WO2023051768A1 - Procédés de préparation de chlorhydrate d'acide (s)-4-chloro-2-aminobutyrique et de (s)-4-chloro-2-aminobutyrate - Google Patents

Procédés de préparation de chlorhydrate d'acide (s)-4-chloro-2-aminobutyrique et de (s)-4-chloro-2-aminobutyrate Download PDF

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WO2023051768A1
WO2023051768A1 PCT/CN2022/123151 CN2022123151W WO2023051768A1 WO 2023051768 A1 WO2023051768 A1 WO 2023051768A1 CN 2022123151 W CN2022123151 W CN 2022123151W WO 2023051768 A1 WO2023051768 A1 WO 2023051768A1
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chloro
reaction
compound
hydrochloride
acid
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PCT/CN2022/123151
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周磊
曾伟
刘永江
程柯
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利尔化学股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/20—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups

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  • the invention relates to a preparation method of (S)-4-chloro-2-aminobutyric acid hydrochloride and (S)-4-chloro-2-aminobutyrate.
  • glufosinate-ammonium As a high-efficiency, low-toxicity, broad-spectrum contact-killing organophosphorus herbicide, glufosinate-ammonium has been used year by year and has a huge market potential.
  • the glufosinate-ammonium usually produced is the racemate of L-glufosinate-ammonium and D-glufosinate-ammonium (that is, the mixture of L-glufosinate-ammonium and D-glufosinate-ammonium), wherein, D-glufosinate-ammonium There is no biological activity, and the biological activity of L-glufosinate-ammonium is twice that of the racemate.
  • the present invention proposes to use HCl as the chlorinating agent for the first time to prepare (S)-4-chloro-2-aminobutyric acid hydrochloride, the relative use of HCl
  • the quantity is small, the cost is low, the chlorination product has few impurities, and the chlorination product has high purity; it can be chlorinated under normal pressure or under pressure, and the operation is flexible and convenient; and HCl can be recycled and used, which is environmentally friendly.
  • the present invention also provides a method for preparing (S)-4-chloro-2-aminobutyrate, which comprises the following steps:
  • 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 heterocyclic group, preferably C 1 -C 6 alkyl, more preferably ethyl.
  • the present invention proposes for the first time a method for preparing (S)-4-chloro-2-aminobutyrate after ring-opening and chlorination followed by esterification , not only the yield is comparable to the known method, but also, by adopting a small amount of recyclable HCl to replace the large amount of thionyl chloride, it is environmentally friendly and avoids the situation of producing a large amount of impurities when using thionyl chloride.
  • Fig. 1 is the proton nuclear magnetic resonance spectrum of (S)-4-chloro-2-aminobutyric acid hydrochloride.
  • Fig. 2 is the carbon nuclear magnetic resonance spectrum of (S)-4-chloro-2-aminobutyric acid hydrochloride.
  • Figure 3 is the hydrogen nuclear magnetic resonance spectrum of (S)-4-chloro-2-aminobutyric acid ethyl ester.
  • Fig. 4 is the carbon nuclear magnetic resonance spectrum of (S)-4-chloro-2-aminobutyric acid ethyl ester.
  • Products and methods according to the present invention may comprise or comprise the essential technical features described in this disclosure, as well as additional and/or optional components, ingredients, steps or other limiting features described herein; The essential technical features described, as well as additional and/or optional components, ingredients, steps or other restrictive features described herein; or essentially consist of the essential technical features described in this disclosure, and additional and/or Optionally present components, ingredients, steps or other limiting features described herein.
  • alkyl refers to a straight-chain or branched saturated aliphatic hydrocarbon group.
  • C 1 -C 6 alkyl refers to an alkyl group having 1 to 6 carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl Base, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl and its isomers.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be halogen, nitro, sulfonyl, etheroxy, etherthio, ester, thioester, cyano, etc.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic or polycyclic) hydrocarbon ring.
  • C 3-10 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic or higher) hydrocarbon ring having 3 to 10 ring-forming carbon atoms.
  • Monocyclic "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]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0] Nonyl, Decalinyl, etc. Cycloalkyl is optionally substituted with 1 or more (such as 1 to 3) substituents, eg methyl substituted cyclopropyl.
  • aryl refers to an all-carbon monocyclic or fused polycyclic group having conjugated ⁇ -electrons.
  • 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 (eg, halogen, -OH, -CN, -NO 2 , or C 1-6 alkyl, etc.).
  • aralkyl refers to an aryl-substituted alkyl group, wherein the aryl and the alkyl are as defined herein.
  • C7-12 aralkyl refers to an aralkyl group having 7 to 12 carbon atoms, wherein the aryl group may have 6-11 carbon atoms and the alkyl group may have 1-6 carbon atoms .
  • Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.
  • heteroaryl refers to a monocyclic or fused polycyclic ring containing conjugated ⁇ electrons and consisting of carbon atoms and at least one heteroatom selected from oxygen, nitrogen and sulfur.
  • heteroaryl refers to a heteroaryl group having 5-14 ring atoms, especially 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, oxadiazole Base, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and their benzo derivatives.
  • heterocyclyl refers to a saturated or unsaturated, monocyclic or polycyclic (such as bicyclic or more polycyclic) groups.
  • 3-10 membered heterocyclic group refers to a heterocyclic group having 3-10 ring atoms, especially 2-9 carbon atoms. Examples of “3-10 membered heterocyclyl” include, but are not limited to, oxiranyl, aziridinyl, azetidinyl (azetidinyl), oxetanyl
  • the term "about” means that the value it defines may have a deviation within ⁇ 10% of the value, for example, the term “about 100°C” means the range of "100 ⁇ 10°C”.
  • atmospheric pressure refers to about 1 atmosphere of pressure.
  • room temperature refers to about 20 to about 25°C, preferably about 25°C.
  • the present invention provides a method for preparing (S)-4-chloro-2-aminobutyric acid hydrochloride, comprising the following steps:
  • hydrogen chloride (HCl) is provided in the form of hydrochloric acid, preferably concentrated hydrochloric acid at a concentration of about 30% to about 38% by weight, more preferably 30% by weight (referred to as “30% concentrated hydrochloric acid”) or 36% by weight (referred to as “36% concentrated hydrochloric acid”) concentrated hydrochloric acid.
  • the molar ratio of hydrogen chloride (HCl) to L-homoserine lactone hydrochloride is about 1 to about 5:1, preferably about 3 to about 4:1, more preferably about 3.5:1.
  • the ring-opening chlorination reaction is carried out under normal pressure (i.e., about 1 atmospheric pressure) or increased pressure (i.e., greater than 1 atmospheric pressure), preferably under increased pressure, for example, about 0.1 to about 1.0 MPa , or about 0.2-about 1.0 MPa, for example, about 0.18 MPa or about 0.22 MPa.
  • the ring chlorination reaction is carried out under heating, preferably the reaction temperature is about 80-about 130°C, more preferably about 90-about 120°C, still more preferably about 90-about 100°C, most preferably about 100°C.
  • 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 ring-opening chlorination reaction is carried out in the absence of a catalyst
  • the ring-opening chlorination reaction is carried out in the absence of a sulfuric acid catalyst.
  • the present invention provides a method for preparing (S)-4-chloro-2-aminobutyric acid hydrochloride, which comprises the following steps:
  • the ring-opening chlorination reaction is carried out in the absence of a catalyst
  • 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 presence of a catalyst.
  • the catalyst is preferably sulfuric acid.
  • Sulfuric acid is preferably concentrated sulfuric acid having a concentration of about 95% to about 98.5% by weight, such as 98% by weight concentrated sulfuric acid (“98% concentrated sulfuric acid” for short).
  • the molar ratio of sulfuric acid to L-homoserine lactone hydrochloride is 0 to about 1:1, preferably about 0.1 to about 0.5:1, more preferably about 0.25:1.
  • the cooling is selected from: allowing the reaction mixture to cool naturally from the reaction temperature, for example, keeping the reaction mixture in the oil bath environment and stirring the reaction mixture after stopping the heating of the oil bath providing heating for the chlorination reaction , making it naturally drop to a temperature of about 25-about 60°C, such as naturally dropping to about 25-about 30°C, about 30-about 35°C, about 35-about 40°C, about 40-about 45°C, about 45- about 50°C, about 50 to about 55°C, or about 55 to about 60°C;
  • the reaction mixture is gradually cooled from the reaction temperature, for example, under stirring, the reaction mixture is cooled from the chlorination reaction temperature (for example, about 100° C.) to about 75° C. at a rate of about 1° C./min, and then Cool down from about 75°C to about 40°C at a rate of about 0.5°C/min, and from about 40°C to about 25°C at a rate of about 0.25°C/min; Precipitation begins within the temperature range, and such step-by-step cooling helps the product to precipitate with high purity (ie, relative content); for example, a jacket can be used to accurately achieve step-by-step cooling;
  • the reaction mixture is exposed directly to ambient temperature, particularly to room temperature air at about 20 to about 25°C. That is to say, after the oil bath that provides heating for the chlorination reaction is stopped heating, the reaction mixture is removed from the oil bath environment, the reaction mixture is placed in a room temperature environment and the reaction mixture is stirred to allow it to naturally drop to room temperature;
  • the reaction mixture is placed in a water bath of about 0 to about 60°C or an ice-water bath of about 0°C, for example, the temperature of the water bath is about 0 to about 5°C, about 5 to about 10°C, about 10 to about 15°C, about 15-about 20°C, about 20-about 25°C, about 25-about 30°C, about 30-about 35°C, about 35-about 40°C, about 40-about 45°C, about 45-about 50°C °C, about 50-about 55 °C, or about 55-about 60 °C; when using a water bath (for example, about 20 °C or lower) or about 0 °C of ice-water bath, the reaction product will change from the chlorination reaction temperature (for example, about 100 °C) Or lower than the temperature of the chlorination reaction (for example, first cool down naturally from about 100°C to about 70°C, and then use a water bath or ice-water bath to cool down) quickly cool down to the temperature of the
  • the reaction mixture is naturally cooled from the reaction temperature to a temperature of about 25 to about 60°C, especially to about 40 to about 50°C, such as about 40°C, about 41°C, about 42°C, under stirring. , about 43°C, about 44°C, about 45°C, about 46°C, about 47°C, about 48°C, about 49°C, or about 50°C.
  • the (S)-4-chloro-2-aminobutyric acid hydrochloride crystals precipitated at reduced temperature are purified, for example, suction filtered, and/or washed (eg, rinsed).
  • Washing can be carried out with hydrophobic organic solvents, preferably selected from ethers, esters, alkylbenzenes (for example, C 1 -C 6 alkylbenzenes) and halogenated hydrocarbons (for example, halogenated C 1 - C 6 alkanes and halogenated C 6-12 aromatic hydrocarbons), more preferably selected from methyl tert-butyl ether, ethyl acetate, toluene, xylene, chlorobenzene, dichloromethane and dichloroethane, and more preferably selected from Methyl tert-butyl ether and dichloromethane.
  • hydrophobic organic solvents preferably selected from ethers, esters, alkylbenzenes (for example, C 1 -C 6 alkylbenzenes) and halogenated hydrocarbons (for example, halogenated C 1 - C 6 alkanes and halogenated C 6-12 aromatic hydrocarbons),
  • the present invention provides the preparation method of (S)-4-chloro-2-aminobutyric acid ester, it comprises the following steps:
  • 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 heterocyclic group, preferably C 1 -C 6 alkyl, more preferably ethyl.
  • the acidic catalyst is selected from 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 at a concentration of about 95 to about 98.5% by weight, such as 98% by weight; HCl is preferably HCl gas.
  • the acid salt of the inorganic acid is preferably an alkali metal bisulfate, such as sodium bisulfate.
  • the organic acid is preferably selected from p-toluenesulfonic acid and acidic cation exchange resins, for example, commercially available Dowex 50WX8 ion exchange resin (from McLean) and Amberlite IR120 cation exchange resin sodium type (from McLean).
  • the molar ratio of concentrated sulfuric acid to (S)-4-chloro-2-aminobutyric acid hydrochloride is about 0.05 to about 0.4:1, preferably about 0.1 to about 0.2:1 , more preferably about 0.1 to about 0.15:1, even more preferably about 0.1:1.
  • the solvent is selected from alcohols, preferably C 1 -C 6 alcohols, more preferably ethanol, even more preferably absolute ethanol.
  • the ratio of the volume of the solvent to the mass of (S)-4-chloro-2-aminobutyric acid hydrochloride is preferably about 2-about 5mL/g, more preferably about 2.5-about 4mL/g, more preferably Preferably about 2.5 mL/g.
  • step b) the absolute ethanol is heated to reflux, preferably heated to about 78-about 85°C, more preferably heated to about 85°C.
  • the reaction time is about 3 to about 20 hours, preferably about 4 to about 8 hours, more preferably about 6 hours.
  • the base is an inorganic base, preferably selected from ammonia, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, alkaline earth metal bicarbonates, alkali metal hydrogen Oxide, alkaline earth metal hydroxide or their combination, more preferably selected from ammonia water, sodium carbonate, sodium bicarbonate, and the combination of sodium bicarbonate and sodium hydroxide, more preferably ammonia water.
  • step c the reaction mixture is extracted.
  • the extractant is a hydrophobic organic solvent, preferably selected from ethers, esters, alkylbenzenes (e.g., C 1 -C 6 alkyl substituted benzenes) and halogenated hydrocarbons (e.g., halogenated C 1 -C 6 alkanes and halogenated C 6-12 aromatic hydrocarbons), preferably selected from methyl tert-butyl ether, ethyl acetate, toluene, xylene, chlorobenzene, dichloromethane and dichloroethane, more preferably selected from Methyl tert-butyl ether and dichloromethane.
  • ethers preferably selected from ethers, esters, alkylbenzenes (e.g., C 1 -C 6 alkyl substituted benzenes) and halogenated hydrocarbons (e.g., halogenated C 1 -C 6 alkanes and halogenated C
  • the extractant may be the same or different, preferably the same, as the hydrophobic organic solvent (if necessary) used to wash the (S)-4-chloro-2-aminobutyric acid hydrochloride crystals in step a).
  • the volume ratio of the extractant to the solvent in step b) is about 1.5-about 6:1, preferably about 3-about 5:1, more preferably about 5:1.
  • the concentrated sulfuric acid used in the examples is concentrated sulfuric acid with a concentration of 98% by weight.
  • the purity of the reaction raw material L-homoserine lactone hydrochloride (hereinafter referred to as "compound I") is 90-95%. Therefore, in the following examples, the yield of (S)-4-chloro-2-aminobutyric acid hydrochloride (hereinafter referred to as "Compound II”) should be the experimental data of the actual yield of Compound II divided by the purity of Compound I earned quotient. 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 experimental data of the actual yield of compound II is 36.22%, then the yield of compound II should be based on 38.03%-40.20%.
  • the experimental data are mainly used to indicate the influence trend of the reaction conditions on the product yield and product purity.
  • the reaction product is separated from the reaction mixture, the residual reaction mixture is used as the reaction raw material for 1 or more recycling so as to exhaust the unreacted raw material, and the total yield of compound II can reach more than 90%.
  • the relative content of compound II in a single chlorination reaction measured by phase chromatography (HPLC) can reach more than 90%. It is considered that the yield can be improved by recovering unreacted raw materials and making them circulate for reaction. In some cases, relative to the yield, the relative content is used as the primary index for evaluating the progress of the reaction.
  • compound III compound III
  • compound IV compound IV
  • Fig. 1 is the hydrogen nuclear magnetic resonance spectrum of white crystal (S)-4-chloro-2-aminobutyric acid hydrochloride (compound II).
  • Fig. 2 is the carbon nuclear magnetic resonance spectrum of white crystal (S)-4-chloro-2-aminobutyric acid hydrochloride (compound II).
  • Aqueous ammonia (496.3 g, 7.59 mol) was added to the crude compound III obtained by distillation under reduced pressure as described above to adjust the pH value to 7-8. Extract with dichloroethane, combine the organic phases and dry over anhydrous sodium sulfate. The organic phase was concentrated to obtain a light yellow oily liquid with a crude compound IV yield of 88.81% (absolute yield 82.58%).
  • Figure 3 is the hydrogen nuclear magnetic resonance spectrum of (S)-ethyl 4-chloro-2-aminobutyrate (compound IV).
  • Fig. 4 is the carbon nuclear magnetic resonance spectrum of (S)-4-chloro-2-aminobutyric acid ethyl ester (compound IV).
  • the equivalent (eq) of concentrated hydrochloric acid is the ratio of the molar weight of concentrated hydrochloric acid (HCl) to the molar weight of compound I.
  • the equivalent (eq) of concentrated sulfuric acid is the ratio of the molar weight of concentrated sulfuric acid to the molar weight of compound I.
  • the molar ratio of HCl to compound I is 3-4:1 is conducive to obtaining compound II with high purity and high yield.
  • Natural cooling in oil bath is more conducive to the precipitation of compound II crystals with high purity and high yield than natural cooling.
  • the yield and/or relative content of compound II will decrease to some extent.
  • the equivalent (eq) of the chlorination reagent is the ratio of the molar amount of concentrated hydrochloric acid (HCl) to the molar amount of compound I.
  • the equivalent (eq) of concentrated sulfuric acid is the ratio of the molar weight of concentrated sulfuric acid to the molar weight of compound I.
  • the crystallization temperature is a specific value or range of values: Stop heating the oil bath, place the reaction mixture in a water bath at the stated temperature and stir to cool down.
  • Pressurization means that the reaction is carried out in a closed container (stuffed tank system) without external pressure, and the reaction pressure has not been measured, but the stuffy tank is similar to pressurized.
  • reaction temperature of 90-120° C. especially the reaction temperature of 100° C. is beneficial to obtain compound II with high purity and high yield.
  • the reaction temperature was higher than 120 °C, the yield and purity of compound II began to decrease.
  • the yield and purity of Compound II were lower than those at 140° C., it is believed that this is an acceptable experimental error that does not affect the yield of Compound II and the overall trend of purity being affected by reaction temperature.
  • the equivalent (eq) of concentrated hydrochloric acid is the ratio of the molar weight of concentrated hydrochloric acid (HCl) to the molar weight of compound I.
  • the equivalent (eq) of concentrated sulfuric acid is the ratio of the molar weight of concentrated sulfuric acid to the molar weight of compound I.
  • the equivalent (eq) of concentrated hydrochloric acid is the ratio of the molar weight of concentrated hydrochloric acid (HCl) to the molar weight of compound I.
  • the equivalent (eq) of concentrated sulfuric acid is the ratio of the molar weight of concentrated sulfuric acid to the molar weight of compound I.
  • the equivalent (eq) of concentrated hydrochloric acid is the ratio of the molar weight of concentrated hydrochloric acid (HCl) to the molar weight of compound I.
  • the equivalent (eq) of concentrated sulfuric acid is the ratio of the molar weight of concentrated sulfuric acid to the molar weight of compound I.
  • the crystallization temperature is a specific value or range of values: Stop heating the oil bath, place the reaction mixture in a water bath at the stated temperature and stir to cool down.
  • the natural cooling of the oil bath is conducive to obtaining compound II with the best relative content and yield.
  • Feeding HCl gas during the chlorination reaction, and/or feeding HCl gas during the crystallization process is beneficial to obtain compound II with a high relative content and yield. If the temperature is rapidly lowered from 100°C to 20°C or even lower (for example, 0°C), a large amount of raw materials will precipitate out together with the product, reducing the relative content of compound II.
  • the equivalent (eq) of concentrated hydrochloric acid is the ratio of the molar weight of concentrated hydrochloric acid (HCl) to the molar weight of compound I.
  • the equivalent (eq) of concentrated sulfuric acid is the ratio of the molar weight of concentrated sulfuric acid to the molar weight of compound I.
  • 0.18MPa or 0.22MPa means reaction in a pressure bottle, and the reaction pressure can be measured.
  • Pressurization means that the reaction is carried out in a closed container (stuffed tank system) without external pressure, and the reaction pressure has not been measured, but the stuffy tank is similar to pressurized.
  • pressurization is more favorable than normal pressure to obtain compound II with high relative content and yield.
  • the equivalent (eq) of concentrated hydrochloric acid is the ratio of the molar weight of concentrated hydrochloric acid to the molar weight of compound I.
  • the total yield of the chlorination reaction is based on the total consumption of compound I to calculate the total yield after each cycle.
  • the amount of compound I is the amount of recovered unreacted compound I, which is used for the recycling reaction.
  • Catalyst equivalent (eq) is the ratio of the molar amount of catalyst to the molar amount of compound II.
  • the amount of absolute ethanol (mL/g) is the ratio of the volume of absolute ethanol to the mass of compound II.
  • the superscripts a, b, c, and d respectively represent a certain batch of raw materials; for example, the superscripts are all a to represent the same batch of raw materials.
  • Catalyst equivalent (eq) is the ratio of the molar amount of catalyst to the molar amount of compound II.
  • the amount of absolute ethanol (mL/g) is the ratio of the volume of absolute ethanol to the mass of compound II.
  • Catalyst equivalent (eq) is the ratio of the molar amount of catalyst to the molar amount of Compound II.
  • the amount of absolute ethanol (mL/g) is the ratio of the volume of absolute ethanol to the mass of compound II.
  • Catalyst equivalent (eq) is the ratio of the molar amount of catalyst to the molar amount of Compound II.
  • the amount of absolute ethanol (mL/g) is the ratio of the volume of absolute ethanol to the mass of compound II.
  • the superscripts a and b respectively represent a certain batch of raw materials; for example, the superscripts are both a and represent the same batch of raw materials.
  • the amount of extractant (V) is the ratio of the volume of extractant to the volume of solvent used in the esterification reaction.
  • the superscripts a and b respectively represent a certain batch of raw materials; for example, the superscripts are both a and represent the same batch of raw materials.
  • ammonia water is preferably used Used as a base in neutralization reactions.
  • dichloromethane and methyl tert-butyl ether are beneficial to obtain the purified target product compound IV with a high extraction rate.
  • the volume of the extractant varies within the range of 3-5 times the volume of the solvent for the esterification reaction
  • the volume of the extractant that is 5 times the volume of the solvent for the esterification reaction is conducive to obtaining the purified target product compound IV with a high extraction rate.

Abstract

L'invention concerne un procédé de préparation de chlorhydrate d'acide (S)-4-chloro-2-aminobutyrique, le procédé comprenant l'étape suivante consistant : à soumettre le chlorhydrate de L-homosérine lactone de formule (I) et du chlorure d'hydrogène à une réaction de chloration par ouverture de cycle pour générer du chlorhydrate d'acide (S)-4-chloro-2-aminobutyrique de formule (II). L'invention concerne en outre un procédé de préparation de (S)-4-chloro-2-amino-rate.
PCT/CN2022/123151 2021-09-30 2022-09-30 Procédés de préparation de chlorhydrate d'acide (s)-4-chloro-2-aminobutyrique et de (s)-4-chloro-2-aminobutyrate WO2023051768A1 (fr)

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