CN1891683A - N-单取代β-氨基醇的制备方法 - Google Patents

N-单取代β-氨基醇的制备方法 Download PDF

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CN1891683A
CN1891683A CNA2006101007056A CN200610100705A CN1891683A CN 1891683 A CN1891683 A CN 1891683A CN A2006101007056 A CNA2006101007056 A CN A2006101007056A CN 200610100705 A CN200610100705 A CN 200610100705A CN 1891683 A CN1891683 A CN 1891683A
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D·麦克尔
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Abstract

本发明涉及通式(I)的N-单取代β-氨基醇和/或质子酸的加成盐的合成方法,其中R1和R2独立地代表烷基、环烷基、芳基或芳烷基,各任选地进一步被烷基、烷氧基和/或卤素通过直接制备通式的N-单取代β-氨基酮及其质子酸的加成盐取代,其中R1和R2如上述所定义。

Description

N-单取代β-氨基醇的制备方法
本申请是国际申请号为PCT/EP2003/007411,国际申请日为2003年07月9日的PCT国际申请进入中国国家阶段后申请号为03816223.7,发明名称为“N-单取代β-氨基醇的制备方法”的发明专利申请的分案申请。
技术领域
本发明涉及制备下列通式的N-单取代β-氨基醇和/或质子酸加成盐的方法,
该方法通过直接合成下列通式的N-单取代β-酮胺和/或质子酸的加成盐。
Figure A20061010070500032
背景技术
通式I的N-单取代β-氨基醇与(S)-(-)-3-N-甲氨基-1-(2-噻酚基)-1-丙醇(LY293628)类似,是制备药药活性化合物有用的关键中间体及构件,像(S)-(+)-甲基-[3-(1-萘氧基)-3-(2-噻酚基)-丙基]-胺((S)-duloxetine)(Liu,H.等人,Chirality 12(2000)26-29),它是潜在的神经活性化合物,能强烈地抑制血清素和降麻黄碱吸收(Deeter,J.等人,Tetrahedron Lett.31(1990)7101-7104)。
Figure A20061010070500041
LY293628                                  (S)-duloetine
下列术语“胺”或者“胺类”包括其相应的质子酸的加成盐。
直接制备通式II的N-单取代β-酮胺为工业生产通式I的N-单取代β-氨基醇确定了可供选择和经济上有利的来源。
1922年,通过在盐酸(Mannich,C.等人,Chem.Ber.55(1922)356-365)的存在下,将酮与甲醛及伯或叔烷基胺反应首先合成了通式II的化合物。在所述与伯烷基胺的反应中,形成通式III的叔β-酮胺的氢氯化物要胜过形成通式II的叔β-酮胺的氢氯化物。Blicke等人(J.Am.Chem.Soc.64(1942)451-454)及Becker等人(Wiss.Z.Tech.Hochsch.Chem.Leuna-Merseburg.11(1969)38-41)支持了这些发现。
Figure A20061010070500042
根据Mannich等人,蒸汽蒸馏通式III的叔β-酮胺导致形成产量相当满意的通式II的叔β-酮胺,伴有乙烯基化合物及其它副产物。
尽管损失超过50%的起始化合物且由于缺乏可供选择的方法,该方法仍用于叔β-酮胺的制备。
目前已知制备叔β-酮胺的方法的另一个缺点是需要从通式III的不需要的副产物中分离结构式II的所需中间体化合物。
EP-A 457 559和EP-A 650 965披露了通过甲基酮与低聚甲醛及二甲基胺进行Mannich型反应,接着将羰基还原制备N,N-二甲基β-氨基醇。羟基反应得到烷基或芳醚衍生物后,需要细致和昂贵的反应除去甲基自由基得到N-单取代化合物。
只有Becker等人披露了一些采用N-甲基草酸铵作为氮来源,N-单甲基β-酮胺产率约60%的例子。然而,Becker等人披露的方法没有优点,因为它严格取决于氨基草酸盐的使用。与游离胺或相应的氢氯化物相反,伯胺的草酸盐市场上买不到,且其制备要求进一步的合成及纯化步骤。
使用草酸盐也是不利的,因为它要求在下一步中使用额外的还原当量,将酮中间体还原为标题化合物。
没有一个已知的生产通式I的N-单取代β-氨基醇及其醚衍生物的方法,包括或涉及能与本发明的通式II的N-单取代β-酮胺相比的中间产物。尽管有许多尝试想发现新的制备方法,但还没有披露本发明直接合成N-单取代β-酮胺和接着还原为N-单取代β-氨基醇的途径。
要解决的问题是提供一个可供选择和有效的方法来合成高产率约的N-单取代β-氨基醇及其衍生物。而且,提出的方法应提供的高产率约与使用的氨基或羰基化合物的空间情况无关。
以上提出的问题可以根据权利要求1来解决。
由市售的甲基酮及伯胺和/或质子酸的加成盐开始,将这些起始物质与甲醛在溶剂以及任选的质子酸存在下,在大于1.5巴压力下反应,得到高产率约的能直接还原为所需N-单取代β-氨基醇的N-单取代β-氨基酮。
即时方法的另一个优点在于,通过直接使用盐酸甲胺能得到高产率约的N-单取代β-氨基酮,盐酸甲胺容易获得且价格便宜,因为它是固体,所以容易处理。
发明概述
本发明披露了通式如下的化合物
和/或质子酸的加成盐的制备方法,其中R1,R2独立地代表烷基、环烷基、芳基或芳烷基,各任选地被烷基、烷氧基和/或卤素进一步取代,该方法包括以下步骤:
a)反应混合物,该混合物包含
(i)通式(IV)的甲基酮
Figure A20061010070500052
其中,R1按照上述定义,
(ii)通式如下的化合物
H2N-R2                        V
和/或质子酸的加成盐,其中R2按照上述定义,
(iii)甲醛或选自由甲醛水溶液、1,3,5-三烷、低聚甲醛以及它们的混合物组成的甲醛来源,
在选自由水、脂肪醇、环脂肪醇以及它们的混合物组成的溶剂,以及任选的质子酸存在下,反应得到通式如下的化合物
Figure A20061010070500061
和/或质子酸的加成盐,和
b)还原所述β-氨基酮的羰基得到通式I的化合物,和/或质子酸的加成盐,
其中,第一步在大于1.5巴的压力下进行。
优选的实施例中,R1及R2可以独立地代表直链或支链的C1-8烷基,C3-8环烷基,苯基,萘基,呋喃基,苯并呋喃基,噻酚基,苯并噻酚基和芳烷基,其中芳烷基残基的烷基部分是直链C1-4烷基,芳基部分选自苯基,萘基,呋喃基,苯并呋喃基,噻酚基和苯并噻酚基,每个芳基或芳烷基可任选地被卤素、直链或支链的C1-4烷基,直链或支链的C1-4烷氧基,C3-6环烷基,CF3,C2F5,OCF3或OC2F5取代。
特别优选的是,R1表示呋喃基或噻酚基。
还特别优选的是,R2表示直链或支链的C1-8烷基。更特别优选R2表示甲基、乙基、丙基、异丙基、丁基、异丁基或叔丁基。
通式V的化合物优选用作游离胺和/或质子酸的加成盐。特别优选的是游离胺、甲酸盐、乙酸盐、草酸盐、氢氯化物、氢溴化物或者它们的混合物。更特别优选的是游离胺和/或氢氯化物。
优选的实施例中,通式V的化合物以至少与通式IV的化合物的等摩尔量存在。通式V的化合物与通式IV的化合物的摩尔比特别优选在1与2之间。
优选的实施例中,溶剂包含水、脂肪醇或环脂肪醇或者它们的混合物。
特别优选的醇是直链或支链的脂肪族C1-12醇,环脂肪族C5-8醇,二-和/或三聚的乙二醇或单C1-4烷基或它们的乙酰基衍生物,每个所述醇包含1至3个羟基。
所述醇的例子是甲醇、乙醇、丙醇、异丙醇、丁醇、异丁醇、叔丁醇、2-丁醇、1-戊醇、2-戊醇、3-戊醇、1-己醇、2-己醇、环戊醇、环己醇、1,2-乙二醇、1,2-丙二醇、1,2-丁二醇、2,3-丁二醇、1,4-丁二醇、1,2,3-丙三醇、1,2,6-己三醇、二甘醇、二甘醇单甲醚、二甘醇单乙醚、二甘醇单丁醚、二甘醇单醋酸酯、三甘醇、三甘醇单甲醚、三甘醇单乙醚、三甘醇单丁醚和三甘醇单醋酸酯。
所述醇优选乙醇、丙醇、异丙醇、丁醇、异丁醇、叔丁醇、二甘醇或三乙二醇。
质子酸可以是任何有机或无机酸,酸优选自甲酸、乙酸、丙酸、草酸、丙二酸、苯甲酸、HF、HCl、HBr、HI、H2SO4和H3PO4。优选实施例中,质子酸可以是多元有机酸或无机酸的酸盐,例如单碱丙二酸盐,碱金属硫酸氢盐,碱金属磷酸氢盐和碱金属碳酸氢盐。质子酸更优选地选自甲酸、乙酸、丙酸、草酸、HCl以及HBr,更优选地选自甲酸、乙酸、HCl和HBr。
优选反应步骤a)在添加的胺或质子酸的加成盐的条件下进行,因为即使蒸馏通式II的游离β-氨基酮也会在存储时分解的形成副产物,而相应的加成盐则可以存储较长时间而不分解。产品中,游离胺和其盐的比例相当于反应步骤a)过程中添加的胺和质子酸的加成盐与整个胺量的比例。
优选实施例中,反应步骤a)过程中的压力大于1.5巴,更优选的是在1.5至10巴之间,尤其优选的范围是在1.5至5巴之间。
与Becker等人的发明方法相反,本发明方法一般能直接制备N-单取代β-酮胺及其质子酸的加成盐。由本发明方法得到的产品能被还原或者接着反应而不进一步转变成其它盐。
本发明还提供了通式如下的化合物
Figure A20061010070500071
及其质子酸的加成盐,
其中R1代表呋喃基、苯并呋喃基、异苯并呋喃基、噻酚基或者苯并噻酚基,每个任选被卤素、直链或支链的C1-4烷基、直链或支链的C1-4烷氧基、C3-6环烷基、CF3、C2F5、OCF3或OC2F5取代,且
其中R2选自直链或支链的C1-8烷基、C3-8环烷基、苯基、萘基、呋喃基、苯并呋喃基、噻酚基、苯并噻酚基和芳烷基,其中芳烷基残基的烷基部分是直链C1-4烷基,芳基部分选自苯基、呋喃基、苯并呋喃基、噻酚基以及苯并噻酚基,每个芳基或芳烷基可以任选被卤素、直链或支链的C1-4烷基、直链或支链的C1-4烷氧基、C3-6环烷基、CF3、C2F5、OCF3或OC2F5取代,R1是噻酚基,R2是苄甲基的化合物除外。
本发明还提供了下列通式的化合物
Figure A20061010070500081
及其质子酸的加成盐,其中R4代表甲基、乙基、异丁基以及叔丁基。
本发明还提供了下列通式的化合物
Figure A20061010070500082
及其质子酸的加成盐。
本发明还提供了下列通式的化合物
Figure A20061010070500083
及其质子酸的加成盐。
本发明还提供了通式如下的化合物
Figure A20061010070500084
和/或质子酸的加成盐的制备方法,其中R1,R2独立地代表烷基、环烷基、芳基或芳烷基,每个任选地进一步被烷基、烷氧基和/或卤素取代,该方法包括反应混合物,该混合物包含
(i)通式(IV)的甲基酮
Figure A20061010070500091
其中,R1按照上述定义,和
(ii)通式如下的化合物
H2N-R2                     V
和/或质子酸的加成盐,其中R2按照上述定义,和
(iii)甲醛或选自甲醛水溶液、1,3,5-三烷、低聚甲醛以及它们的混合物的甲醛来源,
在选自水、脂肪醇、环脂肪醇以及它们的混合物的溶剂,以及任选的质子酸存在下,反应得到通式如下的化合物和/或质子酸的加成盐,
其中,R1及R2按照上述定义,反应在大于1.5巴压力下进行。
优选的实施例中,R1及R2独立地代表直链或支链的C1-8烷基,C3-8环烷基,苯基,萘基,呋喃基,苯并呋喃基,噻酚基,苯并噻酚基或者芳烷基,其中芳烷基残基的烷基部分是直链C1-4烷基,芳基部分选自苯基,萘基,呋喃基,苯并呋喃基,噻酚基和苯并噻酚基,每个芳基或芳烷基任选被卤素、直链或支链的C1-4烷基,直链或支链的C1-4烷氧基,C3-6环烷基,CF3,C2F5,OCF3或OC2F5取代。
特别优选R1代表呋喃基或噻酚基。还特别优选R2代表直链或支链的C1-8烷基。更优选的是,R2代表甲基、乙基、丙基、异丙基、丁基、异丁基或叔丁基。
可以优选将通式V的化合物用作游离胺和/或它的质子酸的加成盐。特别优选的是游离胺、甲酸盐、醋酸盐、草酸盐、氢氯化物、氢溴化物或者它们的混合物。更优选的是游离胺和/或氢氯化物。
一个优选的实施例中,通式V的化合物以至少与通式IV的化合物的等摩尔量存在。通式V的化合物与通式IV的化合物的摩尔比特别优选在1与2之间。
优选的实施例中,溶剂包含水、脂肪醇或环脂肪醇或者它们的混合物。
特别优选的醇是直链或支链的脂肪族C1-12醇,环脂肪族C5-8醇,二-和/或三聚的乙二醇或单C1-4烷基或这们的乙酰基衍生物,每个所述醇包含1至3个羟基。
所述醇的例子是甲醇、乙醇、丙醇、异丙醇、丁醇、异丁醇、叔丁醇、2-丁醇、1-戊醇、2-戊醇、3-戊醇、1-己醇、2-己醇、环戊醇、环己醇、1,2-乙二醇、1,2-丙二醇、1,2-丁二醇、2,3-丁二醇、1,4-丁二醇、1,2,3-丙三醇、1,2,6-己三醇、二甘醇、二甘醇单甲醚、二甘醇单乙醚、二甘醇单丁醚、二甘醇单醋酸酯、三甘醇、三甘醇单甲醚、三甘醇单乙醚、三甘醇单丁醚和三甘醇单醋酸酯。
所述醇优选乙醇、丙醇、异丙醇、丁醇、异丁醇、叔丁醇、二甘醇或三甘醇。
质子酸可以是任何有机或无机酸,酸优选自甲酸、乙酸、丙酸、草酸、丙二酸、苯甲酸、HF、HCl、HBr、HI、H2SO4和H3PO4。优选实施例中,质子酸可以是多元有机酸或无机酸的酸盐,例如单碱丙二酸盐,碱金属硫酸氢盐,碱金属磷酸氢盐和碱金属碳酸氢盐。质子酸更优选的是选自甲酸、乙酸、丙酸、草酸、HCl和HBr,更优选的是选自甲酸、乙酸、HCl和HBr。
一个优选的实施例中,反应过程中压力大于1.5巴,更优选是在1.5至10巴之间,特别优选的是在1.5至5巴之间。
具体实施方式
本发明通过下列没有限制的实施例来说明。
实施例1至8的一般步骤
在高压釜中,将甲基酮(1当量),伯烷基胺和/或它们的加成盐(1.1至1.5当量),甲醛(1.4至1.5当量),溶剂,任选在质子酸存在下混合物在总压力大于1.5巴下加热5至24小时。以后,将反应溶液冷却至20℃。但选部分除去反应溶剂或者完全除去溶剂,如果需要促进产品沉淀的话,可以在剧烈搅拌下加入溶剂如醋酸乙酯或者异丙醇。悬浮液冷却(0至20℃)并在沉淀(0.5至10小时)后过滤,任选进行洗涤并干燥,得到浅黄至白色粉末,产率约在50%至75%之间。如果需要的话,产品可以从异丙醇和/或醋酸乙酯中重结晶。如果游离碱在周围环境中足够稳定的话,用有机溶剂萃取,含水碱提供游离碱。
比较实施例1至6的一般步骤
将甲基酮(1当量),伯烷基胺和/或它们的加成盐(1至1.5当量),甲醛(1.0至1.5当量)的混合物,任选在质子酸存在下,在回流溶剂中加热5至24小时。以后,将反应溶液冷却至20℃。任选部分除去反应溶剂或者完全除去溶剂,如果需要促进产品沉淀的话,可以在剧烈搅拌下加入溶剂如醋酸乙酯或者异丙醇。悬浮液冷却(0至20℃)并在沉淀(0.5至10小时)后过滤,任选进行洗涤并干燥,得到浅黄至白色粉末,产率约在30%至45%之间。如果需要的话,产品可以从异丙醇和/或醋酸乙酯中重结晶。
实施例1:3-(甲氨基)-1-(噻酚基-2-基)丙烷-1-酮氢氯化物(II,R1=噻酚-2-基,R2=甲基)
2-乙酰基噻酚(25.5g,200mmol);盐酸甲胺(14.9g,220mmol,1.1当量);低聚甲醛(8.2g,280mmol,1.4当量);HCl浓缩物(1.0g);乙醇(100mL);110℃,9小时;约2至2.5巴;真空除去乙醇(50mL);添加醋酸乙酯(200mL);产率约的71%。
1H-NMRδ(DMSO-d6,400MHz):9.16(2H,s,br),8.07(1H,dd,J=5.0,1.0),8.01(1H,dd,J=3.8,1.0),7.29(1H,dd,J=5.0,3.8),3.49(2H,t),3.20(2H,t),2.56(3H,s)。
13C-NMRδ(DMSO-d6,100MHz):189.9,142.7,135.4,133.8,128.8,43.1,34.6,32.4。
实施例2:3-(甲氨基)-1-(噻酚-2-基)丙烷-1-酮氢氯化物(II,R1=噻酚-2-基,R2=甲基)
2-乙酰基噻酚(24.9g,197mmol);盐酸甲胺(14.8g,219mmol,1.1当量);低聚甲醛(8.3g,276mmol,1.4当量);HCl浓缩物(1.1g);异丙醇(100mL);110℃,8小时;约2至2.5巴;真空除去异丙醇(50mL);产率约为65%。
比较实施例1:3-(甲氨基)-1-(噻酚-2-基)丙烷-1-酮氢氯化物(II,R1=噻酚-2-基,R2=甲基)
2-乙酰基噻酚(79g,300mmol);盐酸甲胺(30.4g,450mmol,1.5当量);低聚甲醛(12.6g,420mmol,1.4当量);HCl浓缩物(1.5g);异丙醇(200mL);回流(82℃)下加热8小时;添加醋酸乙酯(200mL);产率约43%。
实施例3:3-(乙氨基)-1-(噻酚-2-基)丙烷-1-酮氢氯化物(II,R1=噻酚-2-基,R2=乙基)
2-乙酰基噻酚(6.3g,50mmol);盐酸乙胺(6.1g,75mmol,1.5当量);低聚甲醛(2.1g,75mmol,1.5当量);HCl浓缩物(0.3g);乙醇(35mL);110℃,9小时;约2至2.5巴;真空除去乙醇(25mL);添加醋酸乙酯(50mL);产率约73%。
1H-NMRδ(DMSO-d6,400MHz):9.3(2H,s,br),8.08(1H,dd),8.00(1H,dd),7.28(1H,dd),3.51(2H,t),3.20(2H,t),2.96(2H,q),1.23(3H,t)。
比较实施例2:3-(乙氨基)-1-(噻酚-2-基)丙烷-1-酮氢氯化物(II,R1=噻酚-2-基,R2=乙基)
2-乙酰基噻酚(12.6g,100mmol);盐酸乙胺(12.2g,150mmol,1.5当量);低聚甲醛(4.1g,140mmol,1.4当量);HCl浓缩物(0.5g);乙醇(70mL);回流(78℃)下加热6小时;真空除去乙醇(25mL);添加醋酸乙酯(70mL);产率约31%。
实施例4:3-(异丁基氨基)-1-(噻酚-2-基)丙烷-1-酮氢氯化物(II,R1=噻酚-2-基,R2=异丁基)
2-乙酰基噻酚(6.3g,50mmol);盐酸异丁胺(8.3g,75mmol,1.5当量);低聚甲醛(2.1g,75mmol,1.5当量);HCl浓缩物(0.3g);乙醇(35mL);110℃,9小时;约2至2.5巴;真空除去乙醇(35mL);添加醋酸乙酯(50mL);产率约56%。
1H-NMRδ(DMSO-d6,400MHz):9.0(2H,s,br),8.08(1H,dd),7.99(1H,dd),7.29(1H,dd),3.55(2H,t),3.22(2H,t),2.78(2H,d),2.03(1H,m),0.96(6H,d)。
比较实施例3:3-(异丁基氨基)-1-(噻酚-2-基)丙烷-1-酮氢氯化物(II,R1=噻酚-2-基,R2=异丁基)
2-乙酰基噻酚(12.6g,100mmol);盐酸异丁胺(16.5g,150mmol,1.5当量);低聚甲醛(4.1g,140mmol,1.4当量);HCl浓缩物(0.5g);丁醇(70mL);回流(108℃)下加热6小时;添加醋酸乙酯(100mL);产率约40%。
实施例5:3-(叔丁基氨基)-1-(噻酚-2-基)丙烷-1-酮氢氯化物(II,R1=噻酚-2-基,R2=叔丁基)
2-乙酰基噻酚(6.3g,50mmol);盐酸叔丁胺(8.3g,75mmol,1.5当量);低聚甲醛(2.1g,75mmol,1.5当量);HCl浓缩物(0.3g);丁醇(35mL);117℃,9小时;约2至2.5巴;添加醋酸乙酯(50mL);产率约52%。
1H-NMRδ(DMSO-d6,400MHz):9.2(2H,s,br),8.08(1H,dd),7.98(1H,dd),7.30(1H,dd),3.54(2H,t),3.19(2H,t),1.34(9H,s)。
比较实施例4:3-(叔丁基氨基)-1-(噻酚-2-基)丙烷-1-酮氢氯化物(II,R1=噻酚-2-基,R2=叔丁基)
2-乙酰基噻酚(12.6g,100mmol);盐酸叔丁胺(16.5g,150mmol,1.5当量);低聚甲醛(4.1g,140mmol,1.4当量);HCl浓缩物(0.5g);丁醇(70mL);回流(108℃)下加热18小时;添加醋酸乙酯(100mL);产率约37%。
实施例6:3-(甲氨基)-1-(呋喃基-2-基)丙烷-1-酮氢氯化物(II,R1=呋喃-2-基,R2=甲基)
2-乙酰基呋喃(7.5g,68mmol);盐酸甲胺(6.9g,102mmol,1.5当量);低聚甲醛(3.1g,102mmol,1.5当量);HCl浓缩物(1.15g);乙醇(35mL);110℃,8小时;约2至2.5巴;真空除去乙醇(30mL);添加醋酸乙酯(50mL);产率约64%。
1H-NMRδ(DMSO-d6,400MHz):9.0(2H,s,br),8.05(1H,m),7.53(1H,m),6.77(1H,m),3.34(2H,t),3.2(2H,m),2.57(3H,s,br)。
比较实施例5:3-(甲氨基)-1-(呋喃基-2-基)丙烷-1-酮氢氯化物(II,R1=呋喃-2-基,R2=甲基)
2-乙酰基呋喃(11.0g,100mmol);盐酸甲胺(10.1g,150mmol,1.5当量);低聚甲醛(4.1g,140mmol,1.4当量);HCl浓缩物(0.5g);丁醇(70mL);回流(108℃)下加热7小时;添加醋酸乙酯(100mL);产率约44%。
实施例7:3-(甲氨基)-1-苯基丙烷-1-酮氢氯化物(II,R1=苯基,R2=甲基)
2-乙酰苯(21.0g,175mmol);盐酸甲胺(17.5g,263mmol,1.5当量);低聚甲醛(7.9g,263mmol,1.5当量);HCl浓缩物(1.1g);乙醇(130mL);115℃,24小时;约2至2.5巴;添加醋酸乙酯(50mL);产率约52%。
1H-NMRδ(DMSO-d6,400MHz):9.2(2H,s,br),8.0(2H,m),7.7(1H,m),7.6(2H,m),3.55(2H,t),3.21(2H,m),2.59(3H,s)。
实施例8:3-(甲氨基)-1-(2-萘基)丙烷-1-酮氢氯化物(II,R1=2-萘基,R2=甲基)
2-乙酰萘(8.5g,50mmol);盐酸甲胺(5.1g,75mmol,1.5当量);低聚甲醛(2.1g,75mmol,1.5当量);HCl浓缩物(0.3g);乙醇(35mL);117℃,14小时;约2至2.5巴;真空除去乙醇(35mL);添加醋酸乙酯(50mL);产率约60%。
1H-NMRδ(DMSO-d6,400MHz):9.3(2H,s,br),8.74(1H,s),8.17(1H,d),8.0(3H,m),7.7(2H,m),3.70(2H,t),3.28(2H,m),2.60(3H,s)。
比较实施例6:3-(甲氨基)-1-(2-萘基)丙烷-1-酮氢氯化物(II,R1=2-萘基,R2=甲基)
2-乙酰萘(17.0g,100mmol);盐酸甲胺(10.1g,150mmol,1.5当量);低聚甲醛(4.1g,140mmol,1.4当量);HCl浓缩物(0.5g);乙醇(70mL);回流(78℃)下加热5小时;真空除去乙醇(30mL);添加醋酸乙酯(100mL);产率约42%。
实施例9:3-(甲氨基)-1-(噻酚-2-基)丙烷-1-烷酮(I,R1=噻酚-2-基,R2=甲基)
在4℃,向3-(甲氨基)-1-(噻酚-2-基)丙烷-1-酮氢氯化物(10.3g,50mmol)和乙醇(35mL)的混合物中,在约5分钟内加入氢氧化钠(4.0g的50%水溶液)。以后,在我30分钟内分几部分添加净氢氧化钠(0.95g,25mmol,1.0当量)。添加结束时,在同样温度将悬浮液搅拌4小时,然后在5分钟内滴加丙酮(10.0mL),将混合物再搅拌10分钟。添加水(20mL)。以后,真空下将混合物浓缩约5倍,用叔丁基甲基醚萃取残余物(2×20mL)。最后将所收集的有机相真空浓缩得到橙色油,橙色油几小时后自发结晶。最后,得到橙色固体(7.2g,84%产率约)。然后可以不进一步纯人就使用该化合物。
1H-NMRδ(DMSO-d6,400MHz):7.35(1H,dd,J=4.8,1.0),6.94(1H,dd,J=4.8,3.6),6.90(1H,dd,J=3.6,1.0),4.90(1H,t),3.7(2H,m),2.56(2H,m),2.25(3H,s),1.79(2H,q)。
13C-NMRδ(DMSO-d6,400MHz):150.9,126.3,123.7,122.3,67.8,48.5,38.7,36.0。
实施例10:3-(异丁基氨基)-1-(噻酚-2-基)丙烷-1-醇(I,R1=噻酚-2-基,R2=异丁基)
在4℃,向3-(异丁基氨基)-1-(噻酚-2-基)丙烷-1-酮氢氯化物(4.2g,19.4mmol)和乙醇(10mL)混合物中,在约20分钟内加入氢氧化钠(1.6g的50%水溶液)。然后,在约30分钟内分几部分添加净氢氧化钠(0.37g,9.7mmol,1.0当量)。添加结束时,在同样温度将悬浮液搅拌4小时,然后在20分钟内滴加丙酮(10.0mL),将混合物再搅拌10分钟。以后,过滤除去沉淀,真空浓缩混合物得到橙色油。通过柱色谱,采用40∶10∶1(v∶v∶v)的二氯甲烷/甲醇/氢氧化铵(25%水溶液)混合物提纯粗制品。
1H-NMRδ(DMSO-d6,400MHz):7.20(1H,dd,J=4.8,1.0),6.98(1H,dd),6.94(1H,dd,J=4.8,3.6),5.20(1H,dd),4.98(2H,br),3.02(1H,m),2.93(1H,m),2.43(2H,symm.m),2.03(1H,m),1.97(1H,m),1.80(2H,sept),0.95(6H,d)。
13C-NMRδ(DMSO-d6,100MHz):150.9,126.3,123.8,122.5,72.1,57.8,48.5,37.4,28.2,20.8。

Claims (4)

1.具有下列通式的化合物及其质子酸的加成盐,
Figure A2006101007050002C1
其特征在于,R1代表呋喃基、苯并呋喃基、异苯并呋喃基、噻酚基或者苯并噻酚基,每个任选地被卤素、直链或支链的C1-4烷基、直链或支链的C1-4烷氧基、C3-6环烷基、CF3、C2F5、OCF3或OC2F5取代,和
R2选自直链或支链的C1-8烷基、C3-8环烷基、苯基、萘基、呋喃基、苯并呋喃基、噻酚基、苯并噻酚基和芳烷基,其中芳烷基残基的烷基部分是直链C1-4烷基,芳基部分选自苯基、萘基、呋喃基、苯并呋喃基、噻酚基和苯并噻酚基,每个芳基或芳烷基任选地被卤素、直链或支链的C1-4烷基、直链或支链的C1-4烷氧基、C3-6环烷基、CF3、C2F5、OCF3或OC2F5取代;R1代表噻酚基,R2代表苄基的化合物除外。
2.具有下列通式的化合物及其质子酸的加成盐,
Figure A2006101007050002C2
其特征在于,R4代表甲基、乙基、异丁基或叔丁基。
3.具有下列通式的化合物及其质子酸的加成盐。
4.具有下列通式的化合物及其质子酸的加成盐。
Figure A2006101007050002C4
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