阅读说明：本技术 手性化合物的合成方法 (Method for synthesizing chiral compound ) 是由 岳祥军 王志邦 田磊 邹慧 徐靖坤 陈小峰 刘安友 王瑞 邹春伟 于 2018-12-18 设计创作，主要内容包括：本发明属于化学合成技术领域,涉及手性化合物的合成方法,具体是(1<I>R</I>,2<I>S</I>)-1-苯基-2-(吡咯烷-1-基)丙-1-醇的合成方法。本发明的巧妙合成策略,使得羰基还原时能够实现不对称还原,直接高收率得到目标化合物。改善了现有工艺中无法通过不对称还原高收率得到目标化合物的问题。而且,本发明使用廉价的盐酸、氯化锌即可实现高纯度化合物(A)的合成；此外,本发明无任何异构体浪费；另外,本发明方法避免了使用去甲麻黄碱管控品；本发明的原料廉价易得,降低了合成成本；并且,本发明的制备方法易于工业化大生产。(The invention belongs to the technical field of chemical synthesis, and relates to a synthesis method of a chiral compound, in particular to (1) R ,2 S ) A method for synthesizing (E) -1-phenyl-2- (pyrrolidine-1-yl) propane-1-ol. The ingenious synthesis strategy of the invention enables asymmetric reduction to be realized during carbonyl reduction, and the target compound can be directly obtained with high yield. The problem that the target compound cannot be obtained in high yield through asymmetric reduction in the prior art is solved. In addition, the invention can realize the synthesis of the high-purity compound (A) by using cheap hydrochloric acid and zinc chloride; in addition, the invention has no isomer waste; in addition, the method avoids using a methamphetamine removal control product; the raw materials are cheap and easy to obtain, and the synthesis cost is reduced; moreover, the preparation method is easy for industrial mass production.)

1. A method for synthesizing a chiral compound shown in a formula (II),

the synthesis method comprises an alkylation step, and specifically comprises the following steps: carrying out alkylation reaction on L-alanine (I) and an alkylating reagent to obtain a compound (II);

2. the synthetic method of claim 1, wherein the alkylating agent is an alkane substituted with one or more leaving groups (X); the leaving group is selected from halogen, mesyloxy or p-toluenesulfonyloxy;

preferably, the alkylating agent is selected from alkanes substituted with one or more halogens, such as halogenated alkanes, preferably dihaloalkanes; the halogen is selected from chlorine, bromine or iodine;

for example, the alkylating agent is 1, 4-dichlorobutane, 1, 4-dibromobutane, 1, 4-diiodobutane;

the reaction temperature is 20-150 ℃, preferably 50-100 ℃;

the reaction is carried out in a solvent, wherein the solvent is one or two or more selected from aromatic hydrocarbon solvents, ether solvents, nitrile solvents, ketone solvents, amide solvents and alcohol solvents, and is preferably any one or combination of toluene, xylene, tetrahydrofuran, dioxane, acetonitrile, propionitrile, acetone, butanone, methyl isopropyl ketone, N-dimethylformamide, methanol, ethanol, propanol, isopropanol, butanol and tert-butanol;

preferably, the reaction is carried out in the presence of a base; the alkali is selected from any one or combination of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium bicarbonate;

the molar ratio of the L-alanine (I) to the alkylating agent is 1 (1-3), preferably 1: 1;

HX in compound (II) is the acid corresponding to the leaving group, for example any of hydrochloric acid, hydrobromic acid, hydroiodic acid or a combination thereof.

3. A method for synthesizing a chiral compound shown in a formula (III),

wherein, the synthesis method comprises the following steps:

(1) alkylation: carrying out alkylation reaction on L-alanine (I) and an alkylating reagent to obtain a compound (II);

(2) acylation: reacting the compound (II) with a halogenating agent to convert into acyl halide, and then carrying out Friedel-crafts acylation reaction on the acyl halide and benzene to obtain a compound (III);

4. the synthesis method according to claim 3, wherein, in the step of synthesizing acyl halide in the step (2),

the reaction temperature is 10-100 ℃, and preferably 20-80 ℃;

the reaction is carried out in a solvent selected from halogenated hydrocarbon solvents, such as any one of dichloromethane, 1, 2-dichloroethane, or a combination thereof;

the reaction may be carried out with the addition of a catalyst, such as N, N-dimethylformamide;

the halogenating agent is selected from any one of oxalyl chloride, oxalyl bromide, thionyl chloride, thionyl bromide, bis (trichloromethyl) carbonate or a combination thereof;

in the step (2) of carrying out Friedel-crafts acylation reaction of acyl halide and benzene,

the reaction temperature is 10-100 ℃, and preferably 20-80 ℃;

the reaction may be carried out with the addition of a catalyst selected from the group consisting of aluminum trichloride, ferric trichloride, boron trifluoride, bismuth trichloride, active ferric oxide (alpha-Fe)₂O₃) Any one or a combination thereof.

5. A method for synthesizing the mixture (IV),

wherein, the synthesis method comprises the following steps:

(1) alkylation: carrying out alkylation reaction on L-alanine (I) and an alkylating reagent to obtain a compound (II);

(2) acylation: reacting the compound (II) with a halogenating agent to convert into acyl halide, and then carrying out Friedel-crafts acylation reaction on the acyl halide and benzene to obtain a compound (III);

(3) reduction: reacting the compound (III) with a reducing agent to obtain a mixture (IV);

6. the synthetic method according to claim 5, wherein, in the step (3),

the reaction temperature is-10-100 ℃, preferably-10-60 ℃, and more preferably-5-10 ℃;

the reaction may be carried out in a solvent selected from one, two or more of an ether solvent, an alcohol solvent, such as any one of tetrahydrofuran, dioxane, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, or a combination thereof;

the reducing agent can be any one or combination of lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium aluminum hydride, sodium dihydro bis (2-methoxyethoxy) aluminate and diisobutyl aluminum hydride, and is preferably sodium borohydride;

the reaction can be added with a reduction auxiliary agent, and the reduction auxiliary agent can be any one or the combination of calcium chloride, magnesium bromide, magnesium acetate, zinc chloride, zinc bromide, zinc acetate, zinc sulfate, zinc methanesulfonate and zinc trifluoromethanesulfonate, preferably zinc chloride and zinc bromide;

the molar ratio of the compound (III) to the reducing agent to the reduction auxiliary agent is 1 (1-2) to (0-1), preferably 1 (1-1.5) to (0-0.5);

the reaction time is 30 minutes to 20 hours, preferably 30 minutes to 8 hours.

7. A process for the synthesis of the crude salt (V),

wherein, the synthesis method comprises the following steps:

(1) alkylation: carrying out alkylation reaction on L-alanine (I) and an alkylating reagent to obtain a compound (II);

(2) acylation: reacting the compound (II) with a halogenating agent to convert into acyl halide, and then carrying out Friedel-crafts acylation reaction on the acyl halide and benzene to obtain a compound (III);

(3) reduction: reacting the compound (III) with a reducing agent to obtain a mixture (IV);

(4) salifying: reacting the mixture (IV) with a resolving agent (HY) to obtain a crude salt (V);

in the step (4), the step (c),

the reaction temperature is 0-100 ℃, and preferably 0-80 ℃;

the reaction may be carried out in a solvent, which may be one, two or more of an ether solvent, a nitrile solvent, a ketone solvent, an alcohol solvent, such as any one of tetrahydrofuran, dioxane, acetonitrile, propionitrile, acetone, butanone, methyl isopropyl ketone, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, or a combination thereof;

the resolving agent may be selected from any one of D-tartaric acid, D-malic acid, D-lactic acid, (S) -mandelic acid, (R) -camphorsulfonic acid, D-tartaric acid dibenzoate, L-tartaric acid, L-malic acid, L-lactic acid, (S) -camphorsulfonic acid, L-tartaric acid dibenzoate, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, or combinations thereof;

the reaction time may be 30 minutes to two days, preferably 30 minutes to 30 hours.

8. A process for the synthesis of optically pure salt (VI),

wherein, the synthesis method comprises the following steps:

(1) alkylation: carrying out alkylation reaction on L-alanine (I) and an alkylating reagent to obtain a compound (II);

(2) acylation: reacting the compound (II) with a halogenating agent to convert into acyl halide, and then carrying out Friedel-crafts acylation reaction on the acyl halide and benzene to obtain a compound (III);

(3) reduction: reacting the compound (III) with a reducing agent to obtain a mixture (IV);

(4) salifying: reacting the mixture (IV) with a resolving agent (HY) to obtain a crude salt (V);

(5) and (3) recrystallization: recrystallizing the crude salt (V) to obtain an optically pure salt (VI);

in the step (5), the step (c),

the recrystallization operation may be: mixing the crude salt (V) with a solvent, heating for dissolving, cooling, stirring, and separating out crystals to obtain optically pure salt (VI);

the heating temperature in the recrystallization step is 0-100 ℃, and preferably 0-80 ℃;

the solvent of the recrystallization step is selected from one, two or more of ether solvents, nitrile solvents, ketone solvents, alcohol solvents, such as any one or combination of tetrahydrofuran, dioxane, acetonitrile, propionitrile, acetone, butanone, methyl isopropyl ketone, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol;

the time for heating and the time for lowering the temperature in the recrystallization step are the same or different and are selected independently of each other from 30 minutes to two days, preferably from 30 minutes to 30 hours.

9. A method for synthesizing the compound (A),

wherein, the synthesis method comprises the following steps:

(1) alkylation: carrying out alkylation reaction on L-alanine (I) and an alkylating reagent to obtain a compound (II);

(2) acylation: reacting the compound (II) with a halogenating agent to convert into acyl halide, and then carrying out Friedel-crafts acylation reaction on the acyl halide and benzene to obtain a compound (III);

(3) reduction: reacting the compound (III) with a reducing agent to obtain a mixture (IV);

(4) salifying: reacting the mixture (IV) with a resolving agent (HY) to obtain a crude salt (V);

(5) and (3) recrystallization: recrystallizing the crude salt (V) to obtain an optically pure salt (VI);

(6) desalting: desalting the optically pure salt (VI) to obtain an optically pure compound (A);

in the step (6), the step (c),

the reaction temperature is 0-100 ℃, and preferably 20-50 ℃;

the reaction may be carried out in a solvent, which may be one, two or more of halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, ether solvent, ester solvent, alkane solvent, water, such as any one of dichloromethane, 1, 2-dichloroethane, toluene, xylene, diethyl ether, isopropyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethyl acetate, isopropyl acetate, hexane, cyclohexane, heptane, water, or a combination thereof;

the reaction may be carried out by adding a base, which may be any one of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, ammonia water, or a combination thereof.

10. A method for synthesizing the compound (III),

wherein, the synthesis method comprises the following steps:

1) desalting: combining the mother liquor of the salt forming step according to any one of claims 7 to 9 and the mother liquor of the recrystallization step according to claim 8 or 9, evaporating the volatiles under reduced pressure, and reacting the residue with a base to obtain a mixture (IV);

2) and (3) oxidation: reacting the mixture (IV) with an oxidant to obtain a compound (III);

in the step 1), the step (A) is carried out,

the reaction temperature is 0-100 ℃, and preferably 20-50 ℃;

the reaction may be carried out in a solvent, which may be one, two or more of halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, ether solvent, ester solvent, alkane solvent, water, such as any one or combination of dichloromethane, 1, 2-dichloroethane, toluene, xylene, diethyl ether, isopropyl ether, methyl t-butyl ether, ethylene glycol dimethyl ether, ethyl acetate, isopropyl acetate, hexane, cyclohexane, heptane, water;

the alkali can be any one or the combination of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate and ammonia water;

in the step 2), the step (c) is carried out,

the reaction temperature is-10-100 ℃, and preferably 0-50 ℃;

the reaction may be carried out in a solvent, which may be one, two or more of halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, ether solvent, ester solvent, alkane solvent, water, such as any one or combination of dichloromethane, 1, 2-dichloroethane, toluene, xylene, diethyl ether, isopropyl ether, methyl t-butyl ether, ethylene glycol dimethyl ether, ethyl acetate, isopropyl acetate, hexane, cyclohexane, heptane, water;

the oxidant can be any one or the combination of chromium trioxide, sodium dichromate, potassium permanganate, sodium permanganate, pyridine dichromate, Dess-Martin reagent and manganese dioxide, and is preferably sodium dichromate;

preferably, the reaction may be carried out under acidic conditions followed by adjustment of the pH of the solution with a base;

preferably, the pH of the solution may be adjusted to 8-11, for example 10;

the acid can be selected from any one of sulfuric acid, hydrochloric acid and phosphoric acid or the combination of the sulfuric acid, the hydrochloric acid and the phosphoric acid;

the alkali can be any one of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate and ammonia water or the combination of the lithium hydroxide, the sodium hydroxide, the potassium hydroxide, the sodium carbonate, the potassium carbonate, the cesium carbonate, the sodium bicarbonate and the ammonia water.

Technical Field

The invention belongs to the technical field of chemical synthesis, and relates to a synthesis method of a chiral compound, in particular to a synthesis method of (1R,2S) -1-phenyl-2- (pyrrolidine-1-yl) propane-1-ol.

Background

The synthesis of chiral compounds, particularly compounds having multiple chiral centers, generally suffers from low yields. In designing the synthesis of the chiral center compound, the selection of the synthetic route is important, especially for industrial mass production.

The chiral ligand, (1R,2S) -1-phenyl-2- (pyrrolidine-1-yl) propan-1-ol, plays a crucial role in the chiral control of Efavirenz (Efavirenz) which is a medicament for treating AIDS (US6015926A), and the process flow is shown as the following formula.

US5856492A discloses the preparation of chiral ligands with demethyl ephedrine [ L- (-) -norephrine, (1R,2S) -2-amino-1-phenylpropan-1-ol ] and 1, 4-dibromobutane. The methamphetamine belongs to a control product and has large-scale and commercialization difficulty. The process flow is shown as the following formula.

WO2015063795A2 discloses a method for preparing an optical homochiral ligand, which is realized by six steps of halogenation, amination, sodium borohydride reduction, D-tartaric acid resolution, tartrate recrystallization purification and tartaric acid removal. This method is not economical because only 50% of the desired chiral ligand is theoretically available. The process flow is shown as the following formula.

Disclosure of Invention

In order to improve the problems, the invention provides a method for synthesizing a chiral compound shown in the following formula (II),

the synthesis method comprises an alkylation step, and specifically comprises the following steps: and (3) carrying out alkylation reaction on the L-alanine (I) and an alkylating agent to obtain a compound (II).

According to the invention, the alkylating agent is an alkane substituted with one or more leaving groups (X); the leaving group is selected from halogen, mesyloxy or p-toluenesulfonyloxy;

preferably, the alkylating agent is selected from alkanes substituted with one or more halogens, such as halogenated alkanes, preferably dihaloalkanes; the halogen is selected from chlorine, bromine or iodine;

for example, the alkylating agent may be 1, 4-dichlorobutane, 1, 4-dibromobutane, 1, 4-diiodobutane;

according to the invention, the reaction temperature is 20-150 ℃, preferably 50-100 ℃;

according to the present invention, the reaction may be carried out in a solvent, which may be one, two or more of an aromatic hydrocarbon solvent, an ether solvent, a nitrile solvent, a ketone solvent, an amide solvent, an alcohol solvent, preferably any one or a combination of toluene, xylene, tetrahydrofuran, dioxane, acetonitrile, propionitrile, acetone, butanone, methyl isopropyl ketone, N-dimethylformamide, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol;

according to the invention, the reaction can be carried out in the presence of a base; the alkali can be any one or the combination of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium bicarbonate;

according to the invention, the molar ratio of L-alanine (I) to alkylating agent is 1 (1-3), preferably 1: 1;

according to the invention, HX in compound (ii) is the acid corresponding to the leaving group, for example any one of hydrochloric acid, hydrobromic acid, hydroiodic acid or a combination thereof.

The compound (II) can be used as an intermediate for synthesizing (1R,2S) -1-phenyl-2- (pyrrolidine-1-yl) propan-1-ol, and the (1R,2S) -1-phenyl-2- (pyrrolidine-1-yl) propan-1-ol can be used as a chiral ligand in the synthesis process of Efavirenz (Efavirenz).

The invention also provides a method for synthesizing the chiral compound shown in the following formula (III),

wherein, the synthesis method comprises the following steps:

(1) alkylation: carrying out alkylation reaction on L-alanine (I) and an alkylating reagent to obtain a compound (II);

(2) acylation: the compound (II) reacts with a halogenating agent to be converted into acyl halide, and then the acyl halide and benzene are subjected to Friedel-crafts acylation reaction to obtain a compound (III).

According to the present invention, in the step (1),

the alkylating agent is an alkane substituted with one or more leaving groups (X); the leaving group is selected from halogen, mesyloxy or p-toluenesulfonyloxy;

preferably, the alkylating agent is selected from alkanes substituted with one or more halogens, such as halogenated alkanes, preferably dihaloalkanes; the halogen is selected from chlorine, bromine or iodine;

for example, the alkylating agent may be 1, 4-dichlorobutane, 1, 4-dibromobutane, 1, 4-diiodobutane;

according to the invention, the reaction temperature is 20-150 ℃, preferably 50-100 ℃;

according to the present invention, the reaction may be performed in a solvent, which may be one or two or more of an aromatic hydrocarbon solvent, an ether solvent, a nitrile solvent, a ketone solvent, an amide solvent, and an alcohol solvent, and is preferably any one or a combination of toluene, xylene, tetrahydrofuran, dioxane, acetonitrile, propionitrile, acetone, methyl ethyl ketone, methyl isopropyl ketone, N-dimethylformamide, methanol, ethanol, propanol, isopropanol, butanol, and tert-butanol;

according to the invention, the reaction can be carried out in the presence of a base; the alkali can be any one or the combination of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium bicarbonate;

according to the invention, the molar ratio of L-alanine (I) to alkylating agent is 1 (1-3), preferably 1: 1;

according to the invention, HX in compound (ii) is the acid corresponding to the leaving group, such as any one of hydrochloric acid, hydrobromic acid, hydroiodic acid or a combination thereof;

according to the present invention, in the step of synthesizing an acid halide in the step (2),

the reaction temperature is 10-100 ℃, and preferably 20-80 ℃;

the reaction may be carried out in a solvent, which may be a halogenated hydrocarbon solvent, such as any one of dichloromethane, 1, 2-dichloroethane, or a combination thereof;

according to the invention, the reaction may be carried out with the addition of a catalyst, such as N, N-dimethylformamide;

according to the present invention, the halogenating agent may be any one of oxalyl chloride, oxalyl bromide, thionyl chloride, thionyl bromide, bis (trichloromethyl) carbonate, or a combination thereof;

according to the invention, in the step of Friedel-crafts acylation of acyl halide and benzene in the step (2),

the reaction temperature is 10-100 ℃, and preferably 20-80 ℃;

according to the invention, the reaction can be carried out with the addition of a catalyst, which can be aluminum trichloride, ferric trichloride, boron trifluoride, bismuth trichloride, active ferric oxide (alpha-Fe)₂O₃) Any one or combination thereof;

the compound (III) can be used as an intermediate for synthesizing (1R,2S) -1-phenyl-2- (pyrrolidine-1-yl) propan-1-ol, and the (1R,2S) -1-phenyl-2- (pyrrolidine-1-yl) propan-1-ol can be used as a chiral ligand in the synthesis process of Efavirenz (Efavirenz).

The invention also provides a method for synthesizing the mixture (IV) shown in the formula,

the synthesis method comprises the following steps:

(1) alkylation: carrying out alkylation reaction on L-alanine (I) and an alkylating reagent to obtain a compound (II);

(2) acylation: reacting the compound (II) with a halogenating agent to convert into acyl halide, and then carrying out Friedel-crafts acylation reaction on the acyl halide and benzene to obtain a compound (III);

(3) reduction: and (3) reacting the compound (III) with a reducing agent to obtain a mixture (IV).

Wherein, the step (1) and the step (2) have the reaction conditions;

according to the present invention, in the step (3),

the reaction temperature is-10-100 ℃, preferably-10-60 ℃, and more preferably-5-10 ℃;

the reaction may be carried out in a solvent selected from one, two or more of an ether solvent, an alcohol solvent, such as any one of tetrahydrofuran, dioxane, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, or a combination thereof;

the reducing agent can be any one or combination of lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium aluminum hydride, sodium dihydro bis (2-methoxyethoxy) aluminate and diisobutyl aluminum hydride, and is preferably sodium borohydride;

according to the invention, a reduction auxiliary agent can be added in the reaction, and the reduction auxiliary agent can be any one or combination of calcium chloride, magnesium bromide, magnesium acetate, zinc chloride, zinc bromide, zinc acetate, zinc sulfate, zinc methanesulfonate and zinc trifluoromethanesulfonate, preferably zinc chloride and zinc bromide;

according to the invention, the molar ratio of the compound (III) to the reducing agent to the reduction auxiliary is 1 (1-2) to (0-1), preferably 1 (1-1.5) to (0-0.5);

according to the invention, the reaction time is from 30 minutes to 20 hours, preferably from 30 minutes to 8 hours;

according to the invention, the chiral purity of the mixture (IV) obtained is: 93% or more of (1R,2S), (7% or less of (1S,2S), (0% of (1S, 2R) and (0% of (1R, 2R));

the mixture (IV) can be used as an intermediate for synthesizing (1R,2S) -1-phenyl-2- (pyrrolidine-1-yl) propane-1-alcohol, and the (1R,2S) -1-phenyl-2- (pyrrolidine-1-yl) propane-1-alcohol can be used as a chiral ligand in the synthesis process of Efavirenz (Efavirenz).

The invention also provides a method for synthesizing the crude salt (V) shown in the formula,

the synthesis method comprises the following steps:

(1) alkylation: carrying out alkylation reaction on L-alanine (I) and an alkylating reagent to obtain a compound (II);

(2) acylation: reacting the compound (II) with a halogenating agent to convert into acyl halide, and then carrying out Friedel-crafts acylation reaction on the acyl halide and benzene to obtain a compound (III);

(3) reduction: reacting the compound (III) with a reducing agent to obtain a mixture (IV);

(4) salifying: and (3) reacting the mixture (IV) with a resolving agent (HY) to obtain a crude salt (V).

Wherein, the step (1), the step (2) and the step (3) have the reaction conditions;

according to the present invention, in the step (4),

the reaction temperature is 0-100 ℃, and preferably 0-80 ℃;

the reaction may be carried out in a solvent, which may be one, two or more of an ether solvent, a nitrile solvent, a ketone solvent, an alcohol solvent, such as any one of tetrahydrofuran, dioxane, acetonitrile, propionitrile, acetone, butanone, methyl isopropyl ketone, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, or a combination thereof;

the resolving agent may be selected from any one of D-tartaric acid, D-malic acid, D-lactic acid, (S) -mandelic acid, (R) -camphorsulfonic acid, D-tartaric acid dibenzoate, L-tartaric acid, L-malic acid, L-lactic acid, (S) -camphorsulfonic acid, L-tartaric acid dibenzoate, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, or combinations thereof;

the reaction time may be 30 minutes to two days, preferably 30 minutes to 30 hours;

the chiral purity of the crude salt (v) obtained was: (1R,2S) is more than 99.8%, (1S,2S) is less than 0.2%, (1S, 2R) 0%, (1R, 2R) 0%;

the crude salt (V) can be used as an intermediate for synthesizing (1R,2S) -1-phenyl-2- (pyrrolidine-1-yl) propan-1-ol, and the (1R,2S) -1-phenyl-2- (pyrrolidine-1-yl) propan-1-ol can be used as a chiral ligand in the synthesis process of Efavirenz (Efavirenz).

The invention also provides a method for synthesizing the optically pure salt (VI) shown in the formula,

the synthesis method comprises the following steps:

(1) alkylation: carrying out alkylation reaction on L-alanine (I) and an alkylating reagent to obtain a compound (II);

(2) acylation: reacting the compound (II) with a halogenating agent to convert into acyl halide, and then carrying out Friedel-crafts acylation reaction on the acyl halide and benzene to obtain a compound (III);

(3) reduction: reacting the compound (III) with a reducing agent to obtain a mixture (IV);

(4) salifying: reacting the mixture (IV) with a resolving agent (HY) to obtain a crude salt (V);

(5) and (3) recrystallization: the crude salt (V) was recrystallized to obtain an optically pure salt (VI).

Wherein, the step (1), the step (2), the step (3) and the step (4) have the reaction conditions described above;

according to the present invention, in the step (5),

the recrystallization operation may be: mixing the crude salt (V) with a solvent, heating for dissolving, cooling, stirring, and separating out crystals to obtain optically pure salt (VI);

the heating temperature in the recrystallization step is 0-100 ℃, and preferably 0-80 ℃;

the solvent of the recrystallization step is selected from one, two or more of ether solvents, nitrile solvents, ketone solvents, alcohol solvents, such as any one or combination of tetrahydrofuran, dioxane, acetonitrile, propionitrile, acetone, butanone, methyl isopropyl ketone, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol;

the time of heating and the time of cooling in the recrystallization step are the same or different and are independently selected from 30 minutes to two days, preferably 30 minutes to 30 hours;

the chiral purity of the optically pure salt (VI) obtained by recrystallization was: 100% of (1R,2S), 0% of (1S, 2R) and 0% of (1R, 2R);

the optically pure salt (VI) can be used as an intermediate for synthesizing (1R,2S) -1-phenyl-2- (pyrrolidine-1-yl) propan-1-ol, and the (1R,2S) -1-phenyl-2- (pyrrolidine-1-yl) propan-1-ol can be used as a chiral ligand in the synthesis process of Efavirenz (Efavirenz).

The invention also provides a synthesis method of the compound (A) shown in the formula,

the synthesis method comprises the following steps:

(1) alkylation: carrying out alkylation reaction on L-alanine (I) and an alkylating reagent to obtain a compound (II);

(2) acylation: reacting the compound (II) with a halogenating agent to convert into acyl halide, and then carrying out Friedel-crafts acylation reaction on the acyl halide and benzene to obtain a compound (III);

(3) reduction: reacting the compound (III) with a reducing agent to obtain a mixture (IV);

(4) salifying: reacting the mixture (IV) with a resolving agent (HY) to obtain a crude salt (V);

(5) and (3) recrystallization: recrystallizing the crude salt (V) to obtain an optically pure salt (VI);

(6) desalting: the optically pure salt (VI) is subjected to a desalting step to obtain an optically pure compound (A).

Wherein, the step (1), the step (2), the step (3), the step (4) and the step (5) have the reaction conditions described above;

according to the present invention, in the step (6),

the reaction temperature is 0-100 ℃, and preferably 20-50 ℃;

the reaction may be carried out in a solvent, which may be one, two or more of halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, ether solvent, ester solvent, alkane solvent, water, such as any one of dichloromethane, 1, 2-dichloroethane, toluene, xylene, diethyl ether, isopropyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethyl acetate, isopropyl acetate, hexane, cyclohexane, heptane, water, or a combination thereof;

the reaction can be carried out by adding alkali, wherein the alkali can be any one or combination of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate and ammonia water;

the chiral purity of the compound (a) obtained by desalting was: 100% of (1R, 2S);

the compound (A) can be used as a chiral ligand in the synthesis process of Efavirenz (Efavirenz).

The invention also provides a method for synthesizing a compound (III) from the mother liquor in the salifying step and the mother liquor in the recrystallization step, which comprises the following steps:

1) desalting: combining the mother liquor obtained in the salifying step and the mother liquor obtained in the recrystallization step, evaporating under reduced pressure to remove volatile matters, and reacting residues with alkali to obtain a mixture (IV);

2) and (3) oxidation: the mixture (IV) is reacted with an oxidizing agent to obtain a compound (III).

According to the present invention, in step 1),

the reaction temperature is 0-100 ℃, and preferably 20-50 ℃;

the reaction may be carried out in a solvent, which may be one, two or more of halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, ether solvent, ester solvent, alkane solvent, water, such as any one or combination of dichloromethane, 1, 2-dichloroethane, toluene, xylene, diethyl ether, isopropyl ether, methyl t-butyl ether, ethylene glycol dimethyl ether, ethyl acetate, isopropyl acetate, hexane, cyclohexane, heptane, water;

the alkali can be any one or the combination of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate and ammonia water;

the purity of the mixture (IV) obtained by desalting was: (1R,2S) to 27%, (1S,2S) to 73%;

according to the present invention, in step 2),

the reaction temperature is-10-100 ℃, and preferably 0-50 ℃;

the reaction may be carried out in a solvent, which may be one, two or more of halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, ether solvent, ester solvent, alkane solvent, water, such as any one or combination of dichloromethane, 1, 2-dichloroethane, toluene, xylene, diethyl ether, isopropyl ether, methyl t-butyl ether, ethylene glycol dimethyl ether, ethyl acetate, isopropyl acetate, hexane, cyclohexane, heptane, water;

the oxidant can be any one or the combination of chromium trioxide, sodium dichromate, potassium permanganate, sodium permanganate, pyridine dichromate, Dess-Martin reagent and manganese dioxide, and is preferably sodium dichromate;

according to the invention, the reaction can be carried out under acidic conditions and the pH of the solution subsequently adjusted with a base.

According to the invention, the pH of the solution may be adjusted to 8-11, for example 10;

the acid can be selected from any one of sulfuric acid, hydrochloric acid and phosphoric acid or the combination of the sulfuric acid, the hydrochloric acid and the phosphoric acid;

the alkali can be any one or the combination of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate and ammonia water;

the compound (III) can be used as an intermediate for synthesizing (1R,2S) -1-phenyl-2- (pyrrolidine-1-yl) propan-1-ol, and the (1R,2S) -1-phenyl-2- (pyrrolidine-1-yl) propan-1-ol can be used as a chiral ligand in the synthesis process of Efavirenz (Efavirenz).

The chemical name of the compound is as follows:

compound (I): l-alanine;

compound (ii): (2S) -2- (pyrrolidin-1-yl) propionic acid addition salt;

compound (iii): (2S) -1-phenyl-2- (pyrrolidin-1-yl) propan-1-one;

mixture (iv): (1R/S,2S) -1-phenyl-2- (pyrrolidin-1-yl) propan-1-ol;

compound (v): a crude salt of the (1R,2S) -1-phenyl-2- (pyrrolidin-1-yl) propan-1-ol acid addition salt;

compound (vi): an optically pure salt of the addition salt of (1R,2S) -1-phenyl-2- (pyrrolidin-1-yl) propan-1-ol acid;

compound (A): (1R,2S) -1-phenyl-2- (pyrrolidin-1-yl) propan-1-ol.

Compared with the prior art, the invention has the following beneficial technical effects:

1) high yield; the invention has the advantages that the ingenious synthesis design enables the asymmetric reduction to be realized during the reduction of carbonyl, and the target compound can be directly obtained with high yield. The problem that the target compound cannot be obtained in high yield through asymmetric reduction in the prior art is solved.

2) High purity; the invention can realize the synthesis of the high-purity compound (A) by using cheap hydrochloric acid and zinc chloride (the WO2015063795A2 technology uses expensive tartaric acid and zinc bromide);

3) no isomer is wasted (WO2015063795A2 is uneconomical and lost by half);

4) the method avoids using a methamphetamine removal control product; the raw materials are cheap and easy to obtain, and the synthesis cost is reduced;

5) is easy for industrialized mass production.

Detailed Description

The present invention will be described in further detail with reference to specific examples. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.

Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.

The High Pressure Liquid Chromatography (HPLC) parameters used in the present invention are: column, Chialpak IA,250X4.6mm X5 μm; column temperature, 30 ℃; flow rate, 0.8 ml/min; sample concentration, 1 mg/ml; sample introduction volume, 20 μm; mobile phase, n-hexane, ethanol, diethylamine (95:5:0.1, v/v/v); elution mode, isocratic elution; detection wavelength, 220 nm.

Unless otherwise indicated, when the present invention relates to percentages between liquids, said percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentages between solid and liquid, said percentages being weight/volume percentages; the balance being weight/weight percent.