所述。
以一般式(4)表示的化合物为已知化合物。事实上,以一般式(4)表示的外消旋物已经用作发酵拆分法的底物[美国专利US5,190,867(02.03.1993)]。在Org.Synth.Coll.Vol III的一文中叙述了以甘油为原料制备消旋-异亚丙基甘油。
以一般式(2)表示的4-卤甲基-二氧环戊烷,式中X是氯、溴或碘,可以用一般式(2)表示的相应磺酸盐(X=RSO3-,其中的R同上所述)为原料,通过在惰性溶剂中与碱或碱土金属卤化物反应而制成,而惰性溶剂选自由丙酮、甲乙酮、四氢呋喃、二恶烷、二甲基亚砜、乙腈、C1-C4醇及它们的混合物组成的组。所述化合物的优选合成方法包括如欧洲专利EP0930311(21.07.1999)所述那样,使相应的3-卤-1,2-丙二醇进行二氧环戊烷化反应。特别优选为3-氯-丙-1,2二醇;优选缩醛剂是甲醛、乙醛和苯甲醛、丙酮、二乙酮、二苯甲酮、环己酮、缩醛和/或其烯醇酯,如2,2-二甲氧丙烷、2,2-二甲氧乙烷、2-甲氧基-丙烯。
此外,以一般式(2)(X为氯或溴)表示的二氧环戊烷也可以按照法国专利FR1522153或Blicke FF等人在J.A.C.S(74:1735页,1972年及76:1226页,1954年)所述制备(+)2-氯甲基-1,4-二螺[4,5]-癸烷的方法,以表氯醇或表溴醇与环烷酮进行缩醛作用而制成。
在用于把仲胺转化成叔胺的常规反应条件下,每摩尔以一般式(2)表示的烷基化剂配至少1摩尔或稍稍过量的苯基哌嗪,在至少1摩尔中和碱的存在下使苯基哌嗪与以一般式(2)表示的1,2-甘油基-二氧环戊烷进行烷基化反应。使用的中和碱与以一般式(2)表示的烷基化剂至少等摩尔量,并选自由磨细的无机碱,如碱或碱土金属(钠、钾、镁、钙)的碳酸盐或碳酸氢盐或钙或镁的氧化物,或叔胺,如三乙胺、二甲苯胺或二乙苯胺,芳香胺,如吡啶、甲基吡啶和可力丁,以及若有需要,苯基哌嗪本身组成的组,而苯基哌嗪可在以后再循环进入后续生产循环。
甲基化反应可在加热,选择性地可在诸如甲苯或二甲苯等惰性溶剂中进行,当反应在溶剂回流的条件下进行时,有利于缩短反应时间。
甲基化反应完成后,过滤或通过离心去掉任何不溶性物质,然后用水反复洗涤有机相直至容易除去杂质和副产物,蒸发掉溶剂,得到高产率残余物,其由以一般式(1)表示的基本纯1,3-二氧环戊烷组成,通过直接结晶或与1摩尔等量的羧酸进行成盐作用都可以回收该化合物。
化合物(1)及其盐均很容易从常规溶剂结晶析出:因此,本发明的方法使由于微量缩水甘油和/或表卤代醇以潜在杂质存在的污染危险减至最小。
以一般式(1)表示的化合物的一价盐可通过常规方法制备,如以等分子量所需要的酸在一适当溶剂中进行成盐作用,然后通过结晶析出所生成的盐。
业已发现,化合物(1)与手性酸,特别是与酒石酸的成盐作用是一种高产率回收化合物(1)的S-对映体的有效光学拆分法。
所述(S)(-)对映体及其盐用作镇咳药或者作为以一般式(1)表示的(-)1,3-二氧环戊烷的水溶液进行热水解反应合成(-)3-(4-苯基-1-哌嗪基)-丙-1,2-二醇(左羟丙哌嗪)的中间体,过量1摩尔无机酸,如盐酸,或羧酸,如乙酸、丙二酸或柠檬酸的稀释水溶液可加快水解反应的进行。
具体实施方式
以下,结合实施例对本发明作进一步说明。实施例1
边强烈搅拌边向11.98g(±)2,3-氧-(3-亚戊基)-甘油甲苯磺酸盐的正丁醇溶液(70ml)中加入4.5g磨细的碳酸钠,再加入6ml苯基哌嗪。混合物在搅拌条件下回流,并在回流温度下反应20小时。然后,在减压下蒸发掉正丁醇,用水使残余物溶解,用乙酸乙酯反复萃取。干燥和过滤混合有机相,再在真空条件下蒸发溶剂,将所得的残余物在含水甲醇中结晶析出,得到8.95g(±)1,2-(3-亚戊基)-3-(4-苯基-哌嗪-1-基)-丙-1,2-二醇,也称为4-苯基哌嗪、1-(2,2-二乙基-1,3-二氧环戊烷-4-基-甲基)。实施例2
按实施例1所述步骤,用(±)2,3-氧-(2-亚丙基)-甘油甲苯磺酸盐制成(±)1,2-(2-亚丙基)-3-(4-苯基-哌嗪-1-基)-丙-1,2-二醇,也称为4-苯基哌嗪、1-(2,2-二甲基-1,3-二氧环戊烷-4-基-甲基)。实施例3
在惰性气氛中,向3.28g(±)1,4-二螺-[4,5]癸烷-2-氯甲烷的甲苯溶液(16mL)加入5.45ml苯基哌嗪。然后,使反应混合物回流直至反应完成(约8小时)。将反应混合物冷却至大约50℃,加入10ml水,强烈搅拌至少10分钟。分离有机相和水相,并用水反复洗涤有机相。蒸发掉溶剂,得到溶解在加热异丙醇的粘稠油品(15mL)。所得溶液缓慢地冷却,分离出结晶固体,即(±)1,2-亚环己基-3-(4-苯基哌嗪-1-基)-丙-1,2-二醇。
1H-NMRδ7.26(t,2H,J=7.4Hz);δ6.95(d,2H,J=8.9Hz);δ6.85(t,1H,J=7.28Hz);δ4.3(m,1H,J=6.1Hz);δ4.1(dd,1H,J1=8.0Hz,J2=6.1Hz);δ3.65(dd,1H,J1=8.0,J2=7.1Hz);δ3.2(t,4H,J=5.05Hz);δ2.9÷2.55(m,6H);δ1.7÷1.3(m,10H)。实施例4
按实施例1和3所述步骤,以1,3-二氧环戊烷,其选自下列组成的组:
(±)1,4-二螺-[4,4]壬烷-2-甲醇,甲磺酸盐;
(±)1,4-二螺-[4,4]壬烷-2-氯甲基;
(±)1,4-二螺-[4,5]癸烷-2-甲醇,三氟甲磺酸盐;
(±)1,4-二螺-[4,5]癸烷-2-甲醇,甲磺酸盐;
(±)1,3-二氧环戊烷-4-氯甲基-2,2-二甲基;
(±)1,3-二氧环戊烷-4-溴-甲基-2,2-二甲基;
与苯基哌嗪反应,生成下列化合物:
(±)1,2-亚环戊基-3-(4-苯基-哌嗪-1-基)-丙-1,2-二醇;
(±)1,2-亚环己基-3-(4-苯基-哌嗪-1-基)-丙-1,2-二醇;
(±)1,2-(2-亚丙基)-3-(4-苯基-哌嗪-1-基)-丙-1,2-二醇。实施例5
边搅拌边向(±)1,2-亚环己基-3-(4-苯基-哌嗪-1-基)-丙-1,2-二醇(6.32g)的无水乙醇溶液(70ml)加入3g酒石酸。混合物搅拌至完全溶解,然后,冷却至5-8℃。得到4.05g结晶固体,将所得结晶固体在无水乙醇中再结晶,得到3.82g S(-)-1,2-亚环己基-3-(4-苯基-哌嗪-1-基)丙-1,2-二醇L-酒石酸盐,熔点为131-132℃,[α]D=-9.6°(c=3%;甲醇);
1H-NMRδ7.5(dd,2H,J1=8.7,J2=7.3);δ7.2(m,3H);δ4.8(m,1H);δ4.4(s,2H);δ4.35(dd,1H,J1=8.9Hz,J2=6.7Hz);δ3.86(dd,1H,J1=8.9Hz,J2=5.8Hz);δ3.6-3.4(m,10H);δ1.8-1.48(m,10H)。实施例6
向2.4g S(-)-1,2-亚环己基-3-(4-苯基-哌嗪-1-基)丙-1,2-二醇L-酒石酸盐的水溶液加入2N氢氧化钠,进行碱化作用(pH=8.5),然后用乙酸乙酯完全萃取。用10%磷酸氢钠溶液洗涤混合有机相,以硫酸钠干燥,并使其蒸干,再在异丙醇中结晶析出,得到1.52g S(-)-1,2-亚环己基-3-(4-苯基-哌嗪-1-基)丙-1,2-二醇,熔点为63-64℃,[α]D=-7.8°(1%甲醇)。
1H-NMRδ7.26(t,2H,J=7.4Hz);δ6.95(d,2H,J=8.9Hz);δ6.85(t,1H,J=7.28Hz);δ4.3(m,1H,J=6.1Hz);δ4.1(dd,1H,J1=8.0Hz,J2=7.1Hz);δ3.65(dd,1H,J1=8.0,J2=7.1Hz);δ3.2(t,4H,J=5.05Hz);δ2.9÷2.55(m,6H);δ1.7÷1.3(m,10H)。实施例7
按实施例1至4的方法,使1,3-二氧环戊烷与L-酒石酸进行成盐反应,并把所得的盐分级再结晶,生成下列化合物:
S(-)-1,2-亚环戊基-3-(4-苯基-哌嗪-1-基)-丙-1,2-二醇,L-酒石酸盐;
S(-)-1,2-(2-亚丙基)-3-(4-苯基-哌嗪-1-基)-丙-1,2-二醇,L-酒石酸盐;
S(-)-1,2-(3-亚戊基)-3-(4-苯基-哌嗪-1-基)-丙-1,2-二醇,L-酒石酸盐;
随后按照实施例6的方法中和这些化合物,得到相应的游离碱。实施例8
使70ml含水乙酸(10%重量/体积)与2.8g S(-)-1,2-亚环戊基-3-(4-苯基-哌嗪-1-基)-丙-1,2-二醇的悬浮液回流2小时,使悬浮液中的蒸气冒泡,馏出环戊酮,从而达到分离的目的。加入10%氢氧化钠溶液使水相中和至pH值等于7.5,然后冷却至5-10℃,得到1.97g(-)3-(4-苯基-哌嗪-1-基)-丙二醇,熔点为102-103℃,[α]D=-23.5°(2.8%二氯甲烷)。实施例9
另外,边搅拌边把0.35摩尔当量的实施例6和7所述其中一种1,3-二氧环戊烷衍生物:S(-)1,2-(2-亚丙基)-3-(4-苯基-哌嗪-1-基)-丙-1,2-二醇、S(-)1,2-亚环戊基-3-(4-苯基-哌嗪-1-基)-丙-1,2-二醇、S(-)-1,2-亚环己基-3-(4-苯基-哌嗪-1-基)丙-1,2-二醇,分批加到45ml水中含有36%盐酸(36ml)的溶液中;悬浮液加热至80℃,得到澄清溶液,在该温度再保持30分钟,然后冷却至20-25℃,用二氯甲烷(3×15ml)反复萃取水相,再加入正丁醇(0.5l)。使二相混合物回流,蒸馏出水和正丁醇共沸物,回收大约300ml馏出液,然后冷却以加快(-)3-(4-苯基-哌嗪-1-基)-丙二醇氢氯化物的结晶析出(85g)。
使125ml氢氯化物的水溶液在50℃加热15分钟,并用活性炭(2.2g)脱色,过滤后,再加入氢氧化铵水溶液(30%重量/重量)中和。迅速加热至50℃之后,加入(-)3-(4-苯基-哌嗪-1-基)-丙二醇晶体,溶液就开始结晶。同时,让悬浮液自身冷却,在+2-+4℃保持2小时,最后过滤得到70-72g(-)3-(4-苯基-哌嗪-1-基)-1,2-丙二醇。

Claims (8)

1.以一般式(1)表示的化合物,其特征在于:一般式(1)表示如下
式中,每个Ra和Rb可以相同或不同,表示氢、C1-C6烷基、苯基,或Ra和
Rb与它们连接的碳原子一起形成可选择性取代的4至7个原子的碳环。
2.如权利要求1所述的化合物,其特征在于:Ra和Rb相同。
3.如权利要求1或2所述的化合物,其特征在于:Ra和Rb是甲基或乙基。
4.如权利要求1所述的化合物,其特征在于:所述化合物选自以下化合物:
(±)1,2-亚环戊基-3-(4-苯基-哌嗪-1-基)-丙-1,2-二醇;
(±)1,2-亚环己基-3-(4-苯基-哌嗪-1-基)-丙-1,2-二醇;
(±)1,2-(2-亚丙基)-3-(4-苯基-哌嗪-1-基)-丙-1,2-二醇;
(±)1,2-(3-亚戊基)-3-(4-苯基-哌嗪-1-基)-丙-1,2-二醇;
S(-)-1,2-亚环己基-3-(4-苯基-哌嗪-1-基)-丙-1,2-二醇L-酒石酸盐;
S(-)-1,2-亚环戊基-3-(4-苯基-哌嗪-1-基)-丙-1,2-二醇L-酒石酸盐。
5.一种用苯基哌嗪与以一般式(2)表示的(±)1,2-甘油基-二氧环戊烷反应制备以一般式(1)表示的化合物的方法,其特征在于:所述方法中所用以一般式(2)表示的化合物如下式中,X选自由氯、溴、碘及适当磺酯(R-SO3-)组成的组,其中R选自由C1-C3烷基(优选为甲基)、三氟甲基、苯基、对甲苯基及对甲氧苯基组成的组。
6.如权利要求5所述的方法,其特征在于:以甲苯或二甲苯为溶剂在碱的存在下进行反应。
7.一种通过L-酒石酸的成盐作用权利要求1-4所述化合物的光学拆分方法。
8.如权利要求1-4所述化合物作为合成相应(S)对映体的中间体的应用。
CN018134572A 2000-07-28 2001-07-18 用作镇咳药的2,2-二取代的1,3-二氧环戊烷 Expired - Fee Related CN1216053C (zh)

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