A method for preparing 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one, its intermediates, and applications.

Abstract

This invention discloses a method for preparing 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one, its intermediates, and applications, belonging to the field of synthetic technology. The preparation method uses 1,3-difluoro-5-nitrobenzene as a starting material and follows a synthetic route to obtain the compound described in Formula 6, namely 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one. The preparation method of this invention allows for easy control of reaction conditions, yields 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one with high purity, and is simple to operate, allowing for scale-up production using fluid chemistry.

Description

Technical Field

[0001] This invention belongs to the field of synthetic technology, specifically relating to a method for preparing 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one, its intermediates, and applications. Background Technology

[0002] 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one is a benzisothiazolone inhibitor, a newly discovered soluble phosphatase associated with abnormal bone mineralization and soft tissue ossification.

[0003] There are relevant literature reports on the activity information of this compound (Yalda Bravo, Peter Teriete, Raveendra-Panickar Dhanya, Russell Dahl, Pooi SanLee, Tina Kiffer-Moreira, Santhi Reddy Ganji, Eduard Sergienko, Layton H. Smith, Colin Farquharson, José Luis Millán, Nicholas DPCosford. Design, synthesis and evaluation of benzoisothiazolones as selective inhibitors of PHOSPHO1[J], Bioorganic & Medicinal Chemistry Letters, 2014, 17(24): 4308-4311), but no literature reports its synthesis method. Therefore, it is necessary to develop a method for synthesizing 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazo-3-one with readily available raw materials and simple operation. Summary of the Invention

[0004] This invention addresses the problems existing in the prior art by providing a method for preparing 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one, as well as its intermediates and applications. The preparation method of this invention has fewer steps, easier-to-control reaction conditions, and higher yield, making it suitable for large-scale industrial production.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0006] In a first aspect, the present invention provides a method for preparing 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one, wherein the compound described in Formula 6 is prepared from 1,3-difluoro-5-nitrobenzene via the following synthetic route, which is 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one;

[0007] .

[0008] In some embodiments, the preparation method, step S1, involves reacting 1,3-difluoro-5-nitrobenzene with LDA to obtain the intermediate compound of formula 2;

[0009] .

[0010] Preferably, the solvent for the reaction in step S1 is at least one of DMF, N,N-dimethylethylamine, DCM and THF; more preferably, it is THF.

[0011] Preferably, the molar ratio of 1,3-difluoro-5-nitrobenzene to LDA in step S1 is 1:1.8-2.2; more preferably, it is 1:2.

[0012] Preferably, the reaction conditions in step S1 are: a temperature of -55°C to -45°C; more preferably, a temperature of -50°C.

[0013] In some embodiments, the reaction described in step S1 is followed by a post-processing step, which includes one or more steps of extraction, drying, concentration and purification.

[0014] Specifically, the extraction is performed by adjusting the pH of the mixture after the reaction to 2.8-3.2 and then extracting with ethyl acetate.

[0015] The drying process involves drying the organic phase with anhydrous sodium sulfate.

[0016] The concentration process involves filtering the dried organic phase and concentrating it under vacuum.

[0017] The purification process involved: the crude product was purified by silica gel chromatography and reversed-phase HPLC.

[0018] In some embodiments, the preparation method, step S2, utilizes N,N-dimethylformamide, sulfoxide, and intermediate compound of formula 2 to obtain intermediate compound of formula 2A.

[0019]

[0020] Preferably, the molar ratio of N,N-dimethylformamide, sulfoxide and intermediate compound of formula 2 in step S2 is 0.01:4-6:1; more preferably 0.01:5:1.

[0021] Preferably, the solvent for the reaction in step S2 is at least one of DMF, DCM and THF; more preferably, it is DCM.

[0022] Preferably, the reaction conditions in step S2 are: stirring at 15-25°C for 2-6 hours; more preferably, stirring at 20°C for 4 hours.

[0023] In some implementations, the reaction described in step S2 is followed by a post-processing step, wherein the post-processing is concentration.

[0024] In some embodiments, the preparation method, step S3, involves reacting 4-fluoroaniline, pyridine, and the intermediate compound of formula 2 to obtain the intermediate compound of formula 3.

[0025]

[0026] Preferably, the molar ratio of 4-fluoroaniline, pyridine and the intermediate compound of formula 2 in step S3 is 1.3-1.7:2-4:1; more preferably 1.5:3:1.

[0027] Preferably, the intermediate compound of formula 2 in step S3 is added as follows: 4-fluoroaniline and pyridine are degassed in a solvent and purged with nitrogen at least once, and then the intermediate compound 2 is added at -4°C to -4°C. More preferably, 4-fluoroaniline and pyridine are degassed in a solvent and purged with nitrogen three times, and then the intermediate compound 2 is added at 0°C.

[0028] Preferably, the solvent for the reaction in step S3 is at least one of DMF, N,N-dimethylethylamine, DCM and THF; more preferably, it is THF.

[0029] Preferably, the reaction conditions in step S3 are: stirring at 15-25°C for 8-16 hours under a nitrogen atmosphere; more preferably, stirring at 20°C for 12 hours under a nitrogen atmosphere.

[0030] In some embodiments, the reaction described in step S3 is followed by a post-processing step, which includes one or more of the following steps: extraction, drying, concentration, and recrystallization.

[0031] Specifically, the extraction is performed by adding sodium bicarbonate to the mixture after the reaction and then extracting with ethyl acetate.

[0032] The drying process involves drying the organic phase using anhydrous sodium sulfate.

[0033] The concentration process involves drying the organic phase, filtering it, and then concentrating it under vacuum.

[0034] The recrystallization process involves dissolving the concentrated crude product in a mixture of petroleum ether and ethyl acetate, stirring at 18-22°C, and then filtering.

[0035] Preferably, the volume ratio of petroleum ether to ethyl acetate is 4-6:1; more preferably 5:1.

[0036] In some embodiments, the preparation method, step S4, involves reacting phenylmethanethiol, N,N-diisopropylethylamine, and the intermediate compound of formula 3 to obtain the intermediate compound of formula 4.

[0037]

[0038] Preferably, the molar ratio of phenylmethanethiol, N,N-diisopropylethylamine and the intermediate compound of formula 3 in step S4 is 0.9-1.1:2-4:1; more preferably 1:3:1.

[0039] Preferably, the solvent for the reaction in step S4 is DMSO.

[0040] Preferably, the reaction conditions in step S4 are: stirring at 35-45°C for 4-8 hours under a nitrogen atmosphere; more preferably, stirring at 40°C for 6 hours under a nitrogen atmosphere.

[0041] In some embodiments, the reaction described in step S4 is followed by a post-processing step, which includes one or more of the following steps: extraction, drying, concentration, and recrystallization.

[0042] Specifically, the extraction is performed by adding water and ethyl acetate to the mixture after the reaction for extraction.

[0043] The drying process involves drying the organic phase with anhydrous sodium sulfate.

[0044] The concentration process involves filtering the dried organic phase and then concentrating it under vacuum.

[0045] The recrystallization process involves dissolving the concentrated crude product in a mixture of petroleum ether and acetonitrile, stirring at 15-25°C, and then filtering.

[0046] Preferably, the volume ratio of petroleum ether to acetonitrile is 1-3:1; more preferably 2:1.

[0047] In some embodiments, the preparation method, step S5, involves reacting a thioyl chloride with an intermediate compound of formula 4 to obtain an intermediate compound of formula 5.

[0048]

[0049] Preferably, the molar ratio of the thioyl chloride and the intermediate compound of formula 4 in step S5 is 1:0.9-1.1, and more preferably 1:1.

[0050] Preferably, the method of adding the thioyl chloride in step S5 is as follows: the intermediate compound of Formula 4 and the solvent are degassed and purged with nitrogen at least once, and then the thioyl chloride is added.

[0051] More preferably, the method of adding the thioyl chloride is as follows: the intermediate compound of Formula 4 and the solvent are degassed and purged with nitrogen three times, and then the thioyl chloride is added.

[0052] Preferably, the solvent for the reaction in step S5 is at least one of DMF, N,N-dimethylethylamine, DCM and THF; more preferably, it is DCM.

[0053] Preferably, the reaction conditions in step S5 are: stirring at 15-25°C for 2-6 hours under a nitrogen atmosphere; more preferably, stirring at 20°C for 4 hours under a nitrogen atmosphere.

[0054] In some embodiments, the reaction described in step S5 is followed by a post-processing step, which includes one or more steps of concentrating and recrystallizing the reactants.

[0055] Specifically, the concentration refers to: concentrating the mixture after the reaction under vacuum.

[0056] The recrystallization process involves dissolving the concentrated crude product in a mixture of petroleum ether and ethyl acetate, stirring at 15-25°C, and then filtering.

[0057] Preferably, the volume ratio of petroleum ether to ethyl acetate is 3-5:1; more preferably 4:1.

[0058] In some embodiments, the preparation method, step S6, involves reacting 2,2,2-trifluoroethanol, potassium carbonate, and the intermediate compound of formula 5 to obtain the compound of formula 6.

[0059] Preferably, the molar ratio of 2,2,2-trifluoroethanol, potassium carbonate and the intermediate compound of formula 5 in step S6 is 1.9-2.1:1.9-2.1:1, and more preferably 2:2:1.

[0060] Preferably, the intermediate compound of Formula 5 is added in step S6 by degassing 2,2,2-trifluoroethanol, potassium carbonate and solvent and purging with nitrogen at least once, and then adding the intermediate compound of Formula 5.

[0061] More preferably, the intermediate compound of Formula 5 is added as follows: 2,2,2-trifluoroethanol, potassium carbonate and solvent are degassed and purged with nitrogen three times, and then the intermediate compound of Formula 5 is added.

[0062] Preferably, the solvent for the reaction in step S6 is at least one of DMF, N,N-dimethylethylamine, DCM, and THF; more preferably, it is THF.

[0063] Preferably, the reaction conditions in step S6 are: stirring at 15-25°C for 18-24 hours under a nitrogen atmosphere; more preferably, stirring at 20°C for 20 hours under a nitrogen atmosphere.

[0064] In some embodiments, the reaction described in step S6 is followed by a post-processing step, which includes one or more steps of filtration, concentration and purification.

[0065] Specifically, the filtration is: filtering the mixture after the reaction.

[0066] The concentration is achieved by vacuum concentration of the filtered filtrate.

[0067] The purification process involves purifying the concentrated residue using HPLC.

[0068] Secondly, the present invention provides an intermediate compound having any of the following structural formulas:

[0069] , , , and .

[0070] Thirdly, the present invention provides the use of the above-mentioned intermediate compound in the preparation of 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one.

[0071] In this invention, the English name for 1,3-difluoro-5-nitro-benzene is: 1,3-difluoro-5-nitro-benzene;

[0072] The intermediate compound of Formula 2 is 2,6-difluoro-4-nitro-benzoic acid;

[0073] The intermediate compound of formula 2A is 2,6-difluoro-4-nitro-benzoyl chloride.

[0074] The intermediate compound of Formula 3 is 2,6-difluoro-N-(4-fluorophenyl)-4-nitrobenzamide, and its English name is 2,6-difluoro-N-(4-fluorophenyl)-4-nitro-benzamide.

[0075] The intermediate compound of Formula 4 is 2-benzylsulfanyl-6-fluoro-N-(4-fluorophenyl)-4-nitrobenzamide.

[0076] The intermediate compound of Formula 5 is 4-fluoro-2-(4-fluorophenyl)-6-nitro-1,2-benzothiazol-3-one, with the English name 4-fluoro-2-(4-fluorophenyl)-6-nitro-1,2-benzothiazol-3-one.

[0077] Formula 6 is 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one, with the English name 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one.

[0078] The present invention has the following beneficial effects:

[0079] The preparation method of the present invention allows for easy control of reaction conditions, and the prepared 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one has a high purity (above 98%).

[0080] The preparation method of the present invention is simple to operate and can be scaled up for production using fluid chemistry. Detailed Implementation

[0081] The present invention will be described below through specific embodiments to make the technical solution of the present invention easier to understand and master. However, the present invention is not limited thereto. The described embodiments are only some embodiments of the present invention, and not all embodiments.

[0082] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, which should be understood to include values ​​close to them. For numerical ranges, one or more new numerical ranges can be obtained by combining the endpoint values ​​of the ranges, the endpoint values ​​of the ranges with individual point values, and individual point values ​​with each other, and these numerical ranges should be considered as specifically disclosed herein. Unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “described” as used herein include both singular and plural indicators. Numerical ranges expressed by endpoints include all numerical values ​​and fractions within the corresponding range, as well as the expressed endpoints.

[0083] Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without inventive effort should fall within the scope of protection of this invention. Unless otherwise specified, the experimental methods described in the following embodiments are conventional methods; the reagents and materials described, unless otherwise specified, are commercially available.

[0084] Table 1 Abbreviations and Full Names

[0085]

[0086] Example 1: Synthesis of intermediate compound of Formula 1

[0087] Solution 1: 1,3-Difluoro-5-nitrobenzene, 1 eq, 80 g, 100%, 80 g THF solution, 1600 mL

[0088] Solution 2: LDA, 2 eq, 100.191 g, 1 M, 935.318 mL, 13.39%, 748.255 g

[0089] Solution 1 was pumped to flow reactor 1 (FLR1, PFA, coil reactor, 6.350 (1 / 4") mm, 61.55 mL, -50 °C) at a rate of 37.639 mL / min via pump 1 (S1, P1). Solution 2 was pumped to flow reactor 1 (FLR1, PFA, coil reactor, 6.350 (1 / 4") mm, 61.55 mL, -50 °C) at a rate of 23.911 mL / min via pump 2 (S2, P2). The residence time in flow reactor 1 was 1 min (FLR1). The mixture was collected in a bottle (quenched with dry ice). Pumps 1 and 2 were started simultaneously. The reaction mixture was collected after 1 minute of operation. Samples were taken for analysis after 40 minutes.

[0090] The pH of the mixture was adjusted to 3 with 2N HCl. The aqueous phase was extracted with ethyl acetate (150 mL x 5). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (ISCO®; 330 g SepaFlash® silica gel flash column, 0–70% ethyl acetate / petroleum ether gradient @ 120 mL / min eluent). The crude product was purified by reversed-phase HPLC (neutral, column: 4 kg, Agela C18 column, 110 g; mobile phase: A: water; B: CAN; flow rate: 550 ml / min; stationary phase: 15 μm C18; gradient (percentage of B): 10%-50% 25 min; 50%-100% 30 min; instrument: Orienda) to obtain 2,6-difluoro-4-nitrobenzoic acid (38 g, 159.04 mmol, yield 31.63%, purity 85%) as a yellow solid.

[0091] The specific chemical reaction equation is as follows:

[0092]

[0093] 1H NMR: 2,6-Difluoro-4-nitrobenzoic acid (400 MHz, CDCl3-d)

[0094] δ ppm =7.94 - 7.84 (m, 2H).

[0095] Example 2: Synthesis of intermediate compound of formula 2A

[0096] 2,6-Difluoro-4-nitrobenzoic acid (33 g, 162.48 mmol, 1 eq) was reacted with dichloromethane (330 mL) and N , N A solution of 2,6-dimethylformamide (118.76 mg, 1.62 mmol, 125.01 μL, 0.01 eq) was slowly added dropwise with thionyl chloride (SOCl2) (96.65 g, 812.41 mmol, 59.01 mL, 5 eq). The mixture was stirred at 20°C for 4 hours, and the reaction was confirmed to be complete by TLC. The mixture was concentrated to obtain the residue. This product was used for the next step without purification. Compound 2,6-difluoro-4-nitrobenzyl chloride (36 g, crude) was a yellow oil.

[0097] The specific chemical reaction equation is as follows:

[0098]

[0099] Example 3 Synthesis of intermediate compound of Formula 3

[0100] 4-Fluoroaniline (27.08 g, 243.74 mmol, 23.41 mL, 1.5 eq) and pyridine (38.56 g, 487.48 mmol, 39.35 mL, 3 eq) were degassed in tetrahydrofuran (360 mL) and purged three times with N2. Then, 2,6-difluoro-4-nitrobenzoyl chloride (36 g, 162.49 mmol, 1 eq) was added at 0°C, and the mixture was stirred at 20°C for 12 hours under N2 atmosphere. A NaHCO3 solution (100 mL) was added to the mixture (mixed with another 5 g batch). The mixture was extracted with ethyl acetate (150 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was stirred at 20 °C for 10 minutes with petroleum ether:ethyl acetate (5:1, 60 mL), and filtered to obtain 2,6-difluoro-N-(4-fluorophenyl)-4-nitrobenzamide (16 g, purity 88%) as a yellow solid.

[0101] The specific chemical reaction equation is as follows:

[0102]

[0103] LCMS (2,6-difluoro-N-(4-fluorophenyl)-4-nitrobenzamide): (MS-H)- = 295.0; Rt = 0.543 min.

[0104] 1 ¹H NMR: 2,6-Difluoro-N-(4-fluorophenyl)-4-nitrobenzamide (400 MHz, CDCN-d3)

[0105] δ ppm = 9.19 (br s, 1H), 8.01 - 7.95 (m, 2H), 7.69 - 7.62 (m, 2H), 7.18 - 7.10 (m, 2H).

[0106] Example 4: Synthesis of intermediate compound of formula 4

[0107] 2,6-Difluoro-N-(4-fluorophenyl)-4-nitrobenzamide (8 g, 27.01 mmol, 1 eq), phenylmethanethiol (3.35 g, 27.01 mmol, 3.17 mL, 1 eq) and N , NThe mixture of diisopropylethylamine (10.47 g, 81.03 mmol, 14.11 mL, 3 eq) in DMSO (80 mL) was degassed and purged three times with N2, then stirred at 40°C for 6 hours under N2 atmosphere. Water (70 mL) was added to the mixture. The mixture was extracted with ethyl acetate (75 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was stirred at 20°C for 10 min with petroleum ether:acetonitrile (2:1, 30 mL), and filtered to give 2-benzylsulfonyl-6-fluoro-N-(4-fluorophenyl)-4-nitrobenzamide (7 g, 15.73 mmol, yield 58.26%, purity 90%) as a yellow solid.

[0108] The specific chemical reaction equation is as follows:

[0109]

[0110] 1 ¹H NMR: 2-Benzylsulfonyl-6-fluoro-N-(4-fluorophenyl)-4-nitrobenzamide (400 MHz, DMSO-) d6 )

[0111] δ ppm = 10.89 (s, 1H), 8.04 (d, J = 0.8 Hz, 1H), 7.68 - 7.62 (m, 2H), 7.39 - 7.35 (m, 2H), 7.31 - 7.23 (m, 3H), 7.23 - 7.16 (m, 3H), 4.43 (s, 2H).

[0112] Example 5: Synthesis of intermediate compound of Formula 5

[0113] 2-Benzylsulfonyl-6-fluoro-N-(4-fluorophenyl)-4-nitro-benzamide (5 g, 12.49 mmol, 1 eq) was degassed in dichloromethane (125 mL) and purged three times with N2. Thionyl chloride (1.69 g, 12.49 mmol, 1.25 mL, 1 eq) was then added, and the mixture was stirred at 20 °C for 4 hours under N2 atmosphere. The mixture (combined with another 2 g batch) was concentrated to give the residue. The crude product was stirred in petroleum ether:ethyl acetate (4:1, 30 mL) at 20 °C for 10 minutes and filtered to give 4-fluoro-2-(4-fluorophenyl)-6-nitro-1,2-benzothiazol-3-one (4 g, 95% purity) as a yellow solid.

[0114] The specific chemical reaction equation is as follows:

[0115]

[0116] LCMS (4-fluoro-2-(4-fluorophenyl)-6-nitro-1,2-benzothiazol-3-one): (MS+H) + = 309.1; Rt= 1.227 min.

[0117] 1 ¹H NMR: 4-fluoro-2-(4-fluorophenyl)-6-nitro-1,2-benzothiazol-3-one (400 MHz, DMSO-d6)

[0118] δ ppm = 8.92 (d, J = 1.6 Hz, 1H), 8.08 (dd, J = 1.8, 9.9 Hz, 1H), 7.73 - 7.67 (m, 2H), 7.44 - 7.38 (m, 2H).

[0119] Example 6: Synthesis of Compound 6

[0120] 2,2,2-Trifluoroethanol (324.53 mg, 3.24 mmol, 233.31 μL, 2 eq) and potassium carbonate (448.34 mg, 3.24 mmol, 2 eq) were degassed in tetrahydrofuran (5 mL) and purged three times with N2. Then, 4-fluoro-2-(4-fluorophenyl)-6-nitro-1,2-benzothiazol-3-one (0.5 g, 1.62 mmol, 1 eq) was added. The mixture was stirred at 20 °C for 20 hours under N2 atmosphere. The reaction mixture (combined with 13 other batches of the same scale) was filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (column: Agela DuraShell C18 250*70mm*10um; mobile phase: [H2O (10 mM NH4HCO3)-ACN:THF=1:1]; gradient: mobile phase B 35%-65% within 17.0 min). Compound 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one (1.22 g, 3.04 mmol, yield 14.4%, purity 98.22%) was a yellow solid.

[0121] The specific chemical reaction equation is as follows:

[0122]

[0123] LCMS (2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one):(MS+H) + =389.0; Rt = 3.171 min.

[0124] 1 ¹H NMR: 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one (400 MHz, DMSO- d6 )

[0125] δ ppm = 8.71 (d, J = 1.8 Hz, 1H), 7.84 (d, J = 1.8 Hz, 1H), 7.72 -7.64 (m, 2H), 7.42 - 7.34 (m, 2H), 5.11 (q, J = 8.8 Hz, 2H).

[0126] Comparative Example 1

[0127] The difference between this comparative example and Example 4 is that HTF is used instead of DMSO, specifically:

[0128] 2,6-Difluoro-N-(4-fluorophenyl)-4-nitrobenzamide (8 g, 27.01 mmol, 1 eq), phenylmethanethiol (3.35 g, 27.01 mmol, 3.17 mL, 1 eq) and N , N The mixture of diisopropylethylamine (10.47 g, 81.03 mmol, 14.11 mL, 3 eq) in HTF (120 mL) was degassed and purged three times with N2, then stirred at 40°C for 6 hours under N2 atmosphere. Water (70 mL) was added to the mixture. The mixture was extracted with ethyl acetate (75 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was stirred at 20°C for 10 min with petroleum ether:acetonitrile (2:1, 30 mL), and filtered to give 2-benzylsulfonyl-6-fluoro-N-(4-fluorophenyl)-4-nitrobenzamide (5 g, 12.49 mmol, yield 46.29%, purity 90%) as a yellow solid.

[0129] Comparative Example 2

[0130] The difference between this comparative example and Example 6 is that the molar ratio of 2,2,2-trifluoroethanol, potassium carbonate, and the intermediate compound of formula 5 is 1.5:2.5:1 (the total molar amounts are the same). All other steps are the same. The final compound is 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one (0.05 g, 0.013 mmol, yield 7.9%, purity 98.6%).

[0131] Comparative Example 3

[0132] The difference between this comparative example and Example 6 is that the molar ratio of 2,2,2-trifluoroethanol, potassium carbonate, and the intermediate compound of formula 5 is 2.5:1.5:1 (the total molar amounts are the same). All other steps are the same. The final compound is 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one (0.03 g, 0.008 mmol, yield 4.76%, purity 98%).

[0133] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A process for the preparation of 2-(4-fluorophenyl)-6-nitro-4-(2,2,2- trifluoroethoxy)-1,2-benzothiazol-3-one, characterized in that, The compound described in formula 6 is prepared by using 1,3-difluoro-5-nitrobenzene as raw material through the following synthetic route, i.e. 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one; 。 2. The production method according to claim 1, characterized by, Step S1 utilizes 1,3-difluoro-5-nitrobenzene to react with LDA to obtain the intermediate compound in formula 2; The solvent of the reaction in step S1 is at least one of DMF, N,N-dimethyl ethylamine, DCM and THF; The molar ratio of 1,3-difluoro-5-nitrobenzene to LDA in step S1 is 1:1.8-2.2; The reaction condition in step S1 is that the temperature is-55℃ to-45℃.

3. The production method according to claim 2, characterized by, The solvent of the reaction in step S1 is THF; The molar ratio of 1,3-difluoro-5-nitrobenzene to LDA in step S1 is 1:2; The reaction condition in step S1 is that the temperature is-50℃.

4. The production method according to claim 1, characterized by, Step S2 utilizes N,N-dimethylformamide, sulfurous dichloride and the intermediate compound in formula 2 to react to obtain the intermediate compound in formula 2A; The molar ratio of N,N-dimethylformamide, sulfurous dichloride and the intermediate compound in formula 2 in step S2 is 0.01:4-6:1; The solvent of the reaction in step S2 is at least one of DMF, DCM and THF; The reaction condition in step S2 is that the temperature is 15-25℃ and the stirring time is 2-6h.

5. The preparation method according to claim 4, characterized in that, The molar ratio of N,N-dimethylformamide, sulfurous dichloride and the intermediate compound in formula 2 in step S2 is 0.01:5:1; The solvent of the reaction in step S2 is DCM; The reaction condition in step S2 is that the temperature is 20℃ and the stirring time is 4h.

6. The method of claim 1, wherein, Step S3 utilizes 4-fluoroaniline, pyridine and the intermediate compound in formula 2A to react to obtain the intermediate compound in formula 3; The molar ratio of 4-fluoroaniline, pyridine and the intermediate compound in formula 2A in step S3 is 1.3-1.7:2-4:1; The intermediate compound in formula 2A in step S3 is added in the following way: 4-fluoroaniline and pyridine are degassed and purged with nitrogen at least once in a solvent, and then the intermediate compound in formula 2A is added at-4℃ to 4℃; The solvent in step S3 is at least one of DMF, N,N-dimethyl ethylamine, DCM and THF; The reaction condition in step S3 is that the temperature is 15-25℃, the stirring time is 8-16h and the atmosphere is nitrogen.

7. The production method according to claim 6, characterized by, The molar ratio of 4-fluoroaniline, pyridine and the intermediate compound in formula 2A in step S3 is 1.5:3:1; The solvent in step S3 is THF; The reaction condition in step S3 is that the temperature is 20℃, the stirring time is 12h and the atmosphere is nitrogen.

8. The method of claim 1, wherein, Step S4 utilizes phenylmethanethiol, N,N-diisopropylethylamine and the intermediate compound in formula 3 to react to obtain the intermediate compound in formula 4; The molar ratio of phenylmethanethiol, N,N-diisopropylethylamine and the intermediate compound in formula 3 in step S4 is 0.9-1.1:2-4:1; The solvent of the reaction in step S4 is DMSO; The reaction condition in step S4 is that the temperature is 35-45℃, the stirring time is 4-8h and the atmosphere is nitrogen.

9. The production method according to claim 8, characterized by, The molar ratio of the phenylmethanethiol, N,N-diisopropylethylamine and the intermediate compound of formula 3 in step S4 is 1:3:1; The reaction condition in step S4 is stirring at 40℃ for 6h under nitrogen atmosphere.

10. The method of claim 1, wherein, Step S5 utilizes the reaction of sulfuryl chloride and the intermediate compound of formula 4 to obtain the intermediate compound of formula 5; The molar ratio of the sulfuryl chloride and the intermediate compound of formula 4 in step S5 is 1:0.9-1.1; The sulfuryl chloride is added in step S5 by degassing the intermediate compound of formula 4, potassium carbonate and solvent and purging with nitrogen at least once, then adding the sulfuryl chloride; The solvent in step S5 is at least one of DMF, N,N-dimethyl ethyl amine, DCM and THF; The reaction condition in step S5 is stirring at 15-25℃ for 2-6h under nitrogen atmosphere.

11. The method of claim 10, wherein, The molar ratio of the sulfuryl chloride and the intermediate compound of formula 4 in step S5 is 1:1; The solvent in step S5 is DCM; The reaction condition in step S5 is stirring at 20℃ for 4h under nitrogen atmosphere.

12. The method of claim 1, wherein, Step S6 utilizes the reaction of 2,2,2-trifluoroethanol, potassium carbonate and the intermediate compound of formula 5 to obtain the compound of formula 6; The molar ratio of the 2,2,2-trifluoroethanol, potassium carbonate and the intermediate compound of formula 5 in step S6 is 1.9-2.1:1.9-2.1:1; The intermediate compound of formula 5 is added in step S6 by degassing the 2,2,2-trifluoroethanol, potassium carbonate and solvent and purging with nitrogen at least once, then adding the intermediate compound of formula 5; The solvent in step S6 is at least one of DMF, N,N-dimethyl ethyl amine, DCM and THF; The reaction condition in step S6 is stirring at 15-25℃ for 18-24h under nitrogen atmosphere.

13. The method of claim 12, wherein, The molar ratio of the 2,2,2-trifluoroethanol, potassium carbonate and the intermediate compound of formula 5 in step S6 is 2:2:1; The solvent in step S6 is THF; The reaction condition in step S6 is stirring at 20℃ for 20h under nitrogen atmosphere.

14. An intermediate compound characterized by, Any one of the following structural formula: , and .

15. Use of the intermediate compound of claim 14 in the preparation of 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one.

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