A kind of preparation method of S-flubutyric acid amine

Abstract

The invention discloses a method for preparing S-fluorobutyric acid amide, belongs to the field of organic chemical synthesis, and the method comprises that the S-fluorobutyric acid amide is prepared by a key intermediate R-1; #imgabs0# wherein the key intermediate R-1 is obtained by a halogenation reaction of R-2#imgabs1# wherein R1 is a C1-C6 alkyl, X is Cl or Br, and in the halogenation reaction, the catalyst is a compound containing pyridine and / or including a pyridyl substituent. The present invention uses natural chiral (S)-2-hydroxybutyric acid generated by fermentation in large quantities as a raw material to prepare S-fluorobutyric acid, which has low cost, short route, low pollution, good safety, high yield and high purity.

Description

Technical Field

[0001] The invention belongs to the field of organic chemical synthesis, and particularly relates to a method for preparing S-fluorobutyric acid sulfoxide. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Beflubutamid (UBH-820, CAS registration number 113614-08-7) is a phenoxyamide herbicide developed by Ube Industries, Ltd. of Japan. It is a carotenoid biosynthesis inhibitor and is mainly used to control broadleaf weeds in barley and wheat fields. Beflubutamid is currently sold commercially as a mixture of racemic forms.

[0004] S-Beflubutamid (Beflubutamid-M) is the S-isomer separated from the commercial variety Beflubutamid. It has a stable structure and is more herbicidal than the racemic mixture. The herbicidal activity is at least 1000 times that of the R-isomer.

[0005]

[0006] At present, the method for synthesizing S-fluorobutyric acid amide includes splitting method, chiral source method and asymmetric hydrogenation method. In the process of synthesizing S-fluorobutyric acid amide by splitting method, a chiral splitting agent or biological enzyme is needed to split and obtain a chiral key intermediate, but the chiral splitting agent or biological enzyme is relatively expensive and has a high cost of use. The chiral source method synthesizes S-fluorobutyric acid amide by treating R-2-aminobutyric acid with alkali metal nitrite and hydrobromic acid to obtain R-2-bromobutyric acid, and then further synthesizes S-fluorobutyric acid amide, but R-2-aminobutyric acid is expensive, and the preparation process needs to be diazotized, the amount of wastewater is large, and the safety is poor. In the process of synthesizing S-fluorobutyric acid amide by asymmetric hydrogenation method, it is necessary to use a precious metal chiral catalyst that is expensive and difficult to recover, which greatly increases the production cost. Therefore, a new method for synthesizing S-fluorobutyric acid amide with lower cost, safer, more efficient and cleaner is needed. Summary of the invention

[0007] In order to solve the shortcomings of the prior art, the purpose of the present invention is to provide a method for preparing S-fluorobutyric acid sulfamethoxazole. The synthesis method of S-fluorobutyric acid sulfamethoxazole provided by the present invention has a wide source of raw materials, low cost, and high optical purity. The prepared product S-fluorobutyric acid sulfamethoxazole has high content and good optical activity.

[0008] In order to achieve the above object, the technical solution of the present invention is:

[0009] On the one hand, a method for preparing S-flubutyric acid sulfamethoxazole, wherein the S-flubutyric acid sulfamethoxazole is prepared from a key intermediate R-1;

[0010]

[0011] Among them, the key intermediate R-1 is prepared by halogenation reaction (configuration inversion) of compound R-2;

[0012]

[0013] Wherein, R1 is C1-C6 alkyl, X is Cl or Br;

[0014] In the halogenation reaction, pyridine and / or a compound containing a pyridyl substituent is added as a catalyst.

[0015] Wherein, compound R-2 is obtained by esterification reaction using natural (S)-2-hydroxybutyric acid as raw material.

[0016]

[0017] (S)-2-Hydroxybutyric acid can be produced on a large scale by microbial fermentation.

[0018] The present invention converts the key intermediate R-1 into S-flubutyric acid amine by the following method: treating the key intermediate R-1 with compound 1

[0019]

[0020] To prepare compound R-5;

[0021]

[0022] Wherein, R1 is C1-C6 alkyl;

[0023] Treatment of Compound R-5 with Compound 2

[0024]

[0025] To prepare S-fluorobutyric acid amine.

[0026] The present invention converts the key intermediate R-1 into S-flubutyric acid amine by the following method: the key intermediate R-1 is subjected to a hydrolysis reaction to obtain a compound R-3

[0027]

[0028] Wherein, X is Cl or Br;

[0029] Treatment of Compound R-3 with Compound 1

[0030]

[0031] To prepare compound R-6;

[0032]

[0033] Compound R-6 is subjected to acyl halide reaction to obtain compound R-7

[0034]

[0035] Wherein, X1 is Cl or Br;

[0036] Treatment of Compound R-7 with Compound 2

[0037]

[0038] To prepare S-fluorobutyric acid amine.

[0039] The present invention converts the key intermediate R-1 into S-flubutyric acid amine by the following method: the key intermediate R-1 is subjected to a hydrolysis reaction to obtain a compound R-3

[0040]

[0041] Wherein, X is Cl or Br;

[0042] Compound R-3 is subjected to acyl halide reaction to obtain compound R-8

[0043]

[0044] Wherein, X is Cl or Br, X2 is Cl or Br;

[0045] Treatment of Compound R-8 with Compound 2

[0046]

[0047] To prepare compound R-9;

[0048]

[0049]

[0050] Wherein, X is Cl or Br;

[0051] Treatment of Compound R-9 with Compound 1

[0052]

[0053] To prepare S-fluorobutyric acid amine.

[0054] The beneficial effects of the present invention are:

[0055] The present invention provides a method for preparing S-fluorobutyric acid, using natural chiral (S)-2-hydroxybutyric acid that can be produced in large quantities by fermentation as a raw material, with a wide source of raw materials and low cost. (S)-2-hydroxybutyric acid is subjected to esterification reaction and halogenation reaction (configuration inversion) to prepare a key intermediate R-1. The method has low cost, short route, low pollution, good safety, and the prepared S-fluorobutyric acid product has high content and good optical activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0057] Figure 1 This is the liquid phase spectrum of fluazifop;

[0058] Figure 2 This is the liquid phase spectrum of S-fluorobutyric acid amine prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0059] It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0060] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprising" and / or "including" are used in this specification, it indicates the presence of features, steps, operations, devices, components and / or combinations thereof.

[0061] In view of the disadvantages of the current method for synthesizing S-flubutyric acid sulfoxide, such as high cost, poor safety, and complicated operation, the present invention provides a method for preparing S-flubutyric acid sulfoxide.

[0062] A typical embodiment of the present invention is a method for preparing S-flubutyric acid sulfoxide, wherein the S-flubutyric acid sulfoxide is prepared from a key intermediate R-1;

[0063]

[0064] Among them, the key intermediate R-1 is obtained by halogenation reaction of R-2.

[0065]

[0066] Wherein, R1 is C1-C6 alkyl, X is Cl or Br;

[0067] In the halogenation reaction, pyridine and / or a compound containing a pyridyl substituent is added as a catalyst.

[0068] The catalyst is pyridine, 2-methylpyridine, 3-methylpyridine, 2-chloropyridine, and 2-bromopyridine.

[0069] The added amount of the catalyst is 0.1% to 5% of the molar amount of R-2.

[0070] In some examples of this embodiment, the R1 is C1-C3 alkyl, and the X is Cl.

[0071] In some embodiments of this embodiment, in the process of obtaining the key intermediate R-1 from R-2 by halogenation reaction, the halogenation reaction is a reaction of compound R-2 with a halogenating agent under heating conditions. Preferably, the heating temperature is 30-90° C. The halogenating agent in the halogenation reaction includes but is not limited to acyl halides, sulfonyl halides and phosphoryl halides. Further, the halogenating agent includes thionyl chloride, sulfonyl chloride, oxalyl chloride, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, phosphine tribromide, phosphorus oxybromide.

[0072] The catalyst has a significant impact on the configuration. The heating reaction of compound R-2 with a halogenating agent in the presence of a compound containing pyridine and / or a pyridyl substituent as a catalyst can ensure that the compound R-2 undergoes a configuration flip to obtain a key intermediate, namely, key intermediate R-1.

[0073] In some examples of this embodiment, the halogenation reaction uses thionyl chloride as a halogenating agent and pyridine as a catalyst;

[0074] Pyridine was used as a catalyst to participate in the SN2 substitution reaction, and the chiral center underwent a configuration flip;

[0075]

[0076] Wherein, compound R-2 is obtained by esterification reaction using natural (S)-2-hydroxybutyric acid as raw material;

[0077]

[0078] Wherein, in the process of obtaining compound R-2 by esterification reaction of (S)-2-hydroxybutyric acid, the esterification reaction is a heating reaction of (S)-2-hydroxybutyric acid, alkyl alcohol and acidic catalyst in a solvent;

[0079] The alkyl alcohol includes but is not limited to methanol, ethanol, and propanol; preferably, the alkyl alcohol is one or more of methanol and ethanol. The acid catalyst is concentrated sulfuric acid, concentrated hydrochloric acid, and sulfonic acid resin, preferably concentrated sulfuric acid. The solvent is benzene, toluene, and cyclohexane, preferably benzene;

[0080] The heating reaction temperature is 65-75°C.

[0081] The method described in the present invention provides an efficient and robust synthesis of S-flubutyric acid.

[0082] Solution 1

[0083]

[0084] As in some embodiments of Scheme 1, the key intermediate R-1 is converted into S-flubutyric acid oxadiazine by a method comprising the following:

[0085] Treatment of the key intermediate R-1 with compound 1

[0086]

[0087] To prepare compound R-5;

[0088]

[0089] Wherein, R1 is C1-C6 alkyl;

[0090] Treatment of Compound R-5 with Compound 2

[0091]

[0092] To prepare S-fluorobutyric acid amine.

[0093] In some examples of this embodiment, during the treatment of the key intermediate R-1 with compound 1, the treatment includes heating the compound having formula R-1 and compound 1 to reflux. Preferably, in the heating reaction, the solvent used includes but is not limited to acetone, butanone, acetonitrile, dichloroethane, toluene, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide. Further preferably, the solvent is acetone, dichloroethane, toluene, N,N-dimethylformamide, and more preferably, acetone.

[0094] In some examples of this embodiment, when compound 1 is used to treat the key intermediate R-1, a base is added. The base includes but is not limited to alkali metal hydrides, such as sodium hydride; or alkali metal alcoholates, such as sodium methoxide, sodium ethoxide; or alkali metal hydroxides, such as potassium hydroxide, sodium hydroxide; or alkali metal carbonates, bicarbonates, such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate; or tertiary amines, such as triethylamine, diisopropylethylamine. Further preferably, the base is sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate.

[0095] In some examples of this embodiment, the process of treating the key intermediate R-1 with compound 1 is as follows: potassium carbonate is added to acetone, and the key intermediate R-1 and compound 1 are heated to reflux to carry out an etherification reaction.

[0096] In some examples of this embodiment, during the process of treating compound R-5 with compound 2, the treatment process includes using compound R-5 and compound 2 as raw materials, heating the reaction to obtain S-fluorobutyric acid amide. Preferably, in the heating reaction, the solvent used includes but is not limited to acetonitrile, dichloroethane, toluene, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, and acetone. Further preferably, the solvent is one or more of dichloroethane, toluene, and N,N-dimethylformamide, and more preferably, toluene. Preferably, the heating reaction has a reaction temperature of 30-80°C.

[0097] In some examples of this embodiment, a base is added during the treatment of compound R-5 with compound 2. The base includes but is not limited to alkali metal hydrides, such as sodium hydride; or alkali metal alcoholates, such as sodium ethoxide, sodium methoxide, sodium tert-butoxide; or alkali metal hydroxides, such as potassium hydroxide, sodium hydroxide; or alkali metal carbonates, bicarbonates, such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate; or alkyl bases, such as lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, lithium diisopropylamide; or tertiary amines, such as triethylamine, diisopropylethylamine. Further preferably, the base is sodium ethoxide.

[0098] In some examples of this embodiment, the process of treating compound R-5 with compound 2 is: using compound R-5 and compound 2 as raw materials, adding sodium ethoxide in toluene, and heating the mixture to react to obtain S-fluorobutyric acid amide.

[0099] Solution 2

[0100]

[0101] In some embodiments of Scheme 2, the key intermediate R-1 is converted into S-flubutyric acid amine by a method comprising the following:

[0102] The key intermediate R-1 is hydrolyzed to obtain compound R-3;

[0103]

[0104] Wherein, X is Cl or Br;

[0105] Treatment of Compound R-3 with Compound 1

[0106]

[0107] To prepare compound R-6;

[0108]

[0109] Compound R-6 is subjected to acyl halide reaction to obtain compound R-7;

[0110]

[0111] Where X1 is Cl or Br

[0112] Treatment of Compound R-7 with Compound 2

[0113]

[0114] To prepare S-fluorobutyric acid amine.

[0115] In some examples of this embodiment, X1 is Cl and X is Cl.

[0116] In some examples of this embodiment, during the hydrolysis reaction of the key intermediate R-1 to obtain the compound R-3, a base may be added, and optionally, the solvent used includes but is not limited to one or more of water, ethanol, and methanol. Preferably, the base includes but is not limited to alkali metal hydrides, such as sodium hydride; or alkali metal alcoholates, such as sodium methoxide, sodium ethoxide, sodium isopropoxide, and potassium tert-butoxide; or alkali metal hydroxides, such as potassium hydroxide and sodium hydroxide.

[0117] In some examples of this embodiment, during the process of treating compound R-3 with compound 1, the solvent used includes but is not limited to acetone, butanone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, benzene, toluene, xylene, tetrahydrofuran, dichloroethane, dichloromethane, chloroform. Preferably, when compound 1 treats compound R-3, a base is added and heated to react. Preferably, the temperature is heated to reflux. Preferably, the base is an inorganic base or an organic base. Further preferably, the inorganic base includes sodium hydroxide, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, lithium carbonate, potassium phosphate, sodium phosphate; the organic base includes triethylamine, pyridine, 2-methylpyridine, 3-methylpyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium acetate, potassium acetate.

[0118] In some examples of this embodiment, during the process of treating compound R-3 with compound 1, specifically, potassium carbonate is added to acetone, and the key intermediate R-3 and compound 1 are heated to carry out an etherification reaction to obtain compound R-6.

[0119] In some examples of this embodiment, during the acyl halide reaction of compound R-6 to obtain compound R-7, a halogenating agent is added, and optionally, the solvent used includes but is not limited to toluene, dichloroethane, and acetonitrile. Further preferably, the solvent is toluene. Preferably, the halogenating agent includes but is not limited to thionyl chloride, thionyl bromide, oxalyl chloride, triphosgene, phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, and phosphine tribromide. Further preferably, the halogenating agent is thionyl chloride.

[0120] In some examples of this embodiment, in the process of preparing S-fluorobutyric acid amide by treating compound R-7 with compound 2, the treatment process includes using compound R-7 and compound 2 as raw materials, heating the reaction to obtain S-fluorobutyric acid amide. Preferably, in the heating reaction, the solvent used includes but is not limited to acetonitrile, dichloroethane, toluene, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, and acetone. Further preferably, the solvent is one or more of N,N-dimethylformamide, dichloroethane, and toluene, and more preferably, toluene. Preferably, the heating reaction has a reaction temperature of 10-50°C.

[0121] In some examples of this embodiment, a base is added during the treatment of compound R-7 with compound 2. The base includes, but is not limited to, alkali metal hydrides, such as sodium hydride; or alkali metal alcoholates, such as sodium ethoxide, sodium isopropoxide; or alkali metal hydroxides, such as potassium hydroxide, sodium hydroxide; or alkali metal carbonates, bicarbonates, such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate; or tertiary amines, such as triethylamine and diisopropylethylamine. Further preferably, the base is triethylamine.

[0122] In some examples of this embodiment, the process of treating compound R-7 with compound 2 is: using compound R-7 and compound 2 as raw materials, adding triethylamine in toluene, and heating the reaction to obtain S-fluorobutyric acid amide.

[0123] Solution 3

[0124]

[0125] As in some embodiments of Scheme 3, the key intermediate R-1 is converted into S-flubutyric acid oxadiazine by a method comprising the following:

[0126] The key intermediate R-1 is hydrolyzed to obtain compound R-3;

[0127]

[0128] Wherein, X is Cl or Br;

[0129] Compound R-3 is subjected to acyl halide reaction to obtain compound R-8;

[0130]

[0131]

[0132] Wherein, X2 is Cl or Br;

[0133] Treatment of Compound R-8 with Compound 2

[0134]

[0135] To prepare compound R-9;

[0136]

[0137] Treatment of Compound R-9 with Compound 1

[0138]

[0139] To prepare S-fluorobutyric acid amine.

[0140] In some examples of this embodiment, during the hydrolysis reaction of the key intermediate R-1 to obtain the compound R-3, a base may be added, and optionally, the solvent used includes but is not limited to one or more of water, ethanol, and methanol. Preferably, the base includes but is not limited to alkali metal hydrides, such as sodium hydride; or alkali metal alcoholates, such as sodium methoxide, sodium ethoxide, sodium isopropoxide, and potassium tert-butoxide; or alkali metal hydroxides, such as potassium hydroxide and sodium hydroxide.

[0141] In some examples of this embodiment, during the acyl halide reaction of compound R-3 to obtain compound R-8, a halogenating agent is added, and optionally, the solvent used includes but is not limited to toluene, dichloroethane, and acetonitrile. Further preferably, the solvent is toluene.

[0142] Preferably, the halogenating agent includes, but is not limited to, thionyl chloride, thionyl bromide, oxalyl chloride, triphosgene, phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, and phosphorus tribromide. Further preferably, the halogenating agent is thionyl chloride.

[0143] In some examples of this embodiment, in the process of treating compound R-8 with compound 2 to prepare compound R-9, the treatment process includes using compound R-8 and compound 2 as raw materials, heating the reaction to obtain compound R-9. Preferably, in the heating reaction, the solvent used includes but is not limited to acetonitrile, dichloroethane, toluene, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, acetone. Further preferably, the solvent is one or more of N,N-dimethylformamide, dichloroethane, toluene, more preferably, toluene. Preferably, the heating reaction, the reaction temperature is 10-50 ° C.

[0144] In some examples of this embodiment, a base is added during the process of treating compound R-8 with compound 2 to prepare compound R-9. The base includes, but is not limited to, alkali metal hydrides, such as sodium hydride; or alkali metal alcoholates, such as sodium ethoxide, sodium isopropoxide; or alkali metal hydroxides, such as potassium hydroxide, sodium hydroxide; or alkali metal carbonates, bicarbonates, such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate; or tertiary amines, such as triethylamine and diisopropylethylamine. Further preferably, the base is triethylamine.

[0145] In some examples of this embodiment, the process of treating compound R-8 with compound 2 to prepare compound R-9 is as follows: using compound R-8 and compound 2 as raw materials, adding triethylamine in toluene, and heating the reaction to obtain compound R-9.

[0146] In some examples of this embodiment, in the process of treating compound R-9 with compound 1 to prepare S-flubutyric acid amine, the treatment includes heating the compound having formula R-9 and compound 1 to reflux. Preferably, in the heating reaction, the solvent used includes but is not limited to acetone, butanone, acetonitrile, dichloroethane, toluene, tetrahydrofuran, dimethyl sulfoxide, N, N-dimethylformamide. Further preferably, the solvent is acetone, dichloroethane, toluene, N, N-dimethylformamide, and more preferably, acetone.

[0147] In some examples of this embodiment, during the process of preparing S-flubutyric acid amine by treating compound R-9 with compound 1, a base is added. The base includes but is not limited to alkali metal hydrides, such as sodium hydride; or alkali metal alcoholates, such as sodium methoxide, sodium ethoxide; or alkali metal hydroxides, such as potassium hydroxide, sodium hydroxide; or alkali metal carbonates, bicarbonates, such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate; or tertiary amines, such as triethylamine, diisopropylethylamine. Further preferably, the base is sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate.

[0148] In some examples of this embodiment, the process of treating compound R-9 with compound 1 is as follows: potassium carbonate is added to acetone, and the key intermediate R-1 and compound 1 are heated to reflux to carry out an etherification reaction to prepare S-fluorobutyric acid amide.

[0149] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments.

[0150] Example 1

[0151] A method for preparing S-fluorobutyric acid sulfoxide, the synthetic route is:

[0152]

[0153] The following steps are involved:

[0154] Step 1: Preparation of (S)-ethyl 2-hydroxybutyrate

[0155] Into a 500mL round-bottom flask equipped with a stirrer, a condenser, a water separator and a thermometer, 57.6g (1.25mol) of anhydrous ethanol, 52.1g (0.5mol) of (S)-2-hydroxybutyric acid, 150mL of benzene and 2mL of concentrated sulfuric acid were charged, heated for reaction, and the temperature was raised to reflux. Water was separated by the water separator until no more water was separated. The heating was stopped, and NaHCO3 was added to neutralize to pH=7. The filtrate was filtered, and the filtrate was first distilled at normal pressure to evaporate benzene and unreacted ethanol and recovered for standby use; then distilled under reduced pressure, and the fractions were collected to obtain 61.7g of colorless oily liquid, with a yield of 89% and a purity of 95.3%.

[0156] Step 2: Preparation of (R)-ethyl 2-chlorobutyrate

[0157] To a 100mL round-bottom flask equipped with a stirrer, a dropping funnel, a condenser, a gas absorber and a thermometer, 55.5g (0.4mol, purity 95.3%) of (S)-ethyl 2-hydroxybutyrate and 0.32g (0.004mol) of pyridine were added, and then the temperature was raised to 60°C, 52.4g (0.44mol) of thionyl chloride was added dropwise, and the reaction was kept warm for 9h; cooled, washed with saturated NaHCO3 solution until neutral, the lower organic phase was separated, the organic phase was washed with 20mL of water, and the organic phase was distilled to obtain 57.3g of a yellow oil with a yield of 93% and a purity of 97.8%.

[0158] Step 3: Preparation of (S)-ethyl 2-(4-fluoro-3-trifluoromethylphenoxy)butyrate

[0159] Into a 2L round-bottom flask equipped with a stirrer, a condenser and a thermometer, 800 g of acetone, 207.3 g (1.5 mol) of potassium carbonate, 90.1 g (0.5 mol) of 4-fluoro-3-trifluoromethylphenol, and 81.6 g (0.53 mol, purity 97.8%) of (R)-ethyl 2-chlorobutyrate were placed, heated to reflux, and reacted for 4 h. After the reaction was completed, the filtrate was filtered and the acetone was distilled off by distillation. 200 g of ethylene dichloride was added, 100 g of water was added, and the mixture was washed. The organic phase was distilled to obtain 138 g of a yellow oil with a yield of 90% and a purity of 96%. 1 H NMR: (CDCl3, 400MHz): δ = 7.07-7.12 (m, 2 H),7.00-7.05(m, 1 H),4.53(dd,J=6.5,5.9Hz, 1 H), 4.23(q, J=7.1Hz, 2 H), 1.97-2.05(m, 2 H),1.26(t,J=7.1Hz, 3 H), 1.08(t,J=7.5Hz, 3 H).

[0160] Step 4: Preparation of S-fluorobutyric acid

[0161] Into a 500mL round-bottom flask equipped with a stirrer, a condenser and a thermometer, 30.65g (0.1mol, purity 96%) of (S)-2-(4-fluoro-3-trifluoromethylphenoxy)butyric acid ethyl ester, 11.8g (0.11mol) of benzylamine and 80mL of toluene were charged, and 10.2g (0.03mol) of 20% sodium ethoxide ethanol solution was added under stirring, heated to 50°C, and reacted for 8h. After the reaction was completed, 50mL of 10% hydrochloric acid and 50mL of water were added for washing, the organic phase was evaporated and concentrated, 30mL of ethanol was added, and 33.7g of white crystals were crystallized, with a yield of 93%, a purity of 98%, and an ee value of 96%. 1 HNMR: (CDCl3, 400MHz): δ = 0.96 ( 3 H, CH3), 1.99( 2 H, CH2), 4.46( 2 H, CH2), 4.63( 1 H, CH), 6.75-6.94( 3 H, C6H3), 7.06-7.14( 5 H,C6H5),8.0( 1 H, HN).

[0162] Chromatographic column: Lux Cellulose-2 column (250 mm × 4.6 mm, 5 μm Phenomenex), mobile phase: n-hexane / isopropanol = 97:3, flow rate: 1 mL / min, column temperature: 40 ° C, wavelength: 254 nm, S-fluorobutyric acid retention time: 13 min.

[0163] Example 2

[0164] A method for preparing S-fluorobutyric acid sulfoxide, the synthetic route is:

[0165]

[0166] The following steps are involved:

[0167] Step 1: Preparation of (R)-2-chlorobutyric acid

[0168] Into a 500mL round-bottom flask equipped with a stirrer, a condenser and a thermometer, 150g of anhydrous ethanol, 50g of water, and 71.1g (0.5mol, purity 96%) of (R)-2-chlorobutyric acid methyl ester were charged, 240g of 10% sodium hydroxide solution was slowly added dropwise, the temperature was kept constant at 30°C for about 4h, 20% hydrochloric acid was added to neutralize to pH=7, and the mixture was filtered. The filtrate was first rectified at normal pressure, and the aqueous ethanol was distilled off and recovered for standby use; then the mixture was distilled under reduced pressure, and the fractions were collected to obtain 57.4g of (R)-2-chlorobutyric acid, with a yield of 90% and a purity of 96%.

[0169] Step 2: Preparation of (S)-2-(4-fluoro-3-trifluoromethylphenoxy)butyric acid

[0170] Into a 2L round-bottom flask equipped with a stirrer, a condenser and a thermometer, were placed 800 g of acetone, 207.3 g (1.5 mol) of potassium carbonate, 90.1 g (0.5 mol) of 4-fluoro-3-trifluoromethylphenol, and 67.6 g (0.53 mol, purity 96%) of (R)-2-chlorobutyric acid, heated to 50°C, and reacted for 4 h. After the reaction was completed, the filtrate was filtered and the acetone was distilled off by distillation. 200 g of dichloroethane and 100 g of water were added, and the mixture was washed. The organic phase was distilled to obtain 127.4 g of (S)-2-(4-fluoro-3-trifluoromethylphenoxy)butyric acid with a yield of 89% and a purity of 93%.

[0171] Step 3: Preparation of (S)-2-(4-fluoro-3-trifluoromethylphenoxy)butyryl chloride

[0172] Into a 2L round-bottom flask equipped with a stirrer, a condenser and a thermometer, 800g of toluene and 143.1g (0.5mol, purity 93%) of (S)-2-(4-fluoro-3-trifluoromethylphenoxy)butyric acid were placed, and 65.4g (0.55mol) of thionyl chloride was added dropwise at room temperature. After the addition was completed, the mixture was slowly heated to reflux and reacted for 4h. After the reaction was completed, the solvent was evaporated to obtain 150.2g of (S)-2-(4-fluoro-3-trifluoromethylphenoxy)butyryl chloride with a yield of 95% and a purity of 90%.

[0173] Step 4: Preparation of S-fluorobutyric acid

[0174] Into a 500mL round-bottom flask equipped with a stirrer, a condenser and a thermometer, 31.6g (0.1mol, purity 90%) of (S)-2-(4-fluoro-3-trifluoromethylphenoxy)butyryl chloride, 80mL of toluene and 20.2g of triethylamine were placed, and 11.8g (0.11mol) of benzylamine was added under stirring. The mixture was heated to 50°C and reacted for 8h. After the reaction was completed, 50mL of 10% hydrochloric acid and 50mL of water were added for washing. The organic phase was evaporated and concentrated, and 30mL of ethanol was added. 34.44g of white crystals were obtained by crystallization. The yield was 95%, the purity was 98%, and the ee value was 95%.

[0175] Example 3

[0176] A method for preparing S-fluorobutyric acid sulfoxide, the synthetic route is:

[0177]

[0178] The following steps are involved:

[0179] Step 1: Preparation of (R)-2-chlorobutyryl chloride

[0180] Into a 1L round-bottom flask equipped with a stirrer, a condenser and a thermometer, 500g of toluene and 63.8g (0.5mol, purity 96%) of (R)-2-chlorobutyric acid were placed, and 65.4g (0.55mol) of thionyl chloride was added dropwise at room temperature. After the addition was completed, the mixture was slowly heated to reflux and reacted for 4h. After the reaction was completed, the solvent was evaporated to obtain 75.2g of (R)-2-chlorobutyryl chloride with a yield of 96% and a purity of 90%.

[0181] Step 2: Preparation of (R)-N-benzyl-2-chlorobutyramide

[0182] Into a 500mL round-bottom flask equipped with a stirrer, a condenser and a thermometer, 15.7g (0.1mol, purity 90%) of (R)-2-chlorobutyryl chloride, 80mL of toluene and 20.2g of triethylamine were placed, and 11.8g (0.11mol) of benzylamine was added under stirring. The mixture was heated to 40°C and reacted for 8h. After the reaction was completed, 50mL of 10% hydrochloric acid and 50mL of water were added for washing, the layers were separated, and the organic phase was evaporated and concentrated to obtain 21g of (R)-N-benzyl-2-chlorobutyramide with a yield of 94.2% and a purity of 95%.

[0183] Step 3: Preparation of S-fluorobutyric acid

[0184] Into a 2L round-bottom flask equipped with a stirrer, a condenser and a thermometer, 800 g of acetone, 207.3 g (1.5 mol) of potassium carbonate, 90.1 g (0.5 mol) of 4-fluoro-3-trifluoromethylphenol, and 118.1 g (0.53 mol, purity 95%) of (R)-N-benzyl-2-chlorobutyramide were placed, heated to 60°C, and reacted for 4 h. After the reaction was completed, the filtrate was filtered and the acetone was distilled off from the filtrate. The organic phase was evaporated and concentrated, and 200 mL of ethanol was added. 163.2 g of white crystals were crystallized, with a yield of 90%, a purity of 98%, and an ee value of 96%.

[0185] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing S-fluorobutyric acid sulfamethoxam, characterized in that: The S-flubutyric acid amine is prepared from the key intermediate R-1; R-1； (S)-2-Hydroxybutyric acid was subjected to esterification reaction and configuration-inverting halogenation reaction to prepare the key intermediate R-1; Among them, the key intermediate R-1 is obtained by halogenation reaction of R-2; R-2 Wherein, R1 is C1-C6 alkyl, X is Cl or Br; In the halogenation reaction, the catalyst used is selected from one of pyridine, 2-methylpyridine, 3-methylpyridine, 2-chloropyridine and 2-bromopyridine.

2. The method according to claim 1, characterized in that The R1 is a C1-C3 alkyl group.

3. The method according to claim 1, characterized in that Said X is Cl.

4. The method according to claim 1, characterized in that The halogenating agent in the halogenation reaction includes acyl halides, sulfonyl halides and phosphorus oxyhalides.

5. The method according to claim 4, characterized in that The halogenating agent includes thionyl chloride, sulfonyl chloride, oxalyl chloride, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, phosphine tribromide, and phosphorus oxybromide.

6. The method according to claim 1, characterized in that The key intermediate R-1 is converted into S-flubutyric acid amine by a method comprising the following; Treatment of the key intermediate R-1 with compound 1 1 To prepare compound R-5; R-5 Wherein, R1 is C1-C6 alkyl; Treatment of Compound R-5 with Compound 2 2 To prepare S-fluorobutyric acid amine.

7. The method according to claim 1, characterized in that The key intermediate R-1 is converted into S-flubutyric acid amine by a method comprising the following; The key intermediate R-1 is hydrolyzed to obtain compound R-3; R-3 Wherein, X is Cl or Br; Treatment of Compound R-3 with Compound 1 1 To prepare compound R-6; R-6 Compound R-6 is subjected to acyl halide reaction to obtain compound R-7; R-7 Wherein, X1 is Cl or Br; Treatment of Compound R-7 with Compound 2 2 To prepare S-fluorobutyric acid amine.

8. The method according to claim 7, characterized in that X is Cl, or X1 is Cl.

9. The method according to claim 1, characterized in that The key intermediate R-1 is converted into S-flubutyric acid amine by a method comprising the following; The key intermediate R-1 is hydrolyzed to obtain compound R-3; R-3 Wherein, X is Cl or Br; Compound R-3 is subjected to acyl halide reaction to obtain compound R-8; R-8 Wherein, X2 is Cl or Br, X is Cl or Br; Treatment of Compound R-8 with Compound 2 2 To prepare compound R-9; R-9 Wherein, X is Cl or Br; Treatment of Compound R-9 with Compound 1 1 To prepare S-fluorobutyric acid amine.

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