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Method for producing 1,4-benzoxazine compound

A manufacturing method and technology of benzoxazine, which are applied in the directions of organic chemistry methods, medical preparations containing active ingredients, drug combinations, etc., can solve problems such as difficulty in reasonably predicting the existence of crystal polymorphisms

Active Publication Date: 2016-05-25
MITSUBISHI TANABE PHARMA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it is difficult to reasonably predict the existence of crystals and polymorphs for a given compound

Method used

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  • Method for producing 1,4-benzoxazine compound
  • Method for producing 1,4-benzoxazine compound
  • Method for producing 1,4-benzoxazine compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0160] (1) N-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-N-(methylsulfonyl) Manufacture of methanesulfonamide

[0161] [chemical formula 24]

[0162]

[0163] To a suspension of 7-amino-2,2-dimethyl-2H-1,4-benzoxazin-3-(4H)-one (150 g) in acetonitrile (1500 mL) was added dropwise triethylamine at 40 °C (79 g), and methanesulfonyl chloride (89.4 g) was added dropwise to the mixture (internal temperature: 39 to 50° C.), followed by stirring at this temperature for 20 minutes. After adding triethylamine (79 g) and methanesulfonyl chloride (89.4 g) dropwise to the reaction mixture in this order (inner temperature 42-50 degreeC), it stirred at this temperature for 25 minutes. Triethylamine (39.5 g) and methanesulfonyl chloride (44.7 g) were further added dropwise to the reaction mixture in this order (internal temperature: 42 to 47° C.), followed by stirring at 40° C. for 4 hours. Water (1500 mL) was added dropwise to the reaction mixture, and after stirring the m...

Embodiment 2

[0176] N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonate Production of amides

[0177] [chemical formula 27]

[0178]

[0179] To N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]- A suspension of N-(methylsulfonyl)methanesulfonamide (1 g) in acetone (3 mL) was added dropwise with aqueous sodium hydroxide solution (0.18 g / 3 mL) at 25°C, and the mixture was stirred at that temperature for 90 minutes. Concentrated hydrochloric acid / acetone / water (0.24 g / 0.5 mL / 0.35 mL) was added dropwise to the reaction mixture at 25° C., and the mixture was stirred for 2 hours. The precipitated crystals were collected by filtration, washed with acetone / water (1:1.6mL) solution, and dried under reduced pressure at 50°C to obtain the title compound (0.79g) as Form A crystals (yield: 95%, purity: 100 %).

[0180] M.p.: 240°C.

Embodiment 3

[0182] N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonate Production of amides

[0183] [chemical formula 28]

[0184]

[0185] To N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]- After the suspension of N-(methylsulfonyl)methanesulfonamide (1g) in dimethylsulfoxide (3mL) was added dropwise at 25°C in aqueous sodium hydroxide solution (0.18g / 3mL), dimethylsulfoxide / water (1:1.2 mL), and the mixture was stirred overnight at this temperature. Concentrated hydrochloric acid / dimethylsulfoxide / water (0.24g / 0.5mL / 0.35mL) was added dropwise to the reaction mixture at 25°C, the mixture was stirred for 5 hours, the precipitated crystals were collected by filtration, and dimethylsulfoxide / After washing with water (1:1.6 mL) solution and 10 mL of water, and drying under reduced pressure at 50°C, the title compound (0.81 g) was obtained as Form A crystal (yield: 98%, purity: 100%)

[0186] M.p.: 240°C.

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Abstract

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.

Description

technical field [0001] The present invention relates to a novel production method of a 1,4-benzoxazine compound which has an aldosterone receptor antagonistic action and is useful as a drug such as an antihypertensive agent or a diuretic. Background technique [0002] According to recent studies on aldosterone, the hormone is produced in various organs other than the adrenal gland, such as the heart, blood vessels, or brain, and its receptors are also widely distributed outside the tissues of the cardiovascular system. In addition, aldosterone has been recognized as a dangerous hormone that exhibits various disturbing effects on cardiovascular tissues in addition to being an aggravating factor of hypertension. Under such circumstances, aldosterone receptor antagonists are expected to play a role in the establishment of effective therapeutic methods for cardiovascular system diseases due to recent large-scale clinical trials showing positive effects on severe heart failure or...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D265/36A61K31/538A61P5/40A61P5/42A61P9/00A61P9/12A61P13/12A61P43/00C07B61/00
CPCC07B2200/13C07D265/36A61P3/10A61P5/40A61P5/42A61P7/00A61P7/10A61P9/00A61P9/04A61P9/06A61P9/10A61P9/12A61P9/14A61P13/12A61P43/00
Inventor 冈部智之滨田刚富川香冈本由纪惠饭岛彻赤塚英则外山健一诸田敦杉浦良洋
Owner MITSUBISHI TANABE PHARMA CORP
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