CN1636967A - 新颖化合物,其用途及制法 - Google Patents
新颖化合物,其用途及制法 Download PDFInfo
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- CN1636967A CN1636967A CNA2004100952769A CN200410095276A CN1636967A CN 1636967 A CN1636967 A CN 1636967A CN A2004100952769 A CNA2004100952769 A CN A2004100952769A CN 200410095276 A CN200410095276 A CN 200410095276A CN 1636967 A CN1636967 A CN 1636967A
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Abstract
本发明公开了式I的新颖化合物,及其与生理上可接受的酸所形成的盐:其中R1、R2、R3、R4、R5、R6、R7和Ar同权利要求1中所定义,当此化合物可以旋光异构体形式存在时,所述化合物的消旋混合物及单个对映异构体。此化合物具有抗胆碱能的活性,本发明涉及了作为治疗活性物质的式I化合物,含有式I化合物的药物组合物,式I化合物在制备抗胆碱能药物上的用途,式I化合物在治疗尿失禁上的用途以及制备式I化合物的方法。
Description
本申请是中国发明专利申请No.98803764.5的分案申请,申请日为1998年3月26日,优先权日1997年3月27日。
技术领域
本发明涉及新颖的治疗活化合物、其制备方法、含有该化合物的药物组合物、及该化合物在制备药物上的用途。
发明背景
WO 89/06644及WO 94/11337公开了三级3,3-二苯基丙胺,其具有抗胆碱能活性,特别是用于治疗尿失禁。SE-A-215499公开了二级3,3-二苯基丙胺,其对心脏与血液循环具有促进功效。US-A-3,446,901、GB-A-1,169,944及GB-A-1,169,945公开了具有抗抑郁活性的3,3-二苯基丙胺。DE-B1-1216318公开了对心脏及血液循环有作用的二苯基烷基胺的制法。
发明概述
根据本发明发现了新颖的具有治疗活性的二芳基丙胺类,其类似上述WO 89/06644及WO 94/11337公开的3,3-二苯基丙胺,具良好的抗胆碱能活性,故亦可用于控制乙酰胆碱介导的生理活动,例如排尿。
本发明一方面提供通式I所示的新颖化合物,及其与生理上可接受的酸形成的盐类,以及当此化合物可存在旋光异构体时,其消旋混合物及单个对映异构体:
其中:
R1是氢、羟基、烷基、烷氧基、羟烷基、三氟甲基、氨基、烷羰氨基、烷羰氧基或卤素;
R2和R3独立地为氢、羟基、烷基、烷氧基、羟烷基、卤素、烷氧羰基烷基、氨基甲酰基或胺磺酰基;
R4是ω-羟基烷氧基、ω-氨基烷氧基、ω-氨基烷氨基、烷氧基烷基、羟烷氧基烷氨基烷基、二羟基烷基、甲酰基、烷羰基、烷氧羰基、烷氧羰基烷基、烷羰基氨烷基、氨烷基、烷氨基烷基、二烷基氨基烷基、羧烷基、氨基甲酰基烷基、羧酰氨基烷基、羧基、氨基、硝基、氰基、次氮基、氰烷基、叠氮基、至少2个碳原子的烷基、至少2个碳原子的烷氧基或至少2个碳原子的羟烷基;
R5是氢、卤素或烷基;
Ar是可被选自下列的取代基一次或独立地两次取代的芳基或杂芳基,包括烷基、烷氧基、羟基、羟烷基、卤素、烷氧羰基烷基、氨基甲酰基及胺磺酰基;及
R6和R7是相同或不同的烃基,两者一起含有至少3个碳原子,并带有一个或多个羟基,其中碳原子可通过氧原子互相连接,且其中R6和R7可与胺上的氮原子一起形成环;条件是:(a)
(i)当R2、R3及R5中至少有2个不是氢原子时,或
(ii)当R1不是羟基或甲氧基,且Ar不是邻位被羟基或甲氧基取代的苯基时,或
(iii)当Ar是杂芳基时,或
(iv)当R6及R7至少有一者是芳烃基或环烷基时,则R4亦可为氢原子、甲基、甲氧基、羟基、羟甲基、卤素、氨基甲酰基或胺磺酰基;
以及(b)当Ar是非取代的苯基时,则R1、R2、R3、R4及R5不能都是氢原子。
本发明另一方面是提供具有上述通式I的化合物,其用于治疗,特别是治疗尿失禁相关病症。
本发明再一方面是提供药物组合物,其包含一种或多种上述的通式I化合物作为活性组份,优选一并含有药学上可接受的载体,且如果需要,可含有其它药学活性药剂。
本发明又一方面是提供治疗患有尿失禁相关病症的病患(动物类,包括人类)的方法,该方法包括对该病患施用有效量的上述通式I化合物。
本发明再一方面是提供式I化合物,其是用来作为药物活性物质,特别是作为抗胆碱能药剂。
本发明另一方面是提供上述通式I化合物在制备治疗尿失禁相关病症的药物上的用途。
本发明再一方面是提供制备上述通式I化合物的方法。
发明详述
本发明包括新颖的3,3-二芳基丙胺类及其药学上可接受的盐类,其是以上述式I为特征且可用来作为抗胆碱能药剂。此化合物对治疗尿失禁特别有用。
式I化合物中有一亚类界定如下:取代基R4是ω-羟基烷氧基、ω-氨基烷氧基、ω-氨基烷氨基、烷氧基烷基、羟基烷氧基烷氨基烷基、二羟基烷基、甲酰基、烷羰基、烷氧羰基、烷氧羰基烷基、烷羰基氨烷基、氨烷基、烷氨基烷基、二烷氨基烷基、羧烷基、氨基甲酰基烷基、羧酰氨基烷基、羧基、氨基、硝基、氰基、次氮基、氰烷基或叠氮基。
此亚类有一组化合物,其中R1是氢或甲基,R2、R3和R5或者皆是氢,或者R2、R3和R5中有一者是甲基、甲氧基、羟基、氨基甲酰基、胺磺酰基或卤素,而其余的是氢,Ar是苯基或被下列取代基单次取代或独立地二次取代的苯基:甲基、甲氧基、羟基、羟甲基、氨基甲酰基、胺磺酰基或卤素。
式I化合物的另一亚类界定为,Ar是杂芳基。
此亚类有一组化合物,其中R1是氢或甲基,R2、R3、R4和R5或者皆为氢,或者R2、R3、R4和R5中有一者是甲基、甲氧基、羟基、羟甲基、氨基甲酰基、胺磺酰基或卤素,而余者是氢。
式I化合物还有一亚类界定如下:R1是氢、烷基、羟烷基、三氟甲基、氨基、烷羰基氨基、烷基羰氧基或卤素。优选Ar不是邻位被羟基或烷氧基取代的苯基。
此亚类中有一组化合物,其中R1是氢或甲基,R2、R3、R4或者皆为氢,或者R2、R3、R4及R5中有一者是甲基、甲氧基、羟基、羟甲基、氨基甲酰基、胺磺酰基或卤素,而余者是氢,Ar是苯基或被甲基、甲氧基、羟基、羟甲基、氨基甲酰基、胺磺酰基或卤素一次或独立地两次取代的苯基。
式I化合物另有一亚类界定如下:R6和R7中至少一个是芳烃基、环烷基或烃链,此烃链中,碳原子间通过氧原子在一处或多处互相连接。
此亚类中有一组化合物,其中R1是氢或甲基,R2、R3、R4及R5或者皆为氢,或者R2、R3、R4及R5中有一者是甲基、甲氧基、羟基、羟甲基、氨基甲酰基、胺磺酰基或卤素,余者是氢,Ar是苯基或被甲基、甲氧基、羟基、羟甲基、氨基甲酰基、胺磺酰基或卤素一次或独立地两次取代的苯基。
式I化合物中,单独与组合使用的“烷基”优选是C1-8烷基,即甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基及其异构体,更优选是C1-6烷基,特别是C1-4烷基。
类似地,单独与组合使用的“烷氧基”优选是C1-8烷氧基,即甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基、庚氧基、辛氧基及其异构体,更优选是C1-6烷氧基,特别是C1-4烷氧基。
“芳基”表示苯基或萘基。“杂芳基”表示具有1至3个杂原子的5元或6元杂芳环,此环可与芳族碳环,例如苯环稠合。杂芳基的范例有吗啉基、噻吩基、呋喃基、哌嗪基、哌啶基、咪唑啉基、吡唑啉基、噁唑基、异噁唑基、吡咯基、咪唑基、吡唑基、吡啶基、吡嗪基、嘧啶基或哒嗪基。
“卤素”包括氟、氯、溴及碘。
当芳基被单取代时,优选在2位被取代。当芳基被二取代时,优选在2和4位被取代。优选的取代基为甲基、甲氧基、羟基、羟甲基、卤素、烷氧羰基烷基、氨基甲酰基及胺磺酰基,特别是甲基、羟甲基及卤素。芳基优选是苯基。
优选的杂芳基是噻吩基、吡咯基、噻唑基、噁唑基、甲基噻唑基及甲基吡咯基。
R1优选是羟基、卤素、三氟甲基、氨基、甲氧基或羟甲基、
R2和R3优选选自氢、羟基及甲氧基。
R4优选是氢、甲酰基、烷氧羰基、烷羰基、羟烷基、烷氧基烷基、羧酰氨基烷基、氨基甲酰基烷基、氨烷基、氨基、叠氮基、氰烷基、羧基或羧烷基。R4更优选是氢、甲酰基、羟甲基、羟乙基、羟丙基、羟丁基、羟戊基、羟己基、乙氧甲基、甲氧羰基、氨基、氨丙基、乙酰基、1,2-羟乙基、乙氨基甲基或羟基乙氧乙基氨基乙基。
R5优选是氢。
R6和R7相互独立地优选是饱和烃基,尤其是饱和的脂族烃基,例如C1-8烷基,尤其是C1-6烷基或金钢烷基,R6与R7一起包含有至少3个,优选至少4个碳原子。R6和R7可带有1个或多个羟基,且R6与R7可与氮原子一起形成环。优选R6和R7中至少有一者包含支链碳链。
NR6R7基团的范例有二乙氨基、二异丙基氨基、甲基叔丁基氨基、甲基叔戊基氨基、哌啶子基、2,2,6,6-四甲基哌啶子基、甲基环丁基氨基、甲基环戊基氨基、甲基环己基氨基、甲基环庚基氨基、吡咯烷-1-基、2,2,5,5-四甲基吡咯烷-1-基、N-甲基-N-金钢烷基氨基,尤其是二异丙基氨基。
代表性的式I化合物为:
N,N-二异丙基-3-(2-氟苯基)-3-苯基丙胺盐酸盐,
N,N-二异丙基-3-(5-甲酰基-2-羟基苯基)-3-苯基丙胺,及其(R)-异构体,
N,N-二异丙基-3-(2-羟基-5-甲氧羰基苯基)-3-苯基丙胺,及其(R)-异构体,
N,N-二异丙基-3-(5-乙酰基-2-羟基苯基)-3-苯基丙胺,及其(R)-异构体,
N,N-二异丙基-3-〔2-羟基-5-(2-羟乙基)苯基〕-3-苯基丙胺,及其(R)-异构体,
N,N-二异丙基-3-〔2-羟基-5-(1-羟乙基)苯基〕-3-苯基丙胺,及其3(R)-异构体,
N,N-二异丙基-3(R)-〔5-(1(R*),2-二羟乙基)-2-羟基苯基〕-3-苯基丙胺,及其1(S*)-异构体,
N,N-二异丙基-3-〔2-羟基-5-(6-羟己基)苯基〕-3-苯基丙胺,及其(R)-异构体,
N,N-二异丙基-3-〔5-乙氧甲基-2-羟基苯基〕-3-苯基丙胺,及其(R)-异构体,
N,N-二异丙基-3-〔5-(3-氨基丙基)-2-羟基苯基〕-3-苯基丙胺,及其(R)-异构体,
N,N-二异丙基-3-〔5-(3-乙酰氨基丙基)-2-羟基苯基〕-3-苯基丙胺,及其(R)-异构体,
N,N-二异丙基-3-〔5-(2-氰乙基)-2-羟基苯基〕-3-苯基丙胺,及其(R)-异构体,
N,N-二异丙基-3-(5-氨基-2-羟基苯基)-3-苯基丙胺,及其(R)-异构体,
N,N-二异丙基-3-(5-叠氮基-2-羟基苯基)-3-苯基丙胺,及其(R)-异构体,
N,N-二异丙基-3-〔2-羟基-5-(3-羟丙基)苯基〕-3-苯基丙胺,及其(R)-异构体,
N-环丁基-N-甲基-3-(2-羟基苯基)-3-苯基丙胺
N,N-二异丙基-3-(2-羟基苯基)-3-(2-噻吩基)丙胺,
N,N-二异丙基-3-(2-羟基-5-甲基苯基)-3-(2-噻吩基)丙胺,及其(R)-异构体。
根据本发明,式I化合物可由已知方法制得,尤其是
a)使式II化合物
其中R1至R5和Ar同上述式I化合物中所定义,Y是离去基团,与胺HNR6R7反应,其中R6和R7定义如上;或者
b)还原式III化合物
其中R1至R7和Ar同式I化合物中所定义,且可对任一羟基进行保护;或者
c)使式IV的仲胺进行N-烷化反应
其中R1至R5和Ar同式I化合物中所定义;且可对任一羟基进行保护,其中Z的定义与R6及R7相同;或者
d)还原式Va或Vb化合物
其中R1至R7和Ar同式I化合物中所定义,且可对任一羟基进行保护,W表示羟基或卤素;或者
e)将式VI化合物中的R1a转化为羟基,
其中R2至R7和Ar同式I化合物所定义,且R1a是羧基或烷氧基;或者
f)将式VII化合物中的烯基还原为烷基,羟烷基或二羟基烷基,
其中R1、R6、R7和Ar同式I化合物中所定义,且R2b至R5b中有一者是烯基,而余者同上述R2至R5的定义;或者
g)将上述式I化合物中R1至R5的一个或多个取代基,转化为R1至R5中的其它取代基;或者
h)使式VIII化合物
其中R1至R7同式I化合物中所定义,且X是氧或硫,与式IX化合物反应
CH3N≡C: IX
形成式Ia化合物
其中R1至R7和X定义如上;或者
i)使上述式VIII化合物,其中X是氧,与式X化合物反应
形成式Ib化合物
其中R1至R7同式I化合物中所定义;或者
j)将式XI化合物
其中R1至R7同式I化合物中所定义,转化为式XII合物
其中R1至R7同式I化合物中所定义;或者
k)将式化XIII合物
其中R1至R7同式I化合物中所定义,且X是氧或硫,转化为式XIV化合物
其中R1至R7及X同式I化合物中所定义,且R8和R9各为氢或烷基;且
i)必要时,去掉所得化合物中的羟基保护基;
ii)如果需要,利用生理上可接受的酸,将所制得的式I碱类转化为其盐类,反之亦然;和/或
iii)如果需要,将所得旋光异构体混合物分离为单个对映异构体。
上述反应的适当反应条件对于本领域技术人员来说,参照类似的已知方法和如下特定实施例的合适条件是能轻易选定的。必要的起始物质是已知的或参照已知化合物的制备方法制备的。
根据上述ii),将旋光异构体混合物分离为单个对映异构体的方法,举例而言,可通过其与手性酸形成的盐类的分级结晶,或在手性柱上进行色谱来分离。
根据适用的制药方法,本发明的式I化合物,呈游离碱形式或与生理上可接受的酸类形成盐,可制成适当的药剂形式,例如口服、肠胃外或经鼻喷雾使用的组合物。本发明的这类药物组合物包含有效量的式I化合物,以及可相容且药学上可接受的载体或稀释剂。载体可为任何惰性有机物或无机物,其适合经肠、经皮或肠胃外用药,例如水、明胶、阿拉伯胶、乳糖、微晶纤维素、淀粉、淀粉乙二醇钠、磷酸氢钙、硬脂酸镁、滑石及胶体二氧化硅等。这类组合物亦可包含其它药学活性物质,及常见添加剂,例如稳定剂、润湿剂、乳化剂、调味剂及缓冲剂等。
举例而言,本发明的组合物口服给药时,可制成固体或液体形式,例如片剂、胶囊、粉剂、糖浆剂及酏剂等,肠胃外给药时,可制成无菌溶液、悬浮液或乳液等。
上述化合物及组合物可用于同上述WO 89/06644或WO 94/11337的化合物相同的治疗适应症,即用于治疗乙酰胆碱介导的疾病,例如尿失禁,尤其是尿意失禁。特定化合物的剂量会随其强度、用药方式、病患年龄与体重及欲治疗的病况严重性而改变。举例而言,每日剂量可由每公斤体重约0.01mg至约4mg,以约0.05mg至约200mg的剂量单次给药或多次给药。
本发明将以下列非限定性实施例及药理试验进一步说明。
概论
NMR数据是由Joel JNM-EX 270或Varian Unity 500光谱仪获得。在30℃下以四甲基硅烷(TMS)作为内标记录光谱。红外光谱是采用Perkin-Elmer 841型分光光度计记录。未校正的熔点是用Koeffler仪测定的。气相色谱是采用配备有10m HP-1柱的HP5940来进行的,且炉温以直线温度梯度模式加热。使氢化铝锂还原反应骤止皆采用V.Micovic与M.Mihailovic方法(有机化学杂志
18,1190(1953))。
实施例1
N-(5-羟基-3-氧戊基)-N-异丙基-3-(2-羟基-5-甲基苯基)-3-苯基丙胺盐酸盐
将N-(5-羟基-3-氧戊基)-N-异丙基-3-(2-羟基-5-甲基苯基)-3-苯基丙胺(2.75g,7mmol)的THF(40ml)溶液加至氢化铝锂(LAH,0.50g,13mmol)中,常温搅拌此混合物2小时。骤止反应并蒸发溶剂。残留物进行硅胶层析(甲苯∶三乙胺19∶1)。将游离胺溶于乙醚中并加入氯化氢的乙醚溶液结晶标题化合物。产量0.75g(27%);熔点70-75℃;
1H NMR(DMSO-d6)δ1.17(q,3H),1.23(t,3H),2.18(d,3H),2.47(m,2H),2.84-3.07(m,2H),3.15(m,1H),3.37(m,1H),3.42(d,2H),3.46(s,2H),3.67(m,1H),3.74(m,2H),4.30(m,1H),4.76(br,1H),6.71(d,1H),6.80(d,1H),7.06(d,1H),7.16(t,1H),7.27(t,2H),7.33(d,2H),9.29(d,1H)和10.07(br,1H).分析.(C23H33NO3·HCl)C,H,N.
起始化合物N-(5-羟基-3-氧戊基)-N-异丙基-3-(2-羟基-5-甲基苯基)-3-苯基丙酰胺的制备如下:
1.1反式-3-(2-苄氧基-5-甲基苯基)-3-苯基丙烯酸
在氮气氛下,于15分钟内将磷酰基乙酸三乙酯(22.4g,0.10mol)的THF溶液(150ml)加至氢化钠(80%,2.7g,0.09mol)中。所生成的混合物回流15分钟,然后加入于THF(50mL)中的2-苄氧基-5-甲基-二苯甲酮(15.1g,0.25mol),蒸馏除去大部份的THF。加入乙醇至溶液变澄清,且继续回流数分钟。加水至总体积为1升,用乙醚洗涤此混合液。加入盐酸至水相,获得结晶物。通过结晶,自乙醇中制得纯的反式异构体。产量10.4g(60%)。
1H NMR(DMSO-d6)δ2.24(s,3H),4.92(s,2H),6.41(s,1H),6.87(d,1H),6.98(d,1H),7.03(m,2H)7.12(m,1H),7.22(m,3H),7.29(m,1H),7,30(m,1H)和7.33-7.39(m,3H).
1.2反式-N-(5-羟基-3-氧戊基)-N-异丙基-3-(2-苄氧基-5-甲基苯基)-3-苯基丙烯酰胺
将DCC(5.2g,17mmol)于THF(20mL)中的溶液加入反式-3-(2-苄氧基-5-甲基苯基)-3-苯基丙烯酸(6.9g,20mmol)、2-(2-异丙氨基乙氧基)-乙醇、三乙胺(2.5g,25mmol)和羟基琥珀酰亚胺(2.8g,24mmol)于THF(50mL)的溶液中。搅拌此反应混合物20小时。蒸发溶剂,残留物进行硅胶层析(采用由甲苯至乙酸乙酯的梯度)。产量5.9g(62%)。
1.3反式-N-(5-羟基-3-氧戊基)-N-异丙基-3-(2-羟基-5-甲基苯基)-3-苯基丙酰胺
用Pd/C(10%,0.5g〕氢化反式-N-(5-羟基-3-氧戊基)-N-异丙基-3-(2-苄氧基-5-甲基苯基)-3-苯基丙烯酰胺(5.9g,12mmol)于乙酸(50mL)中的溶液,历时16小时。过滤、蒸发溶剂,留下的残留物进行硅胶层析(乙酸乙酯)。产量2.83(61%)。
实施例2
N-环庚基-N-甲基-3-(2-羟基-5-甲基苯基)-3-苯基丙胺盐酸盐
将N-环庚基-N-甲基-3-(2-羟基-5-甲基苯基)-3-苯丙酰胺(0.93g,2.5mmol)的THF(20mL)溶液加至LAH(0.22g,5.6mmol)中,回流温度下,搅拌此混合物30分钟。骤止反应,蒸发溶剂。残留物进行硅胶层析(氯仿∶甲醇,9∶1)。将游离胺溶于乙醚中,加入含氯化氢的乙醚,制得胺盐。产量0.45g(46%);溶点230-232℃。1H NMR(DMSO-d6)δ1.27-1.70(m,10H),1.88(br,1H),2.05(d,1H),2.17(s,3H),2.42(br,1H),2.60(s,3H),2.85(br,2H),3.34(m,1H),4.30(t,1H),6.72(d,1H),6.80(dd,1H),7.05(br,1H),7.15(t,1H),7.27(t,2H),7.31(d,2H),9.31(s,1H)和10.53(br,1H).分析.(C24H33NO·HCl)C,H,N.
起始化合物N-环庚基-N-甲基-3-(2-羟基-5-甲基苯基)-3-苯基丙酰胺的制备如下:
2.1 N-环庚基-反式-3-(2-苄氧基-5-甲基苯基)-3-苯基丙酰胺
将DCC(5.2g,25mmol)的THF溶液(50mL)加入反式-3-(2-苄氧基-5-甲基苯基)-3-苯基丙烯酸(实施例1.1,6.9g,20mmol),环庚胺(2.6g,23mmol),三乙胺(2.0g,20mmol)和羟基琥珀酰亚胺(2.4g,21mmol)于THF(50mL)的溶液中。室温下,搅拌此反应混合物1小时。加入另一份环庚胺(1.3g),将反应混合物再搅拌1小时。过滤混合物,蒸发滤液。将残留物溶于乙醚,并顺序用盐酸(1M)、水及盐水洗涤。蒸发溶剂后,用甲苯-己烷结晶残留物,制得7.3g(83%)产物。
1H NMR(CDCl3)δ1.06(br,2H),1.25-1.74(m,10H),2.30(s,3H),3.83(m,1H),4.95(s,2H),5.50(d,1H),6.49(s,1H),6.90-7.08(m,4H),和7.12-7.44(m,9H).
2.2 N-环庚基-N-甲基-反式-3-(2-苄氧基-5-甲基苯基)-3-苯基丙烯酰胺
在室温下,将N-环庚基-反式-3-(2-苄氧基-5-甲基苯基)-3-苯基丙烯酰胺(4.4g,10mmol)和甲基碘(4g,30mmol)在DMF(10mL)中的溶液,加入氢化钠(80%,1.2g,40mmol)中,搅拌此混合物60分钟。加入甲醇破坏多余的氢化钠,然后将此混合物在甲苯与水之间分配。干燥有机层(MgSO4)并蒸发溶剂。用甲苯-己烷结晶残留物,制得4.4g(97%)。1H NMR(CDCl3)(几乎1∶1的几何异构体混合物)
δ1.20-1.80(m,12H),2.30(m,3H)2.61(s,1.5H),2.71(s,1.5H),3.93(m,0.5H),4.46(m,0.5H),4.81(m,1H),6.43(m,1H),6.81(m,2H)和7.08-7.35(m,10H).
2.3 N-环庚基-N-甲基-3-(2-羟基-5-甲基苯基)-3-苯基丙酰胺
将N-环庚基-N-甲基-反式-3-(2-苄氧基-5-甲基苯基)-3-苯基丙酰胺(3.15g,7mmol)的醋酸(40mL)溶液,用Pd/C(10%,0.2g)氢化72小时。过滤反应混合物,蒸发溶剂。残留物进行硅胶层析(甲苯∶乙酸乙酯,9∶1)。产量0.95g(37%)。
1H NMR(CDCl3)δ1.26-1.98(m,12H),2.02(s,3H),2.12(s,3H),2.28(m,1H),2.52(m,1H),2.71(m,1H),4.36(dd,1H),6.39(s,1H),6.76(s,2H),7.15(m,2H)和7.25(m,5H).
实施例3
N-环己基-N-甲基-3-(2-羟基-5-甲基苯基)-3-苯基丙胺盐酸盐
将N-环己基-N-甲基-反式-3-(2-苄氧基-5-甲基苯基)-3-苯丙酰胺(4.0g,9mmol)的THF(90mL)溶液,加入于THF(5mL)中的LAH(0.50g,13mmol)中,使此混合物室温搅拌2.5小时。骤止反应,蒸发溶剂。所得油状物在乙酸(70mL)中用Pd/C(10%,1g)氢化20小时。过滤并蒸发溶剂后,残留物进行硅胶层析(氯仿∶甲醇,99∶1)。将游离胺溶于乙醚中并加入于乙醚中的氯化氢。产量1.2g(36%);熔点179-183℃。
1H NMR(DMSO-d6)δ1.05(m,1H),1.21-1.38(m,4H),1.51(d,1H),1.74(br,2H),1.86(br,1H),2.00(d,1H),2.17和2.19(s,3H),2.39-2.56(m,2H),2.63(m,3H),2.82(m,1H),2.93(m,1H),3.17(m,1H),4.32(q,1H),6.73和6.75(d,1H),6.79和6.81(t,1H),7.02和7.10(d,1H),7.14-7.18(m,1H),7.25-7.29(m,2H),7.33(t,2H),9.34(br,1H)和10.78(s,1H).分析.(C23H31NO·HCl)C,H,N.
起始化合物N-环己基-N-甲基-反式-3-(2-苄氧基-5-甲基苯基)-3-苯基丙烯酰胺的制备如下:
3.1 N-环己基-N-甲基-反式-3-(2-苄氧基-5-甲基苯基)-3-苯基丙烯酰胺
将DCC(5.2g,25mmol)的THF溶液(50mL)加入反式-3-(2-苄氧基-5-甲基苯基)-3-苯基丙烯酸(实施例1.1,6.9g,20mmol),N-甲基-环己胺(2.6g,23mmol),三乙胺(2.0g,20mmol)和羟基琥珀酰亚胺(2.4g,21mmol)于THF(50mL)中的溶液中。搅拌此反应混合物2小时。加入第二份DCC(2.5g,13mmol)与N-甲基-环己胺(1.5g,13mmol),并使此反应混合物搅拌16小时。加入乙醚与盐酸(1M),用盐水洗涤有机相。蒸发有机层,残留物进行硅胶层析(甲苯∶乙酸乙酯9∶1)。产量5.5g(63%)。1H NMR(DMSO-d6)(接近1∶1的几何异构体混合物)δ0.88-1.06(m,2H),1.16-1.39(m,5H),1.55(t,2H),1.67(br,1H),2.21(s,1.5H),2.23(s,1.5H)2.56(s,1.5H),2.67(s,1.5H),3.67(m,0.5H),4.05(m,0.5H),4.82(s,1H),4.85(s,1H),6.57(s,0.5H),6.59(s,0.5H),6.84(dd,1H),6.87(d,0.5H),6.89(t,1H),6.95(dd,1H),6.98(d,0.5H),7.12(dd,1H),7.17(m,3H),7.27(m,2H),和7.32(m,3H).
实施例4
N,N-二异丙基-3-(2-三氟甲基苯基)-3-苯基丙胺盐酸盐
将THF(7mL,14mmol)中的甲硼烷·SMe2复合物在弱的氮气流下温和回流30分钟。将N,N-二异丙基-3-(2-三氟甲基苯基)-3-苯基丙酰胺(1.55g,4.2mmol)加入此回流溶液中,并继续回流1小时。将此反应混合物在乙醚与氢氧化钠(1M)之间进行分配。蒸发有机层的溶剂。残留物进行硅胶层析(甲苯∶三乙胺9∶1),制得游离胺。将该游离胺溶于乙醚,并添加氯化氢的乙醚溶液,得到其盐酸盐,所产生的油状物在乙醚中搅拌数次后,产生结晶。产量0.39g(23%);熔点143-144℃。
1H NMR(DMSO-d6)δ1.19(q,6H),1.25(dd,6H),2.53(m,1H),2.70(m,1H),2.87(m,2H),3.59(m,2H),4.38(t,1H),7.24(t,1H),7.35(t,2H),7.39(d,2H),7,45(t,1H),7.68(t,1H),7.74(t,2H)和10.25(br,1H).分析.(C22H28NF3·HCl)C,H,N.
起始化合物N,N-二异丙基-3-(2-三氟甲基苯基)-3-苯基丙酰胺的制备如下:
4.1 N,N-二异丙基乙酰胺磷酸二乙酯
将亚磷酸三乙酯(23g,0.14mol)与N,N-二异丙基-2-溴乙酰胺(29g,0.13mol)的混合物加热至110℃,反应3小时,生成35g(97%)产物。此产物不经纯化即可使用。
4.2 N,N-二异丙基-3-(2-三氟甲基苯基)-3-苯基丙烯酰胺
将N,N-二异丙基乙酰胺磷酸二乙酯(8.4g,30mmol)的THF(20mL)溶液,于30分钟内滴加至氢化钠(80%,0.85g,29mmol)中,使温度保持30℃以下。加入2-三氟甲基-二苯甲酮(5.0g,20mmol)的THF(20mL)溶液,加热此反应混合物至50℃并维持此温度16小时。加入上述制备的第二份磷叶立德(ylide)(15mmol)。在50℃下反应24小时后,使此混合物在乙醚与水之间分配。蒸发乙醚层,残留物进行硅胶层析(甲苯∶乙酸乙酯9∶1),产量3.0g(41%),其为E-与Z-异构体的混合物。符号a与b表示不同的异构体。1H NMR(CDCl3-d)δ0.80(d,6Ha),1.08(d,3Hb),1.24(t,6Hb),1.31(d,3Hb),1.44(d,6Ha),3.32(m,1Ha),3.34(m,1Hb),4.19(m,1Hb),4.32(m,1Ha),6.04(s,1Ha),6.65(s,1Hb) 和7.18-7.75(m,9Ha,9Hb).
4.3 N,N-二异丙基-3-(2-三氟甲基苯基)-3-苯基丙酰胺
在常压下,将N,N-二异丙基-3-(2-三氟甲基苯基)-3-苯基丙烯酰胺(2.95g,8.1mmol)的乙醇(50mL)溶液用Pd/C(10%,300mg)氢化24小时。滤掉催化剂,蒸发部份溶剂,结晶后回收产物。产量1.78g(60%)。
1H NMR(CDCl3-d)δ1.16(m,6H),1.30(m,6H),2.86(dd,1H),3.11(dd,1H),3.41(m,1H),4.03(m,1H),5.12(m,1H)和7.10-7.78(m,9H).
实施例5
N,N-二异丙基-3-(2-羟基苯基)-3-(3-吡啶基)-丙胺二盐酸盐
将N,N-二异丙基-3-(2-甲氧基苯基)-3-(3-吡啶基)-丙酰胺(2.8g,8mmol)的THF(25mL)溶液添加至LAH(1.3g,32mmol)中。反应混合物回流4小时,然后骤止反应并蒸发溶剂。残留物进行硅胶层析(甲苯∶三乙胺99∶1),制得2.2g。将产物(1.3g,4mmol)溶于二氯甲烷(20mL)中,冷却所得溶液至-78℃,并滴加三溴化硼(1g,8mmol),再使反应混合物于1小时内达到室温。用氢氧化钠(1M)和盐水洗涤此反应混合物,干燥有机相(MgSO4)并蒸发溶剂。残留物进行硅胶层析(甲苯∶三乙胺,9∶1),制得0.35g。将游离胺溶于乙醚,加入含氯化氢的乙醚以产生二盐酸盐,其为结晶且快速重排为硬玻璃状。
1H NMR(DMSO-d6)δ1.22(dd,6H),1.28(dd,6H),2.60(m,1H),2.70(m,1H),2.93(m,2H),3.60(m,2H),4.60(t,1H),6.85(t,1H),6.89(d,1),7.11(t,1H),7.38(d,1H),7.96(dd,1H),8.46(d,1H),8.75(d,1H),8.85(s,1H),9.90(br,1H)和10.14(s,1H).
起始化合物N,N-二异丙基-3-(2-甲氧基苯基)-3-(3-吡啶基)-丙酰胺的制备如下:
5.1 2-甲氧基苯基-3-吡啶基-甲酮
将2-溴苯甲醚(21g,0.11mol)的乙醚(100mL)溶液,在45分钟内添加至镁屑中,同时加热。完成添加后,继续回流15分钟。将所得格利雅(Grignard)试剂冷却至0℃,并滴加3-氰基吡啶(10g,0.10mol)的乙醚(100mL)溶液。该混合物回流数分钟。加入盐酸(20mL,0.24mol)和2-丙醇(20mL),继续回流30分钟。加入水与乙醚,分液。碱化水相(2M NaOH)并用乙醚萃取。干燥合并的有机相(MgSO4)之后蒸发,制得17g产物。粗制产物进行硅胶层析(甲苯∶乙酸乙酯19∶1),制得3.75g(19%)产物。
1H NMR(CDCl3-d)δ3.76(s,3H),7.01(d,1H),7.10(t,1H),7.41(dd,1H),7.46(dd,1H),4.53(m,1H),8.12(d,1H),8.75(s,1H)和8.94(s,
5.2 N,N-二异丙基-3-(2-甲氧基苯基)-3-(3-吡啶基)-丙酰胺
将N,N-二异丙基乙酰胺磷酸二乙酯(diethyl N,N-diisopropylacetamide phorphonate)(实施例4.1,9.3g,33mmol)的THF(40mL)溶液,于15分钟内逐滴添加至氢化钠(80%,1.0g,33mol)中。此混合物加热至40℃,历时15分钟,然后冷却至5℃并逐滴加入2-甲氧基苯基-3-吡啶基-酮(4.5g,21mmol)的THF(10mL)溶液。此反应混合物升至室温并搅拌16小时。将此反应混合物在乙醚和水之间进行分配,干燥有机相(MgSO4),之后蒸发,制得7.1g的固体物质。此产物经Pd/C(10%,0.2g)在乙酸(50mL)中氢化48小时。过滤反应混合物,蒸发溶剂。残留物在乙醚和盐酸(1M)之间分配,分离不同相。碱化水相(2M氢氧化钠)并用乙醚萃取。干燥合并的有机相(MgSO4),之后过滤。开始结晶时,用己烷稀释该混合物。过滤得2.9g(40%)产物。
1H NMR(CDCl3-d)δ1.14(dd,6H),1.28(d,6H),3.04(dd,2H),3.38(m,1H),3.74(s,3H),4.05(m,1H),5.00(t,1H),6.84(d,1H),6.92(t,1H),7.19(m,3H),7.57(d,1H),8.39(m,1H)和8.55(d,1H).1H).
实施例6
N,N-二异丙基-3-(2-氟苯基)-3-苯基丙胺盐酸盐
将N,N-二异丙基-3-(2-氟苯基)-3-苯基丙酰胺(3.1g,9.4mmol)的THF(20mL)溶液添加至LAH(1.0g,25mmol)中,回流温度下,搅拌此反应混合物2小时。加入另外的LAH(0.5g),再回流2小时。骤止反应并蒸发溶剂。残留物进行硅胶层析(甲苯∶乙酸乙酯,3∶1),制得0.4g的游离胺,其为淤浆状。将该胺溶于异丙醇/乙醚中,加入含氯化氢的乙醚,制得胺盐。产量0.32g(10%);熔点152-154℃。1H NMR(DMSO-d6)δ1.19(dd,6H),1.26(dd,6H),2.57(m,2H),2.86(m,1H),2.97(m,1H),3.58(m,2H),4.36(t,1H),6.69(dd,1H),7.14(m,1H),7.22(m,2H),7.29(m,1H),7.32(d,2H),7.33(s,2H),7.54(m,1H)和10.24(br,1H).分析.(C21H28NF·HCl)H,N;C:计算值,72.1;实测值,72.6.
分析(C21H28NF·HCl)H,N;C:计算值,72.1;实测值72.6。
起始化合物N,N-二异丙基-3-(2-氟苯基)-3-苯基丙酰胺的制备如下:
6.1反式-N,N-二异丙基-3-(2-氟苯基)-3-苯基丙烯酰胺
于30分钟内,将N,N-二异丙基乙酰胺磷酸二乙酯(实施例4.1,8.4g,30mmol)的THF(20mL)溶液逐滴加至氢化钠(80%,0.85g,25mmol)中,温度保持于40℃以下。加入2-三氟甲基-二苯甲酮(4.0g,20mmol)的THF(10mL)溶液,室温下搅拌此反应混合物30分钟。将混合物在乙醚和盐水之间分配。干燥有机层(MgSO4),之后蒸发,制得结晶物。用己烷重结晶,制得3.9g(60%)产物。
1H NMR(CDCl3-d)δ0.85(d,6H),1.39(d,6H),3.29(m,1H),4.27(m,1H),6.29(s,1H),7.10(m,3H)和7.30(m,6H).
6.2 N,N-二异丙基-3-(2-氟苯基)-3-苯基丙酰胺
将反式-N,N-二异丙基-3-(2-氟苯基)-3-苯基丙烯酰胺(3.25g,10mmol)的溶液,用Pd/C(10%,300mg)在乙酸(30mL)中氢化24小时。滤掉催化剂,蒸发溶剂,制得3.1g(96%)产物。
1H NMR(CDCl3-d)δ1.12(q,6H),1.28(q,6H),3.05(d,2H),3.38(m,1H),4.03(m,1H),4.93(t,1H)和6.94-7.32(m,9H).
实施例7
(R)-N,N-二异丙基-3-(5-甲酰基-2-羟基苯基)-3-苯基丙胺盐酸盐
将含氯化氢的乙醚加入(R)-N,N-二异丙基-3-(5-甲酰基-2-羟基苯基)-3-苯基丙胺(0.81g,2.4mmol)和2-丙醇的乙醚溶液中。过滤结晶,得到0.4g(45%)的产物;熔点178-179℃。〔α〕Hg=-40°(c1.1,甲醇中)。1HNMR(DMSO-d6)δ1.16(d,3H),1.20(d,3H),1.24(d,3H),1.27(d,3H),2.54(m,2H),2.84(m,1H),2.97(m,1H),3.58(br,2H),4.38(t,1H),7.08(d,1H),7.22(t,1H),7.32(m,4H),7.65(dd,1H),7.83(d,1H),9.80(s,1H),9.86(br,1H)10.99(s,1H).分析.(C22H29NO2·HCl)H,N;C:计算值,70.3;实测值,70.8。
分析(C22H29NO2·HCl)H,N;C:计算值,70.3;实测值,70.8。
起始化合物(R)-N,N-二异丙基-3-(5-甲酰基-2-羟基苯基)-3-苯基丙胺的制备如下:
7.1(R)-N,N-二异丙基-3-(5-甲酰基-2-羟基苯基)-3-苯基丙胺
将DDQ(1.1当量.)加入如下组成的溶液中:(R)-N,N-二异丙基-3-(2-羟基-5-羟甲基苯基)-3-苯基丙胺扁桃酸盐(其制备如WO94/11337所述,参见实施例1)(2.46g,5mmol)、二氯甲烷(20mL)及磷酸缓冲液(pH7,0.1mL)。随后加入氢氧化钠溶液(20mL,1M)和乙醚,分离不同相。用二氯甲烷-乙醚(2∶1)萃取水相两次。干燥有机相(MgSO4),之后蒸发。残留物用乙酸乙酯-己烷结晶制得1.35g(80%)产物。
实施例8
(R)-N,N-二异丙基-3-〔5-(7-羟基-2-氮杂-5-氧杂庚基)-2-羟基苯基〕-3-苯基丙胺二-(S)扁桃酸盐
将氰基硼氢化钠(0.25g,3.9mmol)加入(R)-N,N-二异丙基-3-(5-甲酰基-2-羟基苯基)-3-苯基丙胺(实施例7.1,1.25g,3.7mmol)和2-乙氧基-(2-氨基)-乙醇(19.5g,18mmol)在甲醇(10mL)中的溶液里。加入盐酸(浓),调节pH至约3。3小时后,调节pH至约1,蒸发溶剂。残留物在乙醚与水之间分配,蒸发溶剂,残留物进行硅胶层析(氯仿∶三乙胺∶甲醇,88∶10∶2)。将纯化的胺与(S)-扁桃酸(2当量)溶于2-丙醇-乙醚中,结晶出所需产物(结晶不稳定且立刻变成油状物)。产量0.2g(7%);熔点(分解)。
1H NMR(游离胺)(CDCl3-d)δ1.05(d,6H),1.09(d,6H),2.10(m,1H),2.35(m,2H),2.67(m,3H),3.19(m,2H),3.47(m,2H),3.49(t,2H),3.56(d,2H),3.63(t,2H),4.45(dd,1H),6.75(d,1H),6.79(d,1H),6.95(dd,1H),7.18(m,1H)和7.26-7.33(m,4H).
实施例9
(R)-N,N-二异丙基-3-(2-羟基-5-甲氧羰基-苯基)-3-苯基丙胺盐酸盐
将(R)-N,N-二异丙基-3-(2-苄氧基-5-甲氧羰基-苯基)-3-苯基丙胺(制备如WO 94/11337所述,参见实施例1)(0.92g,2mmol),用Pd/C(10%,50mg)在室温下氢化2小时。滤除催化剂,用氯化氢处理溶液而得胺盐。产量0.66g(81%);熔点177-178℃;〔α〕D=-23°(c1.0,甲醇)。1H NMR(DMSO-d6)δ1.19(dd,6H),1.25(dd,6H),2.48(m,2H),2.85(m,1H),2.95(m,1H),3.58(m,2H),3.78(s,3H),4.38(t,1H),6.98(d,1H),7.20(m,1H),7.31(d,2H),7,32(s,2H),7.69(dd,1H),7.81(d,1H),9.85(br,1H),10.74(s,1H).分析.(C23H31NO3·HCl)H,N,C.
实施例10
N,N-二异丙基-3-(2-羟甲基)苯基-3-苯基丙胺盐酸盐
将N,N-二异丙基-3-(2-羧基苯基)-3-苯基丙胺盐酸盐(1.88g,5mmol)的THF(30mL)溶液添加至LAH(1.5g,38mmol)中,室温搅拌此反应混合物2小时。骤止反应,蒸发溶剂。将残留物溶于热的乙醚-2-丙醇(100mL,1∶4),再加入含HCl的乙醚。冷却后,过滤产物,于60℃下(真空)干燥。产量1.2g(68%);熔点223-224℃。1H NMR(DMSO-d6)δ1.18(t,6H),1.25(q,6H),2.91(m,2H),3.26(与溶剂峰重叠,2H),3.57(m,2H),4.38(t,1H),4.43(d,1H),4.74(d,1H),5.22(s,1H),7.20(q,2H),7.25-7.35(m,5H),7.40(dd,2H),9.95(s,1H).分析.(C22H31NO·HCl)H,N,C.
实施例11
(S)-N,N-二异丙基-3-〔2-羟基-5-(2-羟乙基)苯基〕-3-苯基丙胺盐酸盐
在乙醇(20mL)中,将(S)-N,N-二异丙基-3-〔2-苄氧基-5-(2-羟乙基)苯基〕-3-苯基丙胺(0.67g,1.5mmol)用Pd/C(10%,67mg)常压氢化一夜。滤除催化剂,蒸发溶剂。残留物在乙醚与氢氧化钠(1M)之间分配。用乙醚萃取水层。水洗合并的有机层,干燥(MgSO4),蒸发溶剂。将所得胺溶于乙醚-异丙醇中,并在乙醚中与氯化氢反应,制得胺盐。产量0.37g;熔点219-221℃;〔α〕D-11.4°(c=1.0,甲醇);
1H NMR(CD3OD)δ1.30(d,12H),2.36-2.60(m,2H),2.68(t,2H),3.05(t,2H),3.60-3.72(m,4H),4.40(t,1H),6.73(d,1H),6.90(dd,1H),7.0(s,1H),7.17-7.38(m,5H).分析.(C23H33NO2·HCl·0.2H2O)C,H,N.
起始化合物(S)-N,N-二异丙基-3-〔2-苄氧基-5-(2-羟基)乙基苯基〕-3-苯基丙胺的制备如下:
11.1(S)-N,N-二异丙基-3-(2-苄氧基-5-乙烯基苯基)-3-苯基丙胺
氮气氛下,将(S)-N,N-二异丙基-3-(2-苄氧基-5-溴苯基)-3-苯基丙胺(制备如WO 94/11337所述,参见实施例1)(8g,12.7mmol)、Pd(OAc)2(28mg,0.12mmol)、三-邻-甲苯基-膦(74mg,0.14mmol)和三丁胺(5.9mL,24.5mmol)在二甲基乙酰胺(50mL)中的混合物加热至60℃。通入乙烯气体至8巴压力。搅拌一夜后,将反应混合物冷却至室温。使氮气通过反应瓶,加入甲苯与水。用甲苯萃取水相,干燥合并的有机层(MgSO4),之后浓缩。残留物用氢氧化钠(1M)处理,用乙醚和甲苯萃取。干燥有机层(MgSO4),之后真空浓缩。残留物进行硅胶层析(乙酸乙酯-甲醇90∶10至含0.06%NH3的乙酸乙酯-甲醇90∶10的梯度)。产量1g(18%);
1H NMR(CDCl3)δ0.94(d,12H),2.20(br,2H),2.37(br,2H),3.0(br,2H),4.38(t,1H),5.0(s,2H),5.11(d,1H),5.61(d,1H),6.60-6.70(m,1H),6.80(d,1H),7.12-7.19(m,12H).
11.2(S)-N,N-二异丙基-3-〔2-苄氧基-5-(2-羟乙基)-苯基〕-3-苯基丙胺
氮气氛及0℃下,将(S)-N,N-二异丙基-3-(2-苄氧基-5-乙烯基苯基)-3-苯基丙胺(1g,2.34mmol)于THF(25mL)中的溶液,加至9-BBN(THF溶液,0.5M,11.7mL,5.85mmol)中。搅拌3小时后,加入另外的9-BBN(2.3mL,1.2mmol),温度升至室温,搅拌混合物0.5小时。再冷却至0℃,顺序添加1M氢氧化钠(10mL)和H2O2(30%水溶液,10mL)。搅拌1小时后,加水并用乙醚萃取此混合物。用水及盐水洗涤有机层,干燥(MgSO4)后浓缩。残留物进行硅胶层析(乙醚至含1%NH3的乙醚的梯度)。产量0.67g(64%)。1HNMR(CDCl3)δ0.90(d,12H),2.10-2.18(m,2H),2.30-2.37(m,2H),2.80(t,2H),2.90-3.0(m,2H),3.80(br,2H),4.40(t,1H),5.0(s,2H),6.80(d,1H),7.0(m,1H),7.10-7.38(m,11H).
实施例12
(R)-N,N-二异丙基-3-〔2-羟基-5-(2-羟乙基)苯基〕-3-苯基丙胺盐酸盐
标题化合物与起始化合物是以类似于实施例11所述制法制备的,只是将(S)-N,N-二异丙基-3-(2-苄氧基-5-溴苯基)-3-苯基丙胺换为(R)-N,N-二异丙基-3-(2-苄氧基-5-溴苯基)-3-苯基丙胺(其制备如WO94/11337所述,参见实施例1)。
产量0.35g(33%);熔点209-215℃;〔α〕D+9.8°(c=1.0,甲醇);
1H NMR(CD3OD)δ1.29(d,12H),2.40-2.60(m,2H),2.67(t,2H),3.04(t,2H),3.61-3.72(m,4H),4.40(t,1H),6.70(d,1H),6.90(dd,1H),7.0(s,1H),7.18-7.40(m,5H).分析.(C23H33NO2·HCl·0.2H2O)C,H,N.
起始化合物的制备:
12.1(R)-N,N-二异丙基-3-(2-苄氧基-5-乙烯基苯基)-3-苯基丙胺
产量5.5g(53%);1H NMR(CDCl3)δ0.94(d,12H),2.20(br,2H),2.37(br,2H),3.0(br,2H),4.38(t,1H),5.0(s,2H),5.11(d,1H),5.61(d,1H),6.60-6.70(m,1H),6.80(d,1H),7.12-7.19(m,12H).
12.2(R)-N,N-二异丙基-3-〔2-苄氧基-5-(2-羟乙基)-苯基〕-3-苯基丙胺
产量1.2g(75%); 1H NMR(CDCl3)δ0.89(d,12H),2.15(m,2H),2.32(m,2H),2.80(t,2H),2.95(m,2H),3.80(br,2H),4.40(t,1H),4.98(s,2H),6.80(d,1H),6.96(m,1H),7.10-7.35(m,11H).
实施例13
(R)-N,N-二异丙基-3-(5-乙酰基-2-羟基苯基)-3-苯基丙胺盐酸盐
如实施例11所述,处理(R)-N,N-二异丙基-3-(5-乙酰基-2-苄氧基苯基)-3-苯基丙胺(1g,2.25mmol)。产量0.6g(68%);熔点105-115℃;〔α〕D-32.6°(c1.02,甲醇);
1H NMR(DMSO-d6)d 1.18-1.28(m,12H),2.5(m,3H),2.50-2.62(m,2H),2.86(m,1H),2.97(m,1H),3.58(m,2H),4.38(t,1H),6.99(d,1H),7.2(m,1H),7.29-7.35(m,4H),7.73(dd,1H),7.85(d,1H),9.90(br,1H),10.70(s,1H).Anal.(C23H31NO2·HCl·0.4H2O)C,H,N.
起始化合物(R)-N,N-二异丙基-3-(5-乙酰基-2-苄氧基苯基)-3-苯基丙胺的制备如下:
13.1(R)-N,N-二异丙基-3-(5-乙酰基-2-苄氧基苯基)-3-苯基丙胺
氮气氛及室温下,向(R)-N,N-二异丙基-3-(2-苄氧基-5-溴苯基)-3-苯基丙胺(实施例12)(10.2g,21.23mmol)的DMF(100mL)溶液中依次加入三乙胺(2.58g,25.47mmol),TlOAc(6.15g,23.35mmol),异丁基乙烯基醚(14mL,106.14mmol),DPPP(0.87g,2.12mmol)及Pd(OAc)2(0.24g,1.06mmol)。将反应温度升高至100℃且搅拌3小时,冷却至室温,过滤并用HCl(5%,250mL)处理,再搅拌2小时。用二氯甲烷反复萃取反应混合物,干燥合并的有机层(MgSO4),过滤,蒸发溶剂。减压下,蒸馏出三乙胺及DMF,制得9g(98%)产物;
1H NMR(CDCl3)δ1.22(m,12H),2.52-2.70(m,7H),3.40(br,2H),4.34(t,1H),5.10(s,1H),6.90(d,1H),7.17-7.40(m,10H),7.82(m,1H)和7.92(s,1H).
实施例14
N,N-二异丙基-3(R)-〔2-羟基-5-(1-羟乙基)苯基〕-3-苯基丙胺富马酸盐
在乙醇中将N,N-二异丙基-3(R)-〔2-苄氧基-5-(1-羟乙基)-苯基〕-3-苯基丙胺(2.7g,6.05mmol)用Pd/C(0.27g,10%)常压氢化2小时。滤除催化剂,蒸发溶剂。制得的油状物进行硅胶层析(甲苯∶三乙胺,90∶10)。将溶于热乙醇的富马酸(0.13g,1.13mmol)添加至游离碱的乙醚溶液中,制得胺的富马酸盐,为白色结晶(0.44g,83%);熔点240-244℃;〔α〕D+9.8°(c1.02,甲醇);
1H NMR(DMSO-d6)δ1.05(d,6H),1.26(dd,3H),2.20-2.30(m,2H),2.55-2.67(m,2H),3.30(m,2H),4.32(t,1H),4.59(q,1H),6.53(s,2H),6.72(dd,1H),6.93(dd,0.5H),7.12-7.17(m,1H),7.21-7.31(m,5H).分析.(C23H33NO2·C4H4O4·0.3H2O)C,H,N.
起始化合物N,N-二异丙基-3(R)-1〔2-苄氧基-5-(1-羟乙基)苯基〕-3-苯基丙胺的制备如下:
14.1 N,N-二异丙基-3(R)-〔2-苄氧基-5-(1-羟乙基)-苯基〕-3-苯基丙胺
将溶于无水THF的N,N-二异丙基-3(R)-(5-乙酰基-2-苄氧基苯基)-3-苯基丙胺(其制备如实施例13.1所述)(3.5g,7.90mmol)添加至LiAlH4(0.2g,5.41mmol)中。搅拌2小时后,加入另外的LiAlH4(50mg,1.32mmol),搅拌此反应混合物1.5小时。骤止反应,蒸发溶剂。残留物进行硅胶层析(甲苯∶E3N 90∶10),制得2.74g(78%)的油状物,其保存于室温时,会缓慢结晶。
实施例15
(+)-N,N-二异丙基-3(R)-〔5-(1-(R*),2-二羟基乙基)-2-羟基苯基〕-3-苯基丙胺富马酸盐。
以类似于实施例14所述方法处理N,N-二异丙基-3(R)-〔2-苄氧基-5-(1(R*),2-二羟基乙基)苯基〕-3-苯基丙胺(0.55g,1.2mmol),制得白色结晶,0.32g(55%);熔点196-200℃;〔α〕D+13.5°(c1.0,甲醇);1H NMR(CD3OD)δ1.28(m,12H),2.40-2.48(m,1H),2.52-2.60(m,1H),3.03(t,2H),3.55(d,2H),3.66(m,2H),4.42(t,1H),4.57(t,1H),6.7(s,2H),6.79(d,1H),7.05(dd,1H),7.16-7.21(m,2H),7.28(m,2H),7.36(m,2H).分析.(C23H33NO3·C4H4O4)C,H,N。
起始化合物N,N-二异丙基-3(R)-〔2-苄氧基-5-(1(R*),2-二羟基乙基)苯基〕-3-苯基丙胺的制备如下:
15.1 N,N-二异丙基-3(R)-〔2-苄氧基-5-(1(R*),2-二羟基乙基)苯基〕-3-苯基丙胺
向AD-mix-α(5.7g)在水(20mL)和叔丁醇(10mL)的冰冷溶液中加入溶于叔丁醇(10mL)的N,N-二异丙基-3(R)-〔2-苄氧基-5-乙烯基苯基〕-3-苯基丙胺(实施例12.1)(1.74g,4.1mmol)的溶液。搅拌1小时后,移走冰浴,再搅拌反应混合物21小时。加入Na2SO3(6g),搅拌1小时后,将反应混合物在水与乙酸乙酯之间分配。用乙酸乙酯萃取水层3次,干燥合并的有机层(MgSO4),蒸发溶剂。残留物进行硅胶层析(乙酸乙酯∶三乙胺90∶10),制得0.55g产物。
1H NMR(CDCl3)δ0.9(s,6H),0.95(s,6H),2.15-2.20(m,2H),2.30-2.38(m,2H),2.96(m,2H),3.60-3.70(m,2H),4.41(t,1H),4.75(m,1H),5.0(s,2H),6.85(d,1H),7.10-7.35(m,12H).
实施例16
(-)-N,N-二异丙基-3(R)-〔5-(1(S*),2-二羟基乙基)-2-羟基苯基〕-3-苯基丙胺富马酸盐
以类似于实施例11所述方法处理N,N-二异丙基-3(R)-〔2-苄氧基-5-(1(S*),2-二羟基乙基)苯基〕-3-苯基丙胺(1.1g,2.4mmol),制得白色结晶,0.25g(21%);熔点208-211℃;〔α〕D-8°(c1.02,甲醇);1H NMR(CD3OD)δ1.28(m,12H),2.39-2.47(m,1H),2.51-2.59(m,1H),3.03(t,2H),3.51-3.53(m,2H),3.67(m,2H),4.42(t,1H),4.54(dd,1H),6.68(s,2H),6.78(d,1H),7.06(dd,1H),7.16-7.20(m,2H),7.26(m,2H),7.34-7.36(m,2H).分析.(C23H33NO3·C4H4O4)C,H,N.
起始化合物N,N-二异丙基-3(R)-〔2-苄氧基-5-(1(S*),2-二羟基乙基)苯基〕-3-苯基丙胺的制备,是按照实施例15.1所述的方法处理N,N-二异丙基-3(R)-〔2-苄氧基-5-乙烯基苯基〕-3-苯基丙胺(实施例12.1制得者)来进行的,但用AD-mix-β代替AD-mix-α。产量1.2g(44%)。
实施例17
(R)-〔N,N-二异丙基-3-〔2-羟基-5-〔6-羟己基〕-苯基〕-3-苯基丙胺盐酸盐
按照实施例14所述方法,处理N,N-二异丙基-3(R)-〔2-苄氧基-5-(6-羟基己-1-烯基)苯基〕-3-苯基丙胺(0.35g,0.72mmol)。产量0.10g(31%);熔点147-156℃;〔α〕D+8.2°(c1.01,甲醇);
1H NMR(CD3OD)δ1.25-1.32(m,16H),1.45-1.54(m,4H),2.40-2.48(m,3H),2.51-2.59(m,1H),3.0-3.10(m,2H),3.51(t,2H),3.68(m,2H),4.40(t,1H),6.72(d,1H),6.86(dd,1H),6.91(d,1H),7.19(m,1H),7.30(t,2H),7.34-7.36(m,2H).分析.(C27H41NO2·HCl·2H2O)C,N,H:计算值,9.6;实测值,8.3。
起始化合物(R)-N,N-二异丙基-3-〔2-苄氧基-5-(6-羟基己-1-烯基)苯基〕-3-苯基丙胺的制备如下:
17.1(R)-N,N-二异丙基-3-(2-苄氧基-5-甲酰基苯基)-3-苯基丙胺
氮气氛下,将正丁基锂(2.5M己烷溶液,19mL,47.5mmol)加入保持在-40℃的(R)-N,N-二异丙基-3-(2-苄氧基-5-溴苯基)-3-苯基丙胺(其制法如WO 94/11337所述,参见实施例1)(8.9g,18.52mmol)于无水乙醚(100mL)的溶液中。搅拌1.5小时后,加入另外的正丁基锂(10mL,25mmol),再经2小时,加入另外的正丁基锂(5mL,12.5mmol)。搅拌反应15分钟,加入DMF(6mL,77.8mmol),再搅拌20分钟后,加入DMF(5mL,64.8mmol)。升高反应温度至室温,搅拌35分钟后,依次加入NH4Cl(饱和)、水及乙醚。分液,用乙醚萃取水层。干燥合并的有机层(MgSO4),蒸发溶剂。残留物进行硅胶层析(甲苯∶三乙胺90∶10),制得8g(100%)的黄色油状物;1H NMR(CDCl3)δ0.90(m,12H),2.12-2.40(m,4H),2.95(m,2H),4.44(t,1H),5.10(s,2H),6.95(d,1H),7.15-7.36(m,10H),7.70(dd,1H),7.91(s,1H),9.88(s,1H).
17.2(R)-N,N-二异丙基-3-〔2-苄氧基-5-(5-羧基戊-1-烯基)苯基〕-3-苯基丙胺
在氮气氛及-10℃下,将叔丁基醇钾(2.1g,18.62mmol)加入含有溴化4-羧基丁基-三苯基鏻(4.1g,9.31mmol)的THF(25mL)混合物中。混合物变为橙色,搅拌10分钟后,加入(R)-N,N-二异丙基-3-(2-苄氧基-5-甲酰基苯基)-3-苯基丙胺(2g,4.65mmol)于THF(10mL)中的溶液。搅拌4小时后,加入盐酸(1M)及乙醚,分离不同层。用乙酸乙酯萃取水层。干燥合并的有机层(MgSO4),蒸发溶剂。残留物进行硅胶层析(乙酸乙酯∶三乙胺90∶10),随后为甲醇),制得3g含有微量三苯基膦的产物。此产物无需进一步纯化,即可用于下一步骤。
17.3(R)-N,N-二异丙基-3-〔2-苄氧基-5-(6-羟基己-1-烯基)苯基〕-3-苯基丙胺
如实施例10所述,还原(R)-N,N-二异丙基-3-〔2-苄氧基-5-(5-羧基戊-1-烯基)苯基〕-3-苯基丙胺。产量0.35g(15%)。
实施例18
(R)-N,N-二异丙基-3-〔5-(2-二异丙氨基乙基)-2-羟基苯基〕-3-苯基丙胺盐酸盐
将(R)-N,N-二异丙基-3-〔2-苄氧基-5-(2-二异丙氨基乙基)苯基〕-3-苯基丙胺(0.6g,1.13mmol)与浓HCl(25mL)回流过夜。用10M氢氧化钠碱化反应混合物,并用乙醚萃取。干燥有机层(MgSO4)后真空浓缩,制得0.5g油状物,在反相PEP-RPC HR 30/26制备柱上纯化此油,使用乙腈(含0.1%TFA)与milliQ-水(含0.1%TFA)组成的梯度溶剂洗脱。合并纯馏份,用乙醚和10M氢氧化钠萃取。所得乙醚溶液用含有氯化氢的乙醚处理。产量50mg(9%);〔α〕D+1.4°(c0.94,甲醇);
1H NMR(CD3OD)δ1.27-1.34(m,12H),1.36-1.42(m,12H),2.50-2.58(m,1H),2.60-2.67(m,1H),2.95(t,2H),3.05(m,2H),3.15-3.27(m,2H),3.70(m,2H),3.75(m,2H),4.40(t,1H),6.80(d,1H),7.02(dd,1H),7.13(d,1H),7.20(m,1H),7.31(m,1H),7.39-7.41(m,1H).
分析.(C29H46N2O·2HCl·0.4H2O)C,H,N.
起始化合物N,N-二异丙基-3(R)-〔2-苄氧基-5-(2-二异丙氨基乙基)苯基〕-3-苯基丙胺的制备如下:
18.1 N,N-二异丙基-3(R)-(5-甲酰基甲基-2-苄氧基-苯基)-3-苯基丙胺
在氮气氛及-78℃下,将溶于二氯甲烷的DMSO(1.1mL,15.5mmol)逐滴加入草酰氯(0.64mL,7.74mmol)中。搅拌10分钟后,加入(R)-N,N-二异丙基-3-〔2-苄氧基-5-(2-羟乙基)苯基〕-3-苯基丙胺(实施例12.2)(2.3g,5.16mmol)的二氯甲烷溶液,搅拌此反应混合物1小时。加入三乙胺(5.4mL,38.7mmol),使温度升高至室温。将反应混合物溶于水和二氯甲烷中。干燥有机层(MgSO4),真空浓缩,产物无需进一步纯化即可用于下一步骤。
18.2(R)-N,N-二异丙基-3-〔2-苄氧基-5-(2-二异丙氨基乙基)苯基〕-3-苯基丙胺
将二异丙基胺(4.2mL,30mmol)溶于甲醇(12mL)中。依次加入5MHCl的甲醇溶液(2mL)、于甲醇(10mL)中的N,N-二异丙基-3(R)-(5-甲酰基甲基-2-苄氧基苯基)-3-苯基丙胺(5mmol)以及氰基硼氢化钠(0.22g,3.5mmol)。反应混合物室温搅拌过夜,蒸发甲醇,加入乙醚和水。干燥有机层(MgSO4),真空浓缩,制得3g粗产物,产物进行硅胶层析(甲苯∶三乙胺95∶5)。产量0.65g(25%);
1H NMR(CDCl3)δ0.88-0.91(m,18H),1.20(d,9H),2.10-2.20(m,2H),2.30-2.38(m,2H),2.87-3.10(m,4H),4.34(m,1H),4.98(d,2H),6.75-6.97(m,2H),7.10-7.30(m,11H).
实施例19
(R)-N,N-二异丙基-3-(5-乙氧基甲基-2-羟基苯基)-3-苯基丙胺
将(R)-N,N-二异丙基-3-(2-羟基-5-羟甲基-苯基)-3-苯基丙胺(其制备如WO 94/11337所述,参见实施例1)(3.9g,11.5mmol)和Al2O3(115g,1.13mol)在乙酸乙酯(0.5L)中回流60小时。滤除Al2O3,蒸发乙酸乙酯。残留物进行硅胶层析(甲苯∶三乙胺90∶10),制得2.5g(59%)产物。将溶于温热乙醇中的富马酸(0.17g,1.48mmol)添加至游离碱的乙醚溶液中(0.55g,1.48mmol),制得富马酸盐;熔点174-177℃;〔α〕D+5.5°(c 1.02,甲醇);
1H NMR(CD3OD)δ1.15(t,3H),1.27-1.30(m,12H),2.41-2.49(m,1H),2.52-2.60(m,1H),3.04(dd,2H),3.49(q,2H),3.67(m,2H),4.35(s,2H),4.43(t,1H),6.69(s,2H),6.80(d,1H),7.04(dd,1H),7.12(d,1H),7.18-7.37(m,4H).分析.(C24H35NO2·C4H4O4)C,H,N.
实施例20
N-异丙基-3-(5-羧基-2-羟基苯基)-3-苯基丙胺盐酸盐
将N-苄基-N-异丙基-3-(2-苄氧基-5-羧基苯基)-3-苯基丙胺(1.3g,2.6mmol)溶于HOAc中。加入炭附载的钯(10%,0.13g),常温下氢化此混合物48小时。滤除催化剂,蒸发溶剂。所生成的油状物在反相PEP-RPC HR 30/26制备柱上纯化,使用乙腈(含0.1%TFA)及milliQ水(含0.1%TFA)组成的梯度溶剂洗脱。分16批完成纯化,每次约100mg物质。合并纯馏份且冷冻干燥,制得0.57g的三氟乙酸盐。将此结晶溶于1M HCl中,冷冻干燥而制得0.4g(43%)盐酸盐,其为白色结晶;熔点155-160℃;1H NMR(DMSO-d6)δ1.17(d,3H),1.19(d,3H),2.30-2.38(m,1H),2.38-2.46(m,1H),2.72(br,1H),2.80(br,1H),3.25(m,1H),4.40(t,1H),6.94(d,1H),7.18-7.22(m,1H),7.29-7.33(m,4H),7.66(dd,1H),7.76(d,1H);分析.(C19H23NO3·HCl·0.5H2O)C,H,N.
起始化合物N-苄基-N-异丙基-3-(2-苄氧基-5-羧基苯基)-3-苯基丙胺的制备如下:
20.1 3-(2-苄氧基-5-溴苯基)-3-苯基丙醛
如实施例18.1所述,使3-(2-苯氧基-5-溴苯基)-3-苯基丙醇(16.5g,41.5mmol)(其制备如WO 94/11337所述,参见实施例1C)进行反应。合并的有机层用2M HCl、10% NaHCO3、水及盐水洗涤,干燥(MgSO4),蒸发得到16g(98%)黄色结晶产物,其无需进一步纯化即可用于下一步骤;熔点99-100℃;
1H NMR(CDCl3)δ3.10(dd,2H),5.0(s,2H),4.98-5.10(m,1H),6.76(d,1H),7.16-7.38(m,12H),9.65(s,1H).
20.2 N-苄基-N-异丙基-3-(2-苄氧基-5-溴苯基)-3-苯基丙胺
向N-苄基异丙胺(34mL,0.20mol)的甲醇溶液(80mL)中,加入含有5M HCl的甲醇溶液(16.2mL,80.9mmol),再加入3-(2-苄氧基-5-溴苯基)-3-苯丙醛(16.0g,40.5mmol)于甲醇(20ml)中的溶液及氰基硼氢化钠(1.78g,28.3mmol)。所得溶液搅拌17小时。蒸发溶剂,将乙醚加入所得淤浆中。水洗此溶液3次,用MgSO4干燥后蒸发。残留物进行硅胶层析(己烷∶乙酸乙酯75∶25),制得15.9g淤浆。将产物溶于乙醚,加入溶于乙醚的HCl,制得标题化合物的盐酸盐。生成的油状物用乙醚洗涤,溶于10M氢氧化钠,用乙醚萃取3次。使用硅胶层析(使用二氯甲烷至含有1%三乙胺的二氯甲烷所的梯度)纯化,制得7g(33%)产物,为无色油状物。1H NMR(CDCl3)δ0.84(d,3H),0.90(d,3H),2.02-2.12(m,2H),2.38(t,2H),2.90(m,1H),3.50(d,2H),4.50(t,1H),4.95(s,2H),6.70(s,1H),7.10-7.35(m,17H).
20.3 N-苄基-N-异丙基-3-(2-苄氧基-5-羧基苯基)-3-苯基丙胺
温和加热镁屑(1.18g,48.6mmol)与碘(一粒小结晶)的混合物。氮气氛下,将N-苄基-N-异丙基-3-(2-苄氧基-5-溴苯基)-3-苯基丙胺(6.0g,11mmol)与1,2-二溴乙烷(0.2mL,2.3mmol)在无水THF(25mL)中的混合物,逐滴加至该回流的混合物中。回流2小时后,加入1,2-二溴乙烷(0.59mL,6.8mmol)。此混合物在氮气保护下放置过夜。此混合物再与1,2-二溴乙烷(0.93mL,10.8mmol)一起加至经加温的镁屑(1.18g,48.6mmol)和碘(一小颗结晶)中。回流30分钟后,将混合物冷却至室温并通入CO2气体。3小时后,加入氯化铵(水溶液,15%,50mL),再加入乙醚(100mL)。分离不同层,干燥有机层(MgSO4),浓缩而得5.8g油。粗产物进行硅胶层析(使用丙酮至含有5%乙醇的丙酮的梯度溶剂洗脱),制得纯产物(1.3g,23%),为油状物。制得的N-苄基-N-异丙基-3-(2-苄氧基苯基)-3-苯基丙胺(3.1g)为此反应的副产物。
1H NMR(CDCl3)δ0.98(d,3H),1.10(d,3H),2.30-2.40(m,2H),2.46-2.65(m,2H),3.40(br,1H),3.85(br,2H),4.30(br,1H),4.98(br,2H),6.80(d,1H),7.10-7.40(m,15H),7.95(d,1H),7.95(d,1H),8.20(s,1H).
实施例21
N-苄基-N-异丙基-3-(2-羟基苯基)-3-苯基丙胺盐酸盐
如实施例20.3所述制备N-苄基-N-异丙基-3-(2-苄氧基-5-羧基苯基)-3-苯基丙胺(3.1g,6.90mmol),使其在浓HCl(30mL)中回流20小时。使反应混合物冷却至室温,倒掉液体。剩余的油状物用水和乙醚洗涤,然后溶于2-丙醇中。蒸发溶液并用10M氢氧化钠处理,得到游离碱。硅胶层析(己烷∶乙酸乙酯75∶25),制得0.5g化合物,在反相PEP-RPC HR 30/26制备柱上纯化,使用乙腈(含0.1%TFA)与milliQ水(含0.1%TFA)的梯度溶剂洗脱。合并纯馏份,用乙醚及10M氢氧化钠萃取。向所得的乙醚溶液中,逐滴加入饱和的乙醚-HCl(气体)。过滤回收生成的盐酸盐结晶;熔点115-122℃
1H NMR(DMSO-d6)δ1.28(m,6H),2.27-2.38(m,1H),2.48-2.55(m,1H),2.72-2.97(m,2H),3.55(m,1H),4.23(m,2H),4.35(m,1H),6.68-6.74(m,1H),6.82(dt,1H),6.96-7.24(m,7H),7.38-7.42(m,3H),7.64-7.68(m,2H),9.55(d,1H),10.62(br,1H).分析.(C25H29NO·HCl)C,H,N.
实施例22
(R)-N,N-二异丙基-3-〔5-(3-氨丙基)-2-羟基苯基〕-3-苯基丙胺二盐酸盐
将(R)-N,N-二异丙基-3-〔2-苄氧基-5-(2-氰基乙烯基)苯基〕-3-苯基丙胺(3.20g,7.07mmol)溶于100%乙酸,加入10%Pd/C(0.52g)。混合物在室温下氢化一夜(60psi)。滤除催化剂,蒸发溶剂。将残留物溶于水,用氢氧化钠(11M)碱化,乙酸乙酯萃取,干燥有机相(MgSO4)之后蒸发。残留物进行硅胶层析(甲苯∶乙酸乙酯∶三乙胺∶甲醇,20∶5∶1.5∶1)。得到的胺再次溶于乙醚,小心加入经HCl饱和的乙醚溶液。滤出沉淀物,制得0.30g(10%)产物;
1H NMR(CD3OD)δ1.29(m,12H),1.88(m,2H),2.51(m,2H),2.59(t,2H),2.88(t,2H),3.04(t,2H),3.68(m,2H),4.40(t,1H),4.55(bs,1H),6.76(d,1H),6.93(d,1H),7.03(s,1H),7.19(t,1H),7.30(t,2H),7.37(d,2H);mp.226-228℃;[α]D+11.5°(c=1.0,甲醇).分析.(C24H36N2O*2HCl)C,H,N.
起始化合物(R)-N,N-二异丙基-3-〔2-苄氧基-5-(2-氰基乙烯基)苯基〕-3-苯基丙胺的制备如下:
22.1(R)-N,N-二异丙基-3-〔2-苄氧基-5-(2-氰基乙烯基)苯基〕-3-苯基丙胺
向(R)-N,N-二异丙基-3-(2-苄氧基-5-溴苯基)-3-苯基丙胺(13.87g,28.87mmol)(其制备如WO 94/11337所述,参见实施例1)的DMF(140mL)溶液中加入三乙胺(5.00mL,36.10mmol)、Pd(OAc)2(0.32g,1.44mmol)、三(邻-甲苯基)膦(1.76g,5.77mmol)和丙烯腈(2.39mL,36.10mmol)。氮气氛及115℃下,将此反应混合物在装有回流冷凝管的密封烧瓶中搅拌过夜。浓缩所得的混合物,残留物溶于乙醚,用2M氢氧化钠水溶液和水洗涤。干燥有机相(MgSO4),然后将石油醚加入有机相,形成沉淀物。用乙醇重结晶,制得5.50g(42%)产物。
1H NMR(CDCl3)δ0.90(s,6H),0.95(s,6H),2.15(q,2H),2.35(q,2H),2.95(m,2H),4.40(t,1H),5.05(s,2H),5.70(d,1H),6.85(d,1H),7.10-7.50(m,13H).
实施例23
(R)-N,N-二异丙基-3-〔5-3-(乙酰氨基丙基)-2-羟基-苯基〕-3-苯基丙胺盐酸盐
向(R)-N,N-二异丙基-3-〔5-(3-氨丙基)-2-羟基苯基〕-3-苯基丙胺(实施例22)(0.45g,1.23mmol)的甲醇(45mL)溶液中加入醋酸酐(0.23mL,2.47mmol)。室温下,搅拌此混合物3小时,蒸发至干。将残留物溶于水中,用11M氢氧化钠水溶液碱化,甲苯萃取。用MgSO4将有机相干燥,过滤后蒸发。将所得胺溶于乙醚,小心加入经HCl饱和的乙醚溶液。滤出形成的沉淀物,制得0.55g(100%)产物。
1H NMR(CD3OD)δ1.27(m,12H),1.75(m,2H),2.08(s,3H),2.52(m,4H),3.04(t,2H),3.20(t,2H),3.68(m,2H),4.40(t,2H),6.72(d,1H),6.90(d,1H),6.99(s,1H),7.19(t,1H),7.30(m,4H);
熔点171-175℃;〔α〕D+3.6°(c=0.5,甲醇)。(C26H38N2O2*HCl)C,H,N。
实施例24
(R)-N,N-二异丙基-3-〔5-(2-氰乙基-2-羟基苯基〕-3-苯基丙胺盐酸盐
如实施例22所述处理(R)-N,N-二异丙基-3-〔2-苄氧基-5-(2-氰基乙烯基)苯基〕-3-苯基丙胺(实施例22.1),(4.00g,8.84mmol),但氢化反应是在常压下进行。产量1.35g(38%)。
1H NMR(CD3OD)δ1.14(s,6H),1.16(s,6H),2.50(m,2H),2.79(t,2H),3.05(t,2H),3.68(m,2H),4.39(t,2H),6,75(d,1H),6.98(d,1H),7.09(s,1H),7.19(t,1H),7.32(m,4H);熔点156-159℃;〔α〕D+4.0°(c=0.5,甲醇);
分析(C24H32H2O*1.0HCl*0.25H2O)C,H;N:计算值,6.9;实测值,6.4。
实施例25
(R)-N,N-二异丙基-3-〔5-(2-氨基甲酰基乙基)-2-羟基-苯基〕-3-苯基丙胺盐酸盐
在50℃下,搅拌(R)-N,N-二异丙基-3-〔5-(2-氰乙基)-2-羟基苯基〕-3-苯基丙胺(实施例24),(2.00g,5.48mmol)的浓盐酸溶液2小时,然后蒸发。将残留物溶于水,用11M氢氧化钠水溶液碱化并用甲苯萃取。干燥有机层(MgSO4),过滤后蒸发。层析残留物,用甲苯∶乙酸乙酯∶三乙胺∶甲醇(7∶2∶1∶1)洗脱。用乙醚-氯化氢制得产物。产量0.9g(39%);1H NMR(CD3OD)δ1.31(m,12H),2.44(t,2H),2.53(m,2H),2.78(t,2H),3.04(t,2H),3.67(m,2H),4.39(t,1H),6.72(d,1H),6.82(d,1H),7.02(s,1H),7.18(t,1H),7.32(m,4H);
熔点200-202℃;〔α〕D+7.6°(c=0.5,甲醇)。
分析(C24H34N2O2*1.0HCl*0.5H2O)C,H,N。
实施例26
(R)-N,N-二异丙基-3-〔5-(2-羧乙基)-2-羟基苯基〕-3-苯基丙胺盐酸盐
将KOH(3.75g,66.8mmol)加入(R)-N,N-二异丙基-3-〔5-(2-氨基甲酰基乙基)-2-羟基苯基〕-3-苯基丙胺(得自实施例25,0.50g,1.31mmol)于乙醇(15mL)和水(10mL)的溶液中。所得混合物于100℃下搅拌过夜。蒸发溶剂,残留物再次溶于水中,用乙醚洗涤。浓盐酸酸化水层,过滤回收沉淀物,用2M HCl洗涤。产物在反相PEP RPC HP 30/26制备柱(Pharmacia Biotech AB,Sweden)上纯化,使用含0.1% TFA的20-60%乙腈作为梯度洗脱液。合并级份,加入盐酸(2mL,浓),蒸发溶剂。残留物用甲醇-乙醚结晶,制得0.37g(0.96mmol,74%)产物;1HNMR(CD3OD)δ1.28(m,12H),2.48(m,4H),2.76(t,2H),3.04(t,2H),3.67(m,2H),4.39(t,1H),6.72(d,1H),6.92(d,1H),7.00(s,1H),7.19(t,1H),7.32(m,4H);
熔点205-207℃;〔α〕D+3.7°(c=1.0,甲醇)。分析(C24H33NO3*1.0HCl)C,H,N。
实施例27
(R)-N,N-二异丙基-3-(5-氨基-2-羟基苯基〕-3-苯基丙胺二盐酸盐
将(R)-N,N-二异丙基-3-(5-叠氮基-2-苄氧基苯基)-3-苯基丙胺(0.90g,2.03mmol)溶于乙酸,加入10%Pd/C(210mg,催化剂)。搅拌混合物,与氢气(1大气压)接触,室温反应过夜。滤除Pd/C催化剂,干燥(MgSO4),过滤后蒸发。粗产物进行硅胶层析(正己烷∶乙醇∶三乙胺,7∶3∶1)。用乙醚/氯化氢制得盐酸盐。所生成的油状物冷冻干燥以除去水。产量0.30g(37%);
1H NMR(DMSO)δ1.13-1.33(m,12H),2.47(m,2H),2.82(br,1H),2.98(br,1H),3.57(br,2H),4.38(t,1H),6.96(d,1H),7.08(d,1H),7.19(s,1H),7.22(m,1H),7.32(m,4H),10.05(br,2H),10.13(s,1H);
熔点180-183℃;〔α〕D+21.0°(c=0.1,甲醇)。
分析(C21H30N2O*2.0HCl*0.5H2O)C,H,N。
起始化合物(R)-N,N-二异丙基-3-(5-叠氮基-2-苄氧基苯基)-3-苯基丙胺的制备如下:
27.1(R)-N,N-二异丙基-3-(5-叠氨基-2-苄氧基苯基)-3-苯基丙胺
向(R)-N,N-二异丙基-3-(2-苄氧基-5-溴苯基)-3-苯基丙胺(10.00g,20.81mmol)(其制备如WO 94/11337所述,参见实施例1)和镁(1.57g,64.52mmol)在THF(50mL)中的混合物中,加入1,2-二溴乙烷(3.59mL,41.63mmol),使此溶液自回流一阵子。回流此混合物1小时后,冷却溶液,加入甲苯磺酰基叠氮(4.10g,20.81mmol)的乙醚(100mL)溶液,持续搅拌并保持温度于0℃,然后升高温度至室温,反应4小时。加入焦磷酸四钠十水合物(4.46g,10.00mmol)于50mL水中的溶液。滤除沉淀物,蒸发滤液。用乙醚萃取残留物,干燥有机相(MgSO4)后蒸发。残留物进行硅胶层析(正己烷∶乙醇,8∶2)。产物用乙醇结晶,制得1.15g(13%)产品;IR(KBr)2116(N3)cm-1;1HNMR(CDCl3)δ0.92(d,12H),2.10(m,2H),2.33(m,2H),2.95(m,2H),4.40(t,1H),5.00(s,2H),6.81(d,2H),6.97(s,1H),7.10-7.40(m,10H).
实施例28
(R)-N,N-二异丙基-3-(5-叠氮基-2-羟基苯基)-3-苯基丙胺盐酸盐
在-10℃下,向(R)-N,N-二异丙基-3-(5-氨基-2-羟基苯基)-3-苯基丙胺(0.25g,0.76mmol)于0.78M HCl(5.35mL,4.20mmol)溶液中加入溶于水(0.4mL)的NaNO2(0.05g,0.76mmol),搅拌此混合物20分钟。将溶于0.4mL水的NaN3(57mg,0.88mmol)加入该混合物中,于-10℃搅拌此混合物30分钟。用11M氢氧化钠水溶液碱化此混合物(pH7-8),用乙醚萃取。干燥乙醚层(MgSO4),蒸发得到一油状物,进行硅胶层析(甲苯∶乙酸乙酯∶三乙胺,7∶2∶1)。将产物溶于乙醚,加入氯化氢的乙醚溶液。滤出沉淀物,得到淡棕色结晶(0.07g,0.18mmol,24%)。IR(KBr)2111(N3)cm-1;
1H NMR(CD3OD)δ1.29(m,12H),2.50(m,2H),3.04(m,2H),3.68(m,2H),4.40(t,1H),6.68(s,1H),6.81(m,2H),7.23(m,1H),7.35(m,4H);mp.131-134℃;[α]D-5.0°(c=0.1,甲醇)。
起始化合物(R)-N,N-二异丙基-3-(5-氨基-2-羟基苯基)-3-苯基丙胺的制备如下:
28.1(R)-N,N-二异丙基-3-(2-羟基苯基)-3-苯基丙胺
如实施例1.3所述,处理(R)-N,N-二异丙基-3-(2-苄氧基-5-溴苯基)-3-苯基丙胺(其制备如WO 94/11337所述,参见实施例1)(7.30g,15.2mmol)。产量4.47g(94%)。
28.2(R)-N,N-二异丙基-3-〔2-羟基-5-(4-甲基苯基偶氮基)苯基)-3-苯基丙胺
将NaNO2(0.27g,4.30mmol)加入盐酸(0.64mL,7.70mmol,浓)和对甲基苯胺(0.41g,3.80mmol)在冰水(20mL)中的混合物里。使此混合物于0℃搅拌10分钟,再加入(R)-N,N-二异丙基-3-(2-羟基苯基)-3-苯基丙胺(1.00g,3.21mmol)的THF(3mL)溶液,水(12mL)与氢氧化钠(0.69g,17.32mmol)所组成的冰冷溶液。搅拌此混合物20分钟后,用甲苯萃取,干燥(MgSO4),蒸发而得一油状物,层析(甲苯∶乙酸乙酯∶三乙胺,8∶1∶1),制得0.83g,1.93mmol(60%)的标题化合物。1H NMR(CDCl3)δ1.12(d,6H),1.19(d,6H),2.22(m,1H),2.43(m,5H),2.79(m,1H),3.32(m,2H),4.57(d,1H),6.98(d,1H),7.24(m,3H),7.36(m,4H),7.6 6(m,4H).
28.3(R)-N,N-二异丙基-3-(5-氨基-2-羟基苯基)-3-苯基丙胺
在75℃下,将Na2S2O4(1.23g,12.8mmol)的水(10mL)溶液,于15分钟内加入到(R)-N,N-二异丙基-3-〔2-羟基-5-(4-甲苯基偶氮基)苯基〕-3-苯基丙胺(0.55g,1.28mmol)的乙醇(50mL)溶液中。分10份加入另外的无水Na2S2O4(1.23g,12.8mmol)。加水至此溶液中,再用乙醚萃取。干燥有机层(MgSO4),蒸发而得一油状物,硅胶层析(正己烷∶乙醇∶三乙胺,7∶3∶1),制得油状物。将此产物溶于乙醇,加入氯化氢的乙醚溶液。蒸发溶剂,再次溶于水,真空干燥,制得0.25g(60%)产品。
实施例29
(R)-N,N-二异丙基-3-〔2-羟基-5-(3-羟丙基)-苯基)-3-苯基丙胺盐酸盐
将(R)-N,N-二异丙基-3-〔5-(2-乙氧羰基乙基)-2-羟基苯基〕-3-苯基丙胺(2.0g,4.86mmol)的THF溶液(50mL)逐滴加至LAH(0.28g,7.29mmol)中。搅拌2小时后,骤止反应并蒸发溶剂。残留物用乙醇-水重结晶。将产物溶于乙醇中,加入含氯化氢的乙醚。滤出白色结晶,得到0.82g(46%)产品;熔点204-207℃;〔α〕D+12.8°(c=1.0,甲醇);1HNMR(DMSO)δ1.18(t,6H),1.24(t,6H),1.63(m,2H),2.47(m,4H),2.87(br,2H),3.38(q,2H),3.57(br,2H),4.32(t,1H),4.42(t,1H),6.74(d,1H),6.83(d,1H),7.03(s,1H),7.17(t,1H),7.30(m,4H)分析.(C24H35NO2*1.0HCl)C,H,N.
起始化合物(R)-N,N-二异丙基-3-〔5-(2-乙氧羰基乙基)-2-羟基苯基〕-3-苯基丙胺的制备如下:
29.1(R)-N,N-二异丙基-3-〔2-苄氧基-5-(2-乙氧羰基乙基)苯基〕-3-苯基丙胺
使膦酰基醋酸三乙酯(6.93mL,34.92mmol)的THF(50mL)溶液逐滴加至NaH(0.84g,29.10mmol,80%)中。将所得混合物冷却至0℃,并逐滴加入(R)-N,N-二异丙基-3-(2-苄氧基-5-甲酰苯基)-3-苯基丙胺(其制备如实施例17.1所述)(5.00g,11.64mmol)于THF(50mL)中的溶液里。混合物在0℃下搅拌3小时。蒸发溶剂,使残留物再次溶于甲苯,水洗两次。干燥有机层(MgSO4),蒸发溶剂而得5.0g(86%)产品。
29.2(R)-N,N-二异丙基-3-〔5-(2-乙氧羰基乙基)-2-羟基苯基)-3-苯基丙胺
如实施例1.3所述,处理(R)-N,N-二异丙基-3-〔2-苄氧基)-5-(2-乙氧羰基乙基)苯基〕-3-苯基丙胺(3.0g,5.98mmol)。产量2.0g(81%);1H NMR(CDCl3)δ1.08(d,6H),1.12(d,6H),1.18(t,3H),2.05(m,2H),2.37(m,4H),2.72(t,2H),3.22(m,2H),4.03(q,2H),4.48(m,1H),6.55(s,1H),6.86(m,2H),7.28(m,5H).
实施例30
N,N-二异丙基-3-(5-乙氨基甲基-2-羟基苯基)-3-苯基丙胺
将(R)-N,N-二异丙基-3-(5-甲酰基-2-羟基苯基-3-苯基丙胺(实施例7.1制备)(1.23g,3.62mmol)溶于甲醇(20mL)。加入乙胺〔3.62mL,21.7mmol(6M盐酸甲醇溶液)〕和氰基硼氢化钠(0.14g,2.17mmol)。此混合物于室温下搅拌过夜。蒸发溶剂,残留物进行硅胶层析(甲苯∶乙酸乙酯∶三乙胺,7∶3∶1)。产物溶于乙醚,加入含氯化氢的乙醚。所生成的油状物在乙醚中搅拌过夜而得结晶。产量0.70g(44%);熔点140-142℃;〔α〕D-5.0°(c=0.5,甲醇);
1H NMR(CD3OD)δ1.30(m,15H),2.59(m,2H),3.05(m,4H),3.70(m,2H),4.07(s,2H),4.42(t,1H),6.85(d,1H),7.20(m,2H),7.30(t,2H),7.41(d,2H),7.50(s,1H)分析.(C24H36N2O*2.0HCl*0.5H2O)C,H,N.
实施例31
N-环丁基-N-甲基-3-(2-羟基苯基)-3-苯基丙胺盐酸盐
室温下,将N-环丁基-N-甲基-3-(2-苄氧基-5-溴苯基)-3-苯基丙胺(1.60g,3.44mmol)在醋酸中的溶液用Pd/C(160mg,10%)氢化一夜。用氢氧化钠(11M)碱化此溶液,过滤混合物。用乙酸乙酯萃取滤液,干燥(MgSO4),蒸发溶剂。残留物进行硅胶层析(甲苯∶三乙胺,9∶1)。将此游离胺溶于乙醚,加入含氯化氢的乙醚,制得一油状物。此油状物在2-丙醇中结晶,制得0.90g(79%)产品;熔点153-155℃;1H NMR(CD3OD)δ1.78(m,2H),2.22(m,4H),2.48(m,2H),2.72(s,3H),2.95(br,2H),3.68(m,1H),4.44(t,1H),6.78(t,1H),6.79(d,1H),7.03(t,1H),7.12(d,1H),7.18(t,1H),7.28(t,2H),7.34(d,2H);分析(C20H25NO*1.0HCl*0.32-丙醇)C,H,N.
起始化合物N-环丁基-N-甲基-3-(2-苄氧基-5-溴苯基)-3-苯基丙胺的制备如下:
31.1 N-环丁基-3-(2-苄氧基-5-溴苯基)-3-苯基丙胺
将5M HCl-甲醇(3.50mL,17.71mmol)加至环丁胺(4.50mL,53.15mmol)的甲醇(14mL)溶液中。将此混合物加入至3-(2-苄氧基-5-溴苯基)-3-苯基丙醛中(实施例20.1)(3.50g,8.86mmol),再加入氰基硼氢化钠(0.389g,6.20mmol)。使此反应混合物在室温下搅拌过夜。蒸发溶剂,残留物进行硅胶层析(甲苯∶乙酸乙酯∶三乙胺,92∶4∶4)。产量2.61g(65%);1H NNR(CDCl3)δ1.57(m,5H),2.14(m,4H),2.47(t,2H),3.16(m,1H),4.45(t,1H),5.00(s,2H),6.75(d,1H),7.10-7.47(m,12H).
31.2 N-环丁基-N-甲基-3-(2-苄氧基-5-溴苯基)-3-苯基丙胺
将5M HCl-甲醇(0.46mL,2.32mmol)、甲醛(0.870g,28.97mmol)与氰基硼氢化钠(0.255g,4.056mmol)加至N-环丁基-3-(2-苄氧基-5-溴苯基)-3-苯基丙胺(2.61g,5.79mmol)的甲醇(8mL)溶液中。此反应混合物在室温下搅拌过夜。蒸发溶剂,残留物进行硅胶层析(己烷∶三乙胺,9∶1)。产量1.59g(59%);1H NMR(CDCl3)δ1.59(m,2H),1.73(m,2H),1.91(m,2H),2.06(s,3H),2.16(m,4H),2.68(m,1H),4.38(t,1H),5.00(s,2H),6.72(d,1H),7.12-7.58(m,12H).
实施例32
N-环戊基-N-甲基-3-(2-羟基苯基)-3-苯基丙胺盐酸盐
如实施例31所述,处理N-环戊基-N-甲基-3-(2-苄氧基-5-溴苯基)-3-苯基丙胺(2.46g,5.14mmol)。粗产物不进行层析,用乙醇/水结晶。产量1.24g(70%),
1H NMR(DMSO)δ1.48(br,1H),1.66(br,2H),1.85(br,1H),2.46(br,2H),2.68(s,3H),2.87(br,2H),3.53(m,1H),4.35(t,1H),6.77(t,1H),6.83(d,1H),7.01(t,1H),7.16(t,1H),7.27(t,3H),7.33(d,2H),9.57(br,1H),10.85(br,1H);
熔点169-172℃;分析(C21H27NO*HCl)C,H,N。
起始化合物N-环戊基-N-甲基-3-(2-苄氧基-5-溴苯基)-3-苯基丙胺的制备如下:
如实施例31.1所述,使3-(2-苄氧基-5-溴苯基)-3-苯基丙胺(其制备如实施例20.1所述)(7.00g,17.71mmol)与环戊胺反应。产量4.9g(59%);1H NMR(CDCl3)δ1.20(m,2H),1.40-1.80(m,6H),2.18(m,2H),2.55(t,2H),2.98(m,1H),4.45(t,1H),5.00(s,2H),6.75(d,1H),7.10-7.45(m,12H).
32.2 N-环戊基-N-甲基-3-(2-苄氧基-5-溴苯基)-3-苯基丙胺
如实施例31.2所述,处理N-环戊基-3-(2-苄氧基-5-溴苯基)-3-苯基丙胺(3.50g,7.53mmol)的溶液。产量2.46g(68%);
1H NMR(CDCl3)δ1.10-1.80(m,8H),2.19(m,5H),2.36(m,2H),2.58(m,1H),4.37(t,1H),4.98(s,2H),6.72(d,1H),7.10-7.50(m,12H).
实施例33
N,N-二异丙基-3-(2-氨基苯基)-3-苯基丙胺盐酸盐
将LAH(0.94g,24.8mmol)加入N,N-二异丙基-3-(2-氨基苯基)-3-苯基丙胺(1.6g,4.98mmol)的THF(90mL)溶液中。使此混合物于室温搅拌72小时。骤止反应,蒸发溶剂。粗制残留物在反相PEP RPC HR30/26制备柱(Pharmacia Biotech AB,Sweden)上纯化,使用含1%TFA的20%乙腈洗脱。将盐酸加入纯的馏出液中,蒸发溶剂。残留物再次溶于水,冷冻干燥而得88mg(5%)产品;熔点:138-142℃;
1H NMR(DMSO)δ1.25(m,12H),2.47(m,1H),2.65(m,1H),2.87(m,1H),3.13,(m,1H),3.59(br,2H),4.58(t,1H),7.20-7.37(m,5H),7.42(m,2H),7.54(d,2H),9.94(br,2H).
分析C21H30N2·HCl·H2O)C,H,H:计算值:8.5;实测值:7.9。
起始化合物N,N-二异丙基-3-(2-氨基苯基)-3-苯基丙胺的制备如下:
33.1 2-(3,5-二甲基-4-羟基苯基偶氮基二苯甲酮
在搅拌条件下,将冰(500mL)、盐酸(16.8mL,202mmol,浓)、2-氨基二苯甲酮(20.00g,101mmol)和NaNO2(9.0g,131mmol)的淤浆加至2,6-二甲基苯酚(18.40g,151mmol)和氢氧化钠(16.20g,404mmol)的冰水(100mL)溶液中。20分钟后,用乙醚萃取此混合物。用盐酸(6M)、NaHCO3(水溶液)洗涤有机相、干燥(MgSO4)后蒸发溶剂。粗制残留物进行硅胶层析(甲苯),合并纯洗脱液,蒸发而得红色油状物。此油状物用己烷/甲苯结晶,制得7.73g(23%)产品。
33.2 2-(3,5-二甲基-4-甲苯磺酰氧基苯基偶氮基)二苯甲酮
将2-(3,5-二甲基-4-羟基苯基偶氮基)二苯甲酮(7.73g,23.41mmol)和甲苯磺酰氯(9.4g,49mmol)在吡啶(20mL)中的混合物,于90℃搅拌9小时。加水并用乙醚萃取此混合物。用氢氧化钠(2M)和盐酸(2M)洗涤有机相,干燥(MgSO4),蒸发溶剂。产物在乙醇中结晶,得到7.6g(67%)产品。1H NMR(CDCl3)δ2.08(s,6H),2.49(s,3H),7.05(s,2H),7.37(m,4H),7.48(m,1H),7.62(m,3H),7.82(m,5H).
33.3 N,N-二异丙基-3-〔2-(3,5-二甲基-4-甲苯磺酰氧基苯基-偶氮基)苯基〕-3-苯基丙烯酰胺
如实施例4.2所述,处理2-(3,5-二甲基-4-甲苯磺酰氧基苯基偶氮基)二苯甲酮(7.22g,14.9mmol),但其是与3当量的N,N-二异丙基乙酰胺膦酸二乙酯及氢化钠反应。产量4.5g(50%)。1H NMR(CDCl3)δ0.72(d,3H),0.82(br,3H),1.28(d,3H),1.42(d,3H),2.10(s,3H),2.14(s,3H),2.45(s,3H),3.25(m,1H),4.28(m,1H),6.05 and 6.63(s,1H),7.00-7.90(m,15H).
33.4 N,N-二异丙基-3-〔2-(3,5-二甲基-4-羟基苯基-偶氮基)苯基〕-3-苯基丙烯酰胺
将氢氧化钾(10.3mL,6M)和N,N-二异丙基-3-〔2-(3,5-二甲基-4-甲苯磺酰氧基苯基-偶氮基)苯基〕-3-苯基丙烯酰胺(3.5g,5.74mmol)在乙醇(110mL)中的溶液回流1小时。用盐酸(浓)酸化此混合物,蒸发溶剂。使残留物在甲苯与水之间分配。干燥有机层(MgSO4),蒸发溶剂。粗制残留物进行硅胶层析(甲苯∶乙酸乙酯,9∶2)。产量1.3g(50%)。1H NMR(CDCl3)δ0.71(d,3H),0.80(br,3H),1.27(d,3H),1.40(d,3H),2.20(s,3H),2.23(s,3H),3.25(m,1H),4.35(m,1H),5.52(brd,1H),6.05 and 6.60(s,1H),7.00-7.80(m,11H).
33.5 N,N-二异丙基-3-(2-氨基苯基)-3-苯基丙烯酰胺
如实施例28.3所述,处理N,N-二异丙基-3-〔2-(3,5-二甲基-4-羟基苯基-偶氮基)苯基〕-3-苯基丙烯酰胺(2.58g,5.68mmol)。粗制残留物自乙醇水溶液制得结晶。产量1.23g(67%)。
实施例34
N,N-二异丙基-3-(苯并噁唑-2-基)-3-苯基丙胺盐酸盐
将N,N-二异丙基-3-乙氧羰基-3-苯基丙胺(2.51g,8.6mmol)、75%乙醇水溶液(15mL)与2M NaOH(8.5mL,17mmol)的混合物回流一夜。蒸发溶剂后,用2M HCl酸化残留物,蒸发溶剂。氮气氛下,使残留的半结晶油状物混合物与邻氨基苯酚(1.8g,16.5mmol)及多磷酸(12g)一起在200℃加热2小时。将稍冷却的硬固体溶于水,用乙醚洗涤一次。碱化水相(11M NaOH),用乙醚萃取两次。干燥合并的有机相(Na2SO4),蒸发溶剂。粗产物进行硅胶层析(石油醚/三乙胺,97∶3)。自乙醚沉淀出纯胺盐酸盐,白色结晶,1.27g(39%);熔点197-198℃;
1H NMR(CDCl3)δ1.49(m,12H),2.80-3.20(m,4H),3.48(br,2H),4.45(t,1H),7.25-7.48(m,8H),7.70(m,1H),11.48(br,1H).
起始化合物N,N-二异丙基-3-乙氧羰基-3-苯基丙胺的制备如下:
34.1 N,N-二异丙基-3-氰基-3-苯基丙胺
用石油醚洗涤氢化钠(2.82g,94mmol)的80%矿物油分散液,并在氮气流中干燥。加入无水DMF(100mL)。于20分钟内,将苄基氰(12.1g,103mmol)加至搅拌的悬浮液中。使温度升高至大约45℃。再搅拌混合物15分钟。加入2-氯乙基-二异丙胺(15.4g,94mmol)。此胺在30分钟内全部耗尽。减压下,蒸发大部份的DMF,残留物溶于水/乙醚中。用乙醚萃取水相一次,用2M HCl蒸取合并的有机相两次。碱化合并的水相(11M NaOH),用乙醚萃取两次。然后干燥合并的有机相(Na2SO4),蒸发溶剂。粗产物进行硅胶层析(石油醚∶三乙胺,40∶1),制得标题化合物,16.8g(67%),为无色液体。1H NMR(CDCl3)δ1.01(m,12H),1.97(m,2H),2.62(m,2H),3.00(m,2H),4.02(dd,1H),7.17-7.40(m,5H).
34.2 N,N-二异丙基-3-氨基甲酰基-3-苯基丙胺
将N,N-二异丙基-3-氰基-3-苯基丙胺(11.6g,47.5mmol)与H2SO4(90%,100mL)混合,此混合物于100℃下搅拌30分钟。将反应混合物倒入冰中,碱化(11M NaOH),用乙醚萃取两次。干燥合并的有机相(Na2SO4),之后蒸发溶剂,制得无色油状的标题化合物,12.4g(100%);1H NMR(CDCl3)δ1.26(m,12H),2.14(m,1H),2.60(m,1H),2.73(t,2H),3.31(m,2H),3.86(t,1H),6.06(br,2H),7.51-7.61(m,5H).
34.3 N,N-二异丙基-3-乙氧羰基-3-苯基丙胺
将N,N-二异丙基-3-氨基甲酰基-3-苯基丙胺(26.5g,0.100mol)加入含有浓HNO3(13.3g,0.21mol)的乙醇水溶液(90%,300mL)中,回流五天。减压蒸发大部份的溶剂,残留物与水/乙醚混合。水洗有机相一次。碱化(11M NaOH)合并的水相,用乙醚萃取两次。然后干燥有机相(Na2SO4),蒸发溶剂。粗产物进行硅胶层析(石油醚∶三乙胺,97∶3),制得无色液体的标题化合物,20.1g(68.7%);
1H NMR(CDCl3)δ0.96(m,12H),1.21(t,3H),1.81(m,1H),2.22(m,1H),2.40(t,2H),3.66(dd,1H),4.12(m,2H),7.20-7.32(m,5H).
实施例35
N,N-二异丙基-3-(噁唑-5-基)-3-苯基丙胺盐酸盐
氮气氛下,将刚蒸馏过的甲胩(1.66g,40.4mmol)溶于无水THF(75mL)中,使该混合物冷却至-78℃。将1.4M正丁基锂(29mL,40.5mmol)慢慢加入该溶液中,再加入N,N-二异丙基-3-乙氧羰基-3-苯基丙胺(4.71g,16.2mmol)的THF(10mL)溶液。使反应温度升高至-20℃,并在此温度下用HOAc(10mL)骤止反应。蒸发溶剂,残留物与乙醚/水混合。水洗有机相一次,用11M NaOH碱化合并的水相,用乙醚萃取两次。合并有机相,干燥(Na2SO4),蒸发溶剂。粗产物进行硅胶层析(氯仿∶甲醇∶浓氨水,490∶10∶1)。用HCl饱和的乙醚沉淀纯胺,制得标题化合物,为似玻璃的油状物,1.4g(48%)。1H NMR(CD3OD)δ1.21-1.40(m,12H),2.57(m,1H),2.68(m,1H),2.91(m,1H),3.23(m,1H),3.72(m,2H),4.41(dd,1H),7.39(m,5H),7.52(s,1H),9.13(s,1H).
实施例36
N,N-二异丙基-3-(咪唑-4(5)-基)-3-苯基丙胺二盐酸盐
将N,N-二异丙基-3-噁唑-5-基-3-苯基丙酰胺(0.76g,2.6mmol)与甲酰胺(5mL)混合。将混合物加热至175℃,反应6小时。真空(1mmHg)蒸发溶剂,残留物在1M HCl与乙醚之间分配。碱化水相(11M NaOH),用乙醚萃取两次。干燥合并的有机相(Na2SO4),蒸发溶剂。将淡棕色油状物溶于乙醚,再添加至氢化锂铝(LAH)(0.70g,5.4mmol)的乙醚悬浮液中。反应混合物于室温下搅拌过夜。骤止反应,蒸发溶剂。将粗制胺溶于乙酸乙酯,用HCl饱和的乙醚沉淀出盐酸盐,制得吸湿性结晶的标题化合物,0.32g(35%);1H NMR(CDCl3)δ1.38(m,12H),2.80(m,2H),3.00(m,1H),3.16(m,1H),3.64(br,2H),4.41(m,1H),6.89(s,1H),7.27-7.41(m,5H),8.78(s,1H),10.32(br,2H).
起始化合物N,N-二异丙基-3-噁唑-5-基-3-苯基丙酰胺(0.76g,2.6mmol)的制备如下:
36.1 3-氰基-3-苯基丙酸
将肉桂酸乙酯(85.3g,0.484mol)、氰化钾(64.2g,0.986mol)和氯化铵(38.9g,0.726mol)与DMF水溶液(90%,360mL)混合。混合物于105℃下搅拌7小时。过滤稍微冷却的混合物,蒸发大部份的DMF。残留物溶于乙醚和1M HCl中。用乙醚萃取水相两次。蒸发合并的乙醚相,将黑色油状物悬浮于乙醇(200mL)和2M NaOH(250mL)中,室温搅拌2小时。用盐水(200mL)和水(400mL)稀释该混合物,用乙醚洗涤两次。酸化后(2M HCl),用乙醚萃取水相三次。干燥有机相(MgSO4),蒸发溶剂而得标题化合物,其为黑色油状物,74g(87%);
1H NMR(CDCl3)δ1.05(d,3H),1.17(d,3H),1.22(d,6H),2.68(dd,1H),3.16(dd,1H),3.4(br,1H),3.76(m,1H)4.19(dd,1H),7.31(m,5H),8.9(br,1H).
36.2 N,N-二异丙基-3-氰基-3-苯基丙酰胺
将3-氰基-3-苯基丙酸(67.7g,0.389mol)溶于2-PrOH中。将溶于2-PrOH(200mL)的KOH(18.4g,0.33mol)小心加入经过滤的上述酸溶液中,再加入乙醚(100mL),滤出沉淀物。将干燥后的酸的盐(51.9g,0.24mol)悬浮于苯(400mL)中,小心加入草酰氯。使反应混合物于80℃搅拌2小时。蒸发溶剂,残留物与苯共蒸发两次。将棕色油溶于苯(200mL)中,于冰浴中冷却。在搅拌条件下,将二异丙胺(82g,0.81mol)于苯(200mL)中的溶液,于45分钟内加入该反应混合物。使此混合物缓慢加温至室温,反应过夜。蒸发溶剂,残留物溶于乙醚和1M HCl中。依次用水、1M NaOH、水洗涤有机相,然后干燥(Na2SO4),蒸发溶剂而得标题化合物,其为深棕色油状物,41.7g(41%);
1H NMR(CDCl3)δ1.07(d,3H),1.17(d,3H),1.36(m,6H),2.77(m,1H),2.97(m,1H),3,51(br,1H),3.81(m,1H),4.50(dd,1H),7.39(m,5H).
36.3 N,N-二异丙基-3-氨基甲酰基-3-苯基丙酰基胺
将N,N-二异丙基-3-氰基-3-苯基丙酰胺(21.1g,82mmol)溶于乙醇(130mL)和2M NaOH(100mL)中。加入过氧化氢(30%,20.2mL,200mmol),室温搅拌此混合物2小时。过滤所生成的沉淀物,水洗,干燥,得到白色结晶的标题化合物,15.6g(69%):
1H NMR(CDCl3)δ1.09(d,3H),1.19(d,3H),1.31(m,6H),2.51(dd,1H),3.30(dd,1H),3.41(m,1H),4.02(m,1H),4.18(dd,1H),5.7(br,1H),6.4(br,1H),7.21-7.42(m,5H).
36.4 N,N-二异丙基-3-乙氧羰基-3-苯基丙酰胺
如实施例34.3所述,处理N,N-二异丙基-3-氨基甲酰基-3-苯基丙酰胺(回流两天,未层析),制得标题化合物,其为无色半结晶油状物,15.9g(93%);1H NMR(CDCl3)δ1.19(m,9H),1.36(m,6H),2.53(dd,1H),3.18(dd,1H),3.4(br,1H),3.98(m,1H),4.15(m,3H),7.31(m,5H).
36.5 N,N-二异丙基-3-噁唑-5-基-3-苯基丙酰胺
采用上述实施例35所述方法,由N,N-二异丙基-3-乙氧羰基-3-苯基丙酰胺开始。粗产物在硅胶上层析(石油醚∶乙酸乙酯,3∶2),制得标题化合物,其为淡黄色油状物,0.77g(46%);
1H NMR(CDCl3)δ1.00(d,3H),1.14(d,3H),1.29(m,6H),2.98(m,2H),3.4(br,1H),3,93(m,1H),4.79(t,1H),6.82(s,1H),7.28(m,5H),7.76(s,1H).
实施例37
N,N-二异丙基-3-(噁唑-2-基)-3-苯基丙胺盐酸盐
将实施例34.2制备的N,N-二异丙基-3-氨基甲酰基-3-苯基丙胺(4.05g,15.4mmol),1,2-二氯乙基:乙基醚(2.32g,16.2mmol),水(0.300g,16.6mmol)和甲酸(50mL)组成的混合物在75℃下搅拌3小时。蒸去甲酸,将残留物溶于水/乙醚中。碱化水相(11M NaOH),用乙醚萃取两次。干燥有机相(Na2SO4),蒸发溶剂。粗产物在硅胶上层析(石油醚∶三乙胺,97∶3)。此纯胺用HCl饱和的乙醚沉淀得到盐酸盐,制得标题化合物,其为白色结晶,0.61g(12%):熔点157-158℃;
1H NMR(DMSO(d6))δ1.11(m,12H),2.35(m,1H),2.63(m,1H),3.03(m,2H),3.56(m,2H),4.45(m,1H),7.21-7.40(m,6H)8.06(d,1H),10.20(br,1H).
实施例38
N,N-二异丙基-3-苯基-3-(噻唑-2-基)丙胺盐酸盐
以实施例37所述的类似方法制备标题化合物。由N,N-二异丙基-3-苯基-3-硫代氨基甲酰基丙胺(1.11g,4.0mmol)制得白色结晶的标题化合物,1.12g(82%):熔点155-156℃;
1H NMR(CDCl3)δ1.37(m,12H),2.75-3.15(m,4H),3.60(m,2H),4.45(t,1H),7.25-7.36(m,6H),7.71(d,1H),11.30(br,1H).
起始化合物N,N-二异丙基-3-苯基-3-硫代氨基甲酰基丙胺的制备如下:
38.1 N,N-二异丙基-3-苯基-3-硫代氨基甲酰基丙胺
向实施例34.1制备的N,N-二异丙基-3-氰基-3-苯基丙胺(3.45g,14.3mmol)和三乙胺(2.0g,20mmol)在无水吡啶(10mL)中所组成的溶液中,通入H2S气体直到饱和。在于H2S气氛及65℃下搅拌5天。蒸发吡啶,粗产物在硅胶上层析(氯仿∶甲醇∶浓氨水,380∶20∶1),制得标题化合物,其为无色玻璃状油,3.1g(78%):
1H NMR(CDCl3)δ0.99(m,12H),2.07(m,1H),2.40(m,3H),3.05(m,2H),4.10(t,1H),7.20-7.45(m 5H),7.7-8.1(b,1H),8.0-8.5(br,1H).
实施例39
N,N-二异丙基-3-(4-甲基噻唑-2-基)-3-苯基丙胺盐酸盐
以实施例37所述的类似方法制备标题化合物。由实施例38.1制备的N,N-二异丙基-3-苯基-3-硫代氨基甲酰基丙胺(1.5g,5.4mmol)与2-氯丙酮(0.75g,8.1mmol)制得标题化合物,其为白色无定形物质,1.1g(56%):熔点178-181℃;1H NMR(CDCl3)δ1.44(m,12H),2.50(s,3H),2.98(m,3H),3.18(m,1H),3.60(m,2H),6.94(d,1H),7.30-7.47(m,5H),11.15(br,1H).
实施例40
N,N-二异丙基-3-(噻唑-5-基)-3-苯基丙胺盐酸盐
以实施例35所述的类似方法制备标题化合物。与N,N-二异丙基氨基-3-乙氧硫代羰基-3-苯基丙胺(1.14g,3.7mmol)反应制得粗产物,在硅胶上层析(石油醚∶三乙胺,97∶3),制得白色结晶的标题化合物,0.19g(30%);熔点193-194℃;
1H NMR(CDCl3)δ1.1.34(m,12H),2.85(m,4H),5.56(m,2H),4.29(t,1H),7.26-7.39(m,5H),7.73(s,1H),8.71(s,1H)11.61(br,1H).
起始化合物N,N-二异丙氨基-3-乙氧硫代羰基-3-苯基丙胺的制备如下:
40.1 N,N-二异丙基-3-乙氧硫代羰基-3-苯基丙胺
向实施例34.1制备的N,N-二异丙基-3-氰基-3-苯基丙胺(2.9g,12mmol)在无水乙醇(50mL,分子筛3)的冰冷溶液中,通入HCl气体直至饱和。在HCl气氛及室温下搅拌反应过夜。小心蒸发溶剂,残留油状物溶于无水吡啶(100mL)中。向此溶液中加入三乙胺(5.7g,56mmol),向所产生的深色悬浮液中通入H2S气体直至饱和。使颜色为暗橄榄绿的反应混合物在H2S气氛及65℃下静置过夜。蒸发溶剂,残留物在1M HCl与乙醚之间分配,碱化水相(11M NaOH),用乙醚萃取两次。干燥有机相(Na2SO4),蒸发溶剂。粗产物在硅胶上层析(氯仿∶甲醇∶浓氨水,198∶1∶1),制得标题化合物,其为淡黄色液体,1.24g(33%):1H NMR(CDCl3)δ0.95(m,12H),1.34(t,2H),1.97(m,1H),2.37(m,3H),2.98(m,2H),4.10(t,1H)4.46(m,2H),7.13-7.39(m,5H).
实施例41
N,N-二异丙基-3-(2-羟基苯基)-3-(2-噻吩基)-丙胺富马酸盐
向氢化锂铝(LAH)(0.51g,13.3mmol)于THF(30mL)中所形成的悬浮液中,加入N,N-二异丙基-3-(2-羟基苯基)-3-(2-噻吩基)丙酰胺(2.0g,5.33mmol),加热至50℃,过夜。骤止反应混合物,蒸发溶剂。残留物溶于乙醚中,用2M HCl萃取两次,并用乙醚洗涤合并的水相两次。碱化水相(11M NaOH),用乙醚萃取三次,用盐水洗涤合并的有机相一次,干燥(MgSO4),蒸发溶剂。自甲醇中结晶其富马酸盐,制得白色结晶的标题化合物,1.52g(58%):熔点203-205℃;
1H NMR(DMSO)δ1.00(d,12H),2.02(q,2H),2.33(m,2H),3.18(m 2H),4,62(t,1H),6.50(s,1H),6.68-7.18(m,6H),7.28(t,1H).
起始化合物N,N-二异丙基-3-(2-羟基苯基-3-(2-噻吩基)丙酰胺的制备如下:
41.1 N,N-二异丙基-3-(2-噻吩基)丙烯酰胺
氮气氛下,混合2-溴噻吩(2.28g,14.0mmol)、N,N-二异丙基丙烯酰胺(1.55g,10.0mmol)、醋酸钯(II)(34mg,0.15mmol)、三-邻-甲苯基膦(183mg,0.6mmol)、三-正丁胺(2.04g,11.0mmol)和无水DMF(5mL)。加热此混合物至130℃,反应9小时。将乙醚与水加入稍微冷却后的混合物中。用乙醚萃取水相两次。合并的有机相用2M HCl洗涤两次,水洗一次,再用盐水洗涤,干燥(MgSO4),蒸发溶剂。粗产物在硅胶上层析(石油醚∶乙酸乙酯,4∶1),制得黄色油状物,1.58g(66%):1H NNR(CDCl3)δ1.35(br,12H),3.9(br,1H),4.1(br 1H),6.65(d,1H),7.00-7.30(m,3H),7.72(d,1H).
41.2 2-甲氧基苯基锂
将2-甲氧基溴苯(8.44g,45.1mmol)溶于无水乙醚(15mL)中。使此混合物冷却至-78℃。加入正丁基锂(17.8mL,45.0mmol),于-78℃搅拌此混合物一小时,再于-10℃搅拌20分钟。此芳基锂溶液要立即使用。
41.3 N,N-二异丙基-3-(2-甲氧基苯基)-3-(2-噻吩基)丙胺
将溴化铜(I)-二甲硫醚复合物(4.63g,22.5mmol)溶于二甲硫醚(18mL)和乙醚(15mL)中。溶液冷却至0℃,随后加入2-甲氧基苯基锂(实施例41.2)(45mmol)。10分钟后,温度降至-78℃。加入三甲基甲硅烷基氯(4.89g,45.0mmol),再加入N,N-二异丙基-3-(2-噻吩基)丙烯酰胺(实施例41.1)(3.56g,15mmol)的乙醚(20mL)溶液。使温度缓慢升高至室温,过夜。用饱和NH4Cl(10mL)与浓氨水(10mL)骤止反应。加入乙醚(80mL),用硅藻土过滤混合物。用乙醚萃取水相两次。合并的有机相用盐水洗涤一次,干燥(MgSO4)。蒸发溶剂,粗产物在硅胶上层析(石油醚∶乙酸乙酯,3∶1),制得黄色油状物,3.75g(73%):
1H NMR(CDCl3)d1.12(t,6H),1.29(t,6H),3.02(m,2H),3.4(br,1H),3.80(s,3H),4.03(m,1H),5.26(t,1H),6.8-7.3(m,7H).
41.4 N,N-二异丙基-3-(2-羟基苯基)-3-(2-噻吩基)丙酰胺
将N,N-二异丙基-3-(2-甲氧基苯基)-3-(2-噻吩基)丙酰胺(2.37g,6.9mmol)于二氯甲烷(35mL)中的溶液冷却至-78℃,加入三溴化硼(5.9g,23.57mmol)。反应混合物缓慢加热至室温。通过缓慢添加水(20mL)骤止反应。用NaHCO3(固体)将pH调节至约为6,用CH2Cl2萃取此混合物三次。用盐水洗涤合并的有机相一次,干燥(MgSO4)后蒸发溶剂。直接使用此粗产物(2.46g,107%),无需进一步纯化。
1H NMR(CDCl3)δ1.05(d,3H),1.20(m,6H),1.35(d,3H),3.16(m,2H),3.4(br,1H),4.0(m,1H),5.24(dd.1H),6.7-7.2(m,7H).
实施例42-54以及57与58是以实施例41所述方法制备的,其是由适合的丙烯酰胺与芳基溴化物作为起始原料的。
实施例42
N,N-二异丙基-3-(2,4-二羟基苯基)-3-(2-噻吩基)丙胺
粗产物用石油醚/乙酸乙酯结晶而得标题化合物,0.41g,为淡粉红色结晶:熔点102-109℃,1H NMR(CDCl3)δ1.11(m,12H),2.01(m,1H),2.41(m,2H),2.72(m,1H),3.26(m,2H),4.66(dd,1H),6.30(dd,1H),6.45(d,1H),6.73(d,1H),6.91-7.00(m,2H),7.17(dd,1H).
实施例43
N,N-二异丙基氨基-3-(2-甲氧基苯基)-3-(2-噻吩基)丙胺富马酸盐
白色结晶,0.95g:熔点153-155℃;1H NMR(CD3OD)δ1.28(m,12H),2.48(m,2H),3.05(m,2H),3.68(m,2H),3.85(s,3H),4.71(t,1H),6.68(s,2H),6.89-7.03(m,4H),7.20-7.30(m,3H).
实施例44
N,N-二异丙基-3-(2,4-二甲氧基苯基)-3-(2-噻吩基)丙胺富马酸盐
白色结晶,1.52g:熔点103-109℃;1H NMR(CD3OD)δ1.28(m,12H),2.46(m,2H),3.04(m,2H),3.66(m,2H),3.77(s,3H),3.82(s,3H),4.60(t,1H),6.46-6.58(m,2H),6.68(s,2H),6.91-6.97(m,2H),7.09-7.26(m,2H).
实施例45
N,N-二异丙基-3-(3-甲氧基苯基)-3-(2-噻吩基)丙胺盐酸盐
白色结晶,1.16g;熔点95-97℃;1H NMR(CD3OD)δ1.28(d,12H),2.49(m,2H),2.96(m,1H),3.13(m,1H),3.68(m,2H),3.77(s,3H),4.31(t,1H),6.83(m,1H),6.68-7.02(m,4H),7.27(m,2H).
实施例46
N,N-二异丙基-3-(4-甲氧基苯基)-3-(2-噻吩基)-丙胺盐酸盐白色无定形物质,0.50g;熔点157-160℃;1HNMR(CD3OD)δ1.31(m,12H),2.47(m,2H),2.94(m,1H),3.12(m,1H);3.68(br,2H),3.77(s,3H),4.28(t,1H),6.87-7.00(m,4H),7.23-7.32(m,3H).
实施例47
N-异丙基-N-甲基-3-(2-甲氧基苯基)-3-(2-噻吩基)丙胺富马酸盐
白色结晶,1.32g;熔点141-143℃;1H NMR(CD3OD)δ1.24(m,6H),2.50(m,2H),2.73(s,3H),3.04(m,2H),3.58(m,1H),3.84(s,3H),4.73(t,1H),6.68(s,2H),6.96(m,4H),7.24(m,3H).
实施例48
N,N-二异丙基-3-苯基-3-(2-噻吩基)丙胺盐酸盐
白色结晶,0.74g;熔点165-166℃;1H NMR(CD3OD)1.28(d,12H),2.52(m,2H),2.96(m,1H),3.13(m,1H),3.70(br,2H),4.34(t,2H),6.92-7.04(m,2H),7.20-7.42(m,6H).
实施例49
N-环己基-N-甲基-3-苯基-3-(2-噻吩基)丙胺盐酸盐
白色结晶,1.1g;熔点197-199℃;1H NMR(CD3OD)1.15-1.52(br,5H),1.68(br,1H),1.90(br,4H),2.51(br,2H),2.78(s,3H),2.91-3.40(m,3H),4.31(t,1H),6.92-7.04(m,2H),7.20-7.40(m,6H).
实施例50
N,N-二乙基-3-苯基-3-(2-噻吩基)丙胺富马酸盐
白色结晶,1.7g(总收率49%);熔点1 35-137℃;1HNMR(CD3OD)δ1.22(t,3H),2.50(m,2H),2.90-3.26(m,6H),4.30(t,1H),6.68(s,2H),6.92-7.03(m,2H),7.20-7.40(m,6H).
实施例51
N-异丙基-N-甲基-3-苯基-3-(2-噻吩基)丙胺盐酸盐
白色结晶,1.6g;熔点139-144℃;1H NMR(CD3OD)δ1.24(m,6H),2.52(m,2H),2.75(s,3H),3.03(m,2H),3.59(m,1H),4.32(t,1H),6.92-7.04(m,2H),7.20-7.40(m,6H).
实施例52
N-〔3-苯基-3-(2-噻吩基)丙基〕吡咯烷富马酸盐
用2-丙醇结晶,1.1g;熔点144-145℃;
1H NMR(CD3OD)δ2.02(m,4H)2.31(m,2H),2.97-3.42(m,6H),4.29(t,1H),6.69(s,2H),6.91-7.01(m,2H),7.18-7.38(m,6H).
实施例53
N-〔3-苯基-3-(2-噻吩基)丙基〕哌啶盐酸盐
此盐酸盐用乙基甲基酮结晶制得,0.84g;熔点193-194℃;
1H NMR(CD3OD)δ1.40-2.00(b,6H),2.54(m,2H),2.82-3.80(m,6H),4.29(t,1H),6.91-7.03(m,2H),7.20-7.42(m,6H).
实施例54
N,N-二异丙基-3-(2-羟基-5-甲基苯基)-3-(2-噻吩基)丙胺盐酸盐
白色结晶,2.1g;熔点205-210℃;1H NMR(CDCl3)δ1.36(m,12H),2.18(s,3H),2.63(m,2H),2.95(m,2H),3.54(m,4H),4.61(t,1H),6.76-7.01(m,5H),7.16(d,1H).
实施例55
(R*)N,N-二异丙基-3-(2-羟基-5-甲基苯基)-3-(2-噻吩基)丙胺
向N,N-二异丙基-3-(2-羟基-5-甲基苯基)-2-噻吩基丙胺(20g,0.06mol,实施例54制备)的外消旋游离碱在无水乙醇(50g)的溶液中,加入L-(+)-酒石酸(9.5g,0.063mol)的乙醇(60g)溶液。滤出所形成的盐,用乙醇/甲醇(10/1)结晶两次,每克结晶使用10毫升,制得白色结晶的标题化合物(6.8g,14.1mmol):熔点214-215℃;〔α〕Hg=+17.3°(c=3.82,甲醇)。
实施例56
(S*)N,N-二异丙基-3-(2-羟基-5-甲基苯基)-3-(2-噻吩基)丙胺
自第一次结晶所得的母液中回收游离碱,该晶析反应是为了获得实施例55的(R*)N,N-二异丙基-3-(2-羟基-5-甲基苯基)-3-(2-噻吩基)丙胺。如上所述,此胺用过量5%的D-(-)-酒石酸的乙醇溶液处理,制得白色结晶的标题化合物,6.1g(12.7mmol);熔点214℃;〔α〕Hg=-17.5°(c=3.85,甲醇)。
实施例57
N,N-二异丙基-3-苯基-3-(3-噻吩基)丙胺盐酸盐
白色结晶,0.94g;熔点141-142℃;1H NMR(CDCl3)δ1.42(m,12H),2.87(m,4H),3.56(br,2H),3.98(t,1H),6.94(dd,1H),7.27(m,7H),11.4(br,1H).
起始化合物的制备如下:
57.1 N,N-二异丙基-3-(3-噻吩基)丙烯酰胺
用石油醚洗涤氢化钠的60%矿物油分散液(3.9g,98mmol)数次,氮气流下干燥。加入经钠处理的无水THF,再加入N,N-二异丙基乙酰胺膦酸二乙酯(27.4g,98mmol)。停止析出气体时,以不使温度超过45℃的速度加入噻吩-3-甲醛(10.0g,89.2mmol)的THF(50mL)溶液。室温搅拌1小时后,用4mL水骤止反应,再搅拌1小时。蒸发溶剂,残余物溶于乙醚/2M NaOH中。有机相用水洗涤一次,并用盐水洗涤一次,干燥(Na2SO4),之后蒸发。粗产物在硅胶上层析(石油醚∶乙酸乙酯,4∶1),制得标题化合物,其为淡棕色油状物,14.8g(70%):1H NMR(CDCl3)δ1.37(b,12H),3.86(br,1H),4.10(br,1H),6.68(d,1H),7.27-7.41(m,3H),7.59(d,1H).
实施例58
N,N-二异丙基-3-(2-呋喃基)-3-苯基丙胺盐酸盐
白色结晶,60mg;熔点139-141℃;1H NMR(CDCl3)δ1.41(br,12H),2.64(m,1H),2.85(m,3H),3.55(m,2H),3.98(t,1H),6.16(d,1H),6.31(dd,1H),7.30(m,6H),11.4(br,1H).
起始化合物的制备如下:
58.1 N,N-二异丙基-3-(2-呋喃基)丙烯酰胺
按照实施例57.1所述方法,自糠醛制备标题化合物,其为无色油状物,11.2g(75%);
1H NMR(CDCl3)δ1.32(d,12H),4.0(br,2H),6.41(m,2H),6.76(d,1H),7.38(m,2H).
实施例59
N,N-二异丙基-3-(N-甲基吡咯-2-基)-3-苯基-丙胺富马酸盐
将N,N-二异丙基-3-(N-甲基-吡啶-2-基)-3-苯基-丙酰胺(4.92g,15.7mmol)于THF(75mL)中所形成的溶液,滴入LAH(2.38g,62.8mmol)的搅拌混合物中。于50℃继续搅拌过夜。用标准纯化方法制得黄色油状物,分离得到富马酸盐,2.74g(42%):熔点134-6℃;1H NMR(CD3OD)δ1.27(d,6H),1.29(d,6H),2.24(m,1H),2.48(m,1H),2.97(dt,1H),3.26(dt,1H),3,32(s,3H),3.69(七重峰,2H),4.08(t,1H),6.05(t,1H),6.16(m,1H),6.57(dd,1H),6.71(s,2H)and 7.19-7.34(m,5H).
起始化合物的制备如下:
59.1 N,N-二异丙基-3-(N-甲基吡咯-2-基)-丙烯酰胺
参照实施例4.2,由N-甲基-2-吡咯甲醛和N,N-二异丙基-二甲基膦酰基乙酰胺(N,N-diisopropyl-dimethyl phosphonacetamide)制备得到标题化合物,制得产物7.61g(92%):
1H NMR(CDCl3)δ1.32(d,6H),1.35(d,6H),3.68(s,3H),4.00(m,2H),6.13(t,1H),6.55-6.66(3H)和7,57(d,1H).
59.2 N,N-二异丙基-3-(N-甲基吡咯-2-基)-3-苯基-丙酰胺
以实施例41.3所述的类似方法,由N,N-二异丙基-3-(N-甲基吡咯-2-基)-丙烯酰胺制备得到标题化合物,制得4.92g(78%)产品:1HNMR(CDCl3)δ0.85-1.32(4d旋转异构体,12H),2.91(d,2H),3.31(s,3H) 3.45(m,1H),3.88(m,1H),4.65(t,1H),6.07(2H),6.50(dd,1H)and 7.15-7.22(5H).
实施例60
3-(N-甲基吡咯-2-基)-3-苯基-1-吡咯烷基丙烷富马酸盐
参照实施例59,使用N,N-四亚甲基-二甲基膦酰基乙酰胺制备标题化合物,制得950mg(36%,总产率)产品:熔点194-5℃;
1H NMR(CD3OD)δ1.27(d,12H),2.2-2.6(m,2H)3.05(m,2H),3.66(sept.,2H),4.03(t,1H),6.02(两个双峰,2H),6.64(t,1H),6.69(s,2H)和7.28(m,5H).
生物学评估
用活体外方法测试实施例制备的化合物的药学活性。
活体外功能的研究
以击颈的方式杀死重约300g的雄性豚鼠并放血。膀胱的平滑肌束在Krebs-Henseleit溶液(pH7.4)中被解离开。肌束样本纵向置于恒温(37℃)控制的器官浴(5ml)中的2个挂钩上。其中一个挂钩是可调整的,且与测力传感器(FTO3,Grass Instruments)连接。Krebs-Henseleit溶液中持续通入卡波金(93.5% O2/6.5%CO2),以维持pH为7.4。用Grass Polygraph(79D型)记录等长张力(isometrictension)。开始施加在每一个肌束上的静息张力约为5mN,使样本稳定至少45分钟。重复校正静息张力,稳定过程中洗涤样本数次。
用卡巴胆碱(氯化氨甲酰胆碱)作为标准的蕈毒碱受体激动剂。每批实验,通过两次连续添加次高浓度的卡巴胆碱(3×10-6M),首先测试样本的存活性及其收缩反应的再现性。通过累积添加卡巴胆碱至器官浴(即逐步增加激动剂浓度,直到最大收缩反应),随后洗涤,来得到卡巴扣的浓度-反应曲线图,添加固定浓度的测试化合物(拮抗剂)至器官浴的前有至少15分钟的休息期。与拮抗剂一起培养60分钟后,得到卡巴胆碱的第二累积浓度-反应曲线图。反应是用相对于卡巴胆碱最大反应的百分数来表示的。无拮抗剂(对照组)与有拮抗剂时,卡巴胆碱的Ec50值由图形导出并计算出剂量比值(r)。采用方程式(1)计算拮抗剂的解离常值KB(Schild,H.I.,Br.J.Pharmacol.Chemother,1949,4,277-280),其中〔A〕是测试化合物的浓度:
KB=〔A〕/r-1 (1)
所得KB值示于下表1。
表1
实施例编号 | KB值nM | 实施例编号 | KB值nM | 实施例编号 | KB值nM |
13456789101112131415161718192022 | 4992361323361013263.81714311.18154.515323.51722.933152.8 | 2324272829303132333435363738394041424344 | 1.051.917.18.551.5139143656803177326405202072358147.6286292285 | 45464748495051525355565960 | 5128691315901541183501542360690707 |
Claims (24)
1.一种式(I)化合物
其中:
R1是氢、羟基、烷基、烷氧基、羟烷基、三氟甲基、氨基、烷羰基氨基、烷羰氧基或卤素;
R2和R3独立地为氢原子、羟基、烷基、烷氧基、羟烷基、卤素、烷氧羰基烷基、氨基甲酰基或胺磺酰基;
R4是ω-羟基烷氧基、ω-氨基烷氧基、ω-氨基烷氨基、烷氧基烷基、羟基烷氧基烷氨基烷基、烷氧羰基烷基、二羟基烷基、甲酰基、烷羰基、烷氧羰基、烷羰基氨基烷基、氨烷基、烷氨基烷基、二烷基氨基烷基、羧烷基、氨基甲酰基烷基、羧酰氨基烷基、羧基、氨基、硝基、氰基、次氮基、氰烷基、叠氮基、具有至少2个碳原子的烷基、具有至少2个碳原子的烷氧基或具有至少2个碳原子的羟烷基;
R5是氢、卤素或烷基;
Ar是可被选自下列的取代基一次或分别两次取代的芳基或杂芳基,所述取代基包括烷基、烷氧基、羟基、羟烷基、卤素、烷氧羰基烷基、氨基甲酰基和胺磺酰基;及
R6和R7是相同或不同的烃基,两者一起含有至少3个碳原子,并带有一个或多个羟基,其中碳原子可通过氧原子互相连接,且其中R6和R7可与胺上的氮原子一起形成环;
前提条件是:(a)
(i)当R2、R3和R5中至少有2个不是氢原子时,或
(ii)当R1不是羟基或甲氧基,且Ar不是邻位被羟基或甲氧基取代的苯基时,或
(iii)当Ar是杂芳基时,或
(iv)当R6和R7至少有一者是芳烃基或环烷基时,则R4亦可为氢、甲基、甲氧基、羟基、羟甲基、卤素、氨基甲酰基或胺磺酰基;
以及(b)当Ar是非取代的苯基时,则R1、R2、R3、R4和R5不能都是氢原子。
该化合物与生理上可接受的酸类所形成的盐,以及当该化合物可以旋光异构体形式存在时,该化合物的外消旋混合物及单个对映异构体。
2.根据权利要求1的化合物,其中R4是ω-羟基烷氧基、ω-氨基烷氧基、ω-氨基烷氨基、烷氧基烷基、羟基烷氧基烷氨基烷基、二羟基烷基、甲酰基、烷羰基、烷氧羰基、烷氧羰基烷基、烷羰基氨烷基、氨烷基、烷氨基烷基、二烷基氨基烷基、羧烷基、氨基甲酰基烷基、羰酰氨基烷基、羧基、氨基、硝基、氰基、次氮基、氰烷基或叠氮基。
3.根据权利要求2的化合物,其中R1是氢或甲基,R2、R3和R5或者皆为氢,或者R2、R3和R5中有一者是甲基、甲氧基、羟基、氨基甲酰基、胺磺酰基或卤素,而余者是氢;且Ar是苯基,或是被甲基、甲氧基、羟基、羟甲基、氨基甲酰基、胺磺酰基或卤素一次或分别两次取代的苯基。
4.根据权利要求1的化合物,其中Ar是杂芳基。
5.根据权利要求4的化合物,其中R1是氢或甲基,且R2、R3、R4和R5或者皆为氢,或者R2、R3、R4和R5中有一者是甲基、甲氧基、羟基、羟甲基、氨基甲酰基、胺磺酰基或卤素,而余者是氢。
6.根据权利要求1的化合物,其中R1是氢、烷基、羟烷基、三氟甲基、氨基、烷羰基氨基、烷羰氧基或卤素,且Ar不是邻位被羟基或烷氧基取代的苯基。
7.根据权利要求6的化合物,其中R1是氢或甲基,R2、R3、R4和R5或者皆为氢,或者R2、R3、R4和R5中有一者是甲基、甲氧基、羟基、氨基甲酰基、胺磺酰基或卤素,而余者是氢,且Ar是苯基或被甲基、甲氧基、羟基、羟甲基、氨基甲酰基、胺磺酰基或卤素一次或独立地两次取代的苯基。
8.根据权利要求1的化合物,其中R6和R7至少有一者是芳烃基、环烷基或烃基链,其中碳原子在至少一位置是通过氧原子互相连接的。
9.根据权利要求8的化合物,其中R1是氢或甲基,R2、R3、R4和R5或者皆为氢,或者R2、R3、R4和R5中有一者是甲基、甲氧基、羟基、氨基甲酰基、胺磺酰基或卤素,而余者是氢,且Ar是苯基或被甲基、甲氧基、羟基、羟甲基、氨基甲酰基、胺磺酰基或卤素一次或独立地两次取代的苯基。
10.根据权利要求1-9任一项的化合物,其中R1是羟基、卤素、三氟甲基、氨基、甲氧基或羟甲基。
11.根据权利要求1-10任一项的化合物,其中R2和R3独立地为氢、羟基或羟甲基。
12.根据权利要求1-10任一项的化合物,其中R4是氢、甲酰基、烷氧羰基、烷羰基、羟烷基、烷氧基烷基、羧酰氨基烷基、氨基甲酰基烷基、氨烷基、氨基、叠氮基、氰烷基、羧基或羧烷基。
13.根据权利要求12的化合物,其中R4是氢、甲酰基、羟甲基、羟乙基、羟丙基、羟丁基、羟戊基、羟己基、乙氧基甲基、甲氧羰基、氨基、氨丙基、乙酰基、1,2-羟基乙基、乙氨基甲基或羟基乙氧基乙氨基乙基。
14.根据权利要求1至13任一项的化合物,其中R5是氢。
15.根据权利要求1至14任一项的化合物,其中R6和R7各自独立为饱和烃基,尤其是饱和的脂族烃基,例如C1-8烷基,尤其是C1-6烷基或金钢烷基,R6与R7一起含有至少3个碳原子,优选至少4个碳原子。
16.根据权利要求1至14任一项的化合物,其中R6和R7与胺上的氮原子一起形成环。
17.根据权利要求1至16任一项的化合物,其中R6和R7至少有一者含有支链碳链。
18.根据权利要求1至17任一项的化合物,其中Ar是噻吩基、吡咯基、噻唑基、唑基、甲基噻唑基或甲基吡咯基。
19.根据权利要求1的化合物,所述化合物为
N,N-二异丙基-3-(2-氟苯基)-3-苯基丙胺盐酸盐,
N,N-二异丙基-3-(5-甲酰基-2-羟基-苯基)-3-苯基丙胺,或其(R)-异构体,
N,N-二异丙基-3-(2-羟基-5-甲氧羰基苯基)-3-苯基丙胺,或其(R)-异构体,
N,N-二异丙基-3-(5-乙酰基-2-羟基苯基)-3-苯基丙胺,或其(R)-异构体,
N,N-二异丙基-3-〔2-羟基-5-(2-羟乙基)苯基〕-3-苯基丙胺,或其(R)-异构体,
N,N-二异丙基-3-〔2-羟基-5-(1-羟乙基)苯基〕-3-苯基丙胺,或其3(R)-异构体,
N,N-二异丙基-3(R)-〔5-(1(R*),2-二羟基乙基)-2-羟基苯基〕-3-苯基丙胺,或其1(S*)-异构体,
N,N-二异丙基-3-〔2-羟基-5-(6-羟己基)-苯基〕-3-苯基丙胺,或其(R)-异构体,
N,N-二异丙基-3-〔5-乙氧甲基-2-羟基苯基〕-3-苯基丙胺,或其(R)-异构体,
N,N-二异丙基-3-〔5-(3-氨基丙基)-2-羟基苯基〕-3-苯基丙胺,或其(R)-异构体,
N,N-二异丙基-3-〔5-(3-乙酰氨基丙基)-2-羟基苯基〕-3-苯基丙胺,或其(R)-异构体,
N,N-二异丙基-3-〔5-(2-氰乙基)-2-羟基苯基〕-3-苯基丙胺,或其(R)-异构体,
N,N-二异丙基-3-(5-氨基-2-羟基苯基)-3-苯基丙胺,或其(R)-异构体,
N,N-二异丙基-3-(5-叠氮基-2-羟基苯基)-3-苯基丙胺,或其(R)-异构体,
N,N-二异丙基-3-〔2-羟基-5-(3-羟丙基)-苯基〕-3-苯基丙胺,或其(R)-异构体,
N-环丁基-N-甲基-3-(2-羟基苯基)-3-苯基丙胺
N,N-二异丙基-3-(2-羟基苯基)-3-(2-噻吩基)丙胺,或
N,N-二异丙基-3-(2-羟基-5-甲基苯基)-3-(2-噻吩基)丙胺,或其(R)-异构体。
20.根据权利要求1至19任一项的化合物,其是用来作为药学活性物质,尤其是抗胆碱能药剂。
21.一种药物组合物,它含有根据权利要求1至19任一项的化合物,并且优选含有适合的药物载体。
22.根据权利要求1至19任一项的化合物在制备抗胆碱能药物上的用途。
23.一种治疗患有尿失禁相关病症的病患的方法,该方法包括将有效剂量的权利要求1至19任一项的化合物对该病患给药的步骤。
24.一种制备根据权利要求1至19任一项的化合物的方法,该方法包括:
a)使式II化合物
其中R1至R5和Ar同权利要求1中所定义,Y是离去基团,与胺HNR6R7反应,其中R6和R7定义如上;或者
b)还原式III化合物
其中R1至R7和Ar同权利要求1中所定义,且可对任一羟基进行保护;或者
c)使式IV的仲胺进行N-烷基化反应
其中R1至R5和Ar同权利要求1中所定义;且可对任一羟基进行保护,而其中Z的定义与R6及R7的相同;或者
d)还原式Va或Vb化合物
其中R1至R7和Ar同权利要求1中所定义,且可对任一羟基进行保护,W表示羟基或卤素;或者
e)将式VI化合物中的R1a转化为羟基,
其中R2至R7和Ar同权利要求1中所定义,且R1a是羧基或烷氧基;或者
f)将式VII化合物中的烯基还原为烷基、羟烷基或二羟基烷基,
其中R1、R6、R7和Ar同权利要求1中所定义,且R2b至R5b中有一者是烯基,而余者同权利要求1中R2至R5所定义;或者
g)将权利要求1中所定义的式I化合物中R1至R5的一个或多个取代基,转化为R1至R5中的其它取代基;或者
h)使式VIII化合物
其中R1至R7同权利要求1中所定义,且X是氧或硫,与式IX化合物反应
CH3N≡C: IX
形成式Ia化合物
其中R1至R7和X如上定义;或者
i)使上述式VIII化合物,其中X是氧,与式X化合物反应
形成式Ib化合物
其中R1至R7同权利要求1中所定义;或者
j)将式XI化合物
其中R1至R7同权利要求1中所定义,转化为式XII化合物
其中R1至R7同权利要求1所定义;或者
k)将式XIII化合物
其中R1至R7同权利要求1中所定义,且X是氧或硫,转化为式XIV化合物
其中R1至R7和X的定义如上,且R8和R9独立地为氢或烷基;以及
i)必要时,将所得化合物中的羟基保护基去掉;
ii)如果需要,利用生理上可接受的酸,将所制得的式I碱类转化为其盐类,反之亦然;和/或
iii)如果需要,将所得的旋光异构体混合物分离为单个的对映异构体。
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GB1169944A (en) * | 1966-08-25 | 1969-11-05 | Geistlich Soehne Ag | Novel 3,3-Diphenylpropylamines and processes for the preparation thereof |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111559992A (zh) * | 2020-05-29 | 2020-08-21 | 华中科技大学 | 一种2-芳基-γ-氨基丁酸衍生物的制备方法 |
CN111559992B (zh) * | 2020-05-29 | 2022-04-08 | 华中科技大学 | 一种2-芳基-γ-氨基丁酸衍生物的制备方法 |
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