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Method for producing 1,4-benzoxazine compound

A technology of benzoxazine and a manufacturing method, which is applied in the field of 1,4-benzoxazine compounds and can solve problems such as difficulty in reasonably predicting the existence of crystal polymorphisms

Active Publication Date: 2015-04-08
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 a method for producing a 1,4-benzoxazine compound, which is a compound useful as a medicinal agent, in an industrially advantageous manner while avoiding risks with respect to safety and sanitation. Specifically, the present invention provides a method for producing a 1,4-benzoxazine compound [A], comprising three steps illustrated in scheme (1), i.e., a step of converting an amino acid residue located at position-7 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 position-7 in a compound [c] into a monomesylamino group. [In the scheme, Ms represents a methanesulfonyl group; and R' and R" independently represent a hydrogen atom or the like.]

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 Applications(China)
IPC IPC(8): C07D265/36A61K31/538A61P5/40A61P5/42A61P9/00A61P9/12A61P13/12A61P43/00C07B61/00
CPCC07D265/36C07B2200/13A61P3/10A61P5/40A61P5/42A61P7/00A61P7/10A61P9/00A61P9/04A61P9/06A61P9/10A61P9/12A61P9/14A61P13/12A61P43/00
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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