CN103554058B - 一种利奈唑胺衍生物的制备方法 - Google Patents
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
Abstract
本发明公开了一种利奈唑胺衍生物的制备方法,本发明通过大量实验筛选,确定最佳的反应物用量,反应温度,反应时间和反应溶剂等制备工艺,整个制备工艺可操作性强,制备效率高,生产成本低,可实现工业化大生产。
Description
技术领域
本发明涉及一种化合物的制备方法,具体涉及一种抗菌药物,利奈唑胺衍生物的制备方法,属于医药技术领域。
背景技术
利奈唑胺,一种人工合成的唑烷酮类抗细菌药,由Pharmacia和Upjohn公司开发。2000年获得美国FDA批准,用于治疗革兰阳性(G+)球菌引起的感染,包括由MRSA引起的疑似或确诊院内获得性肺炎(HAP)、社区获得性肺炎(CAP)、复杂性皮肤或皮肤软组织感染(SSTI)以及耐万古霉素肠球菌(VRE)感染。
但是利奈唑胺在生产制备过程中,原料药常含有利奈唑胺衍生物或多个结构类似成分,而每个利奈唑胺衍生物的含量有严格的限制标准,实际药物生产过程中,需要这些利奈唑胺衍生物进行含量分析用,从而检测药物安全性。但是现有技术中,作为分析用的利奈唑胺衍生物的标准品难以获得,,目前还未有关利奈唑胺衍生物的制备方法的报道,因此很有必要在现有技术的基础之上研究设计出可实现工业化大生产的利奈唑胺衍生物的制备方法。
发明内容
发明目的:本发明所要解决的技术问题是克服现有技术的不足,提供一种操作简便、生产效率高、分离提纯方便,生产成本低,可实现工业化大生产的利奈唑胺衍生物的制备方法。
技术方案:为了实现以上目的,本发明采用如下技术方案:
一种利奈唑胺衍生物的制备方法,包括以下步骤:
(1)取摩尔比为1:1~1:2的利奈唑胺中间体1和苄溴,在碱性条件下,20℃~80℃反应12~48小时制得中间体2;
(2)取步骤(1)制备得到的中间体2和环氧氯丙烷,在碳酸钠或碳酸钾碱性条件下,在催化剂碘化钾或碘化钠作用下,在60℃~90℃;反应时间12-48小时,制备得到中间体3;
(3)取中间体3在氨气饱和的甲醇溶液中,在20℃~80℃下开环反应24-48小时,得到中间体4;
(4)取摩尔比为1:0.8~1.5的中间体4和乙酰化试剂,在二氯甲烷,四氢呋喃或N-N-二甲基甲酰胺溶剂中,在吡啶或三乙胺碱性条件下,在0℃~60℃下反应制备得到中间体5;
(5)取中间体5加入甲醇,乙醇或异丙醇溶剂,在钯碳或雷尼镍催化作用下,通入1~5个大气压的氢气,反应3~8小时,氢化得到利奈唑胺衍生物(Ⅰ)。
作为优选方案,以上所述的利奈唑胺衍生物的制备方法,步骤(1)所述的碱为三乙胺、吡啶或碳酸钾;碱的用量和中间体1的摩尔比是1:1~1:5。
作为优选方案,以上所述的利奈唑胺衍生物的制备方法,步骤(2)所述的反应溶剂为异丙醇,乙醇,甲醇,四氢呋喃或1,4二氧六环;反应温度为75℃~85℃。
作为优选方案,以上所述的利奈唑胺衍生物的制备方法,步骤(2)中间体2和环氧氯丙烷的摩尔用量比为1:1~1:2。
作为优选方案,以上所述的利奈唑胺衍生物的制备方法,步骤(4)所述的乙酰化试剂为醋酸酐或乙酰氯。
本发明提供的另一种利奈唑胺衍生物的制备方法,其包括以下步骤:
(1)取权利要求2制备得到的中间体3和权利要求3制备得到的中间体4,在甲醇、乙醇或异丙醇溶剂中,在60℃~90℃,反应16~24小时,制备得到中间体6;
(2)取中间体6和乙酰化试剂,在二氯甲烷,四氢呋喃或N-N-二甲基甲酰胺溶剂中,在吡啶或三乙胺碱性条件下,在0℃~60℃下反应制备得到中间体7;
(3)取中间体7加入甲醇,乙醇或异丙醇溶剂,在钯碳或雷尼镍催化作用下,通入1~5个大气压的氢气,反应3~8小时,氢化得到中间体8;
(4)取摩尔比为1:2~1:5的中间体8和碳基二咪唑,在二氯甲烷、三氯甲烷或四氢呋喃溶剂中,在20℃~60℃下,反应3~16小时,得到利奈唑胺衍生物(Ⅱ)。
作为优选方案,以上所述的利奈唑胺衍生物的制备方法,中间体3和中间体4的摩尔比为1:1~1:1.5。
作为优选方案,以上所述的利奈唑胺衍生物的制备方法,步骤(2)所述的乙酰化试剂为醋酸酐或乙酰氯。
作为优选方案,以上所述的利奈唑胺衍生物的制备方法,步骤(2)所述的中间体6和乙酰化试剂的摩尔用量比为1:1~1:1.5。
有益效果:本发明提供的利奈唑胺衍生物制备方法和现有技术相比具有以下有点:
1、本发明通过大量实验筛选,确定最佳的反应物用量,反应温度,反应时间和反应溶剂等制备工艺,整个制备工艺可操作性强,制备效率高,制备得到的化合物纯度高,生产成本低,可实现工业化大生产。
2、本发明制备得到的利奈唑胺衍生物,可作为分析利奈唑胺质量研究分析的标准对照品,便于对原料药的衍生物或杂质含量进行分析和控制,从而能保证用药的安全性。
附图说明
图1为本发明提供的利奈唑胺衍生物(Ⅰ)的制备工艺路线图。
图2为本发明提供的利奈唑胺衍生物(Ⅱ)的制备工艺路线图。
具体实施方式
根据下述实施例,可以更好地理解本发明。然而,本领域的技术人员容易理解,实施例所描述的具体的物料配比、工艺条件及其结果仅用于说明本发明,而不应当也不会限制权利要求书中所详细描述的本发明。
实施例1 利奈唑胺衍生物(Ⅰ)的制备
如图1所示,中间体2的制备: 取利奈唑胺中间体1 (10 g,0.051 mol)溶解于二氯甲烷(100 ml)中,冰浴下加入三乙胺(10.29g,0.101mol),接着再加入苄溴(13g, 0.075 mol)得到的反应液在45℃下回流24小时,点板观察反应有一半左右的原料剩余,向反应液中加入50ml饱和的碳酸氢钠,分出有机相,水相再用二氯甲烷萃取,合并的有机相浓缩得到15克的油状物,然后进一步用硅胶柱色谱分离提纯,洗脱剂为石油醚:乙酸乙酯=95:5,得到5.4克黄色中间体2固体。
中间体2的1H NMR (300 MHz, CDCl3)数据为:
1H NMR (300 MHz, CDCl3) δ: 7.27~7.35 (m, 5H), 6.79~6.85(t, 1H), 6.34~6.41(dd, 2H), 4.27 (s, 2H), 3.94 (br, 1H), 3.83~3.86(m, 4H), 2.94~2.97(m, 4H). MS:287[M+H]+。
中间体3的制备: 取中间体2 (5.7g,0.020mol)溶解在异丙醇(120ml)中,然后依次加入碳酸钾(5.5g,0.040mol)、碘化钾(0.83g, 0.005mol)、环氧氯丙烷(2.77g, 0.030mol)得到的反应液在80℃回流16小时,点板观察有30%左右的原料剩余,将反应液中的异丙醇蒸掉,然后向反应液中加入水50ml,用二氯甲烷萃取,分离出来的有机相浓缩,过柱子提纯得到7.3克中间体3;
中间体3的1H NMR (300 MHz, CDCl3)数据为:
1H NMR (300 MHz, CDCl3) δ: 7.19~7.33 (m, 5H), 6.45~6.86(t, 1H), 6.45~6.54(dd, 2H), 4.57 (s, 2H), 3.82~3.85(m, 4H), 3.65~3.72(dd,1H), 3.39~3.46(dd, 1H), 3.17(m, 1H), 2.95~2.98(m, 4H), 2.76~2.79(t, 1H), 2.52~2.54(m, 1H). MS:343[M+H]+。
中间体4的制备:取中间体3 (2g,0.006mol)溶解于用氨气饱和的甲醇(16 ml)中,在密封管中60℃下反应48小时,点板原料还有约30%左右的剩余,将反应液蒸干,粗产物过柱色谱提纯,展开剂用二氯甲烷:甲醇=95:5得到1.2克的中间体4;
中间体4的1H NMR (300 MHz, DMSO-d6)数据为:
1H NMR (300 MHz, DMSO-d6) δ: 7.14~7.27 (m, 5H), 6.79(t, 1H), 6.49~6.60(d, 1H),6.41(d, 1H), 4.93(br, 1H), 4.58(s, 2H), 3.89(br, 1H), 3.67(m, 4H), 3.41~3.60 (m, 1H), 2.76~2.79(m, 4H), 2.49~2.50(m, 2H). MS:360[M+H]+。
中间体5的制备:中间体4(1g, 0.003mol)溶解在二氯甲烷(5 ml)中加入吡啶(0.44g, 0.006mol)、醋酸酐(0.28g, 0.003mol),反应在室温下进行1.5小时,点板观察反应基本完全,加水用二氯甲烷萃取,合并的有机相蒸干用柱色谱分离提纯,展开剂用二氯甲烷:甲醇=100:1得到0.8克中间体5。
利奈唑胺衍生物(Ⅰ)的制备: 取中间体5 (0.76g, 0.002mol)溶解于甲醇(30ml)中,加入催化剂量的钯碳(10% Pd/C 0.1g), 常压氢化3小时,点板观察原料反应完全,过滤除去钯碳,滤液部分蒸干加入乙醚(10 ml)搅拌半小时过滤得到0.5克的产物,进一步用柱子色谱提纯,展开剂用二氯甲烷:甲醇=100:3得到利奈唑胺衍生物(Ⅰ)0.4克,HPLC测定纯度99.8%。
利奈唑胺衍生物(Ⅰ)的1H NMR (300 MHz, CDCl3) 数据为:
δ6.80~6.90 (t, 1H), 6.36~6.43(m, 2H), 5.92(br, 1H),3.90~4.10(br, 2H), 3.85~3.89(m, 4H), 3.31~3.52(m, 2H), 3.29(d, 1H), 3.01~3.21(m, 2H), 2.93~2.99 (m, 4H), 2.06(s, 3H). MS:312[M+H]+。
实施例2 利奈唑胺衍生物(Ⅰ)的制备
如图1所示,中间体2的制备: 取利奈唑胺中间体1 (10 g,0.051 mol)溶解于二氯甲烷(100 ml)中,冰浴下加入,吡啶(0.201mol),接着再加入苄溴(0.101 mol)得到的反应液在45℃下回流24小时,点板观察反应有一半左右的原料剩余,向反应液中加入50ml饱和的碳酸氢钠,分出有机相,水相再用二氯甲烷萃取,合并的有机相浓缩得到15克的油状物,然后进一步用硅胶柱色谱分离提纯,洗脱剂为石油醚:乙酸乙酯=95:5,得到5.4克黄色中间体2固体。
中间体2的1H NMR (300 MHz, CDCl3)数据为:
1H NMR (300 MHz, CDCl3) δ: 7.27~7.35 (m, 5H), 6.79~6.85(t, 1H), 6.34~6.41(dd, 2H), 4.27 (s, 2H), 3.94 (br, 1H), 3.83~3.86(m, 4H), 2.94~2.97(m, 4H). MS:287[M+H]+
中间体3的制备: 取中间体2 (5.7g,0.020mol)溶解在乙醇(120ml)中,然后依次加入碳酸钠0.040mol)、碘化钠(0.005mol)、环氧氯丙烷(2.77g, 0.030mol)得到的反应液在85℃回流24小时,点板观察有30%左右的原料剩余,将反应液中的异丙醇蒸掉,然后向反应液中加入水50ml,用二氯甲烷萃取,分离出来的有机相浓缩,过柱子提纯得到7.3克中间体3;
中间体3的1H NMR (300 MHz, CDCl3)数据为:
1H NMR (300 MHz, CDCl3) δ: 7.19~7.33 (m, 5H), 6.45~6.86(t, 1H), 6.45~6.54(dd, 2H), 4.57 (s, 2H), 3.82~3.85(m, 4H), 3.65~3.72(dd,1H), 3.39~3.46(dd, 1H), 3.17(m, 1H), 2.95~2.98(m, 4H), 2.76~2.79(t, 1H), 2.52~2.54(m, 1H). MS:343[M+H]+。
中间体4的制备:取中间体3 (2g,0.006mol)溶解于用氨气饱和的甲醇(16 ml)中,在密封管中65℃下反应24小时,点板原料还有约30%左右的剩余,将反应液蒸干,粗产物过柱色谱提纯,展开剂用二氯甲烷:甲醇=95:5得到1.2克的中间体4;
中间体4的1H NMR (300 MHz, CDCl3)数据为: 1H NMR (300 MHz, DMSO-d6) δ: 7.14~7.27 (m, 5H), 6.79(t, 1H), 6.49~6.60(d, 1H),6.41(d, 1H), 4.93(br, 1H), 4.58(s, 2H), 3.89(br, 1H), 3.67(m, 4H), 3.41~3.60 (m, 1H), 2.76~2.79(m, 4H), 2.49~2.50(m, 2H). MS:360[M+H]+
中间体5的制备:中间体4(1g, 0.003mol)溶解在二氯甲烷(5 ml)中加入吡啶(0.44g, 0.006mol)、乙酰氯(0.045mol),反应在室温下进行1.5小时,点板观察反应基本完全,加水用四氢呋喃萃取,合并的有机相蒸干用柱色谱分离提纯,展开剂用二氯甲烷:甲醇=100:1得到0.8克中间体5。
中间体5的1H NMR (300 MHz, CDCl3)数据为:
利奈唑胺衍生物(Ⅰ)的制备: 取中间体5 (0.76g, 0.002mol)溶解于乙醇(30ml)中,加入催化剂量的雷尼镍,通入2个大气压下氢气进行氢化6小时,点板观察原料反应完全,过滤除去雷尼镍,滤液部分蒸干加入乙醚(10 ml)搅拌半小时过滤得到0.5克的产物,进一步用柱子色谱提纯,展开剂用二氯甲烷:甲醇=100:3得到利奈唑胺衍生物(Ⅰ)0.4克,HPLC测定纯度99.8%。
利奈唑胺衍生物(Ⅰ)的1H NMR (300 MHz, CDCl3)数据为:
1H NMR (300 MHz, CDCl3) δ: 6.80~6.90 (t, 1H), 6.36~6.43(m, 2H), 5.92(br, 1H),3.90~4.10(br, 2H), 3.85~3.89(m, 4H), 3.31~3.52(m, 2H), 3.29(d, 1H), 3.01~3.21(m, 2H), 2.93~2.99 (m, 4H), 2.06(s, 3H). MS:312[M+H]+。
实施例3利奈唑胺衍生物(Ⅱ)的制备
如图2所示,中间体6的制备: 取实施例1制备得到的中间体3(2.74g,0.008mol)和中间体4(2.88g, 0.008mol)在异丙醇(55 ml)中80℃反应16h,点板观察有20%左右的原料剩余,将反应液浓缩得到的粗产物过柱子提纯,展开剂用二氯甲烷:甲醇=98:2~90:10,得到2.5克中间体6产物。
中间体7的制备:取中间体6 (2.5g, 0.003mol)溶解在二氯甲烷(30 ml)中加入吡啶(0.56g,0.007mol)、酸酸酐(0.36g, 0.003mol),室温下反应2小时,点板反应基本完全,加入水(50 ml),萃取用二氯甲烷,合并的有机相蒸干过柱子提纯,展开剂用二氯甲烷:甲醇=95:5,得到2克的中间体7。
中间体8的制备:取中间体7 (2g, 0.003mol)溶解在甲醇(30 ml)中,加入钯碳(10% Pd/C, 0.4g),在常压下氢化反应2小时,点板观察反应完全,过滤除去钯碳,滤液蒸干得到中1.4克的中间体8。
中间体8的1H NMR (300 MHz, CDCl3)数据为:
1H NMR (300 MHz, CDCl3) δ: 7.54 (t, 1H), 7.41(t, 1H), 7.08(m, 2H),6.93(m, 2H), 4.93(m, 2H), 4.07~4.18 (m, 3H),3.92~3.98 (m, 1H) 3.85~3.88(m, 8H), 3.68~3.73(m, 3H), 3.5 (m, 1H), 3.06(m, 8H), 2.21 (s,3H). MS:564[M+H]+。
利奈唑胺衍生物(Ⅱ)的制备:取中间体8 (1.4g, 0.0025mol)溶解在干燥的四氢呋喃中,加入羰基二咪唑(1.2g, 0.0075mol),室温下反应24小时,点板观察原料反应完全,加入水(30 ml),用二氯烷萃取,浓缩得到的粗产物用甲醇重结晶得到利奈唑胺衍生物(Ⅱ)1克,HPLC检测纯度为98.6%。
利奈唑胺衍生物(Ⅱ)的1H NMR (300 MHz, CDCl3)数据为:
1H NMR (300 MHz, CDCl3) δ: 7.46 (t, 1H), 7.41(t, 1H), 7.08(m, 2H),6.91~6.95(m, 2H), 4.93(m, 2H), 3.93~4.19 (m, 4H), 3.85~3.88(m, 8H), 3.47~3.73(m, 4H), 3.06(m, 8H), 2.21 (s,3H). MS: 616[M+H]+。
Claims (2)
1.一种利奈唑胺衍生物的制备方法,其特征在于,包括以下步骤:
(1)取摩尔比为1:1~1:2的利奈唑胺中间体1和苄溴,在碱性条件下,20℃~80℃反应12~48小时制得中间体2;中间体1结构式为中间体2结构式为
(2)取步骤(1)制备得到的中间体2和环氧氯丙烷,在碳酸钠或碳酸钾碱性条件下,在催化剂碘化钾或碘化钠作用下,在60℃~90℃;反应时间12-48小时,制备得到中间体3,中间体3结构式为
(3)取中间体3在氨气饱和的甲醇溶液中,在20℃~80℃下开环反应24-48小时,得到中间体4,中间体4结构式为
(4)取摩尔比为1:0.8~1.5的中间体4和乙酰化试剂,在二氯甲烷,四氢呋喃或N-N-二甲基甲酰胺溶剂中,在吡啶或三乙胺碱性条件下,在0℃~60℃下反应制备得到中间体5,中间体5结构式为
(5)取中间体5加入甲醇,乙醇或异丙醇溶剂,在钯碳或雷尼镍催化作用下,通入1~5个大气压的氢气,反应3~8小时,氢化得到利奈唑胺衍生物(Ⅰ)
步骤(1)所述的碱为三乙胺、吡啶或碳酸钾;碱的用量和中间体1的摩尔比是1:1~1:5;
步骤(2)所述的反应溶剂为异丙醇,乙醇,甲醇,四氢呋喃或1,4二氧六环;反应温度为75℃~85℃;
步骤(2)中间体2和环氧氯丙烷的摩尔用量比为1:1.2~1:2;
步骤(4)所述的乙酰化试剂为醋酸酐或乙酰氯。
2.一种利奈唑胺衍生物的制备方法,其特征在于,包括以下步骤:
(1)取权利要求1制备得到的中间体3和权利要求1制备得到的中间体4,在甲醇、乙醇或异丙醇溶剂中,在60℃~90℃,反应16~24小时,制备得到中间体6;中间体3结构式为中间体4结构式为中间体6结构式为
(2)取中间体6和乙酰化试剂,在二氯甲烷,四氢呋喃或N-N-二甲基甲酰胺溶剂中,在吡啶或三乙胺碱性条件下,在0℃~60℃下反应制备得到中间体7,中间体7结构式为
(3)取中间体7加入甲醇,乙醇或异丙醇溶剂,在钯碳或雷尼镍催化作用下,通入1~5个大气压的氢气,反应3~8小时,氢化得到中间体8,中间体8结构式为
(4)取摩尔比为1:2~1:5的中间体8和羰基二咪唑,在二氯甲烷、三氯甲烷或四氢呋喃溶剂中,在20℃~60℃下,反应3~16小时,得到利奈唑胺衍生物(Ⅱ),结构式为
步骤(1)所述的中间体3和中间体4的摩尔比为1:1~1:1.5;
步骤(2)所述的乙酰化试剂为醋酸酐或乙酰氯。
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