CN1502598A - 用于制备顺式-1-{2-[4-（6-甲氧基-2-苯基-1，2，3，4-四氢化萘-1-基）苯氧基]乙基}吡咯烷的中间体 - Google Patents

用于制备顺式-1-{2-[4-（6-甲氧基-2-苯基-1，2，3，4-四氢化萘-1-基）苯氧基]乙基}吡咯烷的中间体 Download PDF

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CN1502598A
CN1502598A CNA200310119668XA CN200310119668A CN1502598A CN 1502598 A CN1502598 A CN 1502598A CN A200310119668X A CNA200310119668X A CN A200310119668XA CN 200310119668 A CN200310119668 A CN 200310119668A CN 1502598 A CN1502598 A CN 1502598A
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Abstract

本发明提供了一种用于顺式－1－{2－[4－(6－甲氧基－2－苯基－1，2，3，4，－四氢化萘－1－基)苯氧基]乙基}吡咯烷的改进的制备方法，该化合物是制备用于治疗骨质疏松症的(－)顺式－6－苯基－5－[4－(2－吡咯烷－1－基－乙氧基)－苯基]－5，6，7，8－四氢化萘－2－酚的中间体。

Description

用于制备顺式-1-{2-[4-(6-甲氧基-2-苯基-1，2，3，4 -四氢化萘-1-基)苯氧基]乙基}吡咯烷的中间体
本发明是申请号为00108576.X、申请日为2000年5月18日、发明名称为“顺式-1-{2-[4-(6-甲氧基-2-苯基-1，2，3，4-四氢化萘-1-基)苯氧基]乙基}吡咯烷的制备方法”的中国专利申请的分案申请。
技术领域
本发明提供了一种用于顺式-1-{2-[4-(6-甲氧基-2-苯基-1，2，3，4，-四氢化萘-1-基)苯氧基]乙基}吡咯烷的改进的制备方法，所制备的该化合物是用于制备治疗骨质疏松症的(-)顺式-6-苯基-5-[4-(2-吡咯烷-1-基-乙氧基)-苯基]-5，6，7，8-四氢化萘-2-酚的中间体。
背景技术
美国专利5,552,241中描述了(-)顺式-6-苯基-5-[4-(2-吡咯烷-1-基-乙氧基)-苯基]-5，6，7，8-四氢化萘-2-酚的制备方法，将该文献引入本文作为参考。这种化合物是雌激素激动剂且用于治疗由雌激素缺乏所导致的疾病。美国专利5,552,241中还描述了通过使萘氧啶氢化而合成顺式-1-{2-[4-(6-甲氧基-2-苯基-1，2，3，4-四氢化萘-1-基)苯氧基]乙基}吡咯烷的方法。
Lednicer等在《药物化学杂志》(J.Med.Chem.)12，881(1969)中描述了下列结构的雌
Figure A20031011966800041
其中R2是苯基或环戊基且R3是H、 或--CH2CHOHCH2OH。
Benze等(《药物化学杂志》( J.Med.Chem.) 10，138(1967))制备了一系列四氢化萘类化合物以用来实现对雌激素的、抗生育和血胆固醇过少的活性的区分。这些结构是下列通式的：
Figure A20031011966800051
其中R1是H或OCH3；R2是H、OH、OCH3、OPO(OC2H5)2、OCH2CH2N(C2H5)2、OCH2COOH或OCH(CH3)COOH。
美国专利3,234,090涉及了具有雌激素的和抗真菌特性的下列通式的化合物、其盐、其N-氧化物、其N-氧化物的盐或其季铵化合物以及这类化合物的制备方法：
Figure A20031011966800052
其中Ph是1，2-亚苯基；Ar是被叔氨基-低级烷基-氧基所取代的单环的碳环芳基，其中叔氨基通过至少两个碳原子与氧隔开；R是氢、脂族基、碳环芳基、碳环芳基脂族基、杂环芳基或杂环芳基脂族基；通式-(CnH2n-2)-代表具有三个至五个碳原子并携带基团Ar和R的非支链的亚烷基。
美国专利3,277,106涉及了具有雌激素的、血胆固醇过少和抗生育作用的碱性醚类，它们是下列通式的化合物、其盐、其N-氧化物、其N-氧化物的盐或其季铵化合物：
Figure A20031011966800053
其中Ph是1，2-亚苯基；Ar是被至少一个氨基-低级烷基-氧基所取代的单环芳基，其中氮原子通过至少两个碳原子与氧原子隔开；R是芳基；且-(CnH2n-2)-部分代表与Ph一起形成六或七节环的低级亚烷基，其环碳原子中的两个携带基团Ar和R。
Lednicer等在《药物化学杂志》(J.Med.Chem.) 10，78(1967)和美国专利3,274,213中涉及了下列通式的化合物：
Figure A20031011966800061
其中R1和R2选自由低级烷基和可彼此连接形成5-7节饱和杂环基的低级烷基组成的组。
参考文献：
1.Kanapure，S.P.；Das，K.G.；Bhawal，B.M.，《合成通讯》(Synth.Comm.)1984，14，1205-1211。
2.Lexa，D.；Saveant，J.M.；Zickler，J.，《美国化学协会杂志》(J.Amer.Chem.Soc.)1977，99，2786-2790。
3.Chan，T.H.；Brook，M.A.；Chaly，T.，《合成》(Synthesis)1983，203-205。
4.Gedye，R.；Smith，F.；Westaway，K.；Ali，H.；Baldisera，L.；Laberge，L.；Rousell，J.《四面体通讯》(Tet.Lett.)1986，27，279-282。
5.McMurry，J.E.；Kees，K.L.，《有机化学杂志》(J.Org.Chem.)1977，42，2655-2656。
发明内容
本发明提供了用于制备(-)顺式-6-苯基-5-[4-(2-吡咯烷-1-基-乙氧基)-苯基]-5，6，7，8-四氢化萘-2-酚的中间体化合物。这些化合物包括：3-(2-溴-5-甲氧基-苯基)1-苯基-丙-1-酮；2-[2-(2-溴-5-甲氧基-苯基)-乙基]-2-苯基-[1，3]二氧戊环；3-[2-(4-苄氧基-苯甲酰基)-5-甲氧基-苯基]-1-苯基-丙-1-酮；和4-(4-苄氧基-苯基)-7-甲氧基-3-苯基-1，2-二氢化萘；以及(4-苄氧基-苯基)-{4-甲氧基-2-[2-(2-苯基-[1，3]二氧戊环-2-基)-乙基]-苯基}-甲酮。
本发明还提供了制备顺式-1-{4-[6-甲氧基-2-苯基-1，2，3，4，-四氢化萘-1-基)苯氧基]乙基}吡咯烷的方法，该方法包括下列步骤：
1)使2-溴-5-甲氧基-甲苯溴化而产生1-溴-2-溴甲基-4-甲氧基苯；
2)将步骤1的产物用于使苯甲酰乙酸乙酯烷基化，随后脱羧而产生3-(2-溴-5-甲氧基苯基)-1-苯基-丙-1-酮；
3)使步骤2的产物与乙二醇反应而产生2-[2-(2-溴-5-甲氧基苯基)-乙基]-2-苯基)-乙基]-2-苯基-[1，3]二氧戊环；
4)将步骤3的产物用正丁基锂进行金属-卤素互变并与4-苄氧基苄腈反应而产生2-[2-(2-(4-苄氧基苯甲酰基)-5-甲氧基苯基)-乙基]-2-苯基-[1，3]二氧戊环，将它进行1，3-二氧戊环的酸水解以产生3-[2-(4-苄氧基-苯甲酰基)-5-甲氧基苯基]-1-苯基-丙-1-酮；
5)将步骤4的产物用氯化钛(III)与锌铜偶处理而产生4-(4-苄氧基苯基)-7-甲氧基-3-苯基-1，2-二氢化萘；
6)将步骤5的产物氢化并用三苯膦、DEAD和1-(2-羟乙基)吡咯烷处理以产生1-{2-[4-(6-甲氧基-2-苯基-1，2，3，4-四氢化萘-1-基)-乙基}-吡咯烷。
本发明还提供了一种使 或
Figure A20031011966800072
与
Figure A20031011966800081
反应而产生 的方法，其中R是被保护的苯酚或
Figure A20031011966800083
该方法包括使2-[2-(2-溴-5-甲氧基-苯基)-乙基]-2-苯基-[1，3]二氧戊环与丁基锂反应、随后与
Figure A20031011966800084
或
Figure A20031011966800085
反应的步骤。
发明详述
本发明提供了如下所示的顺式-1-{2-[4-(6-甲氧基-2-苯基-1，2，3，4，-四氢化萘-1-基)苯氧基]乙基}吡咯烷的新型合成方法。
本说明书中所用的缩略语如下所定义：
NBS       N-溴琥珀酰亚胺
AIBN      2，2’-偶氮二异丁腈
TMSCl     三甲基氯硅烷
THF       四氢呋喃
PPTS      吡啶对甲苯磺酸盐
DEAD      偶氮二羧酸二乙酯
DME       二甲氧基乙烷
术语“被保护苯酚”包括被烷氧基、硝基或卤素以及其它可接受的醇保护基所取代的任选的苄氧基。
顺式-1-{2-[4-(6-甲氧基-2-苯基-1，2，3，4-四氢化萘-1-基)苯氧基]乙基}吡咯烷的合成
Figure A20031011966800091
合成步骤由溴化12-溴-5-甲氧基-甲苯而产生苄基溴1-溴-2-溴甲基-4-甲氧基-苯开始。通过用所述的苄基溴使苯甲酰基乙酸乙酯2烷基化、随后脱羧而产生酮3-(2-溴-5-甲氧基-苯基)-1-苯基-丙-1-酮，它作为酮缩醇2-[2-溴-5-甲氧基-苯基)-2-苯基-[1，3]二氧戊环而被保护3。通过使酮缩醇2-[2-溴-5-甲氧基-苯基)-2-苯基-[1，3]二氧戊环进行金属-卤素互变而产生芳基锂类物质，将其方便地加入4-苄氧基苯甲酸酯或4-苯甲酸基苄腈4并基于酸性起用供给二酮3-[2-(4-苄氧基-苯甲酰基)-5-甲氧基-苯基]-1-苯基-丙-1-酮。使所述的二酮进行钛介导的McMurry型偶合5以产生烯烃4-(4-苄氧基-苯基)-7-甲氧基-3-苯基-1，2-二氢化萘，它具有顺式-1-{2-[4-(6-甲氧基-2-苯基-1，2，3，4，-四氢化萘-1-基)苯氧基]乙基}吡咯烷的碳构架，全部官能基都在适当的位置上。在-种反应罐中通过钯催化氢化实现将烯属双键还原并使二苄醚脱保护。在Mitsunobu条件下引入N-乙基-吡咯烷基并侧链而得到1-{2-[4-(6-甲氧基-2-苯基-1，2，3，4-四氢化萘-1-基)苯氧基]-乙基}-吡咯烷，它是顺式-1-{2-[4-(6-甲氧基-2-苯基-1，2，3，4-四氢化萘-1-基)苯氧基]乙基}吡咯烷的关键前体。如美国专利5,552,241中所述用HBr将这种化合物转化成顺式-6-苯基-5-[4-(2-吡咯烷-1-基-乙氧基)-苯基]-5，6，7，8-四氢化萘-2-酚。
具体实施方式
实施例1
1-溴-2-溴甲基-4-甲氧基-苯
参考文献：《合成通讯》1984，1205-1211
向2-溴-5-甲氧基甲苯(50g，0.25mol)溶于二氯乙烷(375ml)所得到的溶液中加入N-溴琥珀酰亚胺(48.8g，0.275mol)和AIBN(1.36g)并将反应体系回流4小时。过滤冷却的溶液并蒸发溶剂而得到44.8g重的粗产物1-溴-2-溴甲基-4-甲氧基-苯(产率为64％)。
不经过进一步的纯化而将该化合物用于下一步骤。
实施例2
3-(2-溴-5-甲氧基-苯基)-1-苯基-丙-1-酮
参考文献：JACS，1977，2786
向溶于50ml无水乙醇的乙醇钠(5.72g，84mmol)中加入14.8g(77mmol)的苯甲酰基乙酸乙酯，同时进行搅拌。然后将反应混合物进行缓慢回流并在20分钟内加入溶于20ml乙醇的19.6g(70mmol)1-溴-2-溴甲基-4-甲氧基-苯。将反应混合物回流2小时。将所述的反应混合物冷却、过滤并浓缩。使浓缩的混合物进行酸水解并通过在含有40ml冰醋酸、5ml浓硫酸和10ml水的溶液中回流过夜而脱羧。接着将所述的反应混合物用10％的NaOH中和并用二氯甲烷萃取。浓缩所述的萃取物而得到19.43g重的粗产物3-(2-溴-5-甲氧基-苯基)-1-苯基-丙-1-酮(产率：87％)。不经过进一步的纯化而将该化合物用于下一步骤。
实施例3
2-[2-(2-溴-5-甲氧基-苯基)-乙基]-2-苯基-[1，3]二氧戊环
参考文献：《合成》，1983，203
在N2气中向粗产物3-(2-溴-5-甲氧基-苯基)-1-苯基-丙-1-酮(19.43g，61mmol)溶于无水乙二醇(300ml)所得到的溶液中加入氯代三甲基硅烷(31ml，0.25mol)。在室温下将该反应体系搅拌1小时。加入5％的NaHCO3水溶液(300ml)。用二异丙醚萃取所述的混合物并用盐水洗涤所述的萃取物。将合并的醚萃取物用Na2SO4干燥并在减压条件下除去溶剂而得到21.52g重的粗产物2-[2-(2-溴-5-甲氧基-苯基)-乙基]-2-苯基-[1，3]二氧戊环(产率：97％)。
实施例4
4-苄氧基-苄腈
参考文献：《四面体通讯》，1986，279-282
向4-氰基苯酚(25g，0.21mol)和K2CO3(138g，1mol)溶于DMF(300ml)所得到的溶液中一次加入苄基氯(27.9g，0.22mol)。在室温下将反应混合物搅拌过夜。将悬浮液过滤并将滤液倾入冰水。收集所产生的固体而得到43.5g重的产物(产率：99％)。
实施例5
3-[2-(4-苄氧基-苯甲酰基)-5-甲氧基-苯基]-1-苯基-丙-1-酮
将2-[2-(2-溴-5-甲氧基-苯基)-乙基]-2-苯基-[1，3]二氧戊环(0.9g，2.5mmol)溶于10ml无水THF中所得到的溶液冷却至-78℃并逐滴加入正丁基锂(2.5M己烷溶液，1ml)。在-78℃下将该溶液搅拌2小时并加入4-苄氧基-苄腈(0.575g，2.75mmol)溶于2ml THF所得到的溶液。将所述的混合物温至室温并回流过夜。然后用饱和NH4Cl使该溶液骤冷并蒸发溶剂。将残余物溶于20ml湿丙酮、含有PPTS(188mg，0.75mmol)的5ml H2O中所得到的溶液回流过夜。通过常规处理和柱纯化而得到非最佳重量的0.8g 3-[2-(4-苄氧基-苯甲酰基)-5-甲氧基-苯基]-1-苯基-丙-1-酮。
实施例6
4-(4-苄氧基-苯基)-7-甲氧基-3-苯基-1，2-二氢化萘
参考文献：JOC，1977，2656
在N2中将TiCl3(2.062g，13mmol)和Zn-Cu偶(2.02g，30.8mmol)放入200ml圆底烧瓶中。加入无水二甲氧基乙烷(40ml)并将该混合物回流1小时。
注意：通过将锌粉(9.8g，150mmol)加入40ml脱氧合水、用N2气将所得的淤浆清洗15分钟且然后加入CuSO4(0.75g，4.7mmol)来制备Zn-Cu偶。在N2中过滤黑色淤浆，将其用脱氧合H2O、丙酮、乙醚洗涤并在N2中保存。
将溶于80ml DME的3-[2-(4-苄氧基-苯甲酰基)-5-甲氧基-苯基]-1-苯基-丙-1-酮(540mg，1.2mmol)加入上述回流淤浆中并将所得的混合物回流15分钟。过滤悬浮液并蒸发溶剂而得到0.45g重的4-(4-苄氧基-苯基)-7-甲氧基-3-苯基-1，2-二氢化萘(产率：90％，通过X射线证实结构)。
实施例7
1-{2-[4-(6-甲氧基-2-苯基-1，2，3，4-四氢化萘-1-基)-乙基}-吡咯烷
在Paar瓶中将4-(4-苄氧基-苯基)-7-甲氧基-3-苯基-1，2-二氢化萘(0.45g，1.08mmol)溶于一种EtOH(15ml)的混合物中。加入Pd(OH)2(0.3g)的2ml水溶液并在室温下和N2(50psi)中振摇该混合物。将所述溶液过滤并用等当量的三苯膦、DEAD和1-(2-羟乙基)吡咯烷处理。经一般处理后得到1-{2-[4-(6-甲氧基-2-苯基-1，2，3，4-四氢化萘-1-基)-乙基}-吡咯烷。

Claims (6)

1.一种化合物，它是3-[2-(4-苄氧基-苯甲酰基)-5-甲氧基-苯基]-1-苯基-丙-1-酮。
2.一种化合物，它是(4-苄氧基-苯基)-{4-甲氧基-2-[2-(2-苯基-[1，3]二氧戊环-2-基)-乙基]-苯基}-甲酮。
3.一种制备权利要求1所述化合物的方法，该方法包括下列步骤：使(4-苄氧基-苯基)-{4-甲氧基-2-[2-(2-苯基-[1，3]二氧戊环-2-基)-乙基]-苯基}-甲酮水解以产生3-[2-(4-苄氧基-苯甲酰基)-5-甲氧基苯基]-1-苯基-丙-1-酮。
4.一种制备下式化合物的方法，
该方法包括在丁基锂的存在下
使
Figure A20031011966800022
或 与
Figure A20031011966800024
反
应而产生
Figure A20031011966800025
其中R是被保护的苯酚或
5.根据权利要求4的方法，其中R是被保护的苯酚。
6.根据权利要求5的方法，其中R是苄氧基。
CNB200310119668XA 1999-05-24 2000-05-18 用于制备顺式－1－{2－[4－（6－甲氧基－2－苯基－1，2，3，4－四氢化萘－1－基）苯氧基]乙基}吡咯烷的中间体 Expired - Fee Related CN1271030C (zh)

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