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CN103153936A - 改进的培瑞维a酸的合成 - Google Patents

改进的培瑞维a酸的合成 Download PDF

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CN103153936A
CN103153936A CN2011800477621A CN201180047762A CN103153936A CN 103153936 A CN103153936 A CN 103153936A CN 2011800477621 A CN2011800477621 A CN 2011800477621A CN 201180047762 A CN201180047762 A CN 201180047762A CN 103153936 A CN103153936 A CN 103153936A
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peretinoin
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拉斐尔·布玛
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    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
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    • C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
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    • 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
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    • C07F9/02—Phosphorus compounds
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    • C07F9/02—Phosphorus compounds
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
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Abstract

本发明涉及培瑞维A酸的新颖和改进的合成方法。

Description

改进的培瑞维A酸的合成
本发明涉及培瑞维A酸的新颖和改进的合成。
培瑞维A酸(peretinoin，培瑞维甲酸，亦称为NIK333)是一种无环的维甲酸。这种化合物可用于在丙型肝炎病毒(HCV)阳性患者的手术切除或消融之后减少肝细胞癌(HCC)的复发。
肝癌是世界第六大常见癌症，每年新诊断的有超过六十万例。在日本，肝癌是癌症死亡的第三大原因。每年新确诊的患者约40000例，每年死亡约35000例患者。原发性肝癌分为肝细胞癌(HCC)和胆管细胞癌，其中约94%是HCC。HCC主要是由乙型肝炎病毒或HCV（丙型肝炎病毒）感染引起的，而在日本约67%的肝癌是由HCV引起的。已知HCV阳性肝细胞癌(HCC)在根治性切除术后复发率较高，1年、3年和5年内的复发率分别为24%、76%和92%。
培瑞维A酸是用于对抗肝癌的重要化合物。因此，合成该化合物的任何改进方法都很重要。
本发明涉及一种制备培瑞维A酸的改进方法，其中该方法可以作为一锅法进行。新方法的另一个优点为，盐（使用的盐以及在各个步骤中形成的盐）的量很低，这导致产生更少的废品。此外，该方法可以作为一锅法进行，使得处理更加简单（没有中间体的分离）。
因此，所述培瑞维A酸的制备方法的特征在于，其包括下面的反应（步骤a）：
(a)式(I)或式(I’)的化合物与式(II)的化合物反应，
Figure BDA00002997870200011
其中
R2为取代的苯基、未取代的苯基、-(CH2)3-OH、或-(CH2)3-CH3，
R'2为OC1-C4烷基，并且
X为卤素离子，优选为I和Br，
其中R1为H或C1-C4烷基。
从该步骤得到的反应产物为式(III)的化合物
Figure BDA00002997870200022
其中R1为H或C1-C4烷基。
NIK333是式(IIIa)的化合物
Figure BDA00002997870200023
为了得到式(I)的化合物，可以实施下面的制备方法(步骤b)：
式(IV)的化合物与HX以及式(V)的化合物反应
Figure BDA00002997870200024
其中X为卤素原子，优选为I和Br；
其中R2为取代的苯基、未取代的苯基、-(CH2)3-OH、或-(CH2)3-CH3。其反应产物是如上所述的式(I)化合物。
为了得到式(I’)的化合物。可以实施下面的制备方法(步骤b')：
式(IV)的化合物与HX以及式(V’)的化合物反应
其中X为卤素原子，优选为I和Br；
其中R’2为OC1-C4烷基。其反应产物是如上所述的式(I’)化合物。
如上所述，本发明的方法的优点为，该方法为一系列反应步骤中的一部分，其可以作为一锅法进行，并且其中盐（使用的盐以及在各个步骤中形成的盐）的量很低。下面将详细讨论各个反应步骤。
步骤a)
该反应通常在惰性有机溶剂或惰性有机溶剂的混合物中进行。合适的溶剂为例如，醇类，如甲醇、乙醇、正丁醇和异丙醇；CH3CN；CH2Cl2；THF；DMF；乙酸酯（acetic acid ester）；己烷；环己烷和甲苯。
一般，向反应添加碱（或其混合物）。合适的碱为例如BuLi、NaOMe和NaOEt。优选地，反应在大气压下进行。优选地，反应在室温（20°C至25°C）下或在至多60°C的温度下进行。
步骤b)和b')
该反应通常（并且优选地）在与步骤a)相同的惰性有机溶剂或惰性有机溶剂的混合物中进行。合适的溶剂为例如，醇类，如甲醇、乙醇、正丁醇和异丙醇；CH3CN；CH2Cl2；THF；DMF；乙酸酯；己烷；环己烷和甲苯。一般，向反应添加碱（或其混合物）。合适的碱为例如BuLi、NaOMe和NaOEt。
优选地，反应在大气压下进行。优选地，反应在0°C至80°C的温度下进行。
步骤b')的反应条件与步骤b)相同。

Claims (2)

1.一种用于制备培瑞维A酸的方法，其包括下面的反应步骤：
式(I)或式(I’)的化合物与式(II)的化合物反应，
Figure FDA00002997870100011
其中
R2为取代的苯基、未取代的苯基、-(CH2)3-OH、或-(CH2)3-CH3，
R'2为OC1-C4烷基，并且
X为卤素离子，优选为I和Br，
Figure FDA00002997870100012
其中R1为H或C1-C4烷基。
2.如权利要求1所述的方法，其中，式(I)或式(I’)的化合物通过下列反应形成，其中式(IV)的化合物与HX以及式(V)或式(V’)的化合物反应
Figure FDA00002997870100013
其中X为卤素原子，优选为I和Br；
其中R2为取代的苯基、-(CH2)3-OH、或-(CH2)3-CH3；并且
其中R’2为OC1-C4烷基。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1319600A (zh) * 2000-03-02 2001-10-31 Basf公司 制备鏻盐的方法
CN1771227A (zh) * 2003-04-11 2006-05-10 霍夫曼-拉罗奇有限公司 制造9－顺式视黄酸的方法
CN101035748A (zh) * 2003-10-24 2007-09-12 巴斯福股份公司 制备六氢番茄红素的方法

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56140949A (en) * 1980-04-07 1981-11-04 Eisai Co Ltd 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenic acid
JPS57181012A (en) * 1981-04-30 1982-11-08 Eisai Co Ltd Drug composed of polyprenyl compound
JPS57106638A (en) * 1980-12-24 1982-07-02 Eisai Co Ltd Conjugated polyprenylcarboxylic acid and its derivative
JP4290847B2 (ja) * 1999-04-23 2009-07-08 興和株式会社 ポリプレニル系化合物の精製方法
US6703527B2 (en) * 2001-05-24 2004-03-09 Nikken Chemicals Co., Ltd. Method for oxidation of allyl alcohol
WO2003106397A1 (en) * 2002-06-01 2003-12-24 Medestea Research & Production S.R.L. A process for preparing long chain saturated or unsaturated oxygenated compounds
JP4520203B2 (ja) * 2003-04-18 2010-08-04 興和株式会社 ポリプレニル系化合物の製造方法
DE10359434A1 (de) * 2003-12-17 2005-07-21 Basf Ag Verfahren zur Herstellung von Phosphoniumsalzen

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1319600A (zh) * 2000-03-02 2001-10-31 Basf公司 制备鏻盐的方法
CN1771227A (zh) * 2003-04-11 2006-05-10 霍夫曼-拉罗奇有限公司 制造9－顺式视黄酸的方法
CN101035748A (zh) * 2003-10-24 2007-09-12 巴斯福股份公司 制备六氢番茄红素的方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
J.B.DAVIS,ET AL: "Carotenoids and Related Compounds. Part XV.The Structure and Synthesis of Phytoene, Phytofluene, ζ-Carotene, and Neurosporene", 《J.CHEM.SOC.(C)》, 1 January 1966 (1966-01-01), pages 2154 - 2165, XP009044476, DOI: 10.1039/j39660002154 *
TOSHIO ONO ET AL.: "Reaction of α-(Phenylsulfinyl)acetonitrile with Aldehydes and Ketones to γ-Hydroxyalkenenitriles and Syntheses of Terpenoids", 《J. AM. CHEM. SOC.》, vol. 106, no. 25, 31 December 1984 (1984-12-31), pages 7890 - 7893, XP002446198, DOI: 10.1021/ja00337a042 *

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EP2621883A1 (en) 2013-08-07
BR112013007818B1 (pt) 2021-07-13
US20130281736A1 (en) 2013-10-24
JP2013540762A (ja) 2013-11-07
WO2012041949A1 (en) 2012-04-05
BR112013007818A2 (pt) 2016-06-21
EP2621883B1 (en) 2017-09-27
US9296677B2 (en) 2016-03-29

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