阅读说明：本技术 手性3-羟基-1,2,3,6-四氢吡啶的合成方法 (synthesis method of chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine ) 是由 杨杰 方卫国 施国强 于 2019-09-10 设计创作，主要内容包括：本发明涉及有机合成技术领域,为解决手性3-羟基-1,2,3,6-四氢吡啶的传统合成工艺专一性不高、异构体手性纯度低、分离纯化方法复杂,不便于放大生产的问题,提供了手性3-羟基-1,2,3,6-四氢吡啶的合成方法,将式(Ⅳ)所示的化合物于15～30℃温度条件下,在脂肪酶作用下生成手性3-羟基-1,2,3,6-四氢吡啶,所述手性3-羟基-1,2,3,6-四氢吡啶的结构式如式(Ⅴ)所示；所述式(Ⅳ)和式(V)如下所示：<Image he="382" wi="700" file="DDA0002198104330000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中,P＝-CH<Sub>2</Sub>Ar或<Image he="119" wi="208" file="DDA0002198104330000012.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>R是1-8碳烷烃基或-CH<Sub>2</Sub>Ar,所述Ar为芳香环。本发明利用绿色环保的酶催化方法顺利制备该类化合物,其原料简单易得,成本低,合成步骤操作简单,易于实现。(the invention relates to the technical field of organic synthesis, and provides a synthesis method of chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine for solving the problems of low specificity, low chiral purity of isomers, complex separation and purification method and inconvenience for amplification production of the traditional synthesis process of chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine, wherein a compound shown in a formula (IV) is used for generating the chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine under the action of lipase at the temperature of 15-30 ℃, and the structural formula of the chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine is shown in a formula (V); the formula (IV) and the formula (V) are shown as follows: Wherein, P is-CH 2 Ar or R is a 1-8 carbon alkyl group or-CH 2 ar is an aromatic ring. The invention successfully prepares the compounds by utilizing an environment-friendly enzyme catalysis methodThe compound has the advantages of simple and easily obtained raw materials, low cost, simple operation of synthetic steps and easy realization.)

1. The method for synthesizing chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine is characterized in that a compound shown in a formula (IV) is subjected to lipase action at 15-30 ℃ to generate chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine, wherein the structural formula of the chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine is shown in a formula (V);

The formula (IV) and the formula (V) are shown as follows:

Wherein, P is-CH₂ar orR is a 1-8 carbon alkyl group or-CH₂ar is an aromatic ring.

2. the method for synthesizing chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine according to claim 1, wherein the feeding mass ratio of the lipase to the compound represented by the formula (IV) is 1: (0.5-0.6).

3. the method for synthesizing chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine according to claim 1, wherein the compound represented by the formula (IV) is prepared by reacting a compound represented by the formula (III) with NaBH₄and Ce³⁺The salt is combined with the reduction reaction to prepare the compound shown in the formula (III):

4. The method for synthesizing chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine according to claim 1, wherein the compound represented by the formula (IV) is prepared by the following steps:

(1) epoxidizing a double bond of a compound shown as a formula (I) to generate a compound shown as a formula (II); the reaction temperature is-20 to 40 ℃;

(2) Carrying out hydrolytic ring opening and elimination reaction on the compound shown in the formula (II) to generate a compound shown in a formula (IV); the reaction temperature is-70-0 ℃;

The compounds of formula (I) and formula (II) are shown below:

5. The method for synthesizing chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine according to claim 4, wherein in the step (1), the oxidizing agent used in the epoxidation reaction is hydrogen peroxide or alkane peroxy acid or aromatic peroxy acid, wherein R is an alkane group with 1-6 carbons, and the alkane group comprises halogenated alkane group; ar is a benzene ring or substituted benzene ring.

6. the method for synthesizing chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine according to claim 4, wherein in step (2), the hydrolytic ring opening and elimination reaction is performed by using a base, wherein the base is selected from lithium alkylamide, lithium piperidine and alkali metal silylamide, wherein R is 1-6 carbon alkyl, R' is 1-6 carbon alkyl, M is Li, K and Na.

7. The method of synthesizing chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine according to claim 1 or 4, characterized by comprising the steps of:

(1) dissolving an olefin compound shown in a formula (I) in dichloromethane, and then adding an oxidant at-20-40 ℃ to oxidize to generate a compound shown in a formula (II); the oxidant is hydrogen peroxide or peroxy acid;

(2) Cooling the first organic solvent solution of the alkali to 0-5 ℃, adding the first organic solvent solution of the compound shown in the formula (II), and reacting to obtain the compound shown in the formula (IV); the first organic solvent is selected from one of 2-methyltetrahydrofuran, 1, 2-glycol dimethyl ether and methyl tert-butyl ether; the base is lithium diisopropylamide, lithium 2,2,6, 6-tetramethylpiperidine or lithium hexamethyldisilazane;

(3) Dissolving a compound shown as a formula (IV) in toluene, adding vinyl acetate and lipase, and reacting at room temperature to generate chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine.

8. the method of claim 7, wherein the chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine is synthesized,

In the step (1), the equivalent ratio of the compound shown in the formula (I) to the oxidant is 1 (1.1-2.0); the volume ratio of the dichloromethane to the compound shown in the formula (I) is (5.0-10.0): 1;

In the step (2), the equivalent ratio of the compound shown in the formula (I) to the base is 1 (2.0-4.0), and the volume ratio of the first organic solvent to the compound shown in the formula (I) is (5.0-10.0): 1;

In the step (3), the volume ratio of the toluene to the compound shown in the formula (IV) is (30-60): 1; the equivalent ratio of the vinyl acetate to the compound shown as the formula (IV) is (3.0-5.0): 1.

9. A method of synthesizing chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine according to claim 1 or 3, characterized by comprising the steps of:

(a) Dissolving the compound shown in the formula (III) in a second organic solvent in Ce³⁺Under the catalysis of salt, NaBH is added₄Reacting to generate a compound shown in a formula (IV);

(b) Dissolving a compound shown as a formula (IV) in toluene, adding vinyl acetate and lipase, and reacting at room temperature to generate chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine.

10. the method of synthesizing chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine according to claim 9,

In step (a), the second organic solvent is methanol or ethanol or isopropanol or tetrahydrofuran; the compound shown as the formula (III) and NaBH₄The equivalent ratio of (1) is (0.5-1.5); the Ce³⁺the salt is CeCl₃or Ce (NO)₃)₃(ii) a The Ce³⁺The equivalent ratio of the salt to the compound represented by the formula (III) is (1.0-1.2): 1; the volume ratio of the second organic solvent to the compound shown in the formula (III) is (8-20): 1;

In the step (b), the volume ratio of the toluene to the compound shown as the formula (IV) is (30-60): 1; the equivalent ratio of the vinyl acetate to the compound shown as the formula (IV) is (3.0-5.0): 1.

Technical Field

the invention relates to the technical field of organic synthesis, in particular to a synthetic method of chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine based on immobilized lipase kinetic resolution.

background

Chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine (R or S) is an important medical intermediate, and a series of tetrahydropyridine compounds prepared from the chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine can be used for regulating the activity of protein kinase and regulating signal reaction between cells or in cells, and can also be used for treating hyperproliferative diseases.

The invention discloses 'substituted pyridine compounds and a using method and application thereof' in Chinese patent literature, and application publication No. CN103304552A, and further relates to a pharmaceutical composition containing the compounds provided by the invention and a method for treating hyperproliferative diseases of mammals, especially humans by using the pharmaceutical composition. The intermediate can also be used for preparing a series of antibacterial drugs (WO2004002490A, WO2004058144A2, WO2008142285A1, US20130225554A1) and compounds for treating nervous system diseases such as Alzheimer's disease and sleep disorder of Parkinson's disease (WO2018026371A 1).

However, few data reports are available at home and abroad for the preparation of chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine. Reduction Of boron hydrides controlled by chiral ligands has been reported (Russian Journal Of Organic Chemistry, 2008, 44, 282), but the specificity is not high and the post-reaction treatment is complicated. There is also a report of resolution by enzyme-catalyzed reaction (Synthesis, 2000, 4, 521), but its isolation and purification method is complicated and it is not easy to scale up the industrial production. And one of the isomers has a chiral purity of only 89% ee. In view of this, it is of great research significance to explore a more efficient method for synthesizing chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine.

Disclosure of Invention

The invention provides a synthetic method of chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine based on immobilized lipase kinetic resolution, which aims to overcome the problems of low specificity, low isomer chiral purity, complex separation and purification method and inconvenience for industrial production of the traditional synthetic process of chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine.

In order to achieve the purpose, the invention adopts the following technical scheme:

a synthesis method of chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine comprises the steps of generating chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine from a compound shown in a formula (IV) at the temperature of 15-30 ℃ under the action of lipase, wherein the structural formula of the chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine is shown in a formula (V);

The formula (IV) and the formula (V) are shown as follows:

Wherein, P is-CH₂ar orr is a 1-8 carbon alkyl group or-CH₂Ar is an aromatic ring.

the reaction scheme of the invention is as follows:

Wherein, the compound shown in the formula (VI) is a by-product (S) configuration compound acetate.

Preferably, the lipase includes AK, PS, F and CC. The lipase is a commercial lipase sold by Tianye Pharmaceutical Co., Ltd, and comprises Amano lipase AK (derived from Pseudomonas fluorescens), Amano lipase PS (derived from Burkholderia cepacia), Amano lipase F (derived from Rhizopus rhizogenes) and Amano lipase CC (derived from Candida cylindracea).

The invention synthesizes chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine by splitting a compound shown as a formula (IV) through immobilized lipase kinetics, and the reaction mechanism is that the esterification reaction is catalyzed by using lipase: the method is characterized in that a proper lipase is used for selectively catalyzing a specific chiral alcoholic hydroxyl group to carry out acetylation reaction, so that the alcoholic hydroxyl group with one configuration is selectively acetylated into ester, while the alcoholic hydroxyl group with the other configuration is not reacted (not acetylated into ester), and the (R/S) racemic compound is converted into two compounds with different properties (one is ester and the other is alcohol), so that the two compounds are easy to separate and the aim of chiral resolution is achieved. Therefore, under the catalytic action of lipase PS or AK and the like, the chiral alcoholic hydroxyl group with the (S) configuration in the racemic compound shown in the formula (IV) is selectively acetylated to generate the compound shown in the formula (VI), and the chiral alcohol with the (R) configuration is not reacted and is separated to obtain the compound shown in the formula (V).

Preferably, the feeding mass ratio of the lipase to the compound shown in the formula (IV) is 1: (0.5-0.6).

in the preparation of (R/S) racemic compounds of formula (IV), two different reaction schemes, scheme A and scheme B, may be used:

Route a: preferably, the compound shown in the formula (IV) is prepared by reacting a compound shown in a formula (III) with NaBH₄And Ce³⁺The salt is combined with the reduction reaction to prepare the compound shown in the formula (III):

Route B: preferably, the compound represented by the formula (IV) is prepared by the following steps:

(1) Epoxidizing a double bond of a compound shown as a formula (I) to generate a compound shown as a formula (II); the reaction temperature is-20 to 40 ℃;

(2) Carrying out hydrolytic ring opening and elimination reaction on the compound shown in the formula (II) to generate a compound shown in a formula (IV); the reaction temperature is-70-0 ℃;

The compounds of formula (I) and formula (II) are shown below:

The synthetic route of the compound represented by the above formula (IV) is as follows:

the feasible synthetic route of the chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine is shown as follows:

Wherein P is a protecting group: -CH₂Ar orin route B:

Preferably, in the step (1), the oxidant used in the epoxidation reaction in the step (1) is hydrogen peroxide (H)₂O₂) Or an alkane peroxyacid (RCOOOH) or aromatic peroxyacid (aroooh), wherein R is a 1-6 carbon alkane group including halogenated alkane groups; ar is a benzene ring or substituted benzene ring.

preferably, in step (2), the hydrolytic ring-opening and elimination reaction is carried out with the aid of a base which is lithium alkylamide (R)₂NLi), lithium piperidine (TMPLi) or alkali metal silylaminate ((R)'₃Si)₂NM), wherein R ═ 1-6 carbon alkyl, M ═ Li, K, Na.

Optionally, the invention further provides a synthesis method of chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine, which comprises the following steps:

(1) dissolving an olefin compound shown as a formula (I) in dichloromethane, and then adding an oxidant at-20-40 ℃ to oxidize to generate a compound (epoxy compound) shown as a formula (II); the oxidant is hydrogen peroxide (H)₂O₂) Or a peroxy acid;

(2) cooling the first organic solvent solution of the alkali to 0-5 ℃, adding the first organic solvent solution of the compound shown in the formula (II), and reacting to obtain the compound shown in the formula (IV) (racemic compound alcohol); the first organic solvent is selected from one of 2-methyltetrahydrofuran (2-Me-THF), 1, 2-ethylene glycol dimethyl ether (DME) and methyl tert-butyl ether (MTBE); the base is Lithium Diisopropylamide (LDA), lithium 2,2,6, 6-Tetramethylpiperidine (TMPLi) or lithium Hexamethyldisilazide (HMDSLi);

(3) Dissolving a compound shown as a formula (IV) in toluene, adding vinyl acetate and lipase, and reacting at room temperature to generate chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine.

In the step (1), the equivalent ratio of the compound shown in the formula (I) to the oxidant is 1 (1.1-2.0); the volume ratio of the dichloromethane to the compound shown in the formula (I) is (5.0-10.0): 1;

In the step (2), the equivalent ratio of the compound shown in the formula (I) to the base is 1 (2.0-4.0), and the volume ratio of the first organic solvent to the compound shown in the formula (I) is (5.0-10.0): 1;

In the step (3), the volume ratio of the toluene to the compound shown in the formula (IV) is (30-60): 1; the equivalent ratio of the vinyl acetate to the compound shown as the formula (IV) is (3.0-5.0): 1.

Optionally, the invention further provides a synthesis method of chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine, which comprises the following steps:

(a) Dissolving the compound shown in the formula (III) in a second organic solvent in Ce³⁺Under the catalysis of salt, NaBH is added₄reacting to generate a compound (racemic compound alcohol) shown as a formula (IV); (ii) a

(b) dissolving a compound shown as a formula (IV) in toluene, adding vinyl acetate and lipase, and reacting at room temperature to generate chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine.

Preferably, in step (a), the second organic solvent is methanol or ethanol or isopropanol or tetrahydrofuran; the compound shown as the formula (III) and NaBH₄the equivalent ratio of (1) is (0.5-1.5); the Ce³⁺the salt is CeCl₃or Ce (NO)₃)₃(ii) a The Ce³⁺The equivalent ratio of the salt to the compound represented by the formula (III) is (1.0-1.2): 1; the volume ratio of the second organic solvent to the compound shown in the formula (III) is (8-20): 1;

in the step (b), the volume ratio of the toluene to the compound shown as the formula (IV) is (30-60): 1; the equivalent ratio of the vinyl acetate to the compound shown as the formula (IV) is (3.0-5.0): 1.

the invention also provides a synthetic method of chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine, which comprises the following steps: dissolving the compound shown in the formula (IV) (R/S racemic compound alcohol) in toluene, adding vinyl acetate and lipase, and reacting at room temperature to convert into the compound shown in the formula (V) and the compound shown in the formula (S) acetate. Wherein the (R) configuration compound alcohol shown in the formula (V) is chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine, and the (S) configuration compound acetate shown in the formula (VI) is a byproduct.

Preferably, the lipase is selected from lipase PS or AK, and the feeding mass ratio of the lipase to the compound shown in the formula (IV) is 1: (0.5 to 0.6); the dosage of the toluene is 30-60 volumes of the compound shown in the formula (IV); the dosage of the vinyl acetate is 3.0-5.0 eq of the compound shown in the formula (IV).

Therefore, the invention has the following beneficial effects:

(1) Few reports of domestic and foreign data on the preparation of chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine exist, and the compound is successfully prepared by utilizing an environment-friendly enzyme catalysis method; the resolution effect is good, the racemic compound can be resolved into two high-purity chiral products, and the optical purity is more than 99% ee;

(2) The process uses enzyme catalysis to split chiral molecules, and the operation is green and environment-friendly; the immobilized enzyme can be recycled and reused, the efficiency is high, and solid waste is not generated. The immobilized enzyme can be recycled and reused, the used solvent can be completely recycled and reused, and no liquid waste is generated;

(3) the raw materials are simple and easy to obtain, and the cost is low; the racemic compound shown in the formula (IV) can be prepared from an olefin compound shown in the formula (I) or a compound alpha, beta-unsaturated ketone shown in the formula (III), and has no special requirements on reaction reagents and operation steps;

(4) the synthesis steps in the invention are simple to operate and easy to realize, and the reaction is carried out at room temperature, thus being applicable to laboratory synthesis and large-scale industrial production.

Drawings

FIG. 1 shows the compound of formula (V) obtained in example 1Hydrogen spectrum of¹HNMR spectrogram.

FIG. 2 is a hydrogen spectrum of the compound represented by the formula (V) obtained in example 4¹HNMR spectrogram.

Detailed Description

the technical solution of the present invention is further specifically described below by using specific embodiments and with reference to the accompanying drawings.

in the present invention, all the equipment and materials are commercially available or commonly used in the art, and the methods in the following examples are conventional in the art unless otherwise specified.

the lipase of the invention is purchased from Amano Enzyme, and the production batch number is as follows: lipase AK Wako 325-; lipase PS, Wako 321-88523; lipase F: Wako 325-58351; lipase CC: Wako 043-22351.