CN1043932A - 一种制备萘衍生物的方法 - Google Patents
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C67/347—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to unsaturated carbon-to-carbon bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/30—Compounds having groups
- C07C43/315—Compounds having groups containing oxygen atoms singly bound to carbon atoms not being acetal carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
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- Chemical & Material Sciences (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Curing Cements, Concrete, And Artificial Stone (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
一种制备式(I)萘衍生物的新方法,式中R1,R2,R3,R4,R5,R6和R7为低级烷基,并揭示它的一个中间体。所说的萘衍生物(I)和它的在药学上可接受的盐作为低脂血剂(hypolipidemic agent)是有用的。
Description
本发明涉及一种制备萘衍生物的方法。更详细地说它涉及制备式(Ⅰ)萘衍生物的新方法
式中R1、R2、R3、R4、R5、R6和R7为低级烷基。
此萘衍生物和其在药学上可接受的盐类作为低脂血剂(hypolipidemic agent)是有用的。
至今为止已知上述的萘衍生物可用以下方法制备:3,4-(二低级烷氧基)苯甲醛与2-溴代-3,4,5-三(低级烷氧基)苯甲醛二低级烷基缩醛反应,所得产物与乙炔二羧酸二低级烷基酯反应(US.专利No.4,771,072)。
但是已知方法对在工业规模上制备萘衍生物(Ⅰ)是有缺点的,因为用作起始化合物的2-溴代-3,4,5-三(低级烷氧基)苯甲醛二低级烷基缩醛必须在其缩醛化作用前通过溴代3,4,5-三(低级烷氧基)苯甲醛来制备,所以不可能避开使用既有害又很难操纵的溴。
本发明的一个目的在于提供一种制备萘衍生物(Ⅰ)而不使用溴的新方法。本发明的另一个目的在于提供一种可从3,4,5-三(低级烷氧基)苯甲醛二低级烷基缩醛制备萘衍生物(Ⅰ)仅需二步的新方法。本发明的其它目的在于提供工业上有利的制备萘衍生物(Ⅰ)的中间体的方法。
根据各种研究的结果,本发明的发明人现发现在非溴代3,4,5-三(低级烷氧基)苯甲醛二低级烷基缩醛和3,4-二(低级烷氧基)苯甲醛之间发生加成反应,以高收率给出2-[3,4-二(低级烷氧基)-α-羟苄基]-3,4,5-三(低级烷氧基)苯甲醛-低级烷基缩醛。
根据本发明,萘衍生物(Ⅰ)或其在药学上可接受的盐可通过以下步骤制备:
A)式(Ⅱ)的二(低级烷氧基)苯甲醛,式中
R3、R4如上所定义,与式(Ⅲ)的三(低级烷氧基)苯甲醛二低级烷基缩醛,式中R5、R6和R7如上所定义,R8为低级烷基,进行反应,以给出式(Ⅳ)的α-羟苄基苯甲醛化合物,式中R3、R4、R5、R6、R7和R8如上所定义;
B)化合物(Ⅳ)或其盐与式(Ⅴ)乙炔二羧酸酯进行反应,
式中R1和R2如上所定义;
C)如果需要,将产物进一步转化成其在药学上可接受的盐。
在以上所提到的反应中,用R1、R2、R3、R4、R5、R6、R7和R8代号表示的低级烷基包括具有1-4个碳原子的直链或支链烷基,如甲基、乙基、正丙基、异丙基或丁基。
二(低级烷氧基)苯甲醛(Ⅱ)和三(低级烷氧基)苯甲醛二低级烷基缩醛(Ⅲ)的反应,可在溶剂中在有机锂化合物存在下进行。有机锂化合物的例子包括低级烷基锂,例如正丁基锂,芳基锂如苯基锂,以及二低级烷基氨基化锂如二异丙基氨基化锂。以上反应中所用的有机锂化合物的优选量为每摩尔化合物(Ⅲ)1-3摩尔,尤其是1-2摩尔。己烷、四氢呋喃、醚、二氧杂环己烷苯、甲苯、二甲苯等等均可用作溶剂。进行反应温度优选为-70-40℃,尤其是-20-20℃。
α-羟苄基苯甲醛二低级烷基醛化合物(Ⅳ)和乙炔二羧酸酯(Ⅴ)的反应可在酸存在下或是在溶剂中或是没有溶剂下进行。所说的酸的例子包括无机酸类如盐酸或硫酸,以及有机酸类如甲酸、乙酸、三氟乙酸、对甲苯磺酸或甲磺酸。如果反应在溶剂中进行,与化合物(Ⅱ)和化合物(Ⅲ)的反应中所使用的相同溶剂可被优选作为溶剂使用。反应优选在0-150℃温度下进行,尤其是50-100℃。
这样获得的萘衍生物(Ⅰ),能通过用碱如碱金属氢氧化物(例如氢氧化钠),碱土金属氢氧化物(例如氢氧化锂)或氢氧化季铵处理所述化合物,转化成其在药学上可接受的盐。
如前面所提到的,与在US.专利No.4,771,072中公开的已知方法相比,本发明的方法更有利得多,因为可以不用有害的溴来制备萘衍生物(Ⅰ),并且能少用一步骤制备所说的衍生物(Ⅰ)。
实施例1
(1)196.2克3,4,5-三甲氧基苯甲醛、127.3克三甲氧基甲烷、200毫升甲醇和0.1克盐酸的混合物回流3小时。在冷却反应混合物后,加入0.2克24%甲醇钠的甲醇溶液,减压蒸浓混合物以去除溶剂。在残余物中加入150毫升四氢呋喃,减压下蒸浓混合物以去除溶剂。这样得到243克3,4,5-三甲氧基苯甲醛二甲基缩醛,为淡黄色油状物。
Neat
IRν (cm-1):1600,1500,1460,1420,1360,1230,840。
max
(2-a)在含有48.5克3,4,5-三甲氧基苯甲醛二甲基缩醛的485毫升四氢呋喃中,边加入136毫升1.6M正丁基锂的己烷溶液,边在0℃搅拌20分钟。再在0℃搅拌混合物30分钟,加入33.2克3,4-二甲氧基苯甲醛。在0-10℃搅拌混合物2小时后,加入780毫升水与780毫升乙酸乙酯,在摇振混合物后,分离出有机层,用水洗涤,减压蒸浓以去除溶剂。这样得到81.0克2-(3,4-二甲氧基-α-羟苄基)-3,4,5-三甲氧基苯甲醛二甲基缩醛,为黄色油状物。
Neat
IRν (cm-1):3500,2930,1600
max
(2-b)在含有48.5克3,4,5-三甲氧基苯甲醛二甲基缩醛的485毫升苯中,边加入136毫升1.6M正丁基锂的己烷溶液,边在0℃搅拌约20分钟。进一步在0℃搅拌混合物30分钟,加入33.2克3,4-二甲氧基苯甲醛。在0-10℃搅拌混合物2小时后,加入485毫升水和16克柠檬酸。在摇振混合物后,分离出有机层,用水洗涤,减压下蒸浓以去除溶剂。这样得到78.5克2-(3,4-二甲氧基-α-羟苄基)-3,4,5-三甲氧基苯甲醛二甲茎缩醛,为黄色油状物。此产物的物理化学性质是与在(2-a)节中获得的产物一样的。
(2-c)在含有48.5克3,4,5-三甲氧基苯甲醛二甲基缩醛的485毫升四氢呋喃溶液中,边加入136毫升1.6M正丁基锂的甲苯溶液,边在0℃搅拌约20分钟。进一步在℃搅拌混合物30分钟,加入33.2克3,4-二甲氧基苯甲醛。在0-10℃搅拌混合物2小时后,加入780毫升水和780毫升乙酸乙酯。在摇振混合物后,分离出有机层,用水洗涤,减压下蒸浓以去除溶剂,这样得到79.5克2-(3,4-二甲氧基-α-羟苄基)-3,4,5-三甲氧基苯甲醛二甲基缩醛,为黄色油状物。
这产物的物理化学性质是与在(2-a)节中获得的产物相同的。
(3)49.5克2-(3,4-二甲氧基-α-羟苄基)-3,4,5-三甲氧基苯甲醛二甲基缩醛溶解于35毫升甲苯中。向溶液中加入14.2克乙炔二羧酸二甲酯和19毫克对甲苯磺酸-水合物,混合物回流3小时。在冷却反应混合物之后,加入200毫升甲醇,让混合物在-30℃保持过夜。过滤收集析出的晶体,在乙酸乙酯中重结晶,得到33.1克1-(3,4-二甲氧苯基)-2,3-双(甲氧羰基)4-羟基-6,7,8-三甲氧基萘,为无色棱晶。
熔点:182-183℃
Nujol
IRν (cm-1):2950,1740,1660,1510,810
max
(4)含有4.86克1-(3,4-二甲氧苯基)-2,3-双(甲氧羰基)-4-羟基-6,7,8-三甲氧基苯的100毫升四氢呋喃溶液加入到含0.387克62.5%氢化钠的10毫升四氢呋喃悬浮液中,边加入边在室温下搅拌,在同样的温度下搅拌混合物1小时。然后在低于30℃温度下减压蒸浓混合物以去除溶剂,残余物用石油醚研制,以给出4.8克1-(3,4-二甲氧苯基)-2,3-双(甲氧羰基)-4-羟基-6,7,8-三甲氧基萘钠盐,为粉状物。
KBr
IRν (cm-1):1710(s),1680,1600
max
实施例2
40.8克2-(3,4-二甲氧基-α-羟苄基)-3,4,5-三甲氧基苯甲醛二甲基缩醛和17.0克乙炔二羧酸二乙酯经如实施例1-(3)中所述的相同方法处理,产生1-(3,4-二甲氧苯基)-2,3-双(乙氧羰基)-4-羟基-6,7,8-三甲氧基萘。收率43%
熔点:138-140℃
实施例3-6
(1)相应的起始化合物用如实施例1-(1)和(2)中所述相同方法处理,产生在1中所示化合物。
*在实施例4-(1)和6-(1)中获得的产物不经测定其物理化学性质而用于随后的反应。
(2)在节(1)中获得的化合物和乙炔二羧酸二甲酯用如实施例1-(3)中所述的相同方法处理,获得表2中所示的下列化合物。
Claims (10)
2、根据权利要求1的方法,其特征在于其中化合物(Ⅱ)与化合物(Ⅲ)的反应是在有机锂化合物存在下进行。
3、根据权利要求2的方法,其特征在于其中有机锂化合物为低级烷基锂、芳基锂或二低级烷基氨基化锂。
4、根据权利要求2的方法,其特征在于其中有机锂化合物为正丁基锂。
5、根据权利要求2的方法,其特征在于其中R1和R2为甲基或乙基,R3和R4为甲基、乙基或异丙基,以及R5、R6、R7和R8为甲基。
7、根据权利要求6的方法,其特征在于式(Ⅱ)化合物与式(Ⅲ)化合物的反应是在有机锂化合物存在下进行。
8、根据权利要求7的方法,其特征在于其中有机锂化合物为低级烷基锂、芳基锂或二低级烷基氨基化锂。
9、根据权利要求7的方法,其特征在于其中有机锂化合物为正丁基锂。
10、根据权利要求7的方法,其特征在于其中R3、和R4为甲基、乙基或异丙基,以及R5、R6、R7和R8为甲基。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP303335/88 | 1988-11-29 | ||
JP63303335A JPH02149546A (ja) | 1988-11-29 | 1988-11-29 | ナフタレン誘導体の製法 |
Publications (1)
Publication Number | Publication Date |
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CN1043932A true CN1043932A (zh) | 1990-07-18 |
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Application Number | Title | Priority Date | Filing Date |
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CN89108652A Pending CN1043932A (zh) | 1988-11-29 | 1989-11-16 | 一种制备萘衍生物的方法 |
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US (1) | US5066825A (zh) |
EP (1) | EP0371484A3 (zh) |
JP (1) | JPH02149546A (zh) |
KR (1) | KR950013084B1 (zh) |
CN (1) | CN1043932A (zh) |
BG (1) | BG50500A3 (zh) |
CA (1) | CA2002612A1 (zh) |
DK (1) | DK599689A (zh) |
FI (1) | FI895652A0 (zh) |
HU (1) | HU204023B (zh) |
IE (1) | IE893631L (zh) |
IL (1) | IL92303A0 (zh) |
NO (1) | NO170010C (zh) |
PH (2) | PH26342A (zh) |
PT (1) | PT92413A (zh) |
ZA (1) | ZA898900B (zh) |
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US6680344B1 (en) | 1999-06-01 | 2004-01-20 | The University Of Texas Southwestern Medical Center | Method of treating hair loss using diphenylmethane derivatives |
AU3507700A (en) | 1999-06-01 | 2000-12-18 | University Of Texas Southwestern Medical Center, The | Method of treating hair loss using diphenylether derivatives |
MXPA01012494A (es) | 1999-06-01 | 2002-07-02 | Univ Texas Southwestern Med Ct | Metodo para tratar perdida capilar con el uso de compuestos sulfonil tiromimeticos. |
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NO170760C (no) * | 1985-01-10 | 1992-12-02 | Tanabe Seiyaku Co | Analogifremgangsmaate for fremstilling av terapeutisk aktive nafthalenderivater |
-
1988
- 1988-06-24 PH PH37115A patent/PH26342A/en unknown
- 1988-11-29 JP JP63303335A patent/JPH02149546A/ja active Pending
-
1989
- 1989-10-23 PH PH39578A patent/PH26331A/en unknown
- 1989-11-09 CA CA002002612A patent/CA2002612A1/en not_active Abandoned
- 1989-11-10 IE IE893631A patent/IE893631L/xx unknown
- 1989-11-14 IL IL92303A patent/IL92303A0/xx unknown
- 1989-11-16 US US07/437,065 patent/US5066825A/en not_active Expired - Fee Related
- 1989-11-16 CN CN89108652A patent/CN1043932A/zh active Pending
- 1989-11-22 ZA ZA898900A patent/ZA898900B/xx unknown
- 1989-11-24 PT PT92413A patent/PT92413A/pt not_active Application Discontinuation
- 1989-11-27 KR KR1019890017218A patent/KR950013084B1/ko active IP Right Grant
- 1989-11-27 FI FI895652A patent/FI895652A0/fi not_active Application Discontinuation
- 1989-11-28 BG BG90482A patent/BG50500A3/xx unknown
- 1989-11-28 DK DK599689A patent/DK599689A/da not_active Application Discontinuation
- 1989-11-28 NO NO894737A patent/NO170010C/no unknown
- 1989-11-29 HU HU896312A patent/HU204023B/hu not_active IP Right Cessation
- 1989-11-29 EP EP19890122010 patent/EP0371484A3/en not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
US5066825A (en) | 1991-11-19 |
PH26342A (en) | 1992-04-29 |
ZA898900B (en) | 1990-08-29 |
IL92303A0 (en) | 1990-07-26 |
NO894737D0 (no) | 1989-11-28 |
KR900007776A (ko) | 1990-06-01 |
BG50500A3 (en) | 1992-08-14 |
HUT53060A (en) | 1990-09-28 |
DK599689D0 (da) | 1989-11-28 |
NO894737L (no) | 1990-05-30 |
FI895652A0 (fi) | 1989-11-27 |
PT92413A (pt) | 1990-05-31 |
EP0371484A2 (en) | 1990-06-06 |
JPH02149546A (ja) | 1990-06-08 |
AU4551389A (en) | 1990-06-07 |
HU896312D0 (en) | 1990-02-28 |
KR950013084B1 (ko) | 1995-10-24 |
EP0371484A3 (en) | 1991-04-10 |
PH26331A (en) | 1992-04-29 |
CA2002612A1 (en) | 1990-06-29 |
AU613250B2 (en) | 1991-07-25 |
IE893631L (en) | 1990-05-29 |
NO170010B (no) | 1992-05-25 |
DK599689A (da) | 1990-05-30 |
NO170010C (no) | 1992-09-02 |
HU204023B (en) | 1991-11-28 |
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