Preparation method of 2-(4-fluorophenyl)-6-nitro-4-(2, 2, 2-trifluoroethoxyl)-1, 2-benzothiazole-3-ketone as well as intermediate and application of 2-(4-fluorophenyl)-6-nitro-4-(2, 2, 2-trifluoroethoxyl)-1, 2-benzothiazole-3-ketone

Abstract

The invention discloses a preparation method of 2-(4-fluorophenyl)-6-nitro-4-(2, 2, 2-trifluoroethoxyl)-1, 2-benzothiazole-3-ketone as well as an intermediate and application thereof, and belongs to the technical field of synthesis.The preparation method comprises the steps that 1, 3-difluoro-5-nitrobenzene is used as a raw material to prepare a compound shown in the formula 6 through the following synthetic route, and the compound shown in the formula 6 is shown in the description; the invention discloses a preparation method of 2-(4-fluorophenyl)-6-nitro-4-(2, 2, 2-trifluoroethoxyl)-1, 2-benzothiazole-3-ketone, which is characterized in that the 2-(4-fluorophenyl)-6-nitro-4-(2, 2, 2-trifluoroethoxyl)-1, 2- According to the preparation method disclosed by the invention, reaction conditions are easy to control, the prepared 2-(4-fluorophenyl)-6-nitro-4-(2, 2, 2-trifluoroethoxy)-1, 2-benzothiazole-3-ketone is high in purity, the operation is simple, and amplified production can be carried out by using fluid chemistry. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of synthesis technology, and specifically relates to a preparation method of 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one, an intermediate and application thereof. Background Art

[0002] 2-(4-Fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one is an inhibitor of benzisothiazolone, a newly discovered soluble phosphatase involved in bone mineralization and soft tissue ossification abnormalities.

[0003] There are relevant literatures (Yalda Bravo, Peter Teriete, Raveendra-Panickar Dhanya, Russell Dahl, Pooi San Lee, Tina Kiffer-Moreira, Santhi Reddy Ganji, Eduard Sergienko, Layton H. Smith, Colin Farquharson, José Luis Millán, Nicholas D. P. Cosford. Design, synthesis and evaluation of benzoisothiazolones as selective inhibitors of PHOSPHO1[J], Bioorganic & Medicinal Chemistry Letters, 2014, 17(24): 4308-4311) reporting the activity information of the compound, but there is no literature reporting 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-benzothiazol-3-one with easy-to-obtain raw materials and simple operation. Summary of the invention

[0004] The present invention aims to solve the problems existing in the prior art and provides a 2-(4-fluorophenyl)-6-nitro-4-

[0005] The invention discloses a preparation method of (2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one, an intermediate thereof and application thereof. The preparation method of the invention has few steps, the reaction conditions are easy to control, and the yield is high, and the invention is suitable for large-scale industrial production.

[0006] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0007] 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, which uses 1,3-difluoro-5-nitrobenzene as a raw material and is prepared through the following synthetic route to obtain a compound of formula 6, namely 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one;

[0008]

[0009] In some embodiments, the preparation method, step S1 utilizes 1,3-difluoro-5-nitrobenzene to react with LDA to obtain an intermediate compound of formula 2;

[0010]

[0011] Preferably, the solvent for the reaction in step S1 is at least one of DMF, N,N-dimethylethylamine, DCM and THF; more preferably THF.

[0012] Preferably, the molar ratio of 1,3-difluoro-5-nitrobenzene to LDA in step S1 is 1:1.8-2.2; more preferably 1:2.

[0013] Preferably, the reaction conditions in step S1 are: temperature is -55°C to -45°C; more preferably, the temperature is -50°C.

[0014] In some embodiments, after the reaction in step S1, a post-treatment step is further included, and the post-treatment includes one or more steps of extraction, drying, concentration and purification.

[0015] Specifically, the extraction is: adjusting the pH value of the reaction mixture to 2.8-3.2, and extracting with ethyl acetate.

[0016] The drying step is as follows: the organic phase is dried with anhydrous sodium sulfate.

[0017] The concentration is as follows: the dried organic phase is filtered and concentrated in vacuo.

[0018] The purification is as follows: the crude product is purified by silica gel chromatography and reverse phase HPLC.

[0019] In some embodiments, in the preparation method, step S2 utilizes N,N-dimethylformamide, dichlorothionyl and the intermediate compound of formula 2 to react to obtain the intermediate compound of formula 2A.

[0020]

[0021] Preferably, the molar ratio of N,N-dimethylformamide, thionyl chloride and the intermediate compound of formula 2 in step S2 is 0.01:4-6:1; more preferably 0.01:5:1.

[0022] Preferably, the solvent for the reaction in step S2 is at least one of DMF, DCM and THF; more preferably DCM.

[0023] 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.

[0024] In some embodiments, after the reaction in step S2, a post-treatment step is further included, and the post-treatment is concentration.

[0025] In some embodiments, in the preparation method, step S3 utilizes 4-fluoroaniline, pyridine and the intermediate compound of formula 2 to react to obtain the intermediate compound of formula 3.

[0026]

[0027] 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.

[0028] Preferably, the intermediate compound of formula 2 in step S3 is added in the following manner: 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. Further preferably, 4-fluoroaniline and pyridine are degassed in a solvent and purged with nitrogen 3 times, and then the intermediate compound 2 is added at 0°C.

[0029] Preferably, the solvent for the reaction in step S3 is at least one of DMF, N,N-dimethylethylamine, DCM and THF; more preferably THF.

[0030] Preferably, the reaction conditions in step S3 are: stirring at 15-25° C. for 8-16 h under a nitrogen atmosphere; more preferably, stirring at 20° C. for 12 h under a nitrogen atmosphere.

[0031] In some embodiments, after the reaction in step S3, a post-treatment step is further included, and the post-treatment includes one or more steps of extraction, drying, concentration and recrystallization.

[0032] Specifically, the extraction is: adding sodium bicarbonate to the mixture after the reaction, and then extracting with ethyl acetate.

[0033] The drying step is as follows: the organic phase is dried using anhydrous sodium sulfate.

[0034] The concentration is as follows: after drying, the organic phase is filtered and concentrated in vacuo.

[0035] The recrystallization is as follows: dissolving the concentrated crude product in a mixture of petroleum ether and ethyl acetate, stirring at 18-22° C., and filtering.

[0036] Preferably, the volume ratio of petroleum ether to ethyl acetate is 4-6:1; more preferably 5:1.

[0037] In some embodiments, in the preparation method, step S4 utilizes phenylmethyl mercaptan, N,N-diisopropylethylamine and the intermediate compound of formula 3 to react to obtain the intermediate compound of formula 4.

[0038]

[0039] Preferably, the molar ratio of phenylmethyl mercaptan, 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.

[0040] Preferably, the solvent for the reaction in step S4 is DMSO.

[0041] Preferably, the reaction conditions in step S4 are: stirring at 35-45° C. for 4-8 h under a nitrogen atmosphere; more preferably, stirring at 40° C. for 6 h under a nitrogen atmosphere.

[0042] In some embodiments, after the reaction in step S4, a post-treatment step is further included, and the post-treatment includes one or more steps of extraction, drying, concentration and recrystallization.

[0043] Specifically, the extraction is: adding water and ethyl acetate to the reaction mixture for extraction.

[0044] The drying step is: drying the organic phase with anhydrous sodium sulfate.

[0045] The concentration is as follows: the dried organic phase is filtered and concentrated in vacuo.

[0046] The recrystallization is as follows: dissolving the concentrated crude product in a mixture of petroleum ether and acetonitrile, stirring at 15-25° C., and filtering.

[0047] Preferably, the volume ratio of petroleum ether to acetonitrile is 1-3:1; more preferably 2:1.

[0048] In some embodiments, in the preparation method, step S5 utilizes sulfuryl chloride to react with the intermediate compound of formula 4 to obtain the intermediate compound of formula 5.

[0049]

[0050] Preferably, the molar ratio of sulfuryl chloride to the intermediate compound of formula 4 in step S5 is 1:0.9-1.1, and more preferably 1:1.

[0051] Preferably, the sulfuryl chloride is added in step S5 by degassing the intermediate compound of formula 4 and the solvent and purging with nitrogen at least once, and then adding sulfuryl chloride.

[0052] Further preferably, the sulfuryl chloride is added by degassing the intermediate compound of formula 4 and the solvent and purging with nitrogen for 3 times, and then adding the sulfuryl chloride.

[0053] Preferably, the solvent for the reaction in step S5 is at least one of DMF, N,N-dimethylethylamine, DCM and THF; more preferably DCM.

[0054] Preferably, the reaction conditions in step S5 are: stirring at 15-25° C. for 2-6 h under a nitrogen atmosphere; more preferably, stirring at 20° C. for 4 h under a nitrogen atmosphere.

[0055] In some embodiments, after the reaction in step S5, a post-treatment step is further included, and the post-treatment includes one or more steps of concentrating and recrystallizing the reactants.

[0056] Specifically, the concentration is: concentrating the mixture after the reaction in vacuum.

[0057] The recrystallization is as follows: the concentrated crude product is added into a mixture of petroleum ether and ethyl acetate to dissolve, stirred at 15-25° C., and filtered.

[0058] Preferably, the volume ratio of petroleum ether to ethyl acetate is 3-5:1; more preferably 4:1.

[0059] In some embodiments, in the preparation method, step S6 utilizes 2,2,2-trifluoroethanol, potassium carbonate and the intermediate compound of formula 5 to react to obtain the compound of formula 6.

[0060] 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.

[0061] Preferably, the intermediate compound of Formula 5 in step S6 is added 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.

[0062] Further preferably, the intermediate compound of formula 5 is added in the following manner: 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.

[0063] Preferably, the solvent for the reaction in step S6 is at least one of DMF, N,N-dimethylethylamine, DCM and THF; more preferably THF.

[0064] Preferably, the reaction conditions in step S6 are: stirring at 15-25° C. for 18-24 h under a nitrogen atmosphere; more preferably, stirring at 20° C. for 20 h under a nitrogen atmosphere.

[0065] In some embodiments, after the reaction in step S6, a post-treatment step is further included, and the post-treatment includes one or more steps of filtration, concentration and purification.

[0066] Specifically, the filtering is: filtering the mixture after the reaction.

[0067] The concentration is as follows: concentrating the filtrate after filtration in vacuo.

[0068] The purification is as follows: the concentrated residue is purified by HPLC.

[0069] In a second aspect, the present invention provides an intermediate compound, which is any one of the following structural formulas:

[0070]

[0071] In a third aspect, the present invention provides the use of the above intermediate compound in the preparation of 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one.

[0072] The English name of 1,3-difluoro-5-nitrobenzene in the present invention is: 1,3-difluoro-5-nitro-benzene;

[0073] The intermediate compound of formula 2 is 2,6-difluoro-4-nitrobenzoic acid, and its English name is 2,6-difluoro-4-nitro-benzoic acid;

[0074] The intermediate compound of formula 2A is 2,6-difluoro-4-nitrobenzoyl chloride, and its English name is 2,6-difluoro-4-nitro-benzoyl chloride;

[0075] 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.

[0076] The intermediate compound of formula 4 is 2-benzylsulfanyl-6-fluoro-N-(4-fluorophenyl)-4-nitrobenzamide, and its English name is 2-benzylsulfanyl-6-fluoro-N-(4-fluorophenyl)-4-nitro-benzamide

[0077] The intermediate compound of formula 5 is 4-fluoro-2-(4-fluorophenyl)-6-nitro-1,2-benzothiazol-3-one, and its English name is 4-fluoro-2-(4-fluorophenyl)-6-nitro-1,2-benzothiazol-3-one.

[0078] Formula 6 is 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one, and its English name is 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one.

[0079] The present invention has the following beneficial effects:

[0080] The preparation method of the invention has easy control of reaction conditions and the prepared 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one has high purity (more than 98%).

[0081] The preparation method of the present invention is simple to operate and can be scaled up for production using fluid chemistry. DETAILED DESCRIPTION

[0082] The present invention is described below through specific embodiments to make the technical solution of the present invention easier to understand and grasp, but the present invention is not limited thereto, and the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments.

[0083] The endpoints and any value of the scope disclosed in this article are not limited to the accurate scope or value, and these scopes or values ​​should be understood to include values ​​close to these scopes or values. For numerical ranges, between the endpoint values ​​of each scope, between the endpoint values ​​of each scope and a separate point value, and between separate point values, one or more new numerical ranges can be combined with each other, and these numerical ranges should be considered as specifically disclosed in this article. Unless the context clearly indicates otherwise, the singular form "one", "a kind of" and "described" as used herein include singular and plural indicators. The numerical range described by the endpoint is included in all numerical values ​​and fractions within the corresponding range, as well as the described endpoint.

[0084] Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work should fall within the scope of protection of the present invention. The experimental methods described in the following embodiments are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.

[0085] Table 1 Abbreviations and full names

[0086]

[0087]

[0088] Example 1 Synthesis of intermediate compound of formula 1

[0089] Solution 1: 1,3-difluoro-5-nitrobenzene, 1eq, 80g, 100%, 80g THF solution, 1600mL

[0090] Solution 2: LDA, 2 eq, 100.191 g, 1 M, 935.318 mL, 13.39%, 748.255 g

[0091] Solution 1 was pumped to flow reactor 1 FLR1, PFA, coil reactor, 6.350 (1 / 4") mm, 61.55 mL, -50 °C by pump 1 S1, P1 at a rate of 37.639 mL / min. Solution 2 was pumped to flow reactor 1 FLR1, PFA, coil reactor, 6.350 (1 / 4") mm, 61.55 mL, -50 °C by pump 2 S2, P2 at a rate of 23.911 mL / min. The residence time in flow reactor 1 was FLR1, 1 min. The mixture was collected in a bottle (quenched with dry ice). Pump 1 and pump 2 were started simultaneously. The reaction mixture was collected after 1 minute of operation. Samples were taken for analysis after 40 minutes.

[0092] The pH value of the mixture was adjusted to 3 with 2N HCl. The aqueous phase was extracted with ethyl acetate (150 mL*5). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel ( 330g Silica gel flash column, 0-70% ethyl acetate / petroleum ether gradient@

[0093] The crude product was purified by reverse phase HPLC (neutral, column: 4kg, Agela C18 column, 110g, mobile phase: A: water; B: CAN; flow rate: 550ml / min, stationary phase: 15um C18;; gradient (percentage of B): 10%-50% 25min; 50%-100% 30min; instrument: Orienda) to obtain 2,6-difluoro-4-nitrobenzoic acid (38g, 159.04mmol, yield 31.63%, purity 85%) as a yellow solid.

[0094] The specific chemical reaction equation is as follows:

[0095]

[0096] 1H NMR: 2,6-Difluoro-4-nitrobenzoic acid (400MHz, CDCl3-d)

[0097] δppm=7.94-7.84(m,2H).

[0098] Example 2 Synthesis of intermediate compound of formula 2A

[0099] A solution of 2,6-difluoro-4-nitrobenzoic acid (33 g, 162.48 mmol, 1 eq) in dichloromethane (330 mL) and N,N-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 complete by TLC detection. The mixture was concentrated to obtain a residue. The product was used in the next step without purification. Compound 2,6-difluoro-4-nitrobenzoyl chloride (36 g, crude product) was a yellow oil.

[0100] The specific chemical reaction equation is as follows:

[0101]

[0102] Example 3 Synthesis of intermediate compound of formula 3

[0103] 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 with N2 three times, 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 under N2 atmosphere for 12 hours. NaHCO3 solution (100 mL) was added to the mixture (mixed with another 5 g batch). The mixture was extracted with ethyl acetate (150 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was stirred with petroleum ether:ethyl acetate (5:1, 60 mL) at 20 °C for 10 minutes and filtered to give 2,6-difluoro-N-(4-fluorophenyl)-4-nitrobenzamide (16 g, purity 88%) as a yellow solid.

[0104] The specific chemical reaction equation is as follows:

[0105]

[0106] LCMS (2,6-difluoro-N-(4-fluorophenyl)-4-nitrobenzamide): (MS-H)-=295.0; Rt=0.543 min.

[0107] 1 H NMR: 2,6-difluoro-N-(4-fluorophenyl)-4-nitrobenzamide (400MHz, CDCN-d3)

[0108] δppm=9.19(br s,1H),8.01-7.95(m,2H),7.69-7.62(m,2H),7.18-7.10(m,2H).

[0109] Example 4 Synthesis of intermediate compound of formula 4

[0110] A mixture of 2,6-difluoro-N-(4-fluorophenyl)-4-nitrobenzamide (8 g, 27.01 mmol, 1 eq), phenylmethyl mercaptan (3.35 g, 27.01 mmol, 3.17 mL, 1 eq) and N,N-diisopropylethylamine (10.47 g, 81.03 mmol, 14.11 mL, 3 eq) in DMSO (80 mL) was degassed and purged with N2 three times, 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*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was stirred with petroleum ether:acetonitrile (2:1, 30 mL) at 20°C for 10 min 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.

[0111] The specific chemical reaction equation is as follows:

[0112]

[0113] 1 H NMR: 2-Benzylsulfonyl-6-fluoro-N-(4-fluorophenyl)-4-nitrobenzamide (400 MHz, DMSO-d6)

[0114] δppm=10.89(s,1H),8.04(d,J=0.8Hz,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).

[0115] Example 5 Synthesis of the intermediate compound of formula 5

[0116] 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 with N2 for 3 times, then sulfuryl chloride (1.69 g, 12.49 mmol, 1.25 mL, 1 eq) was 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 a residue. The crude product was stirred with 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, purity 95%) as a yellow solid.

[0117] The specific chemical reaction equation is as follows:

[0118]

[0119] LCMS(4-Fluoro-2-(4-fluorophenyl)-6-nitro-1,2-benzothiazol-3-one):(MS+H) + =309.1; Rt=1.227min.

[0120] 1 H NMR: 4-Fluoro-2-(4-fluorophenyl)-6-nitro-1,2-benzothiazol-3-one (400 MHz, DMSO-d6)

[0121] δppm=8.92 (d, J=1.6Hz, 1H), 8.08 (dd, J=1.8, 9.9Hz, 1H), 7.73-7.67 (m, 2H), 7.44-7.38 (m, 2H).

[0122] Example 6 Synthesis of Compound of Formula 6

[0123] 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 with N2 three times, and 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 was filtered (combined with 13 other batches of the same size), and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (chromatographic column: Agela DuraShell C18 250*70mm*10um; mobile phase: [H2O(10mMNH4HCO3)-ACN:THF=1:1]; gradient: mobile phase B was 35%-65% in 17.0min. 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.

[0124] The specific chemical reaction equation is as follows:

[0125]

[0126] LCMS(2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one):(MS+H) + =389.0; Rt=3.171min.

[0127] 1 H NMR: 2-(4-Fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one (400 MHz, DMSO-d6)

[0128] δppm=8.71 (d, J=1.8Hz, 1H), 7.84 (d, J=1.8Hz, 1H), 7.72-7.64 (m, 2H), 7.42-7.34 (m, 2H), 5.11 (q, J=8.8Hz, 2H).

[0129] Comparative Example 1

[0130] The difference between this comparative example and Example 4 is that HTF is used instead of DMSO, specifically:

[0131] A mixture of 2,6-difluoro-N-(4-fluorophenyl)-4-nitrobenzamide (8 g, 27.01 mmol, 1 eq), phenylmethyl mercaptan (3.35 g, 27.01 mmol, 3.17 mL, 1 eq) and N,N-diisopropylethylamine (10.47 g, 81.03 mmol, 14.11 mL, 3 eq) in HTF (120 mL) was degassed and purged with N2 three times, then stirred at 40 °C under N2 atmosphere for 6 hours. Water (70 mL) was added to the mixture. The mixture was extracted with ethyl acetate (75 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was stirred with petroleum ether:acetonitrile (2:1, 30 mL) at 20°C for 10 min 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.

[0132] Comparative Example 2

[0133] 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 amount is the same). The other steps are the same. The final compound 2-

[0134] (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%).

[0135] Comparative Example 3

[0136] 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 amount is the same). The other steps are the same. The final compound 2-

[0137] (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%).

[0138] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one, characterized in that: The compound of formula 6 is prepared by the following synthetic route using 1,3-difluoro-5-nitrobenzene as a raw material, namely 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one; 2. The preparation method according to claim 1, characterized in that: Step S1: 1,3-difluoro-5-nitrobenzene is reacted with LDA to obtain an intermediate compound of formula 2; The solvent for the reaction in step S1 is at least one of DMF, N,N-dimethylethylamine, DCM and THF; more preferably THF; The molar ratio of 1,3-difluoro-5-nitrobenzene to LDA in step S1 is 1:1.8-2.2; more preferably 1:2; The reaction conditions in step S1 are: temperature is -55°C to -45°C, and more preferably -50°C.

3. The preparation method according to claim 1, characterized in that: Step S2: using N,N-dimethylformamide, thionyl chloride and the intermediate compound of formula 2 to react to obtain the intermediate compound of formula 2A; The molar ratio of N,N-dimethylformamide, thionyl chloride and the intermediate compound of formula 2 in step S2 is 0.01:4-6:1; more preferably 0.01:5:1; The solvent for the reaction in step S2 is at least one of DMF, DCM and THF; more preferably DCM; 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.

4. The preparation method according to claim 1, characterized in that: Step S3: using 4-fluoroaniline, pyridine and the intermediate compound of formula 2 to react to obtain the intermediate compound of formula 3; 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; Preferably, the intermediate compound of formula 2 in step S3 is added in the following manner: 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; The solvent in step S3 is at least one of DMF, N,N-dimethylethylamine, DCM and THF; more preferably THF; The reaction conditions in step S3 are: stirring at 15-25° C. for 8-16 h under a nitrogen atmosphere; more preferably, stirring at 20° C. for 12 h under a nitrogen atmosphere.

5. The preparation method according to claim 1, characterized in that: Step S4: using phenylmethyl mercaptan, N,N-diisopropylethylamine and the intermediate compound of formula 3 to react to obtain the intermediate compound of formula 4; The molar ratio of phenylmethyl mercaptan, 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; The solvent for the reaction in step S4 is DMSO; The reaction conditions in step S4 are: stirring at 35-45° C. for 4-8 h under a nitrogen atmosphere; more preferably, stirring at 40° C. for 6 h under a nitrogen atmosphere.

6. The preparation method according to claim 1, characterized in that: Step S5: using sulfuryl chloride to react with the intermediate compound of formula 4 to obtain the intermediate compound of formula 5; The molar ratio of sulfuryl chloride to the intermediate compound of formula 4 in step S5 is 1:0.9-1.1, more preferably 1:1; The method of adding sulfuryl chloride in step S5 is: degassing the intermediate compound of formula 4 and the solvent and purging with nitrogen at least once, and then adding sulfuryl chloride; The solvent in step S5 is at least one of DMF, N,N-dimethylethylamine, DCM and THF; more preferably DCM; The reaction conditions in step S5 are: stirring at 15-25° C. for 2-6 h under a nitrogen atmosphere; more preferably, stirring at 20° C. for 4 h under a nitrogen atmosphere.

7. The preparation method according to claim 1, characterized in that: Step S6: using 2,2,2-trifluoroethanol, potassium carbonate and the intermediate compound of formula 5 to react to obtain the compound of formula 6; 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; The method of adding the intermediate compound of formula 5 in step S6 is: degas 2,2,2-trifluoroethanol, potassium carbonate and solvent and purge with nitrogen at least once, and then add the intermediate compound of formula 5; The solvent in step S6 is at least one of DMF, N,N-dimethylethylamine, DCM and THF; more preferably THF; The reaction conditions in step S6 are: stirring at 15-25° C. for 18-24 h under a nitrogen atmosphere; more preferably, stirring at 20° C. for 20 h under a nitrogen atmosphere.

8. The preparation method according to any one of claims 2 to 7, characterized in that: After the reaction of step S1 to step S6, a post-treatment step is further included, and the post-treatment includes at least one step of extraction, drying, concentration, recrystallization and purification.

9. An intermediate compound, characterized in that Any of the following structural formulas:

10. Use of the intermediate compound according to claim 9 in the preparation of 2-(4-fluorophenyl)-6-nitro-4-(2,2,2-trifluoroethoxy)-1,2-benzothiazol-3-one.

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