3,4-dimethyl-5-isoxazolamine -Drug Synthesis Database

【结构式】

【分子编号】26891

【品名】3,4-dimethyl-5-isoxazolamine

【CA登记号】19947-75-2

【分子式】C₅H₈N₂O

【分子量】112.1314

【元素组成】C 53.56% H 7.19% N 24.98% O 14.27%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(II)

The intermediate protected sulfonamide (IV) was prepared by condensation of 2-bromobenzenesulfonyl chloride (I) with 5-amino-3,4-dimethylisoxazole (II), followed by protection of the resulting sulfonamide (III) with (2-methoxyethoxy)methyl chloride and NaH.

参考文献中间体

合成目标

【1】 Biphenylsulfonamide endothelin antagonists: Structure-activity relationships of a series of mono- and disubstituted analogues and pharmacology of the orally active endothelin antagonist 2'-amino-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-methylpropyl)[1,1'-biphe. J Med Chem 1998, 41, 26, 5198.
【2】 Murugesan, N.; Hunt, J.T. (Bristol-Myers Squibb Co.); Phenyl sulfonamide and their use as endothelin antagonists. EP 0569193; JP 1994049046; US 5514696 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	40670	2-(chloromethoxy)ethyl methyl ether; 1-(chloromethoxy)-2-methoxyethane; (2-methoxyethoxy)methyl chloride	3970-21-6	C₄H₉ClO₂	详情	详情
(I)	26890	2-bromobenzenesulfonyl chloride	2905-25-1	C₆H₄BrClO₂S	详情	详情
(II)	26891	3,4-dimethyl-5-isoxazolamine	19947-75-2	C₅H₈N₂O	详情	详情
(III)	26892	2-bromo-N-(3,4-dimethyl-5-isoxazolyl)benzenesulfonamide		C₁₁H₁₁BrN₂O₃S	详情	详情
(IV)	26893	2-bromo-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]benzenesulfonamide		C₁₅H₁₉BrN₂O₅S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Coupling between 2-(methoxycarbonyl)-3-thiophenesulfonyl chloride (I) and 5-amino-3,4-dimethylisoxazole (II) afforded the corresponding sulfonamide (III). The sulfonamide NH group of (III) was then protected by reaction with bromomethyl methyl ether to produce the methoxymethyl derivative (IV). Basic hydrolysis of the methyl ester function of (IV), followed by treatment of the resultant carboxylic acid (V) with oxalyl chloride, furnished the acid chloride (VI). This was then coupled with 2'-amino-3',5'-dimethylacetophenone (VII) to yield amide (VIII). The methoxymethyl protecting group of (VIII) was finally removed by acidic treatment to provide the title compound.

参考文献中间体

合成目标

【1】 Blok, N.; Holland, G.W.; Wu, C. (Texas Biotechnology Corp.); Sulfonamides and derivs. thereof that modulate the activity of endothelin. WO 0149685 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	17836	Methyl 3-(chlorosulfonyl)-2-thiophenecarboxylate; Methyl-3-chlorosulfonylthiophene-2-carboxylate		C₆H₅ClO₄S₂	详情	详情
(II)	26891	3,4-dimethyl-5-isoxazolamine	19947-75-2	C₅H₈N₂O	详情	详情
(III)	48185	methyl 3-[[(3,4-dimethyl-5-isoxazolyl)amino]sulfonyl]-2-thiophenecarboxylate		C₁₁H₁₂N₂O₅S₂	详情	详情
(IV)	48186	methyl 3-[[(3,4-dimethyl-5-isoxazolyl)(methoxymethyl)amino]sulfonyl]-2-thiophenecarboxylate		C₁₃H₁₆N₂O₆S₂	详情	详情
(V)	48187	3-[[(3,4-dimethyl-5-isoxazolyl)(methoxymethyl)amino]sulfonyl]-2-thiophenecarboxylic acid		C₁₂H₁₄N₂O₆S₂	详情	详情
(VI)	48188	3-[[(3,4-dimethyl-5-isoxazolyl)(methoxymethyl)amino]sulfonyl]-2-thiophenecarbonyl chloride		C₁₂H₁₃ClN₂O₅S₂	详情	详情
(VII)	47990	1-(2-amino-3,5-dimethylphenyl)-1-ethanone		C₁₀H₁₃NO	详情	详情
(VIII)	48189	N-(2-acetyl-4,6-dimethylphenyl)-3-[[(3,4-dimethyl-5-isoxazolyl)(methoxymethyl)amino]sulfonyl]-2-thiophenecarboxamide		C₂₂H₂₅N₃O₆S₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

Coupling of 2-bromobenzenesulfonyl chloride (I) with 5-amino-3,4-dimethylisoxazole (II) affords sulfonamide (III), which is further protected as the N-methoxyethoxymethyl derivative (IV) employing MEM-chloride in DMF. Lithiation of bromosulfonamide (IV), followed by treatment with trimethyl borate and acidic work up leads to the boronic acid intermediate (V). This is then subjected to Suzuki coupling with 4-bromo-3-methylbenzaldehyde (VI) to yield the biphenyl adduct (VII). After reduction of aldehyde (VII) to the benzylic alcohol (VIII) with NaBH4, reaction with methanesulfonyl chloride and diisopropylethylamine gives rise to the mesylate (IX) (1-3).

参考文献中间体

合成目标

【1】 Tellew, J.E.; Baska, R.A.F.; Beyer, S.M.; Carlson, K.E.; Cornelius, L.A.; Fadnis, L.; Gu, Z..; Kunst, B.L.; Kowala, M.C.; Monshizadegan, H.; Murugesan, N.; Ryan, C.S.; Valentine, M.T.; Yang, Y.; Macor, J.E.; Discovery of 4'-[(Imidazol-1-yl)methyl]biphenyl-2-sulfonamides as dual endothelin/Angiotensin II receptor antagonists. Bioorg Med Chem Lett 2003, 13, 6, 1093.
【2】 Macor, J.E.; Murugesan, N.; Gu, Z.; Tellew, J.E. (Bristol-Myers Squibb Co.); Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists. EP 1094816; JP 2002519380; US 2002143024; WO 0001389 .
【3】 Macor, J.E.; Murugesan, N.; Gu, Z.; Tellew, J.E. (Bristol-Myers Squibb Co.); Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists. EP 1237888; WO 0144239 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	26890	2-bromobenzenesulfonyl chloride	2905-25-1	C₆H₄BrClO₂S	详情	详情
(II)	26891	3,4-dimethyl-5-isoxazolamine	19947-75-2	C₅H₈N₂O	详情	详情
(III)	26892	2-bromo-N-(3,4-dimethyl-5-isoxazolyl)benzenesulfonamide		C₁₁H₁₁BrN₂O₃S	详情	详情
(IV)	26893	2-bromo-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]benzenesulfonamide		C₁₅H₁₉BrN₂O₅S	详情	详情
(V)	60918	2-({(3,4-dimethyl-5-isoxazolyl)[(2-methoxyethoxy)methyl]amino}sulfonyl)phenylboronic acid		C₁₅H₂₁BN₂O₇S	详情	详情
(VI)	64344	4-bromo-3-methylbenzaldehyde		C₈H₇BrO	详情	详情
(VII)	64345	N-(3,4-dimethyl-5-isoxazolyl)-4'-formyl-N-[(2-methoxyethoxy)methyl]-2'-methyl[1,1'-biphenyl]-2-sulfonamide		C₂₃H₂₆N₂O₆S	详情	详情
(VIII)	64346	N-(3,4-dimethyl-5-isoxazolyl)-4'-(hydroxymethyl)-N-[(2-methoxyethoxy)methyl]-2'-methyl[1,1'-biphenyl]-2-sulfonamide		C₂₃H₂₈N₂O₆S	详情	详情
(IX)	64347	[2'-({(3,4-dimethyl-5-isoxazolyl)[(2-methoxyethoxy)methyl]amino}sulfonyl)-2-methyl[1,1'-biphenyl]-4-yl]methyl methanesulfonate		C₂₄H₃₀N₂O₈S₂	详情	详情

Extended Information