Preparation method of 3-fluoropyruvic acid

Abstract

The invention provides a preparation method of 3-fluoropyruvic acid, and belongs to the field of medicinal chemistry. The method comprises the following steps: by taking diethyl oxalate and ethyl fluoroacetate as raw materials, reacting under an alkaline condition to generate an intermediate fluoro-oxaloacetic acid ethyl ester sodium salt; then hydrolyzing under an acidic condition to generate a target product 3-fluoropyruvic acid; the method is simple to operate, mild in condition and suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a method for preparing methimazole, a raw material medicine. Background Art

[0002] 3-Fluoropyruvic acid is a white crystal, which is widely used in pesticides and medicines. Chinese patent CN 107056606A discloses a method of using diethyl oxalate and ethyl fluoroacetate as raw materials, NaH as a strong base catalyst to undergo an ester condensation reaction, and distilling to obtain diethyl 2-fluoro-3-oxosuccinate. Diethyl 2-fluoro-3-oxosuccinate is subjected to hydrolysis and decarboxylation in an acidic solution, and then distilled to remove water to obtain a crude product, and finally refined by sublimation to obtain a method of 3-fluoropyruvic acid. The document Synthesis and Resolution of 3-Fluoro-D,L-alanine-2-d:A Selective Deuteration via Reductive Amination with Sodium Borodeuteride (J.Org.Chem.,Vol.43,No.9,1978) discloses a method for preparing 3-fluoropyruvic acid by using diethyl oxalate and ethyl fluoroacetate as raw materials and sodium methoxide as a strong base to undergo an ester condensation reaction, which is then hydrolyzed with an acid to form 3-fluoropyruvic acid monohydrate, which is then salted with lithium hydroxide monohydrate to form 3-fluoropyruvic acid lithium monohydrate, and then freeze-dried and sublimated by a cation exchange resin. The document Improved synthesis of D,L-fluorocitric acid (Journal of Fluorine Chemistry 132 (2011) 920-924) discloses a synthetic route using diethyl oxalate and ethyl fluoroacetate as raw materials, sodium ethoxide as a strong base to undergo an ester condensation reaction, and then hydrolyze with acid to generate two components: Oxalylfluoroacetic diethyl ester.110–112℃(5mm Hg)17.5g(69.4%); a,a0-Difluorocitric ethyl ester.140–160℃(5mm Hg),4.5g(12.6%).Crystalline solid,mp68–69℃. Literature Studies of Organic Fluorine Compounds. Part IV. *Synthesis of Esters of Fluoro-oxaloacetic and of Fluopyruvic Acid. Using diethyl oxalate and ethyl fluoroacetate as raw materials and sodium ethoxide as a strong base, an ester condensation reaction is carried out to obtain the intermediate ethyl fluorooxaloacetate sodium salt; the intermediate sodium salt is hydrolyzed in dilute hydrochloric acid at 130°C, concentrated and filtered to remove inorganic salts, the filtrate is extracted with ether, concentrated and then evaporated under reduced pressure to obtain the target product 3-fluoropyruvic acid.

[0003] However, the existing reported routes have many side reactions, expensive catalysts and low atomic utilization, which makes it difficult to meet the needs of industrial production. Summary of the invention

[0004] In view of the defects of the prior art, a method for producing 3-fluoropyruvic acid is provided, which has the advantages of simple process, readily available raw materials, mild reaction conditions, short production cycle and adaptability to industrialization.

[0005] Specifically, this application is implemented through the following technical routes:

[0006] The present application provides a method for preparing 3-fluoropyruvic acid, and the preparation steps are as follows:

[0007] 1) adding a base to solvent I, and dropping diethyl oxalate and ethyl fluoroacetate in sequence at a temperature of 10-15° C.; then controlling the temperature at 20° C.-30° C. to react until the reaction of ethyl fluoroacetate is complete (the remaining amount of ethyl fluoroacetate is less than 0.3% of the initial mass); filtering the reaction liquid, taking the filter cake, adding solvent I to pulp, filtering, and taking the filter residue to dry at 50° C. to obtain the intermediate ethyl fluorooxaloyl acetate sodium salt (III).

[0008] The solvent I comprises at least one of ethanol, 2-methyltetrahydrofuran, methanol, methyl tert-butyl ether and tetrahydrofuran, preferably ethanol;

[0009] The base includes at least one of sodium ethoxide, sodium methoxide, potassium tert-butoxide, and sodium hydrogen hydride, preferably sodium ethoxide;

[0010] The molar ratio of the added base to ethyl fluoroacetate is 1 to 1.5:1, preferably 1.2:1;

[0011] The molar ratio of the added diethyl oxalate to ethyl fluoroacetate is 1 to 2.0:1, preferably 1.04:1;

[0012] 2) adding the intermediate ethyl fluorooxalyl acetate sodium salt (III) obtained in step 1) to an acid, heating to 95°C to 100°C for reaction for 2h, and hydrolyzing the intermediate (III) under acidic conditions; then concentrating the reaction solution to dryness under reduced pressure at 70°C to 75°C to obtain a residue; then adding solvent II to the residue for extraction, filtering, and concentrating the filtrate to dryness under reduced pressure at 50 to 55°C to obtain an oily substance, which is the target product 3-fluoropyruvic acid. The above acid includes at least one of hydrochloric acid, sulfuric acid, hydrobromic acid, and phosphoric acid, preferably hydrochloric acid;

[0013] The solvent II comprises at least one of ethyl acetate, dichloromethane, toluene and acetone, preferably ethyl acetate;

[0014] The molar ratio of the added acid to the intermediate ethyl fluorooxalyl acetate sodium salt is 1 to 6:1, preferably 3.5:1.

[0015] The chemical equations involved in the above reactions are as follows:

[0016]

[0017] This application uses diethyl oxalate and ethyl fluoroacetate as raw materials, reacts in the presence of sodium ethoxide to generate an intermediate sodium fluoroethyl oxaloyl acetate; then hydrolyzes under acidic conditions, extracts after concentration, and concentrates the filtrate after filtration to obtain 3-fluoropyruvic acid. This synthesis method is simple to operate, has mild conditions, does not involve harsh operations such as column passing, vacuum distillation, and sublimation, and is more suitable for large-scale industrial production. Compared with the existing synthesis route of 3-fluoropyruvic acid, the preparation method provided in this application has the following beneficial effects:

[0018] 1) Compared with patent CN107056606A, the synthetic route of the present application does not require distillation to obtain diethyl 2-fluoro-3-oxosuccinate, and does not require sublimation purification to obtain 3-fluoropyruvic acid; 2) Compared with the literature Synthesis and Resolution of 3-Fluoro-D,L-alanine-2-d: A Selective Deuteration via Reductive Amination with Sodium Borodeuteride (J.Org.Chem.,Vol.43,No.9,1978), the synthetic route of the present application does not require cation exchange resin and sublimation operation; compared with the literature Improved synthesis of D,L-fluorocitric acid (Journal of Fluorine Chemistry 132 (2011) 920-924) uses diethyl oxalate and ethyl fluoroacetate as raw materials and sodium ethoxide as a strong base to undergo an ester condensation reaction, which is then hydrolyzed with an acid to generate two components; the method of the present application does not require purification to obtain a relatively pure intermediate ethyl fluorooxaloacetate sodium salt, thereby increasing the yield by about 9%; compared with the document "Studies of Organic Fluorine Compounds. Part IV.*Synthesis of Esters of Fluoro-oxaloaceticand of Fluopyruvic Acid", the hydrolysis in the synthetic route of the present application does not require a high temperature of 130°C, and the product 3-fluoropyruvic acid does not require a reduced pressure distillation operation, thereby reducing energy consumption.

[0019] 2) The synthetic route provided in the present application simplifies the operation and saves costs. The crude product obtained after the reaction concentration can be extracted with ethyl acetate and then filtered to remove most of the impurities, which meets the requirements and is more suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 is a high performance liquid chromatogram of the intermediate III prepared in Example 1;

[0021] Figure 2 is the HPLC chromatogram of the target product IV prepared in Example 2;

[0022] Figure 3 The target product IV prepared in Example 2 1 H-NMR spectrum. DETAILED DESCRIPTION

[0023] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available.

[0024] The raw materials diethyl oxalate (I) and ethyl fluoroacetate (II) were purchased from Shanghai Anaiji Chemical Co., Ltd.; sodium ethoxide and hydrochloric acid were purchased from Shanghai MacLean Biochemical Technology Co., Ltd.

[0025] Example 1

[0026] Add 320g of ethanol and 69.2g (1.016mol, 1.2eq) of sodium ethoxide into a 1L three-necked flask, stir evenly at room temperature, the system gradually becomes clear, control the internal temperature at 10-15°C and start to drop 129g (0.883mol, 1.04eq) of diethyl oxalate, the dropwise addition lasts for about half an hour, and the stirring is continued for half an hour after the dropwise addition is completed, the stirring rate is 480 rpm, and the internal temperature is 10-15°C.

[0027] Then slowly add 90g (0.848mol, 1eq) of ethyl fluoroacetate, control the internal temperature at 10-15°C, and complete the dripping in about 1 hour, then control the temperature at 20-30°C and stir for 6 hours, and a lot of solids will precipitate out during the reaction. Sampling and testing (chromatograph: Agilent; chromatographic column: 4.6mmx25 cm, 5um (C18 column); mobile phase: acetonitrile: 0.1% phosphoric acid aqueous solution = 45:55; wavelength 210nm, column temperature 30°C, flow rate 0.8ml / min. Same below), until the ethyl fluoroacetate remaining is less than 0.3%, which is the end point of the reaction. The filter cake had a wet weight of 218 g. It was slurried with 270 g of ethanol at room temperature for half an hour and filtered. The filter residue (solid) was dried at 50° C. and weighed 151.76 g, which was the intermediate ethyl fluorooxalyl acetate sodium salt (III). The sample was tested (chromatograph: Agilent; chromatographic column: 4.6 mm x 25 cm, 5 um (C18 column); mobile phase: acetonitrile: 0.1% phosphoric acid aqueous solution = 45:55; wavelength 210 nm, column temperature 30° C., flow rate 0.8 ml / min. The same below) and the purity was 92.40% and the yield was 78.49%. The chromatogram is shown in FIG. Figure 1 shown.

[0028] Example 2

[0029] 169g of water and 42.42g (0.422mol, 3.5eq) of concentrated hydrochloric acid (mass concentration 38%) were added to a 500ml three-necked flask, stirred evenly, and then 27.36g (0.12mol, 1eq) of the intermediate (III) prepared in Example 1 was added to react at a temperature of 95°C to 100°C for 2h. The reaction solution was then concentrated to dryness under reduced pressure at 70°C to 75°C to obtain a residue; 55g of ethyl acetate was added to the residue and stirred at room temperature for half an hour; then filtered, and the filtrate was concentrated to dryness under reduced pressure at 50 to 55°C to obtain 10g of an oily substance, which was the target product 3-fluoropyruvic acid (IV).

[0030] The target product was sampled and tested (chromatograph: Agilent; chromatographic column: 4.6 mm x 25 cm, 5 um (C18 column); mobile phase: acetonitrile: 0.1% phosphoric acid aqueous solution = 45:55; wavelength 210 nm, column temperature 30 ° C, flow rate 0.8 ml / min.) The purity was 98.26%, the yield was 78.6%, and its chromatogram was as follows Figure 2 shown. 1 H-NMR images Figure 3 As shown, 2H is the hydrogen on the methylene group connected to the F atom, and it is the target product after comparison with the reference substance.

[0031] The specific implementation methods described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above description is only a specific implementation method of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing 3-fluoropyruvic acid, characterized in that: The specific steps are as follows; 1) Add a base to solvent I, and at a temperature of 10-15°C, dropwise add diethyl oxalate and ethyl fluoroacetate in sequence, and then react at 20-30°C until the reaction of ethyl fluoroacetate is complete; then filter the reaction liquid, take the filter cake, add solvent I to pulp, filter, take the filter residue and dry it to obtain an intermediate; The solvent I comprises at least one of ethanol, 2-methyltetrahydrofuran, methanol, methyl tert-butyl ether and tetrahydrofuran; The base includes at least one of sodium ethoxide, sodium methoxide, potassium tert-butoxide, and sodium hydrogen, preferably sodium ethoxide; The molar ratio of the added base to ethyl fluoroacetate is 1 to 1.5:1; the molar ratio of the added diethyl oxalate to ethyl fluoroacetate is 1 to 2.0:1; 2) adding the intermediate to an acid, heating to 95° C. to 100° C. and reacting for 2 hours, and then concentrating the reaction solution to dryness to obtain a residue; adding solvent II to the residue, and concentrating the filtrate to dryness to obtain the 3-fluoropyruvic acid; the acid comprises at least one of hydrochloric acid, sulfuric acid, hydrobromic acid, and phosphoric acid; The solvent II includes at least one of ethyl acetate, dichloromethane, toluene and acetone; the molar ratio of the added acid to the intermediate is 1 to 6:

1.

2. The method for preparing 3-fluoropyruvic acid according to claim 1, characterized in that: In step 1), the molar ratio of the added base to ethyl fluoroacetate is 1.2:

1.

3. The method for preparing 3-fluoropyruvic acid according to claim 1, characterized in that: In step 1), the molar ratio of diethyl oxalate to ethyl fluoroacetate added is 1.04:

1.

4. The method for preparing 3-fluoropyruvic acid according to claim 1, characterized in that: In step 2), concentrating the reaction solution to dryness refers to concentrating the reaction solution to dryness under reduced pressure at 70° C. to 75° C.

5. The method for preparing 3-fluoropyruvic acid according to claim 1, characterized in that: In step 2), the filtrate is concentrated to dryness, which means that the filtrate is concentrated to dryness under reduced pressure at 50-55°C.

6. The method for preparing 3-fluoropyruvic acid according to claim 1, characterized in that: In step 2), the molar ratio of the added acid to the intermediate is 3.5:1.

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