Benzothiazinone derivative, preparation method thereof and application of benzothiazinone derivative as antituberculosis drug
A technology of benzothiazinone and derivatives is applied in the fields of benzothiazinone derivatives and their preparation and application as anti-tuberculosis drugs, can solve problems such as poor drugability and the like, and achieves low cLogP value, good drugability, The effect of excellent inhibitory effect
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[0027] The preparation method of benzothiazinone derivative of the present invention is as follows:
[0028] (1) Compound A5 is reacted with an amine compound to obtain a benzothiazinone derivative;
[0029] (2) Reducing the benzothiazinone derivative prepared in step (1) to obtain compound A7; compound A7 undergoes a substitution reaction to obtain a benzothiazinone derivative.
[0030] Further, compound A3 is chlorinated to obtain acid chloride A4; compound A4 is reacted with isothiocyanate to obtain compound A5; A4 to A6 are one-pot reactions.
[0031] Specifically, the preparation of each compound of the present invention can refer to the following schematic route:
[0032]
[0033] The chemical structural formula of the amine compound is as follows:
[0034]
[0035] Wherein, the definition of the substituent is the same as above.
[0036] More specifically, the above reaction pathway can be exemplified as follows:
[0037] The steps of A1→A3 are: compound A1 is...
Embodiment 1
[0042] Example 1 Compound 1: 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(methylsulfonyl)-8-nitro-4 H -Benzo[ e ][1,3]thiazin-4-one
[0043]
[0044] Dissolve ammonium thiocyanate (46 mg, 1.2 eq.) in 5 mL of anhydrous acetone, add polyethylene glycol (0.05 eq., based on compound A3) dropwise, and stir until dissolved at room temperature to obtain isothiocyanate ammonium acid solution;
[0045] Compound A3 (50 mg, 1eq. , R 3 is methyl) dissolved in dichloromethane (anhydrous) (5 mL), dropwise N, N - Dimethylformamide (0.05eq., based on compound A3), add dropwise oxalyl chloride (0.25 mL, 2.5eq.), stir at room temperature for 0.5 hours after the addition is complete, spin dry the solvent and excess oxalyl chloride to obtain the corresponding intermediate acid chloride compound (compound A4, R 3 is methyl); then dropwise add the above-mentioned ammonium isothiocyanate solution, stir at room temperature for 20 minutes after the dropwise addition is completed, and the reactio...
Embodiment 2
[0047] Example 2 Compound 3: 2-(3-(methoxyimino)azetidin-1-yl)-6-(methylsulfonyl)-8-nitro-4 H -Benzo[ e ][1,3]thiazin-4-one
[0048]
[0049] The operation was the same as in Example 1, except that the amine used was azetidine-3-oxo-methyloxime, and the rest remained unchanged to obtain compound 3 as a white solid (yield 46%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.34 (s, 1H), 9.08 (s, 1H), 5.05 – 5.04 (m, 4H), 3.93 (s, 3H), 3.19 (s, 3H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 165.3, 162.0, 146.0, 144.1, 139.8, 135.6, 134.3, 128.3, 126.1, 62.5, 60.2, 43.52. MS-ESI (m / z): 384.6 [M+H] + .
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