CN116171270A

CN116171270A - Preparation method of (S) -4-chloro-2-aminobutyric acid hydrochloride and (S) -4-chloro-2-aminobutyric acid ester

Info

Publication number: CN116171270A
Application number: CN202280005506.4A
Authority: CN
Inventors: 周磊; 曾伟; 刘永江; 程柯
Original assignee: Lier Chemical Co Ltd
Current assignee: Lier Chemical Co Ltd
Priority date: 2021-09-30
Filing date: 2022-09-30
Publication date: 2023-05-26
Also published as: TWI835325B; TW202321190A; AR127219A1; WO2023051768A1

Abstract

The invention provides a preparation method of (S) -4-chloro-2-aminobutyric acid hydrochloride, which comprises the following steps: the L-homoserine lactone hydrochloride of formula (I) is subjected to ring-opening chlorination with hydrogen chloride to produce (S) -4-chloro-2-aminobutyric acid hydrochloride of formula (II). Also provides a preparation method of the (S) -4-chloro-2-aminobutyric acid ester.

Description

Preparation method of (S) -4-chloro-2-aminobutyric acid hydrochloride and (S) -4-chloro-2-aminobutyric acid ester

Technical Field

The invention relates to a preparation method of (S) -4-chloro-2-aminobutyric acid hydrochloride and (S) -4-chloro-2-aminobutyric acid ester.

Background

The glufosinate-ammonium is used as an efficient, low-toxicity and broad-spectrum contact-killing type organophosphorus herbicide, the use amount of the glufosinate-ammonium is increased year by year, and the market potential is huge. The glufosinate is typically produced as racemate of L-glufosinate and D-glufosinate (i.e. a mixture of L-glufosinate and D-glufosinate each half), wherein D-glufosinate has no biological activity and L-glufosinate has a biological activity 2 times that of the racemate.

The preparation of (S) -4-chloro-2-aminobutyrate as an intermediate for the synthesis of L-glufosinate has attracted considerable attention. U.S. patent application No. 20060135602A1 discloses the use of L-homoserine (i.e., L-2-amino-4-hydroxybutyric acid) with thionyl chloride and ethanol to produce (S) -4-chloro-2-aminobutyric acid ester. However, in this method, the amount of thionyl chloride is excessively large, the cost is excessively high, and a large amount of waste acid and waste water is generated.

Chinese patent application CN109369432a discloses that (S) -4-chloro-2-aminobutyric acid ester is prepared by subjecting (S) -2-aminobutyric acid hydrochloride (i.e., L-homoserine lactone hydrochloride) to ring opening alcoholysis to obtain (S) -homoserine ester, followed by chlorination.

However, there is still a need to develop alternatives for the preparation of (S) -4-chloro-2-aminobutyrate in order to achieve the goals of environmental protection, cost saving and high yields at the same time.

Disclosure of Invention

For this reason, the inventors of the present invention have first proposed a method for preparing (S) -4-chloro-2-aminobutyric acid hydrochloride, which comprises the steps of:

subjecting L-homoserine lactone hydrochloride of formula (I) to ring-opening chlorination with hydrogen chloride to produce (S) -4-chloro-2-aminobutyric acid hydrochloride of formula (II)

Compared with the prior art that thionyl chloride is used as a chlorinating agent, the invention firstly provides that HCl is used as the chlorinating agent to prepare (S) -4-chloro-2-aminobutyric acid hydrochloride, the relative dosage of HCl is less, the cost is low, the impurity of chlorinated products is less, and the purity of the chlorinated products is high; the chlorination can be carried out under normal pressure or pressure, and the operation is flexible and convenient; and HCl can be recycled, and is environment-friendly.

In addition, the present invention also provides a method for preparing (S) -4-chloro-2-aminobutyric acid ester, comprising the steps of:

step a): subjecting L-homoserine lactone hydrochloride of formula (I) to ring-opening chlorination with hydrogen chloride to produce (S) -4-chloro-2-aminobutyric acid hydrochloride of formula (II)

Step b): esterifying (S) -4-chloro-2-aminobutyric acid hydrochloride of formula (II) with alcohol ROH in the presence of acidic catalyst and solvent to obtain (S) -4-chloro-2-aminobutyric acid hydrochloride of formula (III)

Step c): neutralizing (S) -4-chloro-2-aminobutyric acid ester hydrochloride of formula (III) with alkali to obtain (S) -4-chloro-2-aminobutyric acid ester of formula (IV)

Wherein in formula (III) and formula (IV), R is selected from C ₁ -C ₆ Alkyl, C _3-10 Cycloalkyl, C _6-10 Aryl, C _7-12 Aralkyl, 5-14 membered heteroaryl and 3-10 membered heterocyclyl, preferably C ₁ -C ₆ Alkyl groups, more preferably ethyl groups.

Compared with the known method of carrying out ring-opening alcoholysis and then chlorination in the prior art, the method of preparing (S) -4-chloro-2-aminobutyric acid ester by carrying out ring-opening chlorination and esterification is provided for the first time, the yield is comparable with that of the known method, and the method is environment-friendly by adopting a small amount of recoverable HCl to replace the sulfoxide chloride with a large amount of impurity, and the situation of generating a large amount of impurity when the sulfoxide chloride is adopted is avoided.

Various other features, aspects, and advantages of the present invention will become more apparent with reference to the following drawings.

Drawings

FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of (S) -4-chloro-2-aminobutyrate.

FIG. 2 is a nuclear magnetic resonance carbon spectrum of (S) -4-chloro-2-aminobutyrate.

FIG. 3 shows the nuclear magnetic resonance hydrogen spectrum of ethyl (S) -4-chloro-2-aminobutyrate.

FIG. 4 is a nuclear magnetic resonance carbon spectrum of ethyl (S) -4-chloro-2-aminobutyrate.

Detailed Description

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. If there is a discrepancy, the definition provided in this application controls.

Unless otherwise indicated, the numerical ranges set forth herein are intended to include the endpoints of the ranges, and all numbers and subranges within the range.

The materials, amounts, methods, apparatus, figures, and examples herein are illustrative and, unless otherwise indicated, should not be construed as limiting.

The terms "comprising," "including," and "having," as used herein, are intended to include other components or steps that do not affect the end result. These terms encompass the meanings of "consisting of … …" and "consisting essentially of … …". Products and methods according to the present disclosure may include or incorporate the necessary features described in this disclosure, as well as additional and/or optional components, ingredients, steps, or other limiting features described herein; or may consist of the essential features described in this disclosure, as well as additional and/or optional components, ingredients, steps, or other restrictive features described herein; or consist essentially of the essential features described in this disclosure, as well as additional and/or optional components, ingredients, steps, or other limitations described herein.

All materials and reagents used in the present disclosure are commercially available unless explicitly indicated otherwise.

Unless indicated otherwise or clearly contradicted by context, the operations performed herein may be performed at room temperature and at atmospheric pressure.

As used herein, the term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group. For example, the term "C ₁ -C ₆ Alkyl "refers to an alkyl group having 1 to 6 carbon atoms and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl and isomers thereof and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be halogen, nitro, sulfonyl, ether oxy, ether thio, ester, thioester, cyano, or the like.

As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic or more) hydrocarbon ring. For example, the term "C _3-10 Cycloalkyl "refers to a saturated monocyclic or polycyclic ring having 3 to 10 ring-forming carbon atoms (such as bicyclic or morePolycyclic) hydrocarbon rings. Monocyclic ring "C _3-10 Cycloalkyl "includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl; polycyclic "C _3-10 Cycloalkyl ", including spiro, fused and bridged systems, such as bicyclo [1.1.1 ]]Amyl, bicyclo [2.2.1]Heptyl, bicyclo [3.2.1]Octyl or bicyclo [5.2.0]Nonyl, decalin, and the like. Cycloalkyl is optionally substituted with 1 or more (such as 1 to 3) substituents, for example methyl substituted cyclopropyl.

As used herein, the term "aryl" refers to an all-carbon monocyclic or fused polycyclic group having conjugated pi electrons. For example, the term "C _6-10 Aryl "refers to an aromatic group having 6 to 10 carbon atoms such as phenyl or naphthyl. Aryl is optionally substituted with 1 or more (such as 1 to 3) substituents (e.g., halogen, -OH, -CN, -NO) ₂ Or C _1-6 Alkyl, etc.) substitution.

As used herein, the term "aralkyl" refers to an aryl substituted alkyl group, wherein the aryl and the alkyl are as defined herein. For example, the term "C _7-12 Aralkyl "refers to aralkyl groups having 7 to 12 carbon atoms, where aryl groups may have 6-11 carbon atoms and alkyl groups may have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

As used herein, the term "heteroaryl" refers to a single ring or a fused multiple ring comprising conjugated pi electrons and consisting of carbon atoms and at least one heteroatom selected from oxygen, nitrogen and sulfur. The term "5-14 membered heteroaryl" refers to heteroaryl groups having 5-14 ring atoms, in particular having 1-10 carbon atoms. Examples of "5-14 membered heteroaryl" include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and benzo derivatives thereof.

As used herein, the term "heterocyclyl" refers to a saturated or unsaturated, monocyclic or polycyclic (such as bicyclic or more) group consisting of carbon atoms and at least one heteroatom selected from oxygen, nitrogen and sulfur. The term "3-10 membered heterocyclic group" means a heterocyclic group having 3 to 10 ring atoms, particularly having 2 to 9 carbon atoms. Examples of "3-to 10-membered heterocyclyl" include, but are not limited to, oxiranyl, aziridinyl, azetidinyl (azetidinyl), oxetanyl

(oxytanyl), tetrahydrofuranyl, dioxolyl (dioxanyl), pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl (dithianyl), thiomorpholinyl, piperazinyl and trithianyl.

As used herein, the term "about" refers to a deviation of a defined value thereof from within 10% of the value, e.g., the term "about 100 ℃ refers to a range of" 100±10℃.

As used herein, the term "atmospheric pressure" refers to about 1 atmosphere.

As used herein, the term "room temperature" refers to about 20 to about 25 ℃, preferably about 25 ℃.

Examples of the present disclosure will be described in detail below.

Preparation method of (S) -4-chloro-2-aminobutyric acid hydrochloride

In one aspect, the present invention provides a process for preparing (S) -4-chloro-2-aminobutyrate comprising the steps of:

In some examples, hydrogen chloride (HCl) is provided in the form of hydrochloric acid, preferably concentrated hydrochloric acid having a concentration of about 30 to about 38 wt.%, more preferably 30 wt.% (abbreviated as "30% concentrated hydrochloric acid") or 36 wt.% (abbreviated as "36% concentrated hydrochloric acid").

In some examples, the molar ratio of hydrogen chloride (HCl) to L-homoserine lactone hydrochloride is from about 1 to about 5:1, preferably from about 3 to about 4:1, more preferably about 3.5:1.

In some examples, the ring-opening chlorination reaction is conducted at atmospheric pressure (i.e., about 1 atmosphere) or elevated pressure (i.e., greater than 1 atmosphere), preferably elevated pressure, e.g., about 0.1 to about 1.0MPa, or about 0.2 to about 1.0MPa, e.g., about 0.18MPa or about 0.22MPa.

In some examples, the epoxidation reaction is carried out with heat, preferably at a reaction temperature of from about 80 to about 130 ℃, more preferably from about 90 to about 120 ℃, still more preferably from about 90 to about 100 ℃, and most preferably about 100 ℃.

In some examples, the ring-opening chlorination reaction has a reaction time of about 8 to about 24 hours, preferably about 12 to about 18 hours, and more preferably about 16 hours.

In some examples, the ring-opening chlorination reaction is performed in the absence of a catalyst,

in particular, the ring-opening chlorination reaction is carried out in the absence of a sulfuric acid catalyst.

The ring-opening chlorination reaction is carried out in the absence of a catalyst,

In other examples, the ring-opening chlorination reaction is performed in the presence of a catalyst. The catalyst is preferably sulfuric acid. The sulfuric acid is preferably concentrated sulfuric acid having a concentration of about 95 to about 98.5% by weight, for example 98% by weight concentrated sulfuric acid (referred to as "98% concentrated sulfuric acid").

In some examples, the molar ratio of sulfuric acid to L-homoserine lactone hydrochloride is from 0 to about 1:1, preferably from about 0.1 to about 0.5:1, more preferably about 0.25:1.

In some examples, after the ring-opening chlorination reaction is completed, heating is stopped, and the reaction mixture is cooled down so as to precipitate (S) -4-chloro-2-aminobutyrate crystals,

preferably, after the ring-opening chlorination reaction is completed, heating is stopped, and the reaction mixture is cooled under stirring so as to precipitate (S) -4-chloro-2-aminobutyrate crystals.

Preferably, the cooling is selected from: naturally cooling the reaction mixture from the reaction temperature, e.g., after stopping heating the oil bath providing heating for the chlorination reaction, maintaining the reaction mixture in an oil bath environment and agitating the reaction mixture to a temperature of about 25 to about 60 ℃, e.g., naturally cooling to about 25 to about 30 ℃, about 30 to about 35 ℃, about 35 to about 40 ℃, about 40 to about 45 ℃, about 45 to about 50 ℃, about 50 to about 55 ℃, or about 55 to about 60 ℃;

gradually cooling the reaction mixture from the reaction temperature, e.g., cooling the reaction mixture from the chlorination reaction temperature (e.g., about 100 ℃) to about 75 ℃ at a rate of about 1 ℃/min, then from about 75 ℃ to about 40 ℃ at a rate of about 0.5 ℃/min, and from about 40 ℃ to about 25 ℃ at a rate of about 0.25 ℃/min, with stirring; such gradual cooling facilitates precipitation of the product in high purity (i.e., relative content) as the chlorinated product begins to precipitate in a temperature range of about 45 ℃ to about 75 ℃; for example, a jacket kettle can be adopted to accurately realize gradual cooling;

the reaction mixture is directly exposed to ambient temperature, particularly to room temperature air at about 20 to about 25 ℃. That is, after stopping heating the oil bath that provides heating for the chlorination reaction, the reaction mixture is removed from the oil bath environment, the reaction mixture is allowed to stand in a room temperature environment and the reaction mixture is stirred to naturally cool to room temperature;

the reaction mixture is placed in a water bath or ice-water bath at about 0 to about 60 ℃, e.g., at a temperature of about 0 to about 5 ℃, about 5 to about 10 ℃, about 10 to about 15 ℃, about 15 to about 20 ℃, about 20 to about 25 ℃, about 25 to about 30 ℃, about 30 to about 35 ℃, about 35 to about 40 ℃, about 40 to about 45 ℃, about 45 to about 50 ℃, about 50 to about 55 ℃, or about 55 to about 60 ℃; with an ice water bath (e.g., about 20 ℃ or less) or about 0 ℃ water bath, the reaction product is rapidly cooled from the chlorination reaction temperature (e.g., about 100 ℃) or below the chlorination reaction temperature (e.g., from about 100 ℃ to about 70 ℃ naturally followed by cooling with the water bath or ice water bath) to a water bath temperature (e.g., about 20 ℃ or less) or less (e.g., about 0 ℃), and large amounts of starting materials precipitate with the product, undesirably reducing the purity (i.e., relative content) of the chlorinated product;

and combinations thereof.

Preferably, the reaction mixture is naturally cooled from the reaction temperature to a temperature of about 25 to about 60 ℃, particularly to about 40 to about 50 ℃, such as about 40 ℃, about 41 ℃, about 42 ℃, about 43 ℃, about 44 ℃, about 45 ℃, about 46 ℃, about 47 ℃, about 48 ℃, about 49 ℃ or about 50 ℃, with stirring. In some examples, the cooled precipitated (S) -4-chloro-2-aminobutyrate crystals are purified, e.g., suction filtered, and/or washed (e.g., rinsed). Washing may be performed with a hydrophobic organic solvent, preferably selected from ethers, esters, alkylbenzenes (e.g., C ₁ -C ₆ Alkylbenzenes) and halogenated hydrocarbons (e.g., halogenated C's) ₁ -C ₆ Alkanes and halogenated C _6-12 Aromatic hydrocarbon), more preferably from the group consisting of methyl tert-butyl ether, ethyl acetate, toluene, xylene, chlorobenzene, dichloromethane and dichloroethane, still more preferably from the group consisting of methyl tert-butyl ether and dichloromethane.

Preparation method of (S) -4-chloro-2-aminobutyric acid ester

In another aspect, the present invention provides a method for preparing (S) -4-chloro-2-aminobutyric acid ester, comprising the steps of:

In some examples, in step b), the acidic catalyst is selected from the group consisting of inorganic acids, acid salts of inorganic acids, and organic acids.

The mineral acid is preferably selected from sulfuric acid and HCl; preferably sulfuric acid, more preferably concentrated sulfuric acid having a concentration of about 95 to about 98.5 weight percent, for example 98 weight percent; HCl is preferably HCl gas.

The acid salt of the mineral acid is preferably an alkali metal bisulfate salt, such as sodium bisulfate.

The organic acid is preferably selected from the group consisting of p-toluene sulfonic acid and acidic cation exchange resins, such as the commercially available Dowex 50WX8 ion exchange resins (available from microphone) and Amberlite IR120 cation exchange resins sodium (available from microphone).

In some examples, in step b), the molar ratio of concentrated sulfuric acid to (S) -4-chloro-2-aminobutyrate is from about 0.05 to about 0.4:1, preferably from about 0.1 to about 0.2:1, more preferably from about 0.1 to about 0.15:1, still more preferably about 0.1:1.

In some examples, in step b), the solvent is selected from alcohols, preferably C ₁ -C ₆ Alcohols, more preferably ethanol, still more preferably absolute ethanol.

Wherein the ratio of the volume of the solvent to the mass of the (S) -4-chloro-2-aminobutyrate is preferably from about 2 to about 5mL/g, more preferably from about 2.5 to about 4mL/g, still more preferably about 2.5mL/g.

In some examples, in step b), the anhydrous ethanol is heated to reflux, preferably to about 78 to about 85 ℃, more preferably to about 85 ℃.

In some examples, in step b), the reaction time is from about 3 to about 20 hours, preferably from about 4 to about 8 hours, more preferably about 6 hours.

In some examples, in step c), the base is an inorganic base, preferably selected from the group consisting of ammonia, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, alkali metal hydroxide, alkaline earth metal hydroxide, or a combination thereof, more preferably selected from the group consisting of ammonia, sodium carbonate, sodium bicarbonate, and a combination of sodium bicarbonate and sodium hydroxide, even more preferably ammonia.

In some examples, after step c), the reaction mixture is extracted.

In some examples, the extractant is a hydrophobic organic solvent, preferably selected from ethers, esters, alkylbenzenes (e.g., C ₁ -C ₆ Alkyl substituted benzene) and halogenated hydrocarbons, e.g., haloC ₁ -C ₆ Alkanes and halogenated C _6-12 Aromatic hydrocarbon), preferably selected from methyl tertiary butyl ether, ethyl acetate, toluene, xylene, chlorobenzene, dichloromethane anddichloroethane, more preferably selected from methyl tertiary butyl ether and dichloromethane.

In some examples, the extractant may be the same as or different, preferably the same as, the hydrophobic organic solvent (if desired) used to wash the (S) -4-chloro-2-aminobutyrate hydrochloride crystals of step a).

In some examples, the volume ratio of the extractant to the solvent in step b) is from about 1.5 to about 6:1, preferably from about 3 to about 5:1, more preferably about 5:1.

Unless otherwise indicated, the concentrated sulfuric acid used in the examples was concentrated sulfuric acid having a concentration of 98% by weight.

It is noted that the following examples are only for illustrative purposes and are not intended to limit the present invention.

In the following examples, the purity of the reaction starting material L-homoserine lactone hydrochloride (hereinafter referred to as "Compound I") was 90 to 95%. Thus, in the following examples, the yield of (S) -4-chloro-2-aminobutyrate (hereinafter abbreviated as "Compound II") should be the quotient of the experimental data of the actual yield of Compound II divided by the purity of Compound I. In other words, the yield of compound II should be 1.05-1.11 times the experimental data of its actual yield. For example, in example 1, the actual yield of compound II was 36.22%, and the yield of compound II was 38.03% -40.20%.

The starting materials in the examples were not reacted to completion, and thus, experimental data were mainly used to represent the trend of the influence of the reaction conditions on the product yield and the product purity, limited by the experimental conditions. After separation of the reaction product from the reaction mixture, the residual reaction mixture is recycled 1 or more times as the reaction raw material so as to consume the unreacted raw material, the total yield of the compound II can reach more than 90%, and the relative content of the compound II in single chlorination reaction measured by High Performance Liquid Chromatography (HPLC) can reach more than 90%. It is contemplated that the yield may be increased by recovering unreacted starting materials and recycling them for reaction, and in some cases, the relative content with respect to the yield is a primary index for evaluating the extent of progress of the reaction.

In the following examples, high performance liquid chromatography was used to measure the relative content of compound II, (S) -4-chloro-2-aminobutyrate ethyl ester hydrochloride (hereinafter abbreviated as "compound III") and (S) -4-chloro-2-aminobutyrate ethyl ester (hereinafter abbreviated as "compound IV").

Synthesis example 1 (example 1): preparation of (S) -4-chloro-2-aminobutyric acid hydrochloride (Compound II)

L-homoserine lactone hydrochloride (absolute content 90 to 97%, compound I,400g,2.92 mol) was weighed and added to a 2L three-necked flask. Then, 36% by weight concentrated hydrochloric acid (1035 g,10.22 mol) was added to the three-necked flask, and concentrated sulfuric acid (73 g,0.73 mol) was added dropwise. The three-necked flask was gradually warmed to 100℃in an oil bath, and reacted with stirring for 16 hours. After the reaction is finished, the heating of the oil bath is stopped, the reaction mixture is naturally cooled to room temperature, and crystallization is gradually carried out. Suction filtering, eluting the filter cake with methyl tertiary butyl ether, and drying to obtain a white crystal compound II crude product, wherein the actual yield is 32% -37% and the relative content is 90% -96%.

FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of white crystalline (S) -4-chloro-2-aminobutyrate (compound II). FIG. 2 is a nuclear magnetic resonance carbon spectrum of white crystalline (S) -4-chloro-2-aminobutyrate (compound II).

¹ H NMR(400MHz,D ₂ O)：δ4.20(t,J＝6.7Hz,1H),3.78-3.63(m,2H),2.45-2.37(m,1H),2.31-2.21(m,1H)。

¹³ C NMR(101MHz,D ₂ O):δ171.21(C＝O),50.40,40.25,32.42。

As shown in tables 1 to 6, the reaction conditions and/or crystallization conditions were changed, and the reaction results were recorded.

Synthesis example 1 (example 1-A): preparation of (S) -4-chloro-2-aminobutyric acid hydrochloride (Compound II)

L-homoserine lactone hydrochloride (1000 g,7.3 mol) was weighed and added to a 5L three-necked flask. Then, 36 wt% concentrated hydrochloric acid (2587.6 g,25.55 mol) was added to the three-necked flask, and concentrated sulfuric acid (182.5 g,1.83 mol) was added dropwise. The three-necked flask was gradually warmed to 100℃in an oil bath, and reacted with stirring for 16 hours. After the reaction is finished, the heating of the oil bath is stopped, the reaction mixture is naturally cooled to room temperature, and crystallization is gradually carried out. Suction filtering, eluting the filter cake with methyl tertiary butyl ether, and drying to obtain white crystal (S) -4-chloro-2-aminobutyric acid hydrochloride, wherein the absolute yield is 33.6%, and the relative content is 98.2%.

Cyclic preparation of (S) -4-chloro-2-aminobutyrate (compound II): the filtrate obtained by suction filtration was concentrated by distillation under reduced pressure at 60℃to remove hydrochloric acid, to give unreacted L-homoserine lactone hydrochloride (Compound I, 264 g,4.85mol,1 eq). This was placed in another 5L three-necked flask, and then concentrated hydrochloric acid (1472.6 g,14.5mol,3 eq) was added to the three-necked flask, and the temperature of the three-necked flask was gradually raised to 100℃in an oil bath, followed by stirring for 16 hours. After the reaction is finished, the heating of the oil bath is stopped, the reaction mixture is naturally cooled to room temperature, and crystallization is gradually carried out. Suction filtering, eluting the filter cake with methyl tertiary butyl ether, and drying to obtain white crystal (S) -4-chloro-2-aminobutyric acid hydrochloride, wherein the absolute yield is 31.6%, and the relative content is 98.03%.

The recycling operation was further carried out 5 times in the same manner, namely, the unreacted L-homoserine lactone hydrochloride (compound I) was recovered and concentrated hydrochloric acid was fed so that the chlorination reaction of L-homoserine lactone hydrochloride (compound I) occurred as completely as possible, achieving a total yield of chlorination of 92.3%. The recovery amount of the unreacted compound I, the addition amount of the concentrated hydrochloric acid and the reaction results are shown in Table 1-A below.

Synthesis example 2: preparation of (S) -4-chloro-2-aminobutyric acid ester ethyl ester (Compound IV)

Example 92: (S) -4-chloro-2-aminobutyric acid ethyl ester hydrochloride (Compound III)

Absolute ethanol (4000 mL) and (S) -4-chloro-2-aminobutyrate (compound II,1000g,5.75 mol) prepared by the method of synthesis example 1 were placed in a 5L jacketed reaction kettle. 98% concentrated sulfuric acid (57.6 g,0.58 mol) was added dropwise to the jacketed kettle, and the temperature was gradually raised to 85℃and reacted under stirring and reflux for 15 hours. After monitoring the reaction was complete, the reaction was stopped and the reaction mixture was allowed to cool to room temperature. The reaction mixture was distilled under reduced pressure to remove most of the ethanol, giving a crude product of compound III.

Example 114: (S) -4-chloro-2-aminobutyric acid ethyl ester (Compound IV)

To the crude product of compound III obtained by distillation under reduced pressure as described above, ammonia water (496.3 g,7.59 mol) was added to adjust the pH to 7-8. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated to give a pale yellow oily liquid, crude compound IV yield 88.81% (absolute yield 82.58%).

FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of ethyl (S) -4-chloro-2-aminobutyrate (compound IV). FIG. 4 is a nuclear magnetic resonance carbon spectrum of ethyl (S) -4-chloro-2-aminobutyrate (compound IV).

¹ H NMR(400MHz,CDCl ₃ )：δ4.19(q,J＝7.1Hz,2H),3.80-3.59(m,3H),2.21(dddd,J＝14.7,8.5,6.4,4.6Hz,1H),2.00-1.83(m,3H),1.29(t,J＝7.2Hz,3H)。

¹³ C NMR(101MHz,CDCl ₃ )：δ175.27(C＝O),61.03,51.60,41.45,37.01,14.06。

As shown in tables 7 to 11, the reaction conditions and/or the post-treatment mode were changed, and the reaction results were recorded.

TABLE 1 influence of hydrochloric acid usage and crystallization conditions on the chlorination reaction

*1: the equivalent weight (eq) of concentrated hydrochloric acid is the ratio of the molar amount of concentrated hydrochloric acid (HCl) to the molar amount of compound I.

*2: the equivalent weight (eq) of concentrated sulfuric acid is the ratio of the molar amount of concentrated sulfuric acid to the molar amount of compound I.

*3: in synthesis example 1, the crude yield of compound II was calculated by: the weight of the dry solid mixture containing compound II divided by the theoretical yield of compound II calculated for compound I.

*4: in synthesis example 1, the actual yield of compound II was calculated by: the yield of crude compound II multiplied by the relative amount of compound II.

*5: naturally cooling in an oil bath: the heating of the oil bath was stopped, the reaction mixture was stirred in an oil bath environment and naturally cooled slowly to room temperature.

*6: naturally cooling: the heating of the oil bath was stopped, the reaction mixture was moved from the oil bath environment to room temperature environment with stirring, and naturally cooled slowly to room temperature.

As can be seen from Table 1, a molar ratio of HCl to compound I of 3-4:1 is advantageous for obtaining compound II in high purity and yield. The natural cooling of the oil bath is more favorable for separating out the compound II crystals with high purity and high yield than the natural cooling. As the amount of hydrochloric acid increases, the yield and/or relative content of compound II decreases to some extent.

TABLE 2 influence of the reaction temperature on the chlorination reaction

*1: the equivalent (eq) of the chlorinating agent is the ratio of the molar amount of concentrated hydrochloric acid (HCl) to the molar amount of compound I.

*5: the crystallization temperature is a specific value or a range of values: the heating in the oil bath is stopped, and the reaction mixture is placed in the water bath with the temperature and stirred for cooling.

*6: naturally cooling in an oil bath: the heating of the oil bath was stopped, the reaction mixture was stirred in an oil bath environment and naturally cooled slowly to room temperature.

*7: cooling to 5 ℃ in an oil bath: the heating of the oil bath is stopped, the reaction mixture is stirred in the oil bath environment and naturally and slowly cooled to room temperature, crystals are precipitated, and the reaction mixture is further placed in a water bath at 5 ℃ to cool, thereby increasing the amount of the precipitated crystals.

*8: indicating that the reaction was carried out at normal pressure.

*9: pressurization means that the reaction is carried out in a closed vessel (a closed tank system) to which no external pressure is applied, and the reaction pressure is not measured, but the closed tank is similar to pressurization.

As can be seen from Table 2, a reaction temperature of 90 to 120℃and particularly a reaction temperature of 100℃is advantageous for obtaining compound II in high purity and high yield. When the reaction temperature is higher than 120 ℃, the yield and purity of the compound II start to decrease. Without wishing to be bound by theory, although at a reaction temperature of 130 ℃, the yield and purity of compound II are lower than at 140 ℃, it is believed that it is an acceptable experimental error that does not affect the overall trend of the yield and purity of compound II being affected by the reaction temperature.

TABLE 3 influence of reaction time on the chlorination reaction

As can be seen from Table 3, the relative content and yield of compound II increased significantly with increasing time and the reaction proceeded, but after the reaction reached equilibrium, the continued extension of the reaction time did not significantly contribute to the increase of the relative content and yield of the product. Preferably a reaction time of 16h.

TABLE 4 influence of sulfuric acid equivalent on the chlorination reaction

*3: in synthesis example 1, the crude yield of compound II was calculated by: the weight of the dry solid mixture containing compound II divided by the theoretical yield of compound II calculated as compound I.

As can be seen from Table 4, the yield of the chlorination reaction and the purity of the reactants were good without using sulfuric acid catalyst. When a concentrated sulfuric acid catalyst is used, a sulfuric acid equivalent of 0.25eq is advantageous for obtaining compound II in the best relative content and yield.

TABLE 5 influence of different crystallization conditions on the chlorination

*7: naturally cooling in an oil bath: the heating of the oil bath was stopped, the reaction mixture was stirred in an oil bath environment and naturally cooled slowly to room temperature.

*8: cooling the oil bath to 40 ℃ or 50℃: the heating of the oil bath was stopped, the reaction mixture was stirred in an oil bath environment and naturally slowly cooled to 40 ℃ or 50 ℃.

*9: oil bath cooling +10deg.C (or 0deg.C): stopping heating the oil bath, stirring the reaction mixture in the oil bath environment, naturally and slowly cooling to room temperature to precipitate crystals, and further cooling the reaction mixture in a water bath at 10 ℃ or an ice water bath at 0 ℃ to increase the amount of the precipitated crystals.

*10: after the reaction is finished, cooling, stirring and crystallizing, wherein the cooling rate is 100 ℃ -75 ℃ (the cooling rate is about 1 ℃/min), the cooling rate is 75 ℃ -40 ℃ (the cooling rate is about 0.5 ℃/min), and the cooling rate is 40 ℃ -25 ℃ (the cooling rate is about 0.25 ℃/min), and gradually crystallizing.

As can be seen from table 5, natural cooling of the oil bath is advantageous for obtaining compound II in optimal relative amounts and yields. HCl gas is introduced in the chlorination reaction process and/or HCl gas is introduced in the crystallization process, so that the compound II can be obtained with high relative content and yield. If rapid cooling from 100℃to 20℃or even lower (e.g.0℃), substantial precipitation of starting materials with the product occurs, reducing the relative content of compound II.

TABLE 6 influence of reaction pressure on the chlorination reaction

*5: indicating that the reaction was carried out at normal pressure.

*6:0.18MPa or 0.22MPa means that the reaction is carried out in a pressure bottle, and the reaction pressure can be measured.

*7: pressurization means that the reaction is carried out in a closed vessel (a closed tank system) to which no external pressure is applied, and the reaction pressure is not measured, but the closed tank is similar to pressurization.

As can be seen from Table 6, pressurization is more advantageous than normal pressure to obtain compound II at a high relative content and yield.

TABLE 1 recycle reaction and Chlorination yield of Compound I

*1: the equivalent weight (eq) of concentrated hydrochloric acid is the ratio of the molar amount of concentrated hydrochloric acid to the molar amount of compound I.

*2: the total yield of the chlorination reaction is calculated after each cycle as the total consumption of compound I. For example, the total yield of 1-c is calculated as follows: [ mass of compound (1-a)/(mass of 1-d) ]/mass of compound (1-a), i.e. (1000-308)/1000 x 100% = 69.2%.

*3: the amount of compound I is the amount of unreacted compound I recovered, which is used for the recycle reaction.

*4: purity of compound II in a single chlorination reaction.

As can be seen from tables I-A, although the starting compounds I in most of the examples listed herein are not completely reacted under the experimental conditions, the total yield of the compound II can be 90% or more and the relative content of the compound II can be 90% or more as measured by High Performance Liquid Chromatography (HPLC) when the unreacted starting compounds I are recovered and recycled for chlorination reaction.

TABLE 7 influence of different types of catalysts on esterification reactions

*1: the catalyst equivalent (eq) is the ratio of the molar amount of catalyst to the molar amount of compound II.

*2: the absolute ethanol amount (mL/g) is the ratio of the absolute ethanol volume to the mass of compound II.

*3: both Dowex 50WX8 ion exchange resin and Amberlite IR120 cation exchange resin sodium were purchased from microphone.

*4: the actual yield (absolute yield) of compound III was 89.42%.

*5: the actual yield (absolute yield) of compound III was 91.89%.

-superscript a, b, c, d each represents a batch of raw materials; for example, the superscript a indicates the same batch of material.

As can be seen from Table 7, sulfuric acid has the best catalytic activity for the esterification reaction to produce compound III. Wherein, the organic acid catalyst has stronger catalyst residue in the reaction mixture and is not easy to be thoroughly cleaned; HCl gas has good catalytic effect, but is complex to operate. The addition of a drying agent (anhydrous sodium sulfate or anhydrous magnesium sulfate) to the catalyst has no obvious influence on the reaction effect.

TABLE 8 influence of absolute ethanol usage on esterification reactions

As can be seen from Table 8, the reaction was not greatly affected when the ratio of the volume of the solvent to the mass of the compound II was varied in the range of 2.5-4 mL/g. In view of cost economy and ease of operation, it is preferable to use 2.5mL/g of absolute ethanol in a small amount.

TABLE 9 influence of reaction time on esterification reaction

As can be seen from Table 9, the relative content and yield of compound III increased significantly with increasing time and the reaction proceeded, but after the reaction reached equilibrium, the continued extension of the reaction time did not significantly contribute to the increase in the relative content and yield of the product. Preferably a reaction time of 6 hours.

TABLE 10 influence of catalyst usage on esterification reactions

-superscripts a, b represent a batch of raw materials, respectively; for example, the superscript a indicates the same batch of material.

As can be seen from Table 10, the relative content and yield of compound III increased significantly with increasing catalyst levels, but when the catalyst levels exceeded 0.1 equivalent, continued increase in catalyst did not significantly contribute to the product relative content and yield. Preferably, 0.1 equivalent of catalyst is used.

TABLE 11 influence of the work-up (neutralization of the deprotection groups and extraction) on the content and yield of compound IV

*1: the extractant amount (V) is the ratio of the volume of extractant to the volume of solvent used in the esterification reaction.

*2: in synthesis example 2, absolute content of compound IV: and (3) calibrating the actual content of the obtained compound IV sample by using a standard substance by an internal standard method.

*3: in synthesis example 2, absolute yield of compound IV: (compound IV product mass x absolute compound IV content)/theoretical yield x 100%.

As can be seen from Table 11, in the neutralization reaction with a base to remove the HCl protecting group on the amino group in the compound III, ammonia water is preferably used as a base in the neutralization reaction from the viewpoints of reducing three wastes, improving the utilization ratio of the reaction raw materials, and improving the handling convenience.

In the extraction and purification of the compound IV, methylene dichloride and methyl tertiary butyl ether are beneficial to obtaining the purified target product compound IV with high extraction rate.

When the volume of the extractant is changed in the range of 3 to 5 times of the volume of the esterification reaction solvent, the volume of the extractant which is 5 times of the volume of the esterification reaction solvent is favorable for obtaining the purified target product compound IV with high extraction rate.

Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other publications) is incorporated herein by reference in its entirety.

Claims

A process for the preparation of (S) -4-chloro-2-aminobutyric acid hydrochloride comprising the steps of:

subjecting L-homoserine lactone hydrochloride of formula (I) to ring-opening chlorination with hydrogen chloride to produce (S) -4-chloro-2-aminobutyric acid hydrochloride of formula (II)
The process according to claim 1, wherein the hydrogen chloride is provided in the form of hydrochloric acid, preferably concentrated hydrochloric acid having a concentration of about 30 to about 38 wt%, more preferably 30 wt% or 36 wt%.
The process according to claim 1 or 2, wherein the molar ratio of hydrogen chloride to L-homoserine lactone hydrochloride is from about 1 to about 5:1, preferably from about 3 to about 4:1, more preferably about 3.5:1.
A process according to any one of claims 1 to 3, wherein the ring-opening chlorination reaction is carried out at atmospheric or elevated pressure, preferably under elevated pressure.
The process according to any one of claims 1 to 4, wherein the ring-opening chlorination reaction is carried out under heating, preferably at a reaction temperature of about 80 to about 130 ℃, more preferably about 90 to about 120 ℃, still more preferably about 90 to about 100 ℃, most preferably about 100 ℃.
The process of any one of claims 1-5, wherein the reaction time of the ring-opening chlorination reaction is about 8 to about 24 hours, preferably about 12 to about 18 hours, more preferably about 16 hours.
The process according to any one of claims 1 to 6, wherein the ring-opening chlorination reaction is carried out in the absence of a catalyst,

in particular, the ring-opening chlorination reaction is carried out in the absence of a sulfuric acid catalyst.
The process according to any one of claims 1 to 6, wherein the ring-opening chlorination reaction is carried out in the presence of a catalyst,

the catalyst is preferably sulfuric acid, wherein the sulfuric acid is preferably concentrated sulfuric acid having a concentration of about 95 to about 98.5 weight percent, such as 98 weight percent.
The process according to claim 8, wherein the molar ratio of sulfuric acid to L-homoserine lactone hydrochloride is from 0 to about 1:1, preferably from about 0.1 to about 0.5:1, more preferably about 0.25:1.
The process according to any one of claims 1 to 9, wherein after the ring-opening chlorination reaction has ended, heating is stopped and the reaction mixture is cooled down so as to precipitate (S) -4-chloro-2-aminobutyric acid hydrochloride crystals,

preferably, after the ring-opening chlorination reaction is completed, heating is stopped, and the reaction mixture is cooled under stirring so as to precipitate (S) -4-chloro-2-aminobutyrate crystals,

preferably, the cooling is selected from: naturally cooling the reaction mixture from the reaction temperature, gradually cooling the reaction mixture from the reaction temperature, directly exposing the reaction mixture to ambient temperature, placing the reaction mixture in a water bath at about 0 to about 60 ℃ or an ice water bath at about 0 ℃, and combinations thereof,

preferably, the reaction mixture is naturally cooled from the reaction temperature to a temperature of 25-60℃with stirring,

preferably, the reaction mixture is cooled from the reaction temperature to about 75 ℃ at a rate of about 1 ℃/min, then from about 75 ℃ to about 40 ℃ at a rate of about 0.5 ℃/min, and from about 40 ℃ to about 25 ℃ at a rate of about 0.25 ℃/min, with stirring.
A process for the preparation of (S) -4-chloro-2-aminobutyric acid ester comprising the steps of:

step a): the process according to any one of claims 1 to 10, wherein the L-homoserine lactone hydrochloride of formula (I) is subjected to ring-opening chlorination with hydrogen chloride to form (S) -4-chloro-2-aminobutyric acid hydrochloride of formula (II)

Step b): esterifying (S) -4-chloro-2-aminobutyric acid hydrochloride of formula (II) with alcohol ROH in the presence of acidic catalyst and solvent to obtain (S) -4-chloro-2-aminobutyric acid hydrochloride of formula (III)

Step c): neutralizing (S) -4-chloro-2-aminobutyric acid ester hydrochloride of formula (III) with alkali to obtain (S) -4-chloro-2-aminobutyric acid ester of formula (IV)

Wherein in formula (III) and formula (IV), R is selected from C ₁ -C ₆ Alkyl, C _3-10 Cycloalkyl, C _6-10 Aryl, C _7-12 Aralkyl, 5-14 membered heteroaryl and 3-10 membered heterocyclyl, preferably C ₁ -C ₆ Alkyl groups, more preferably ethyl groups.
The process according to claim 11, wherein in step b) the acidic catalyst is selected from the group consisting of inorganic acids, acid salts of inorganic acids and organic acids,

the mineral acid is preferably selected from sulfuric acid and HCl, preferably sulfuric acid, more preferably concentrated sulfuric acid having a concentration of about 95 to about 98.5 wt%, for example 98 wt%; the HCl is preferably HCl gas and,

the acid salt of the mineral acid is preferably an alkali metal bisulfate salt, such as sodium bisulfate,

the organic acid is preferably selected from p-toluene sulfonic acid and acidic cation exchange resins.
The process according to claim 12, wherein in step b) the molar ratio of concentrated sulfuric acid to (S) -4-chloro-2-aminobutyrate is from about 0.05 to about 0.4:1, preferably from about 0.1 to about 0.2:1, more preferably from about 0.1 to about 0.15:1, still more preferably about 0.1:1.
A process according to any one of claims 11-13, wherein in step b) the solvent is selected from alcohols, preferably C ₁ -C ₆ Alcohols, more preferably ethanol, still more preferably absolute ethanol,

wherein the ratio of the volume of the solvent to the mass of the (S) -4-chloro-2-aminobutyrate is preferably from about 2 to about 5mL/g, more preferably from about 2.5 to about 4mL/g, still more preferably about 2.5mL/g.
A process according to claim 14, wherein in step b) the anhydrous ethanol is heated to reflux, preferably to 78-85 ℃, more preferably to about 85 ℃.
The process according to any one of claims 11-15, wherein in step b) the reaction time is from about 3 to about 20 hours, preferably from about 4 to about 8 hours, more preferably about 6 hours.
The process according to any one of claims 11-16, wherein in step c) the base is an inorganic base, preferably selected from the group consisting of ammonia, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, alkali metal hydroxide, alkaline earth metal hydroxide or a combination thereof, more preferably selected from the group consisting of ammonia, sodium carbonate, sodium bicarbonate, and a combination of sodium bicarbonate and sodium hydroxide, even more preferably ammonia.
The process according to any one of claims 11 to 17, wherein, after step c), the reaction mixture is extracted with an extractant,

the extractant is a hydrophobic organic solvent, preferably selected from ethers, esters, alkylbenzenes and halogenated hydrocarbons, preferably selected from methyl tertiary butyl ether, ethyl acetate, toluene, xylene, chlorobenzene, dichloromethane and dichloroethane, more preferably selected from methyl tertiary butyl ether and dichloromethane.
The process according to claim 18, wherein the volume ratio of extractant to solvent in step b) is from about 1.5 to about 6:1, preferably from about 3 to about 5:1, more preferably about 5:1.