Thiazole carboxamide compounds and their use for treatment of mycobacterial infections
A compound, methoxy technology, applied in the field of thiazole carboxamide compound and its use in the treatment of mycobacterial infection, can solve the problems of drug ineffectiveness, global drug resistance of tuberculosis, etc.
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[0068] The present disclosure is further illustrated by the following examples, which should not be construed to limit the scope or spirit of the disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments and are not thereby intended to limit the scope of the present disclosure. It should be further understood that various other embodiments, modifications and equivalents thereof, which may occur to those skilled in the art, may be resorted to without departing from the spirit of the present disclosure and / or the scope of the appended claims.
[0069] Abbreviations used: ABPR, automatic back pressure regulator; ACN, acetonitrile; aq., aqueous CDI, 1,1'-carbonyldiimidazole; DCM, dichloromethane; DEA, diethylamine; DMF, dimethylformamide ; DMSO, dimethyl sulfoxide; EtOAc, ethyl acetate; EDCI, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide; ESI, electrospray ionization; eq, equivalent; FA , form...
example 1
[0073] Example 1, MPL-020 scheme:
[0074]
[0075] Step 1, Synthesis of (Z)-2-azido-3-(2-methylthiazol-5-yl)prop-2-enoic acid ethyl ester
[0076]
[0077] To a stirred solution of Na (723.15 mg, 31.46 mmol, 745.52 μL, 4 eq) in absolute EtOH (46 mL) at 0 °C was added dropwise 2-methylthiazole-5-carbaldehyde (1 g, 7.86 mmol, 1 eq) and A solution of ethyl 2-azidoacetate (4.06 g, 31.46 mmol, 4.41 mL, 4 eq) in EtOH (50 mL). The reaction was stirred at 0°C for 2 hours. TLC showed that the reaction was complete. The reaction mixture was poured into saturated ammonium chloride solution (30 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed once with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / EtOAc=20 / 1 to 3 / 1) purification. Compound (Z)-ethyl 2-azido-3-(2-methylthiazol-5-yl)prop-2-enoate (780 mg, 3.11 mmol, ...
example 2
[0091] Example 2, MPL-021 scheme:
[0092]
[0093] Step 1, Synthesis of 4H-pyrrolo[2,3-d]thiazole-5-carbonyl chloride
[0094]
[0095] To (COCl) 2(2.90 g, 22.85 mmol, 2 mL, 38.42 eq) in DCM (1 mL) was added DMF (2.17 mg, 29.73 μmol, 2.29 μL, 0.05 eq) and 4H-pyrrolo[2,3-d]thiazole- 5-carboxylic acid (100 mg, 594.63 μmol, 1 eq) (diluted with DCM 1 mL). The mixture was stirred at 25°C for 1.5 hours. LCMS (MeOH 0.5 mL) showed that starting material 1 was consumed and the desired product formed. The mixture was directly concentrated under reduced pressure to give a residue. The residue was used directly in the next step without any purification. The compound 4H-pyrrolo[2,3-d]thiazole-5-carbonyl chloride (100 mg, 428.68 μmol, 72.09% yield, 80% purity) was obtained as a white solid. LCMS(ESI)m / z 182.9[M+H] +
[0096] Step 2, Synthesis of N-(4,4-Dimethylcyclohexyl)-4H-pyrrolo[2,3-d]thiazole-5-carboxamide
[0097]
[0098] To a solution of 4H-pyrrolo[2,3-d]thiazole-...
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