RWJ-69442, -Drug Synthesis Database

【结构式】

【药物名称】RWJ-69442

【化学名称】2-[4-(Dimethylamino)phenyl]-N-[2(S)-hydroxy-3-[4-(2-isopropoxyphenyl)piperazin-1-yl]propyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxamide

【CA登记号】239807-61-5

【分子式】C₃₃H₃₉N₅O₅

【分子量】585.70928

【开发单位】Ortho-McNeil (Originator)

【药理作用】Benign Prostatic Hyperplasia Therapy, RENAL-UROLOGIC DRUGS, alpha1A-Adrenoceptor Antagonists

合成路线1 合成路线2 合成路线3

合成路线1

Alkylation of 1-(2-isopropoxyphenyl)piperazine (I) with 1-azido-3-(p-toluenesulfonyloxy)-2-propanol (II) in hot NMP gave (III). Subsequent hydrogenation of the azido group of (III) over Pd/C provided the intermediate amine (IV).

参考文献中间体

【1】 Prouty, C.; Wang, J.; Kuo, G.-H.; Pulito, V.; Murray, W.V.; Cheung, P.; Jolliffe, L.; Varga, S.; Evangelisto, M.; Design, synthesis, and structure-activity relationships of phthalimide-phenylpiperazines: A novel series of potent and selective alpha1a-adrenergic receptor antagonists. J Med Chem 2000, 43, 11, 2183.
【2】 Murray, W.V.; Kuo, G.-H.; Prouty, C.P. (Ortho-McNeil Pharmaceutical, Inc.); Phthalimido arylpiperazines as alpha 1a receptor antagonists useful in the treatment of benign prostatic hyperplasia. US 6063785; WO 9942445 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	35066	isopropyl 2-(1-piperazinyl)phenyl ether; 1-(2-isopropoxyphenyl)piperazine	C₁₃H₂₀N₂O	详情	详情
(II)	35067	(2S)-3-azido-2-hydroxypropyl 4-methylbenzenesulfonate	C₁₀H₁₃N₃O₄S	详情	详情
(III)	35068	(2R)-1-azido-3-[4-(2-isopropoxyphenyl)-1-piperazinyl]-2-propanol	C₁₆H₂₅N₅O₂	详情	详情
(IV)	35069	(2S)-1-amino-3-[4-(2-isopropoxyphenyl)-1-piperazinyl]-2-propanol	C₁₆H₂₇N₃O₂	详情	详情

合成路线2

(S)-Epichlorhydrin (V) was treated with benzylamine to afford aminoalcohol (VI). After protection of the amino group of (VI) as the tert-butyl carbamate (VII) with Boc2O, displacement of the chlorine of (VII) with arylpiperazine (I) furnished (VIII). Deprotection of the N-Boc group of (VIII) by means of trifluoroacetic acid gave (IX). Then, the N-benzyl group of (IX) was removed by transfer hydrogenolysis employing ammonium formate and Pd/C to provide the intermediate amine (IV).

参考文献中间体

【1】 Prouty, C.; Wang, J.; Kuo, G.-H.; Pulito, V.; Murray, W.V.; Cheung, P.; Jolliffe, L.; Varga, S.; Evangelisto, M.; Design, synthesis, and structure-activity relationships of phthalimide-phenylpiperazines: A novel series of potent and selective alpha1a-adrenergic receptor antagonists. J Med Chem 2000, 43, 11, 2183.
【2】 Murray, W.V.; Kuo, G.-H.; Prouty, C.P. (Ortho-McNeil Pharmaceutical, Inc.); Phthalimido arylpiperazines as alpha 1a receptor antagonists useful in the treatment of benign prostatic hyperplasia. US 6063785; WO 9942445 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	15147	Benzylamine; Phenylmethanamine	100-46-9	C₇H₉N	详情	详情
(I)	35066	isopropyl 2-(1-piperazinyl)phenyl ether; 1-(2-isopropoxyphenyl)piperazine		C₁₃H₂₀N₂O	详情	详情
(IV)	35069	(2S)-1-amino-3-[4-(2-isopropoxyphenyl)-1-piperazinyl]-2-propanol		C₁₆H₂₇N₃O₂	详情	详情
(V)	13917	(S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin	67843-74-7	C₃H₅ClO	详情	详情
(VI)	35070	(2S)-1-(benzylamino)-3-chloro-2-propanol		C₁₀H₁₄ClNO	详情	详情
(VII)	35071	tert-butyl benzyl[(2S)-3-chloro-2-hydroxypropyl]carbamate		C₁₅H₂₂ClNO₃	详情	详情
(VIII)	35072	tert-butyl benzyl[(2R)-2-hydroxy-3-[4-(2-isopropoxyphenyl)-1-piperazinyl]propyl]carbamate		C₂₈H₄₁N₃O₄	详情	详情
(IX)	35073	(2S)-1-(benzylamino)-3-[4-(2-isopropoxyphenyl)-1-piperazinyl]-2-propanol		C₂₃H₃₃N₃O₂	详情	详情

合成路线3

Condensation of 1,2,4-benzenetricarboxylic anhydride (X) with N,N-dimethyl-p-phenylenediamine (XI) in boiling AcOH produced phthalimide (XII). The title amide was then obtained by coupling of acid (XII) with amine (IV) in the presence of HATU, or EDC, HOBt and DMAP in dichloromethane.

参考文献中间体

【1】 Prouty, C.; Wang, J.; Kuo, G.-H.; Pulito, V.; Murray, W.V.; Cheung, P.; Jolliffe, L.; Varga, S.; Evangelisto, M.; Design, synthesis, and structure-activity relationships of phthalimide-phenylpiperazines: A novel series of potent and selective alpha1a-adrenergic receptor antagonists. J Med Chem 2000, 43, 11, 2183.
【2】 Murray, W.V.; Kuo, G.-H.; Prouty, C.P. (Ortho-McNeil Pharmaceutical, Inc.); Phthalimido arylpiperazines as alpha 1a receptor antagonists useful in the treatment of benign prostatic hyperplasia. US 6063785; WO 9942445 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	35069	(2S)-1-amino-3-[4-(2-isopropoxyphenyl)-1-piperazinyl]-2-propanol		C₁₆H₂₇N₃O₂	详情	详情
(X)	35074	1,3-dioxo-1,3-dihydro-2-benzofuran-5-carboxylic acid	552-30-7	C₉H₄O₅	详情	详情
(XI)	35075	N-(4-aminophenyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,4-benzenediamine	6219-73-4	C₈H₁₂N₂	详情	详情
(XII)	35076	2-[4-(dimethylamino)phenyl]-1,3-dioxo-5-isoindolinecarboxylic acid		C₁₇H₁₄N₂O₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)