CN111108086A - 用于维生素a合成的新中间体 - Google Patents

用于维生素a合成的新中间体 Download PDF

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CN111108086A
CN111108086A CN201880061082.7A CN201880061082A CN111108086A CN 111108086 A CN111108086 A CN 111108086A CN 201880061082 A CN201880061082 A CN 201880061082A CN 111108086 A CN111108086 A CN 111108086A
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vitamin
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拉斐尔·布玛
维尔纳·邦拉蒂
马克-安德烈·米勒
贝蒂娜·乌斯腾伯格
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B49/00—Grignard reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
    • C07C403/08—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
    • C07C403/12—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/293—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/14—Acetic acid esters of monohydroxylic compounds
    • C07C69/145—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

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Abstract

本发明涉及式(I)的化合物。本发明还涉及式(II)的化合物。本发明还涉及这些化合物的合成及其在有机合成中的用途，特别是在维生素A或p‑胡萝卜素及其衍生物(例如角黄素、虾青素或玉米黄质)的合成中的用途。

Description

用于维生素A合成的新中间体
本发明涉及新的化合物，它们的合成及其在有机合成中的用途，特别是在维生素A、维生素A乙酸酯或β-胡萝卜素及其衍生物(例如角黄素、虾青素或玉米黄质)的合成中的用途。
特别要提到的是，这些新化合物可用作维生素A或β-胡萝卜素合成中的中间体(结构单元)，优选在维生素A(或维生素A乙酸酯)合成中的中间体(结构单元)。
维生素A或其衍生物，例如维生素乙酸酯
Figure BDA0002418667290000011
是许多应用的重要成分。维生素A在整个(人类)身体的各种功能中发挥作用，例如视觉过程、基因转录、免疫功能、骨骼代谢、造血作用、皮肤和细胞健康以及抗氧化功能。
由于维生素A(及其衍生物)的重要性及其合成的复杂性，始终需要改进的生产方法。
本发明的目的是找到易于获得的化合物，这样的化合物然后可用于维生素A或其衍生物或β-胡萝卜素的改进合成中，优选维生素A(乙酸酯)的改进合成中。
该目的通过如下公开和描述的化合物和合成得以实现。
发现了作为有用中间体的三种新化合物：
β-环香叶基香叶基乙酸酯(式(I)的化合物)
Figure BDA0002418667290000021
以及β-环香叶基芳樟基乙酸酯(式(II)的化合物)
Figure BDA0002418667290000022
它是式(I)的化合物的前体化合物。
因此，本发明的一个实施方案是式(I)的化合物
Figure BDA0002418667290000023
因此，本发明的另一个实施方案是式(II)的化合物
Figure BDA0002418667290000024
新的合成使用6-甲基-8-(2,6,6-三甲基-1-环己烯-1-基)-5-辛烯-2-酮(式(III)的化合物)作为起始材料
Figure BDA0002418667290000025
根据文献已知的方法，例如，以下方式，合成6-甲基-8-(2,6,6-三甲基-1-环己烯-1-基)-5-辛烯-2-酮(式(III)的化合物)：
Figure BDA0002418667290000031
[1]L.Ruzicka，W.Fischer.Helv.Chim.Acta 1934，17，633-639.
可以通过标准有机化学方法，例如通过格氏反应，将6-甲基-8-(2，6，6-三甲基-1-环己烯-1-基)-5-辛烯-2-酮转化为β-环香叶基芳樟醇(式(IV)的化合物)。
生产式(I)和(II)的化合物的反应方案如下：
Figure BDA0002418667290000032
因此，本发明涉及生产式(II)的化合物的方法
Figure BDA0002418667290000033
其中式(IV)的化合物
Figure BDA0002418667290000041
与化合物(乙酸酐或类似物)反应，以形成式(II)的化合物。
步骤(i)：
步骤(i)可以根据标准有机化学方法(例如格氏反应)进行。
步骤(ii)：
式(IV)的化合物被乙酰化。这可以通过通常已知的化合物(例如乙酸酐)来完成。
步骤(ii)的反应在叔胺、优选三乙胺的存在下进行。非常常见且优选的是，还使用至少一种亲核催化剂，例如二甲基氨基吡啶。
通常，步骤(ii)的反应在惰性气体气氛下进行。
步骤(ii)的反应通常在升高的温度下进行，通常高于30℃(在30-80℃的范围内)下进行。
然后可以分离得到的产物(式(II)的化合物)，如果需要可以进一步纯化。所获得的产率通常高于80％。
步骤(iii)：
通过式(II)的化合物的反应获得了式(I)的化合物。这是重排反应。
(步骤(iii))。
Figure BDA0002418667290000042
通常，步骤(iii)的反应在有机溶剂中进行。合适的溶剂是醚类，例如THF、甲苯、甲基-THF、甲基环戊基醚、叔丁基甲基醚、叔丁基乙基醚、叔戊基甲基醚或它们的混合物。最优选的溶剂是醚类，例如THF或2-MeTHF。
通常，步骤(iii)的反应在催化剂(例如双(乙腈)-二氯钯或双(苄腈)-二氯钯)的存在下进行。
然后分离产物，通常通过公知的方法纯化。通常以大于50％的总产率(基于式(II)的化合物)获得式(I)的化合物。
根据本发明的式(I)和(II)的化合物可以用于有机合成中。
优选地，新化合物可用作维生素A或β-胡萝卜素或其衍生物(优选维生素A)的合成中的中间体(结构单元)。因此，本发明的另一个实施方案涉及式(I)和(II)的化合物在维生素A或β-胡萝卜素(优选维生素A)的合成中作为中间体(结构单元)的用途。
下列实施例用于说明本发明。温度以℃为单位，所有百分比均与重量有关。
实施例1：β-环香叶基芳樟醇的合成
在惰性气体气氛下，将22mmol的(E)-6-甲基-8-(2,6,6-三甲基环己基-1-烯-1-基)辛-5-烯-2-酮(III)溶解在22毫升无水THF中。用冰浴将溶液冷却至0–5℃。在2小时内，滴加33mmol乙烯基溴化镁溶液(在THF中为1M)，使温度保持在0–5℃之间。加完后，继续搅拌1小时。之后，移去冰浴，并将反应温热至室温。在24℃下1小时后，在10分钟内(放热)逐滴加入饱和NH4Cl溶液(30ml)。再搅拌30分钟后，将混合物用二氯甲烷(100ml)稀释，并用盐水(2×45ml)洗涤。用二氯甲烷(2×100ml)再次萃取水层。合并的有机层经硫酸钠干燥、过滤并减压浓缩。粗产物通过柱色谱法纯化(SiO2，环己烷/二异丙醚8：2)。
实施例2：β-环香叶基芳樟醇乙酸酯的合成
在惰性气体气氛下，将3.44mmol的β-环香叶基芳樟醇溶解在6.9ml甲苯中。在室温下，加入8.61mmol的三乙胺和1.722mmol的二甲基氨基吡啶(DMAP)。向无色溶液中加入8.61mmol乙酸酐。然后将反应混合物加热至50℃并搅拌2小时。
将反应混合物冷却至室温，转移至分液漏斗中，并用15ml二乙醚稀释。随后将有机层用半饱和的NaHCO3溶液(30ml)、水(30ml)和盐水(30ml)洗涤。用二乙醚(30ml)再次萃取水层。合并的有机层经Na2SO4干燥、过滤并在减压下浓缩。通过柱色谱法(SiO2，环己烷/二异丙醚8：2)纯化粗产物。获得的纯化产物为无色液体，产率为81％。
实施例3：β-环香叶基香叶醇乙酸酯的合成
在惰性气体气氛下，将0.05mmol双(乙腈)-二氯钯溶解在1ml无水THF中。在室温下，在20分钟内加入1mmol的β-环香叶基芳樟醇乙酸酯在4ml的无水THF中的溶液。在室温下搅拌4小时后，反应完成。除去溶剂，并通过柱色谱法(SiO2，正己烷/乙酸乙酯95：5)纯化粗产物。得到的纯化产物为黄色液体，产率为50％。

Claims (8)

1.式(I)的化合物
Figure FDA0002418667280000011
2.式(II)的化合物
Figure FDA0002418667280000012
3.式(II)的化合物的生产方法
Figure FDA0002418667280000013
其中式(IV)的化合物
Figure FDA0002418667280000014
与乙酸酐或类似物反应，以形成式(II)的化合物。
4.式(I)的化合物的生产方法，
Figure FDA0002418667280000015
其中式(II)的化合物进行催化重排
Figure FDA0002418667280000016
5.式(I)的化合物在有机合成中的用途。
6.根据权利要求5的用途，其中生产维生素A或β-胡萝卜素(优选维生素A)。
7.式(II)的化合物在有机合成中的用途。
8.根据权利要求7的用途，其中生产维生素A或β-胡萝卜素(优选维生素A)。
CN201880061082.7A 2017-09-22 2018-09-13 用于维生素a合成的新中间体 Pending CN111108086A (zh)

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BR112021020443A2 (pt) * 2019-04-15 2022-03-03 Dsm Ip Assets Bv Enol-acetatos(ii)
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