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CN1271030C - 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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CN1271030C
CN1271030C CNB200310119668XA CN200310119668A CN1271030C CN 1271030 C CN1271030 C CN 1271030C CN B200310119668X A CNB200310119668X A CN B200310119668XA CN 200310119668 A CN200310119668 A CN 200310119668A CN 1271030 C CN1271030 C CN 1271030C
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赵国锋
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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
激素拮抗剂：
Figure C20031011966800031
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 C20031011966800041
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：
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 C20031011966800043
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：
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.；A1i，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 C20031011966800062
与
Figure C20031011966800071
反应而产生
Figure C20031011966800072
的方法，其中R是被保护的苯酚或
Figure C20031011966800073
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 C20031011966800074
或 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
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。在一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已烷溶液，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温丙酮、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 (4)

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，
Figure C2003101196680002C1
该方法包括在丁基锂的存在下使
Figure C2003101196680002C2
或
Figure C2003101196680002C3
与
Figure C2003101196680002C4
反应而产生
Figure C2003101196680002C5
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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