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AssigneeMitsubishi Tanabe Pharma Corporation
InventorsTomoyuki Okabe, Takeshi Hamada, Kaori Tomikawa, Yukie Okamoto, Toru Iijima, Hidenori Akatsuka, Kenichi Toyama, Atsushi Moroda, Yoshihiro Sugiura
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The present invention provides an industrially advantageous method for producing a 1,4-benzoxazine compound useful as a medicine while avoiding safety and health risks. Specifically, the present invention provides a method for producing a 1,4-benzoxazine compound [A], which comprises the three steps in the following scheme, namely, a step of converting the amino group at 7-position in a compound [a] into a dimesylamino group, a step of coupling a compound [b] with a boronic acid compound, and a step of converting the 7-position in a compound [c] into a monomesylamino group. In the above scheme, Ms is a methanesulfonyl group, and each of R′ and R″ is a hydrogen atom etc.
A method for producing a 1,4-benzoxazine compound of the following formula [A]:
A method for producing a compound of the following formula [A]:
A crystal (Form A crystal) of N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide, which has at least one diffraction peak at 6.7° to 11.0° , and has diffraction peaks at 18.1° and 23.7° as the diffraction angle)(2θ±0.2°) in the X-ray powder diffraction.
A crystal (Form B crystal) of N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide, which has at least one diffraction peak at 6.7° to 11.0° , and has diffraction peaks at 14.8° and 18.3° as the diffraction angle)(2θ±0.2°) in the X-ray powder diffraction.
A crystal (Form C crystal) of a dimethylsulfoxide monosolvate of N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide, which has diffraction peaks at 19.3° and 29.6° as the diffraction angle)(2θ±0.2°) in the X-ray powder diffraction.
A method for producing a Form A crystal of N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide having at least one diffraction peak at 6.7° to 11.0° , and having diffraction peaks at 18.1° and 23.7° as the diffraction angle)(2θ±0.2°) in the X-ray powder diffraction, which comprises the step of heating a crystal (Form D crystal) of N[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide having no diffraction peak at 6.7° to 11.0° , but having diffraction peaks at 6.0° , 11.9° , 17.0° , 17.6° and 19.0° as the diffraction angle)(2θ±0.2°), or a crystal (Form B crystal) of N[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide having at least one diffraction peak at 6.7° to 11.0° , and having diffraction peaks at 14.8° and 18.3° as the diffraction angle)(2θ±0.2°) in the X-ray powder diffraction in a liquid medium or in the absence of a medium.
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