CN104725334A - (4-(2-(氮杂环庚烷-1-基)乙氧基)苯基)甲醇的制备方法 - Google Patents

(4-(2-(氮杂环庚烷-1-基)乙氧基)苯基)甲醇的制备方法 Download PDF

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CN104725334A
CN104725334A CN201310713159.3A CN201310713159A CN104725334A CN 104725334 A CN104725334 A CN 104725334A CN 201310713159 A CN201310713159 A CN 201310713159A CN 104725334 A CN104725334 A CN 104725334A
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phenyl
azepan
formula
preparation
compound
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温光辉
宛六一
付冀峰
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BEIJING LABWORLD BIO-MEDICINE TECHNOLOGY Co Ltd
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BEIJING LABWORLD BIO-MEDICINE TECHNOLOGY Co Ltd
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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
    • C07D295/08—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 bound oxygen or sulfur atoms
    • C07D295/084—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 bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—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 bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明提供了一种适合于工业化生产（4-（2-（氮杂环庚烷-1-基）乙氧基）苯基）甲醇的制备方法，其特点在于以低毒的2-（氮杂环庚烷）-1-乙醇为起始原料，经过三步反应得到合成巴多昔芬的关键中间体“（4-（2-（氮杂环庚烷-1-基）乙氧基）苯基）甲醇”。该方法涉及的反应不仅原料低毒便宜，而且操作简单、条件温和、后处理简单、收率高，是一条非常适合工业化的制备路线。

Description

(4-(2-(氮杂环庚烷-1-基)乙氧基)苯基)甲醇的制备方法
技术领域
本发明属于药物合成技术领域，具体地，本发明涉及治疗绝经后妇女骨质疏松症药物醋酸巴多昔芬关键中间体的合成。 
背景技术
醋酸巴多昔芬，英文名为Bazedoxifene Acetate，其结构式为： 
醋酸巴多昔芬最初由惠氏公司研制，后转让给辉瑞制药，是第三代选择性雌激素受体调节剂，主要用于治疗绝经后妇女骨质疏松症。2009年4月在意大利和西班牙上市，商品名为Conbriza，2010年在日本上市，商品名为Viviant，2013年10月在美国批准上市，商品名为Duavee。 
目前，报道的制备巴多昔芬的方法比较简单可行的有以下两种： 
由路线图可知，两种方法都需要用到中间体“1-（2-氯乙基）氮杂环庚烷盐酸盐”通过该中间制备关键中间体“（4-（2-（氮杂环庚烷-1-基）乙氧基）苯基）甲醇”。目前，1-（2-氯乙基）氮杂环庚烷盐酸盐国内供应厂家比较少而且都不能工业化生产价格昂贵，并且该化合物本身具有相当大的毒性，不利于环保和劳动保护，采用该路线实现工业化较困难。 
我公司开发的一种新的制备（4-（2-（氮杂环庚烷-1-基）乙氧基）苯基）甲醇方法，不仅所用操作简单、收率高，整个过程没有使用到毒性特别大的原料，三 废少，对环保不会造成太大的压力，是一条绿色、环保的工业化路线，可极大地降低醋酸巴多昔芬的合成成本，有利于该药品的国产化，极具市场价值和社会价值。 
发明内容
本发明提供了以低毒的2-（氮杂环庚烷）-1-乙醇为起始原料制备（4-（2-（氮杂环庚烷-1-基）乙氧基）苯基）甲醇的方法，不仅解决了现有工艺过程原料毒性大的问题，而且产品质量好、收率高。 
技术方案 
（4-（2-（氮杂环庚烷-1-基）乙氧基）苯基）甲醇的制备方法经过下面的反应过程。 
过程一： 
以2-（氮杂环庚烷）-1-乙醇为原料和对甲苯磺酰氯为原料、有机碱作为缚酸剂，在二氯甲烷中反应得到2-（氮杂环庚烷-1-基）乙基-4-甲基苯磺酸酯。 
过程二： 
以2-（氮杂环庚烷-1-基）乙基-4-甲基苯磺酸酯和4-苯酚钠衍生物为原料发生磺酸酯醇解成醚反应得到式（Ⅲ）。 
如果R’=-CH2OH，则得到如式（Ⅰ）的化合物：（4-（2-（氮杂环庚烷-1-基）乙氧基）苯基）甲醇 
如果R’=-CHO，得到的中间体还需要经过一步还原反应得到如式（Ⅰ）的化合物。 
具体实施例
实施例一：2-（氮杂环庚烷-1-基）乙基-4-甲基苯磺酸酯的制备 
称取2.15克2-（氮杂环庚烷）-1-乙醇（15.0mmol）与20ml无水吡啶混合，搅拌降温至0℃，加入2.86克对甲苯磺酰氯（15.0mmol）。加毕，于室温下反应3小时，加入水淬灭反应，继续搅拌30分钟，加入二氯甲烷，搅拌下滴加入1M盐酸调PH=6-7，搅拌30分钟后静置分层，二氯甲烷层先后用水和饱和盐水洗涤，然后干燥（无水硫酸钠），过滤，减压蒸出二氯甲烷，得到一紫色油状物，不用纯化直接用于下一步反应。 
实施例二：4-（2-(氮杂环庚烷-1-基）乙氧基)苯甲醛的制备 
一定量的2-（氮杂环庚烷-1-基）乙基-4-甲基苯磺酸酯与等摩尔量的4-甲酰基苯酚钠混合于DMF中，搅拌加热至80℃，监控反应完全。反应毕，冷却至室温，将反应液倒入水中，加入二氯甲烷提取，合并二氯甲烷相，先后用水和饱和盐水洗涤，干燥（无水硫酸镁）、过滤、蒸馏除去二氯甲烷，残留物经过柱层析纯化（正己烷/乙酸乙酯=98：2）得到无色油状物4-（2-(氮杂环庚烷-1-基）乙氧基)苯甲醛，收率80%。IR(nujol):2926,2853,1695,1603,1507,1312,1259,1160,1021and834cm-1.1H NMR(300MHz,CDCl3):δ1.65-1.70(8H,m,4×CH2),2.87(4H,brs,2×NCH2),3.06(2H,t,NCH2),4.22(2H,t,OCH2),7.05(2H,d,2×Ar-H),7.86(2H,d,2×Ar-H),9.9(CHO)。HRMS m/z计算值C15H21NO2[M+H]+248.1643,实测值248.1645 
实施例三：（4-（2-（氮杂环庚烷-1-基）乙氧基）苯基）甲醇的制备 
4.5mmol的上一步反应产物与25ml甲醇混合，室温下分批加入3.1mmol的硼氢化钠，加毕于室温下反应3-5小时，TLC监控反应（展开剂：甲醇/二氯甲烷=1：9）。反应毕，减压蒸出甲醇，残留物中加入15ml水，用乙酸乙酯提取3次（50ml×3次），合并乙酸乙酯相用水洗涤3次（50ml×3次），干燥（无水硫酸钠）、过滤、减压蒸出乙酸乙酯得到一油状物，收率80-90%。IR(nujol):3360,2934,2867,1610，1513,1456，1325，1300,1247,1176，1055,1010，823cm-1。1HNMR(CDCl3/TMS):7.28(d,2H),6.86(d,2H),4.61(s,2H),4.06(t,2H),2.94(t,2H),2.76(m,4H),1.7-1.5(m,8H)。 

Claims (4)

1.（4-（2-（氮杂环庚烷-1-基）乙氧基）苯基）甲醇（式Ⅰ）的制备方法，其特征在于以2-（氮杂环庚烷）-1-乙醇为起始原料，经酯化反应、成醚反应、还原反应或者是酯化反应、成醚反应得到如式（Ⅰ）的化合物。 
。
2.如权利要求1所述，酯化反应是将2-（氮杂环庚烷）-1-乙醇与磺酰氯（RSO2Cl）在缚酸剂存在下反应生成如式（Ⅱ）所示的中间体1。 
。
其中R代表甲基、乙基、三氟甲基等小于三个碳的烷基或者含苯环的基团，如：苯基、对甲苯基等，优选对甲苯基。缚酸剂为含氮的有机碱，如：三乙胺、吡啶等。 
3.如权利要求1所述，中间体1与苯酚钠衍生物发生成醚反应得到如式（Ⅲ）所示的中间体2。 
其中当R’=-CH2OH时式（Ⅲ）所示的化合物为（Ⅰ）。 
4.如权利要求1所述，当式（Ⅲ）中的R’=-CHO时经过还原反应得到如式（Ⅰ）所示的化合物，该化合物可以用于制备醋酸巴多昔芬。 
CN201310713159.3A 2013-12-20 2013-12-20 (4-(2-(氮杂环庚烷-1-基)乙氧基)苯基)甲醇的制备方法 Pending CN104725334A (zh)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001019839A1 (en) * 1999-09-13 2001-03-22 American Home Products Corporation Glucopyranosides conjugates of 2-(4-hydroxy-phenyl)-1-[4-(2-amin-1-yl-ethoxy)-benzyl]-1h-indol-5-ols
US20130109661A1 (en) * 2011-11-01 2013-05-02 Hoffmann-La Roche Inc. Imidazopyridazine compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001019839A1 (en) * 1999-09-13 2001-03-22 American Home Products Corporation Glucopyranosides conjugates of 2-(4-hydroxy-phenyl)-1-[4-(2-amin-1-yl-ethoxy)-benzyl]-1h-indol-5-ols
US20130109661A1 (en) * 2011-11-01 2013-05-02 Hoffmann-La Roche Inc. Imidazopyridazine compounds

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