Method for synthesizing S-fluorobutyric acid amide from (R)-2-sulfonylbutyric acid alkyl ester

Abstract

The invention discloses a method for synthesizing S-fluorobutyric acid amide from (R)-2-alkyl sulfonylbutyrate, which belongs to the field of organic chemical synthesis. The method comprises: the S-fluorobutyric acid amide is prepared from a compound R-1; wherein the compound R-1 is obtained by treating a compound R-2 with a compound 1; and wherein R 1 It is a C1-C6 alkyl group, and R is selected from a C1-C6 alkyl group, a C1-C6 haloalkyl group, a phenyl group, or a phenyl group independently selected from a C1-C6 alkyl group or substituted with a halogen. The present invention uses (R)-2-hydroxybutyric acid produced by large-scale microbial fermentation as a raw material, and prepares compound R-2 through esterification reaction and sulfonylation reaction. The key chiral intermediate R-1 is obtained by a classical SN2 substitution reaction in which intermediate 1 and compound R-2 undergo a configuration flip. After the preparation of R-1, S-fluorobutyric acid is prepared, which has low cost, low pollution, good safety, high yield, and excellent optical purity.

Description

Technical Field

[0001] The invention belongs to the field of organic chemical synthesis, and specifically relates to a method for synthesizing S-fluorobutyric acid amide from (R)-2-sulfonylbutyric acid alkyl ester. 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 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 and more efficient, cleaner and more convenient is needed. Summary of the invention

[0007] In order to solve the deficiencies of the prior art, the object of the present invention is to provide a method for synthesizing S-fluorobutyric acid amide from (R)-2-sulfonylbutyric acid alkyl ester. The synthesis method of S-fluorobutyric acid amide provided by the present invention has a wide source of raw materials, low cost, and fewer synthesis steps.

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

[0009] In one aspect, a method for synthesizing S-fluorobutyric acid amide from (R)-2-alkyl sulfonylbutyrate, wherein the S-fluorobutyric acid amide is prepared from compound R-1;

[0010]

[0011] Wherein, compound R-1 is obtained by treating compound R-2 with compound 1;

[0012]

[0013]

[0014] Wherein, R1 is C1-C6 alkyl;

[0015] R is selected from C1-C6 alkyl, C1-C6 haloalkyl, phenyl or phenyl substituted by 1 to 3 groups independently selected from C1-C6 alkyl or halogen.

[0016] Wherein, compound R-2 is prepared by sulfonylation reaction of compound R-5, and compound R-5 is obtained by esterification reaction using (R)-2-hydroxybutyric acid as raw material.

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

[0018]

[0019] The present invention converts compound R-1 into S-fluorobutyric acid amine by the following method:

[0020] Compound R-1 is treated with Compound 2 to prepare S-flubutyric acid sulfoxide.

[0021]

[0022] The present invention converts compound R-1 into S-fluorobutyric acid amine by the following method:

[0023] Compound R-1 is subjected to hydrolysis reaction to obtain compound R-3;

[0024]

[0025] Compound R-3 is subjected to acyl halide reaction to obtain compound R-4;

[0026]

[0027] Wherein, X is Cl or Br;

[0028] Preferably, said X is Cl;

[0029] Treatment of Compound R-4 with Compound 2

[0030]

[0031] To prepare S-fluorobutyric acid amine.

[0032] The beneficial effects of the present invention are:

[0033] The present invention discloses a method for synthesizing S-fluorobutyric acid amide from (R)-2-sulfonylbutyric acid alkyl ester, wherein the intermediate (R)-2-sulfonylbutyric acid alkyl ester can be prepared by esterification reaction and sulfonylation reaction using (R)-2-hydroxybutyric acid obtained by biological fermentation as a raw material, with a wide source of raw materials, low cost and high optical purity. The intermediate R-1 undergoes a classic SN2 configuration inversion substitution reaction with the intermediate 1 and the (R)-2-sulfonylbutyric acid alkyl ester, with high yield and excellent optical purity. The present invention has the advantages of low cost, low pollution and good safety, and the prepared S-fluorobutyric acid amide product has high content and good optical activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] 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.

[0035] Figure 1 This is the liquid phase spectrum of fluazifop;

[0036] Figure 2 This is the liquid phase spectrum of S-fluorobutyric acid amine prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0037] 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.

[0038] 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.

[0039] 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 synthesizing S-flubutyric acid sulfoxide from (R)-2-alkyl sulfonylbutyrate.

[0040] A typical embodiment of the present invention is a method for synthesizing S-fluorobutyric acid amide from (R)-2-sulfonylbutyric acid alkyl ester, wherein the S-fluorobutyric acid amide is prepared from compound R-1;

[0041]

[0042] Wherein, compound R-1 is obtained by treating compound R-2 with compound 1;

[0043]

[0044] Wherein, R1 is C1-C6 alkyl;

[0045] R is selected from C1-C6 alkyl, C1-C6 haloalkyl, phenyl or phenyl substituted by 1 to 3 groups independently selected from C1-C6 alkyl or halogen.

[0046] Wherein, the R1 is a C1-C3 alkyl group.

[0047] When compound 1 is treated with compound R-2, an SN2 substitution reaction is performed, and the configuration of the chiral center is flipped, as follows:

[0048]

[0049] In some examples of this embodiment, when compound 1 treats compound R-2, the solvent used includes but is not limited to acetone, butanone, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, benzene, toluene, xylene, tetrahydrofuran, dichloroethane, dichloromethane, and chloroform.

[0050] In some examples of this embodiment, when compound 1 treats compound R-2, a base is added and the reaction is heated. Preferably, the heating temperature is reflux.

[0051] Wherein, the base is an inorganic base or an organic base.

[0052] Preferably, the inorganic base includes 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.

[0053] In some examples of this embodiment, compound R-1 is converted into S-flubutyric acid amine by a method comprising the following:

[0054] Treatment of compound R-1 with compound 2

[0055]

[0056] To prepare S-fluorobutyric acid amine.

[0057] Wherein, when compound 2 is treated with compound R-1, preferably, the treatment comprises heating the compound having formula R-1 and compound 2 at 30° C. to 100° C. Optionally, a solvent such as toluene or acetonitrile may be used.

[0058] Wherein, when compound 2 treats compound R-1, a base is added.

[0059] Preferably, the base includes 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; or alkali metal carbonates and bicarbonates such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and cesium carbonate; or alkali amides such as lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide and lithium diisopropylamide; or tertiary amines such as triethylamine and diisopropylethylamine.

[0060] In some examples of this embodiment, the process of treating compound R-1 with compound 2 is: using compound R-1 and compound 2 as raw materials, adding sodium ethoxide in toluene, and heating the mixture to react to obtain S-fluorobutyric acid amide.

[0061] In some examples of this embodiment, compound R-1 is converted into S-flubutyric acid amine by a method comprising the following:

[0062] Compound R-1 is subjected to hydrolysis reaction to obtain compound R-3;

[0063]

[0064] Compound R-3 is subjected to acyl halide reaction to obtain compound R-4;

[0065]

[0066] Wherein, X is Cl or Br;

[0067] Preferably, said X is Cl;

[0068] Treatment of Compound R-4 with Compound 2

[0069]

[0070] To prepare S-fluorobutyric acid amine.

[0071] In the process of preparing compound R-3 by hydrolysis reaction of compound R-1, a base may be added, and optionally, the solvent used includes but is not limited to one or more of water, ethanol, and methanol. The ratio of water to alcohol is 1:0.1-5.

[0072] 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. Further preferably, the base is sodium hydroxide.

[0073] Wherein, during the preparation of compound R-4 by acyl halide reaction of compound R-3, 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.

[0074] 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.

[0075] Wherein, in the process of preparing S-flubutyric acid amide by treating compound R-4 with compound 2, a base is added to a suitable solvent.

[0076] Preferably, the base includes but is not limited to alkali metal hydrides, such as sodium hydride; or alkali metal alcoholates, such as sodium isopropoxide and potassium tert-butoxide; or alkali metal carbonates and bicarbonates, such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and cesium carbonate; or tertiary amines, such as triethylamine and diisopropylethylamine. Further preferably, the base is sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, triethylamine.

[0077] Preferably, the solvent includes but is not limited to acetonitrile, dichloroethane, toluene, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide. Further preferably, the solvent is one or more of N,N-dimethylformamide, dichloroethane, toluene, acetonitrile, and more preferably, toluene.

[0078] In some examples of this embodiment, the compound R-2 is prepared by a method comprising:

[0079] (R)-2-Hydroxybutyric acid is subjected to esterification reaction to obtain compound R-5;

[0080] Wherein, R1 is C1-C6 alkyl;

[0081] Compound R-5 is subjected to sulfonylation reaction to obtain compound R-2.

[0082] Wherein, the R1 is a C1-C3 alkyl group.

[0083]

[0084] Wherein, in the process of obtaining compound R-5 by esterification reaction of (R)-2-hydroxybutyric acid, the esterification reaction is a heating reaction of (R)-2-hydroxybutyric acid, alkyl alcohol and acidic catalyst in a solvent.

[0085] 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.

[0086] The heating reaction temperature is 65-75°C.

[0087] Wherein, in the process of obtaining compound R-2 by sulfonylation reaction of compound R-5, the sulfonylation reaction is carried out by reacting compound R-5, a sulfonylation agent and an acid binding agent in a solvent at low temperature.

[0088] The sulfonylating agent includes but is not limited to methanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride or p-nitrobenzenesulfonyl chloride. Preferably, the sulfonylating agent is methanesulfonyl chloride, benzenesulfonyl chloride or p-toluenesulfonyl chloride.

[0089] The acid binding agent is triethylamine or pyridine. The low temperature condition is -10°C to 20°C.

[0090] The solvent includes, but is not limited to, benzene, toluene, ethylene dichloride, dichloromethane, chloroform, acetonitrile, and tetrahydrofuran. Preferably, the solvent is toluene or ethylene dichloride.

[0091] 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.

[0092] Example 1

[0093] The synthetic route is:

[0094]

[0095] The following steps are involved:

[0096] Step 1: Preparation of (R)-ethyl 2-hydroxybutyrate

[0097] In a 500mL round-bottom flask equipped with a stirrer, condenser, water separator and thermometer, 57.5g (1.25mol) of anhydrous ethanol, 52.1g (0.5mol) of (R)-2-hydroxybutyric acid, 150mL of benzene and 2mL of concentrated sulfuric acid were placed and heated for reaction. The temperature was kept constant at 70°C for about 4h, until the temperature rose to 75°C and no more water appeared. Stop heating, add NaHCO3 to neutralize to pH=7, filter, and distill the filtrate at normal pressure to distill off benzene and unreacted ethanol for recovery. Then distill under reduced pressure and collect the fraction to obtain 61.9g of colorless oily liquid, with a yield of 89% and a purity of 95%.

[0098] Step 2: Preparation of (R)-ethyl 2-benzenesulfonylbutyrate

[0099] To a 500mL round-bottom flask equipped with a stirrer, a dropping funnel, a condenser, a gas absorber and a thermometer, 52.99g (0.3mol) benzenesulfonyl chloride, 150mL dichloroethane, and 41.7g (0.3mol, purity 95%) (R)-ethyl 2-hydroxybutyrate were added, the temperature was lowered to 0°C, and triethylamine (33.3g, 0.33mol) was added dropwise with stirring for 1h, and the reaction was continued for 3h. After the reaction was complete, the mixture was filtered, and the filtrate was adjusted to pH=7 with 5% hydrochloric acid, and then washed with 100mL water. The organic phase was evaporated and concentrated to obtain 80.85g of a colorless oily liquid with a yield of 96% and a purity of 97%.

[0100] Step 3: Preparation of (S)-ethyl 2-(4-fluoro-3-trifluoromethylphenoxy)butyrate

[0101] Into a 2L round-bottom flask equipped with a stirrer, a condenser and a thermometer, 800 g of acetone, 124.4 g (0.9 mol) of potassium carbonate, 54.1 g (0.3 mol) of 4-fluoro-3-trifluoromethylphenol, and 92.6 g (0.33 mol, purity 97%) of (R)-ethyl 2-benzenesulfonylbutyrate 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 mL of dichloroethane and 100 g of water were added, and the mixture was washed. The organic phase was distilled to obtain 82.8 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).

[0102] Step 4: Preparation of S-fluorobutyric acid

[0103] 30.6 g (0.1 mol, purity 96%) of (S)-2-(4-fluoro-3-trifluoromethylphenoxy)butyric acid ethyl ester, 11.8 g (0.11 mol) of benzylamine and 80 mL of toluene were placed in a 500 mL round-bottom flask equipped with a stirrer, a condenser and a thermometer, and 10.2 g (0.03 mol) of 20% (mass percentage) sodium ethoxide ethanol solution was added under stirring, heated to 50°C, reacted for 8 hours, and the reaction was completed. 50 mL of 10% hydrochloric acid and 50 mL of water were added for washing, the organic phase was evaporated and concentrated, 30 mL of ethanol was added, and 33.7 g of white crystals were obtained by crystallization, with a yield of 93%, a purity of 98%, and an ee value of 96%. 1 H NMR: (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).

[0104] Chromatographic column: Lux Cellulose-2column (250mm×4.6mm, 5μm Phenomenex), mobile phase: n-hexane:isopropanol=97:3, flow rate: 1mL / min, column temperature: 40°C, wavelength: 254nm, S-fluorobutyric acid retention time: 13.05min.

[0105] Example 2

[0106] The synthetic route is:

[0107]

[0108] The following steps are involved:

[0109] Step 1: Preparation of (R)-ethyl 2-methanesulfonylbutyrate

[0110] To a 500mL round-bottom flask equipped with a stirrer, a dropping funnel, a condenser, a gas absorber and a thermometer, 34.4g (0.3mol) of methanesulfonyl chloride, 150mL of dichloroethane and 41.7g (0.3mol, purity 95%) of (R)-ethyl 2-hydroxybutyrate were added, the temperature was lowered to 0°C, triethylamine (33.3g, 0.33mol) was added dropwise with stirring for 1h, and the reaction was continued for 3h. After the reaction was complete, the mixture was filtered, the filtrate was adjusted to pH=7 with 5% hydrochloric acid, and then washed with 100mL of water. The organic phase was evaporated and concentrated to obtain 62.4g of a colorless oily liquid with a yield of 96% and a purity of 97%.

[0111] Step 2: Preparation of (S)-ethyl 2-(4-fluoro-3-trifluoromethylphenoxy)butyrate

[0112] Into a 2L round-bottom flask equipped with a stirrer, a condenser and a thermometer, 800 g of acetone, 124.4 g (0.9 mol) of potassium carbonate, 54.1 g (0.3 mol) of 4-fluoro-3-trifluoromethylphenol, and 71.5 g (0.33 mol, purity 97%) of (R)-ethyl 2-methylsulfonylbutyrate 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 mL of dichloroethane was added, and 100 g of water was added for washing. The organic phase was distilled to obtain 83.7 g of a yellow oil with a yield of 91% and a purity of 96%.

[0113] Step 3: Preparation of (S)-2-(4-fluoro-3-trifluoromethylphenoxy)butyric acid

[0114] Into a 500mL round-bottom flask equipped with a stirrer, a condenser and a thermometer, 150g of anhydrous ethanol, 50g of water, and 153.3g (0.5mol, purity 96%) of (S)-ethyl 2-(4-fluoro-3-trifluoromethylphenoxy)butyrate were charged, 240g of 10% sodium hydroxide solution was slowly added dropwise, the temperature was kept constant at 30°C and the reaction was carried out for about 4h, 20% hydrochloric acid was added to neutralize to pH=7, the filtrate was filtered, and the filtrate was first distilled at normal pressure, and the aqueous ethanol was distilled off and recovered for standby use; the solvent was evaporated to obtain 124.8g of (S)-2-(4-fluoro-3-trifluoromethylphenoxy)butyric acid with a yield of 90% and a purity of 96%.

[0115] Step 4: Preparation of (S)-2-(4-fluoro-3-trifluoromethylphenoxy)butyryl chloride

[0116] 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%.

[0117] Step 5: Preparation of S-flubutyric acid sulfoxide

[0118] 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%.

[0119] 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 synthesizing S-fluorobutyric acid amide from (R)-2-sulfonyl butyric acid alkyl ester, characterized in that: The S-flubutyric acid amine is prepared from compound R-1; R-1 Wherein, compound R-1 is obtained by treating compound R-2 with compound 1. 1 R-2； Wherein, R1 is C1-C6 alkyl; R is selected from C1-C6 alkyl, C1-C6 haloalkyl, phenyl, or phenyl substituted by 1 to 3 groups independently selected from C1-C6 alkyl or halogen; When compound 1 is treated with compound R-2, an SN2 substitution reaction is carried out, a base is added, and the mixture is heated to reflux to react, thereby obtaining compound R-1; The base is an inorganic base salt; The inorganic alkali salt is any one of potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate and lithium carbonate.

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 When compound 1 treats compound R-2, the solvents used include acetone, butanone, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, benzene, toluene, xylene, tetrahydrofuran, dichloroethane, dichloromethane, and chloroform.

4. The method according to claim 1, characterized in that Compound R-1 is converted to S-flubutyric acid amine by a process comprising: Treatment of compound R-1 with compound 2 2 To prepare S-fluorobutyric acid amine.

5. The method according to claim 1, characterized in that Compound R-1 is converted to S-flubutyric acid amine by a process comprising: Compound R-1 is subjected to hydrolysis reaction to obtain compound R-3; R-3 Compound R-3 is subjected to acyl halide reaction to obtain compound R-4; R-4 Wherein, X is Cl or Br; Treatment of compound R-4 with compound 2 2 To prepare S-fluorobutyric acid amine.

6. The method according to claim 5, characterized in that Said X is Cl.

7. The method according to claim 1, characterized in that The compound R-2 is prepared by a method comprising: (R)-2-Hydroxybutyric acid is subjected to esterification reaction to obtain compound R-5; R-5 Wherein, R1 is C1-C6 alkyl; Compound R-5 is treated with a sulfonylating agent to produce a compound having formula R-2.

8. The method according to claim 7, characterized in that The R1 is a C1-C3 alkyl group.

Images