# US 9,751,846 B2 · Method for producing 1,4-benzoxazine compound

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- Number: US 9,751,846 B2
- Document ID: US9751846B2
- Status: Granted
- Kind: B2
- Application number: 15/205,922
- Filed: 2016-07-08
- Published: 2016-12-15
- Granted: 2017-09-05
- Earliest claimed: 2012-08-08
- Assignees: Mitsubishi Tanabe Pharma Corporation
- Applicants: Mitsubishi Tanabe Pharma Corporation
- Inventors: Tomoyuki Okabe; Takeshi Hamada; Kaori Tomikawa; Yukie Okamoto; Toru Iijima; Hidenori Akatsuka; Kenichi Toyama; Atsushi Moroda; Yoshihiro Sugiura
- Web page: https://patentgrep.com/patent/US9751846B2

## CPC

- C07D 265/36: condensed with one six-membered ring
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/40: Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
- A61P 5/42: for decreasing, blocking or antagonising the activity of mineralocorticosteroids
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/10: Antioedematous agents; Diuretics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/06: Antiarrhythmics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 9/14: Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
- A61P 13/12: of the kidneys
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## 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.

## Claims

### Claim 1

A method for producing a 1,4-benzoxazine compound of the following formula [A]:
which comprises the following steps of:
(step a) reacting a compound of the following formula [a]:
with methanesulfonyl halide in the presence of a base to produce a compound of the following formula [b]:
wherein Ms is a methanesulfonyl group,
(step b) reacting said compound [b] with a boronic acid compound of the following formula [d]:
wherein R and R′ are the same or different and each of them is a hydrogen atom or an alkyl group, or both of them combine together to form an alkylene group,
or an equivalent thereof, in the presence of a copper catalyst, in the presence or absence of a base, and in the presence or absence of a ligand to produce a compound of the following formula [c]:
wherein the symbol is the same as defined above,
and
(step c) converting the substituent at 7-position (dimesylamino group) in said compound [c] into a monomesylamino group to produce the compound of the above formula [A].

### Claim 2 (depends on 1)

The method according to claim 1, wherein the methanesulfonyl halide is methanesulfonyl chloride.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the compound [d] is a compound of the following formula:
or an equivalent thereof.

### Claim 4 (depends on 1)

The method according to claim 1, characterized in that
the step a is carried out in a solvent selected from the group consisting of acetonitrile, methyl ethyl ketone, ethyl acetate, tetrahydrofuran and acetone, and in the presence of a base selected from triethylamine, tetramethylethylenediamine and 1,8-diazabicyclo[5.4.0]undec-7-ene,
the step b is carried out in a solvent selected from dimethylsulfoxide and N,N-dimethylacetamide, in the presence of a copper catalyst selected from the group consisting of copper acetate, copper halide, copper nitrate and a copper salt of trifluoromethanesulfonic acid, in the presence or absence of one or more bases selected from triethylamine, diisopropylethylamine, tributylamine, tripropylamine, trioctylamine, dimethylbenzylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, N-ethylmorpholine, N-methylmorpholine, sodium hydrogen carbonate and an aqueous ammonia, in the presence or absence of one or more ligands selected from dimethylaminopyridine, 2-aminopyridine, 4-methylpyridine, 2,6-dimethylpyridine, 3,5-dimethylpyridine, pyridine, N-methylimidazole, N-butylimidazole and pyrazine, and under oxygen supply to the reaction system, and
the step c is carried out in a solvent selected from ethanol, isopropanol, n-propanol, acetone, methyl ethyl ketone and dimethylsulfoxide or a mixture of said solvent and water, and in the presence of a base selected from potassium carbonate and sodium hydroxide.

### Claim 5

A method for producing a compound of the following formula [A]:
which comprises the step of converting the substituent at 7-position (dimesylamino group) in a compound of the following formula [c]:
wherein Ms is a methanesulfonyl group,
into a monomesylamino group.

### Claim 6 (depends on 5)

The method according to claim 5, characterized in that the conversion of the substituent at 7-position (dimesylamino group) into the monomesylamino group is carried out in a solvent selected from ethanol, isopropanol, n-propanol, acetone, methyl ethyl ketone and dimethylsulfoxide or a mixture of said solvent and water, and in the presence of a base selected from potassium carbonate and sodium hydroxide.

### Claim 7

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.

### Claim 8 (depends on 7)

The crystal of N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide according to claim 7, which has an additional diffraction peak at 10.2° as the diffraction angle (2θ±0.2°).

### Claim 9

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.

### Claim 10 (depends on 9)

The crystal of N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide according to claim 9, which has additional diffraction peaks at 10.8° and 23.2° as the diffraction angle)(2θ±0.2°).

### Claim 11

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.

### Claim 12 (depends on 11)

The crystal of the dimethylsulfoxide monosolvate of N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane sulfonamide according to claim 11, which has an additional diffraction peak at 11.3° as the diffraction angle)(2θ±0.2°).

### Claim 13 (depends on 7)

A pharmaceutical composition comprising the crystal of N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide or a dimethylsulfoxide monosolvate thereof according to claim 7 and a pharmacologically acceptable carrier.

### Claim 14 (depends on 13)

A method for treating various diseases or disease states caused by enhanced MR activity and/or elevated aldosterone level, comprising:
administering the pharmaceutical composition according to claim 13 to a patient in need thereof.

### Claim 15 (depends on 13)

A method for treating hypertension, heart failure, myocardial infarction, angina, cardiac hypertrophy, myocarditis, myocardial/vascular fibrosis, baroreceptor dysfunction, volume overload or arrhythmia, comprising:
administering the pharmaceutical composition according to claim 13 to a patient in need thereof.

### Claim 16 (depends on 13)

A method for treating primary/secondary aldosteronism, Addison's disease, Cushing's syndrome or Bartter's syndrome, comprising:
administering the pharmaceutical composition according to claim 13 to a patient in need thereof.

### Claim 17 (depends on 13)

A method for treating a renal disease, comprising:
administering the pharmaceutical composition according to claim 13 to a patient in need thereof.

### Claim 18 (depends on 17)

The method according to claim 17, wherein the renal disease is diabetic nephropathy.

### Claim 19

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.

### Claim 20 (depends on 19)

The method for producing the Form A crystal of N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide according to claim 19, characterized by heating the Form B crystal in ethanol as the liquid medium at 75° C. to 85° C.