Process route for preparing 4-fluorothiophene-2-formate

Abstract

The invention relates to the field of organic synthesis, in particular to a process route for preparing 4-fluorothiophene-2-formate. The process route comprises the following steps: 3-nitrothiophene-2, 5-dicarboxylic acid is sequentially subjected to a decarboxylation reaction, an esterification reaction, a reduction reaction, an azidation reaction and a thermal decomposition reaction, and 4-fluorothiophene-2-formate is prepared; or the 3-nitrothiophene-2, 5-dicarboxylic acid diester is sequentially subjected to a degreasing reaction, a reduction reaction, an azidation reaction and a thermal decomposition reaction to prepare the 4-fluorothiophene-2-formate; according to the route, 3-nitrothiophene-2, 5-dicarboxylic acid or ester thereof can be selected as a starting raw material, and the whole process route is high in yield, simple in post-treatment and beneficial to industrial production. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and particularly relates to a process route for preparing 4-fluorothiophene-2-carboxylate. Background Art

[0002] 4-Fluorothiophene-2-carboxylate is an important pharmaceutical intermediate. For example, methyl 4-fluorothiophene-2-carboxylate can be used as an inhibitor of cysteine proteases cathepsin S (CatS) and cathepsin K (CatK) for the treatment of diseases regulated by CatS and CatK (WO2015161928A1).

[0003] In the prior art, Ring fluorinated thiophenes: applications to liquid crystal synthesis (Tetrahedron Letters 42 (2001) 8797-8800) discloses a synthetic route for synthesizing methyl 4-fluorothiophene-2-carboxylate as shown in the following formula. However, the yield of step 2 is only 60%, which not only brings a large amount of by-products but also severely limits the application of this synthetic route in industrial production.

[0004]

[0005] On this basis, the applicant proposed the following reaction route. It was found in practice that in the nitration step, due to the lack of selectivity, methyl 4-nitrothiophene-2-carboxylate could only be obtained in a yield of about 17% (see JACS Au 2022, 2, 2152-2161), which also hindered the application of this route.

[0006]

[0007] As can be seen from the above, there is a lack of a process production method for 4-fluorothiophene-2-carboxylate with high yield based on industrially easy-to-prepare raw materials in the prior art. Summary of the Invention

[0008] The present invention is made to solve the above problems, and aims to provide a process route for preparing 4-fluorothiophene-2-carboxylate based on industrially easy-to-prepare raw materials. This process route has high selectivity, high yield, and is more convenient, short, and conducive to industrial application.

[0009] The present invention provides a process route for preparing 4-fluorothiophene-2-carboxylate, which comprises the following steps:

[0010] i) Decarboxylation of 3-nitrothiophene-2,5-dicarboxylic acid to obtain 4-nitrothiophene-2-carboxylic acid;

[0011] ii) 4-Nitrothiophene-2-carboxylic acid is esterified to obtain 4-nitrothiophene-2-carboxylate;

[0012] iii) 4-Nitrothiophene-2-carboxylate is reduced to obtain 4-aminothiophene-2-carboxylate;

[0013] iv) 4-Aminothiophene-2-carboxylate is azidated to obtain 2-(alkoxycarbonyl)thiophene-4-diazonium hexafluorophosphate;

[0014] v) 2-(alkoxycarbonyl)thiophene-4-diazonium hexafluorophosphate undergoes thermal decomposition to obtain 4-fluorothiophene-2-carboxylate;

[0015]

[0016] Among them, R 1 is C 1-6 alkyl.

[0017] In a certain embodiment, the R 1 is preferably C 1-4 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0018] The decarboxylation reaction includes the following steps: in a first solvent, in the presence of sodium chloride, 3-nitrothiophene-2,5-dicarboxylic acid undergoes decarboxylation to obtain 4-nitrothiophene-2-carboxylic acid.

[0019] In the decarboxylation reaction, the first solvent is N,N-dimethylformamide and / or N,N-dimethylacetamide.

[0020] In the decarboxylation reaction, the mass ratio of sodium chloride to 3-nitrothiophene-2,5-dicarboxylic acid can be 1:(3 - 20), preferably 1:(3 - 15), for example 1:5.2 or 1:10.

[0021] In the decarboxylation reaction, the volume-mass ratio of the first solvent to 3-nitrothiophene-2,5-dicarboxylic acid can be (3 - 20) mL:1 g, preferably (3 - 10) mL:1 g, for example 4.9 mL:1 g or 6.4 mL:1 g.

[0022] In the decarboxylation reaction, the reaction temperature can be 80 - 120 °C, preferably 90 - 110 °C.

[0023] In the decarboxylation reaction, the reaction time can be 2 - 5 h.

[0024] The decarboxylation reaction comprises the following steps: 3-nitrothiophene-2,5-dicarboxylic acid is dispersed in N,N-dimethylacetamide, and in the presence of sodium chloride, the reaction is carried out at 80-120 °C for 2-5 h. After the reaction is completed, most of the N,N-dimethylacetamide is removed, water and ethyl acetate are added for extraction, the ethyl acetate phase is taken, concentrated, and 4-nitrothiophene-2-carboxylic acid is obtained.

[0025] The esterification reaction comprises the following steps: in the presence of an activating reagent, 4-nitrothiophene-2-carboxylic acid reacts with R 1 OH to produce 4-nitrothiophene-2-carboxylate.

[0026] In the esterification reaction, the R 1 OH is preferably methanol, ethanol or n-propanol.

[0027] In the esterification reaction, the volume-mass ratio of the R 1 OH to the 4-nitrothiophene-2-carboxylic acid can be (5-20) mL:1 g, preferably (10-15) mL:1 g, for example 10.4 mL:1 g.

[0028] In the esterification reaction, the activating reagent is preferably oxalyl chloride or thionyl chloride, for example thionyl chloride.

[0029] In the esterification reaction, the molar ratio of the activating reagent to the 4-nitrothiophene-2-carboxylic acid can be (1-2):1.

[0030] In the esterification reaction, the reaction temperature can be 50-70 °C, preferably 55-65 °C.

[0031] In the esterification reaction, the reaction time can be 6-12 h.

[0032] The esterification reaction comprises the following steps: in R 1 OH, in the presence of an activating reagent, 4-nitrothiophene-2-carboxylic acid reacts at 50-70 °C for 6-12 h. After the reaction is completed, part of the solvent and the acylating reagent are removed by concentration, and the solid is taken to obtain 4-nitrothiophene-2-carboxylate.

[0033] The reduction reaction can occur by means of active metal reduction, catalytic hydrogenation reduction, sulfur-containing compound reduction or metal hydride reduction. The active metal in the active metal reduction can be iron, tin or zinc; the sulfur-containing compound in the sulfur-containing compound reduction can be Na2S, Na2S2 or Na2S2O4; the metal hydride in the metal hydride reduction can be LiAlH4 or NaBH2S3.

[0034] The reduction reaction can be carried out by catalytic hydrogenation reduction, which includes the following steps: in an alcohol solvent, in the presence of hydrogen and a metal catalyst, 4-nitrothiophene-2-carboxylate undergoes a reduction reaction to obtain 4-aminothiophene-2-carboxylate.

[0035] In the reduction reaction, the metal catalyst can be nickel, palladium or platinum, preferably nickel, such as Raney nickel.

[0036] In the reduction reaction, the mass ratio of the metal catalyst to the 4-nitrothiophene-2-carboxylate can be 1:(5 - 20), such as 1:10.

[0037] In the reduction reaction, the alcohol solvent can be methanol, ethanol or n-propanol.

[0038] In the reduction reaction, the volume-mass ratio of the alcohol solvent to the 4-nitrothiophene-2-carboxylate can be (3 - 10)L:1kg, such as 6.3L:1kg.

[0039] In the reduction reaction, the hydrogen pressure can be 1.0 - 2.0MPa, preferably 1.0 - 1.5MPa.

[0040] In the reduction reaction, the reaction temperature can be 20 - 30°C.

[0041] In the reduction reaction, the reaction time can be 12 - 24h.

[0042] The reduction reaction includes the following steps: 4-nitro-2-thiophenecarboxylate in an alcohol solvent, in the presence of hydrogen and a metal catalyst, reacts at a hydrogen pressure of 1.0 - 2.0MPa and 20 - 30°C for 12 - 24h. After the reaction is completed, it is filtered, the filtrate is concentrated to remove part of the solvent, and then filtered again to obtain the solid, thus obtaining 4-amino-2-thiophenecarboxylate.

[0043] The azidation reaction includes the following steps: using water as a solvent, in the presence of an acid, a nitrite and hexafluorophosphoric acid, 4-aminothiophene-2-carboxylate undergoes an azidation reaction to obtain 2-(alkoxycarbonyl)thiophene-4-diazonium hexafluorophosphate.

[0044] In the azidation reaction, the acid can be an inorganic acid, preferably hydrochloric acid or sulfuric acid, such as 6mol / L hydrochloric acid.

[0045] In the azidation reaction, the volume ratio of the 6mol / L hydrochloric acid to water can be (0.1 - 2):1, preferably 0.6:1.

[0046] In the azidation reaction, the nitrite can be an alkali metal nitrite, preferably sodium nitrite or potassium nitrite.

[0047] In the azidation reaction, the mass-volume ratio of 4-aminothiophene-2-carboxylate to water can be 1 g:(5-20) mL, preferably 1 g:(5-10) mL.

[0048] In the azidation reaction, the molar ratio of 4-aminothiophene-2-carboxylate to the nitrite can be 1:(1-2), for example, 1:1.4.

[0049] In the azidation reaction, the molar ratio of 4-aminothiophene-2-carboxylate to hexafluorophosphoric acid can be 1:(1-2), for example, 1:1.5.

[0050] In the azidation reaction, the reaction temperature can be 0-10 °C.

[0051] In the azidation reaction, the reaction time can be 1-3 h.

[0052] In the azidation reaction, using water as the solvent, under the action of an acid, a nitrite, and hexafluorophosphoric acid, 4-aminothiophene-2-carboxylate reacts at 0-10 °C for 1-3 h. After the reaction ends, filtration is carried out, and the filter cake is taken to obtain 2-(alkoxycarbonyl)thiophene-4-diazonium hexafluorophosphate.

[0053] The thermal decomposition reaction includes the following steps: In 1,2,4-trichlorobenzene, 2-(alkoxycarbonyl)thiophene-4-diazonium hexafluorophosphate undergoes thermal decomposition to obtain 4-fluorothiophene-2-carboxylate.

[0054] [[ID=2l]]In the thermal decomposition reaction, the mass-volume ratio of 2-(alkoxycarbonyl)thiophene-4-diazonium hexafluorophosphate to 1,2,4-trichlorobenzene can be 1 g:(5-30) mL, preferably 1 g:(10-20) mL.

[0055] In the thermal decomposition reaction, the reaction is carried out under the protection of an inert gas, and the inert gas can be nitrogen or a noble gas.

[0056] In the thermal decomposition reaction, the reaction temperature is 170-220 °C, preferably 190-200 °C.

[0057] In the thermal decomposition reaction, the reaction time can be 5-30 min, preferably 10-20 min.

[0058] The thermal decomposition reaction includes the following steps: In 1,2,4-trichlorobenzene, at 170-220 °C, 2-(alkoxycarbonyl)thiophene-4-diazonium hexafluorophosphate undergoes a decomposition reaction for 5-30 min. After the reaction ends, the temperature is lowered, rectification is carried out, column chromatography is performed, and concentration is carried out to obtain 4-fluorothiophene-2-carboxylate.

[0059] In a certain embodiment, R 1 is methyl.

[0060] In one embodiment, the process route for preparing 4-fluorothiophene-2-carboxylate includes the following steps:

[0061] i) 3-Nitrothiophene-2,5-dicarboxylic acid undergoes a decarboxylation reaction to obtain 4-nitrothiophene-2-carboxylic acid;

[0062] ii) 4-Nitrothiophene-2-carboxylic acid undergoes an esterification reaction to obtain methyl 4-nitrothiophene-2-carboxylate;

[0063] iii) Methyl 4-nitrothiophene-2-carboxylate undergoes a reduction reaction to obtain methyl 4-aminothiophene-2-carboxylate

[0064] iv) Methyl 4-aminothiophene-2-carboxylate undergoes an azidation reaction to obtain 2-(methoxycarbonyl)thiophene-4-diazonium hexafluorophosphate;

[0065] v) 2-(Methoxycarbonyl)thiophene-4-diazonium hexafluorophosphate undergoes a thermal decomposition reaction to obtain methyl 4-fluorothiophene-2-carboxylate;

[0066]

[0067] In one embodiment, the reaction conditions for each step of the process route for preparing 4-fluorothiophene-2-carboxylate are as described above.

[0068] In one embodiment, 4-nitrothiophene-2-carboxylate can also be obtained by subjecting 3-nitrothiophene-2,5-dicarboxylic acid diester to a de-esterification reaction to obtain 4-nitrothiophene-2-carboxylate;

[0069]

[0070] In one embodiment, the de-esterification reaction includes the following steps: In a second solvent, in the presence of sodium chloride, 3-nitrothiophene-2,5-dicarboxylic acid diester undergoes a de-esterification reaction to obtain 4-nitrothiophene-2-carboxylate.

[0071] In the de-esterification reaction, the second solvent is N,N-dimethylformamide and / or N,N-dimethylacetamide.

[0072] In the de-esterification reaction, the mass ratio of sodium chloride to 3-nitrothiophene-2,5-dicarboxylic acid diester can be 1:(5 - 20), preferably 1:(10 - 20), for example 1:10.

[0073] In the de-esterification reaction, the volume-mass ratio of the second solvent to 3-nitrothiophene-2,5-dicarboxylic acid diester can be (3 - 10) mL:1 g, preferably 5 mL:1 g.

[0074] In the de-esterification reaction, the reaction temperature can be 80 - 110 °C, preferably 90 - 100 °C.

[0075] In the de-esterification reaction, the reaction time can be 15 - 30 h.

[0076] The de-esterification reaction includes the following steps: 3-nitrothiophene-2,5-dicarboxylic acid diester reacts in N,N-dimethylacetamide in the presence of sodium chloride at 80 - 110 °C for 15 - 30 h. After the reaction is completed, N,N-dimethylacetamide is removed, water and ethyl acetate are added for extraction, the ethyl acetate phase is taken, concentrated, and 4-nitrothiophene-2-carboxylate is obtained.

[0077] The present invention also provides another process route for preparing 4-fluorothiophene-2-carboxylate, which includes the following steps:

[0078] vi) 3-nitrothiophene-2,5-dicarboxylic acid diester undergoes a de-esterification reaction to obtain 4-nitrothiophene-2-carboxylate;

[0079] iii) 4-nitrothiophene-2-carboxylate undergoes a reduction reaction to obtain 4-aminothiophene-2-carboxylate;

[0080] iv) 4-aminothiophene-2-carboxylate undergoes an azidation reaction to obtain 2-(alkoxycarbonyl)thiophene-4-diazonium hexafluorophosphate;

[0081] v) 2-(alkoxycarbonyl)thiophene-4-diazonium hexafluorophosphate undergoes a thermal decomposition reaction to obtain 4-fluorothiophene-2-carboxylate;

[0082]

[0083] Wherein, R 1 is a C 1-6 alkyl group.

[0084] In a certain embodiment, the R 1 is preferably a C 1-4 alkyl group, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0085] In a certain embodiment, the reaction conditions of each step of the process route for preparing 4-fluorothiophene-2-carboxylate are as described above.

[0086] In a certain embodiment, the process route for preparing 4-fluorothiophene-2-carboxylate includes the following steps:

[0087] vi) 3-nitrothiophene-2,5-dimethyl dicarboxylate undergoes a de-esterification reaction to obtain methyl 4-nitrothiophene-2-carboxylate;

[0088] iii) Methyl 4-nitrothiophene-2-carboxylate undergoes a reduction reaction to obtain methyl 4-aminothiophene-2-carboxylate;

[0089] iv) Methyl 4-aminothiophene-2-carboxylate undergoes an azidation reaction to obtain 2-(methoxycarbonyl)thiophene-4-diazonium hexafluorophosphate;

[0090] v) 2-(Methoxycarbonyl)thiophene-4-diazonium hexafluorophosphate undergoes a thermal decomposition reaction to obtain methyl 4-fluorothiophene-2-carboxylate;

[0091]

[0092] In a certain embodiment, the reaction conditions of each step of the process route for preparing methyl 4-fluorothiophene-2-carboxylate are as described above.

[0093] Functions and effects of the invention

[0094] According to a process route for preparing methyl 4-fluorothiophene-2-carboxylate provided by the present invention, since the applicant creatively selects 3-nitrothiophene-2,5-dicarboxylic acid or its ester as the starting material, and 3-nitrothiophene-2,5-dicarboxylic acid or its ester can be prepared from thiophene-2,5-dicarboxylic acid or its ester with extremely high yields, it makes the application of this process route in industry possible.

[0095] Furthermore, the present invention discloses a route for preparing methyl 4-fluorothiophene-2-carboxylate using 3-nitrothiophene-2,5-dicarboxylic acid as the starting material, which successively undergoes a decarboxylation reaction, an esterification reaction, a reduction reaction, an azidation reaction, and a thermal decomposition reaction. It has a high yield and simple post-treatment, which is beneficial to industrial production. Description of the drawings

[0096] Figure 1 It is the HPLC chart of methyl 4-nitrothiophene-2-carboxylate in Example 2 of the present invention;

[0097] Figure 2 It is the HPLC chart of methyl 4-aminothiophene-2-carboxylate in Example 2 of the present invention;

[0098] Figure 3 It is the HPLC chart of methyl 4-fluorothiophene-2-carboxylate in Example 2 of the present invention;

[0099] Figure 4 It is the HPLC chart of the product obtained in the 5th line of Example 6 of the present invention;

[0100] Figure 5 It is the HPLC chart of the product obtained in the 7th line of Example 6 of the present invention;

[0101] Figure 6 It is the HPLC chart of the product obtained in the 8th line of Example 6 of the present invention. Detailed implementation manners

[0102] In order to make the technical means, creative features, achieved objectives and functions realized by the present invention easy to understand, the present invention will be specifically described below in conjunction with embodiments and the accompanying drawings.

[0103] Unless otherwise specified, the reagents and raw materials used in the present invention are commercially available.

[0104] Calculation method of the yield in the examples: Yield = product quality * purity / theoretical yield * 100%.

[0105] Example 1

[0106] This example provides a preparation method of dimethyl 3-nitrothiophene-2,5-dicarboxylate, and the reaction formula is as follows:

[0107]

[0108] It includes the following reaction steps:

[0109] At 20 - 30 °C, under nitrogen protection, 19.1 L of methanol and 3.06 kg of thiophene-2,5-dicarboxylic acid (17.78 mol, 1.0 eq) are added to a reaction kettle (the reaction kettle is connected to a device equipped with an alkali solution to absorb SO2 and HCl gases generated by the reaction), and stirring is started; the temperature of the system is raised to 60 ± 5 °C, and 3.06 kg of thionyl chloride (subscript: 25.72 mol, 1.45 eq) is dropped in. After the dropping is completed, the reaction is carried out for 4 hours. The temperature of the system is lowered to 0 ± 5 °C, and the reaction solution is centrifuged to obtain the solid, and 3.69 kg of wet dimethyl thiophene-2,5-dicarboxylate with a purity of 99.1% is obtained.

[0110] At 20 - 30 °C, under nitrogen protection, 3.69 kg of wet dimethyl thiophene-2,5-dicarboxylate and 30.6 kg of concentrated sulfuric acid (mass fraction 98%) are added to the reaction kettle, and stirring is started; the temperature of the reaction system is lowered to 0 - 10 °C, and 1.68 kg of nitric acid (mass fraction 68%, 18.13 mol) is dropped into the reaction kettle, and the system is maintained at 0 - 10 °C. After the dropping is completed, the reaction is carried out for 1 hour. After the reaction is completed, 30.6 L of water is added to quench the reaction, and the reaction solution is centrifuged to obtain the solid, and 10.3 kg of wet dimethyl 3-nitrothiophene-2,5-dicarboxylate is obtained, wherein the content of dimethyl 3-nitrothiophene-2,5-dicarboxylate is 41.3%.

[0111] Example 2

[0112] This example provides a preparation method of methyl 4-fluorothiophene-2-carboxylate, and the reaction formula is as follows:

[0113]

[0114] It includes the following reaction steps:

[0115] Preparation of 3-Nitrothiophene-2,5-dicarboxylic Acid

[0116]

[0117] Under nitrogen protection, 3 L of water and 3 L of hydrochloric acid (6 mol / L) were added to the reaction kettle, and stirring was started; while controlling the temperature at 20 - 30°C, 3.0 kg of wet dimethyl 3-nitrothiophene-2,5-dicarboxylate (content of dimethyl 3-nitrothiophene-2,5-dicarboxylate was 41.3%, 5.05 mol, 1.0 eq, prepared by the preparation method of Example 1) was added to the reaction kettle. The system was heated to 90 - 100°C and reacted for 6 hours. After the reaction was completed, the temperature was lowered to 10 - 30°C, and 9 kg of methyl tert-butyl ether was added for extraction. The organic phase was taken and concentrated to dryness to obtain 0.77 kg of 3-nitrothiophene-2,5-dicarboxylic acid, with a purity of 94.8% and a yield of 66.6%.

[0118] Preparation of 4-Nitro-2-thiophenecarboxylic Acid:

[0119]

[0120] 0.62 kg of 3-nitrothiophene-2,5-dicarboxylic acid (2.71 mol, 1.0 eq), 3.96 L of N,N-dimethylacetamide and 0.12 kg of sodium chloride were added to the reaction kettle, and the temperature was raised to 100°C and reacted for 3 h. After the reaction was completed, most of the N,N-dimethylacetamide was removed by vacuum concentration. The temperature was lowered to 10 - 30°C, 2.48 L of water and 2.48 L of ethyl acetate were added for extraction. The ethyl acetate phase was taken and concentrated to dryness to obtain 0.53 kg of crude 4-nitrothiophene-2-carboxylic acid, with a purity of 88.4%.

[0121] Preparation of Methyl 4-Nitrothiophene-2-carboxylate:

[0122]

[0123] 0.53 kg of crude 4-nitrothiophene-2-carboxylic acid (purity 88.4%, 2.71 mol, 1.0 eq) was added to 5.5 L of methanol and stirred until clear. While controlling the system at 60 ± 5°C, 0.35 kg of thionyl chloride (2.94 mol, 1.08 eq) was dropped in, and the temperature was kept for 8 hours. After the reaction was completed, most of the methanol was removed by vacuum concentration until the reaction system was about 800 mL. The reaction system was cooled to 0 - 10°C and then centrifuged. The solid was taken and dried to obtain 0.43 kg of methyl 4-nitrothiophene-2-carboxylate, with a purity of 99.5%( Figure 1 , Rt = 7.916 min), and the yield was 84.8%.

[0124] Preparation of Methyl 4-Aminothiophene-2-carboxylate:

[0125]

[0126] At 20 - 30 °C, under nitrogen protection, 33.4 L of methanol, 5.29 kg of methyl 4 - nitrothiophene - 2 - carboxylate (28.3 mol, 1.0 eq), and 0.53 kg of Raney nickel (10 wt%) were added to an autoclave. The reaction system was pressurized with hydrogen to 1.0 - 1.5 MPa and reacted for 17 h. After the reaction, the system was cooled to 10 °C, the Raney nickel was filtered off, the filtrate was concentrated under reduced pressure to 5 L, filtered, the solid was taken, and dried to obtain 3.64 kg of methyl 4 - aminothiophene - 2 - carboxylate, with a purity of 99.7%( Figure 2 , Rt = 4.332 min), and the yield was 81.8%.

[0127] Preparation of 2 - (methoxycarbonyl)thiophene - 4 - diazonium hexafluorophosphate:

[0128]

[0129] Under nitrogen protection, while controlling the temperature at 20 - 30 °C, 400 mL of water, 240 mL of hydrochloric acid (6 mol / L), and 40 g of methyl 4 - aminothiophene - 2 - carboxylate (0.25 mol, 1.0 eq) were added to the reaction kettle. While controlling the temperature at 0 - 10 °C, an aqueous solution of 124 g of sodium nitrite (mass fraction 20%, 0.36 mol, 1.44 eq) was added dropwise to the reaction kettle, stirred for one hour while maintaining the temperature, then an aqueous solution of 95 g of hexafluorophosphoric acid (mass fraction 60%, 0.39 mol, 1.56 eq) was added dropwise, and the reaction was stirred for two hours. Filtered, the filter cake was dried in a forced - air oven at 50 °C to obtain 78.0 g of 2 - (methoxycarbonyl)thiophene - 4 - diazonium hexafluorophosphate, with a yield of 97.6%.

[0130] Preparation of methyl 4 - fluorothiophene - 2 - carboxylate:

[0131]

[0132] At 20 - 30 °C, under nitrogen protection, 4 L of 1,2,4 - trichlorobenzene was added to the reaction kettle, the stirring was started, the temperature was raised to 190 - 200 °C, 200 g of 2 - (methoxycarbonyl)thiophene - 4 - diazonium hexafluorophosphate (0.64 mol, 1.0 eq) was added, and the mixture was stirred for 10 minutes while maintaining the temperature. Then the reaction kettle was cooled to 20 - 30 °C, the system was rectified, a mixture of the product and trichlorobenzene was obtained, passed through a column, and concentrated to obtain 68.0 g of the product, with a yield of 63.4% and a purity of 95.6% (Rt = 7.654 min, as Figure 3 ).

[0133] Example 3

[0134]

[0135] Preparation of methyl 4-nitrothiophene-2-carboxylate:

[0136]

[0137] Add 100 g of dimethyl 3-nitrothiophene-2,5-dicarboxylate (commercially available, purity 98%, 0.41 mol, 1.0 eq), 500 mL of N,N-dimethylacetamide, and 10 g of sodium chloride into the reaction kettle, heat up to 90 - 100 °C, and react for 20 h. After the reaction is completed, concentrate under reduced pressure to remove N,N-dimethylacetamide until the volume of the reaction system is 100 mL, cool down to 10 - 30 °C, add 400 mL of water and 400 mL of ethyl acetate for extraction, take the ethyl acetate phase, concentrate to dryness, and obtain 65.0 g of methyl 4-nitrothiophene-2-carboxylate by column chromatography, with a yield of 85.2% and a purity of 99.0%.

[0138] The preparation of methyl 4-aminothiophene-2-carboxylate, the preparation of 2-(methoxycarbonyl)thiophene-4-diazonium hexafluorophosphate, and the preparation of methyl 4-fluorothiophene-2-carboxylate are as described in Example 2.

[0139] Example 4

[0140] Preparation of 4-nitro-2-thiophenecarboxylic acid:

[0141]

[0142] Add 567 g of 3-nitrothiophene-2,5-dicarboxylic acid (2.61 mol, 1.0 eq), 2.8 L of N,N-dimethylacetamide, and 57 g of sodium chloride into the reaction kettle, heat up to 90 - 110 °C, and react for 3 h. After the reaction is completed, concentrate under reduced pressure to remove most of the N,N-dimethylacetamide at 80 - 100 °C, cool down to 10 - 30 °C, add 2 L of water and 2 L of ethyl acetate for extraction, take the ethyl acetate phase, concentrate to dryness to obtain 415 g of crude 4-nitro-2-thiophenecarboxylic acid, with a yield of 87.5% and a purity of 91.4%.

[0143] Example 5

[0144]

[0145] At 20 - 30 °C, add 2 L of 1,2,4-trichlorobenzene into the reaction kettle under nitrogen protection, start stirring, heat up to 190 - 200 °C, add 200 g of 2-(methoxycarbonyl)thiophene-4-diazonium hexafluorophosphate (0.64 mol, 1.0 eq), keep stirring for 10 minutes, cool down the reaction kettle to 20 - 30 °C, rectify the system, pass through the column, and concentrate to obtain 69.7 g of the product with a yield of 64.6% and a purity of 95.0%.

[0146] Example 6

[0147] According to the following steps, the reaction temperature and the dispersant were screened, and the screening conditions and reaction results are shown in Table 1 below:

[0148]

[0149] At 20 - 30 °C, under nitrogen protection, 100 mL of the dispersant was added to the reaction kettle, the stirring was started, the temperature was raised to the reaction temperature, 10 g of 2-(methoxycarbonyl)thiophene-4-diazonium hexafluorophosphate (0.032 mol, 1.0 eq) was added, and the mixture was stirred at a constant temperature for 10 minutes. A sample was taken for in-process control and detected by HPLC. The experiments with serial numbers 1 - 7 in Table 1 were carried out according to the above steps, and the experiment with serial number 8 in Table 1 was Example 2. The in-process control results are shown in Table 1.

[0150] Table 1. In-process control results of the reaction system under different dispersants and different reaction temperatures

[0151] Number Dispersant type Reaction temperature Intermediate control content 1 o-Xylene 150-160℃ - 2 m-Xylene 150-160℃ - 3 p-Xylene 150-160℃ - 4 Paraffin oil 150-160℃ - 5 Paraffin oil 190-200℃ 19.1% (such as Figure 4 , Rt = 7.684 min) 6 Quartz sand 190-200℃ - 7 1,2,4-Trichlorobenzene 140-150℃ 26.9% (such as Figure 5 , Rt = 7.707 min) <![CDATA[8 * > 1,2,4-Trichlorobenzene 190-200℃ 67.6% (such as Figure 6 , Rt = 7.682 min)

[0152] "-" indicates that the product was not detected in the in-process control.

[0153] “ * ” was the in-process control of the reaction solution in the preparation of "methyl 4-fluorothiophene-2-carboxylate" in Example 2.

[0154] As can be seen from the above table, the dispersant has a very great influence on the thermal decomposition reaction of 2-(methoxycarbonyl)thiophene-4-diazonium hexafluorophosphate. In xylene-based dispersants and quartz sand, the thermal decomposition reaction of 2-(methoxycarbonyl)thiophene-4-diazonium hexafluorophosphate is very difficult to proceed, and almost no target product can be obtained. Only a small amount of product is obtained in the system with paraffin oil as the dispersant. The thermal decomposition reaction of 2-(methoxycarbonyl)thiophene-4-diazonium hexafluorophosphate shows a good reaction effect only in trichlorobenzene, and more target products can be converted.

[0155] According to the process route for the preparation of 4-fluorothiophene-2-carboxylate involved in Examples 2 - 3, the applicant selected 3-nitrothiophene-2,5-dicarboxylic acid or its ester as the starting material, and 3-nitrothiophene-2,5-dicarboxylic acid can be prepared from thiophene-2,5-dicarboxylic acid or its ester with extremely high yield, thus making the application of this process route in industry possible.

[0156] According to the process route for preparing 4-fluorothiophene-2-carboxylate involved in Example 2, the applicant creatively developed a method for selectively decarboxylating 3-nitrothiophene-2,5-dicarboxylic acid. In this method, only 3-nitrothiophene-2,5-dicarboxylic acid needs to be dissolved in N,N-dimethylacetamide, and sodium chloride accounting for about 10-20% of the mass of 3-nitrothiophene-2,5-dicarboxylic acid is added, so that the carboxyl group on the side adjacent to the nitro group can be selectively removed to obtain 4-nitrothiophene-2-carboxylic acid in a relatively high yield, which also lays a foundation for the completion of the entire route.

[0157] According to the process route for preparing 4-fluorothiophene-2-carboxylate involved in Example 3, on the basis of Example 2, the applicant further optimized the synthesis route. A 3-nitrothiophene-2,5-dicarboxylate was directly selected as the raw material, N,N-dimethylacetamide was used as the raw material, and sodium chloride accounting for about 10% of the mass of 3-nitrothiophene-2,5-dicarboxylate was added. It is also possible to selectively remove the formate group on the side adjacent to the nitro group, while the formate group on the other side remains, which is beneficial to shortening the synthesis route and further improving the reaction yield.

[0158] According to the optimization of the conditions for the synthesis step of 4-fluorothiophene-2-carboxylate involved in Examples 5-6, in the prior art, the reaction can only reach a yield of 59% at 250 °C (WO2015161928A1). In other similar reactions, although there are literature reports that the yield can reach 92% (The behaviour of vicinal alkyl aminothiophenecarboxylates in the sandmeyer and schiemann reactions, Hetercrocycles. 23, 6, 1985), however, this condition may have limitations on the reaction substrates, and it is difficult to reproduce such substrates in this application (i.e., the reactions recorded in items 1-3 of Example 6). On the basis of the prior art, the applicant further optimized the reaction conditions for this step. The applicant unexpectedly found that when 1,2,4-trichlorobenzene was selected as the dispersant, not only the target product could be obtained in a yield of nearly 70%, but also the reaction time was only 10 min and the reaction temperature was only 190-200 °C, which is beneficial to industrial production.

[0159] The above embodiments are preferred cases of the present invention and are not used to limit the protection scope of the present invention.

Claims

1. A process route for preparing 4-fluorothiophene-2-carboxylate, characterized in that, The process route is Route 1 or Route 2: Route 1 includes the following steps: i) 3-Nitrothiophene-2,5-dicarboxylic acid undergoes decarboxylation to obtain 4-nitrothiophene-2-carboxylic acid; ii) 4-Nitrothiophene-2-carboxylic acid undergoes esterification to obtain 4-nitrothiophene-2-carboxylate; iii) 4-Nitrothiophene-2-carboxylate undergoes reduction to obtain 4-aminothiophene-2-carboxylate; iv) 4-Aminothiophene-2-carboxylate undergoes azidation to obtain 2-(alkoxycarbonyl)thiophene-4-diazonium hexafluorophosphate; v) 2-(Alkoxycarbonyl)thiophene-4-diazonium hexafluorophosphate undergoes thermal decomposition to obtain 4-fluorothiophene-2-carboxylate; Route 2 includes the following steps: vi) 3-Nitrothiophene-2,5-dicarboxylic acid diester undergoes deesterification to obtain 4-nitrothiophene-2-carboxylate; iii) 4-Nitrothiophene-2-carboxylate undergoes reduction to obtain 4-aminothiophene-2-carboxylate; iv) 4-Aminothiophene-2-carboxylate undergoes azidation to obtain 2-(alkoxycarbonyl)thiophene-4-diazonium hexafluorophosphate; v) 2-(Alkoxycarbonyl)thiophene-4-diazonium hexafluorophosphate undergoes thermal decomposition to obtain 4-fluorothiophene-2-carboxylate; Among them, R 1 is C 1-6 alkyl.

2. The process route according to claim 1, wherein In Route 1, the decarboxylation reaction includes the following steps: In a first solvent, in the presence of sodium chloride, 3-nitrothiophene-2,5-dicarboxylic acid undergoes decarboxylation to obtain 4-nitrothiophene-2-carboxylic acid.

3. The process route according to claim 2, characterized in that, In Route 1, the reaction conditions of the decarboxylation reaction satisfy one or more of the following conditions: ① The first solvent is N,N-dimethylformamide and / or N,N-dimethylacetamide; ② The mass ratio of sodium chloride to 3-nitrothiophene-2,5-dicarboxylic acid is 1:(3 - 20); ③ The volume-mass ratio of the first solvent to 3-nitrothiophene-2,5-dicarboxylic acid is (3 - 20) mL:1 g; ④ The reaction temperature is 80 - 120 °C.

4. The process route according to claim 1, characterized in that, In Route 2, the deesterification reaction includes the following steps: In a second solvent, in the presence of sodium chloride, 3-nitrothiophene-2,5-dicarboxylic acid diester undergoes deesterification to obtain 4-nitrothiophene-2-carboxylate.

5. The process route according to claim 4, wherein In Route 2, the reaction conditions of the deesterification reaction satisfy one or more of the following conditions: ① The second solvent is N,N-dimethylformamide and / or N,N-dimethylacetamide; ② The mass ratio of sodium chloride to 3-nitrothiophene-2,5-dicarboxylic acid diester is 1:(5 - 20); ③ The volume-mass ratio of the second solvent to 3-nitrothiophene-2,5-dicarboxylic acid diester is (3 - 10) mL:1 g; ④ The reaction temperature is 80 - 110 °C.

6. The process route according to claim 1, wherein In Route 1 or Route 2, the thermal decomposition reaction includes the following steps: In 1,2,4-trichlorobenzene, 2-(alkoxycarbonyl)thiophene-4-diazonium hexafluorophosphate undergoes thermal decomposition to obtain 4-fluorothiophene-2-carboxylate.

7. The process route according to claim 6, wherein In Route 1 or Route 2, the reaction conditions of the thermal decomposition reaction satisfy one or more of the following conditions: ① The mass-volume ratio of 2-(alkoxycarbonyl)thiophene-4-diazonium hexafluorophosphate to 1,2,4-trichlorobenzene is 1 g:(5 - 30) mL; ② The thermal decomposition reaction is carried out under the protection of a protective gas, and the protective gas is nitrogen or a noble gas; ③ The temperature of the thermal decomposition reaction is 170 - 220 °C; ④ The time of the thermal decomposition reaction is 5 - 30 min.

8. The process route according to claim 1, wherein, R 1 is methyl.

9. The process route according to claim 1, wherein Route 1 includes the following steps: i) 3-Nitrothiophene-2,5-dicarboxylic acid undergoes a decarboxylation reaction to obtain 4-nitrothiophene-2-carboxylic acid; ii) 4-Nitrothiophene-2-carboxylic acid undergoes an esterification reaction to obtain methyl 4-nitrothiophene-2-carboxylate; iii) Methyl 4-nitrothiophene-2-carboxylate undergoes a reduction reaction to obtain methyl 4-aminothiophene-2-carboxylate; iv) Methyl 4-aminothiophene-2-carboxylate undergoes an azidation reaction to obtain 2-(methoxycarbonyl)thiophene-4-diazonium hexafluorophosphate; v) 2-(Methoxycarbonyl)thiophene-4-diazonium hexafluorophosphate undergoes a thermal decomposition reaction to obtain methyl 4-fluorothiophene-2-carboxylate; 10. The process route according to claim 1, characterized in that, Route 2 includes the following steps: vi) Dimethyl 3-nitrothiophene-2,5-dicarboxylate undergoes a deesterification reaction to obtain methyl 4-nitrothiophene-2-carboxylate; iii) Methyl 4-nitrothiophene-2-carboxylate undergoes a reduction reaction to obtain methyl 4-aminothiophene-2-carboxylate; iv) Methyl 4-aminothiophene-2-carboxylate undergoes an azidation reaction to obtain 2-(methoxycarbonyl)thiophene-4-diazonium hexafluorophosphate; v) 2-(Methoxycarbonyl)thiophene-4-diazonium hexafluorophosphate undergoes a thermal decomposition reaction to obtain methyl 4-fluorothiophene-2-carboxylate;

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