5-bromo-2-pyrimidinamine; 5-bromo-2-pyrimidinylamine -Drug Synthesis Database

【结构式】

【分子编号】34822

【品名】5-bromo-2-pyrimidinamine; 5-bromo-2-pyrimidinylamine

【CA登记号】7752-82-1

【分子式】C₄H₄BrN₃

【分子量】173.99998

【元素组成】C 27.61% H 2.32% Br 45.92% N 24.15%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VIII)

3-Cyanobenzaldehyde (I) was converted to oxime (II) by reaction with hydroxylamine in pyridine. The intermediate nitrile oxide, generated from chlorination and further elimination of HCl, underwent a [2+3] cycloaddition with itaconic acid monomethyl ester (III) to produce the isoxazoline (IV). The carboxylate group of (IV) was then activated as the corresponding acid chloride (V) upon treatment with SOCl2. Boronic acid (VII) was prepared from N-tert-butyl benzenesulfonamide (VI) by lithiation with n-butyllithium, followed by reaction with triisopropyl borate and quenching with HCl. Subsequent Suzuki coupling of (VII) with 2-amino-5-bromopyrimidine (VIII) using Pd(PPh3)4 and Na2CO3 afforded the 2-amino-4-arylpyrimidine (IX). Condensation of amine (IX) with acid chloride (V) in the presence of Et3N gave amide (X). The N-tert-butyl group of (X) was then deprotected by means of trifluoroacetic acid to yield (XI) as the trifluoroacetate salt. The cyano group of (XI) was converted to imidate (XII) with HCl and MeOH. This was finally reacted with ammonium acetate in MeOH to furnish the title amidine.

参考文献中间体

合成目标

【1】 Quan, M.L.; Liauw, A.Y.; Ellis, C.D.; et al.; Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 1. J Med Chem 1999, 42, 15, 2752.
【2】 Quan, M.L.; Wityak, J.; Galemmo, R.A. Jr.; Stouten, P.F.W.; Pruitt, J.R. (DuPont Pharmaceuticals Co.); Isoxazoline, isothiazoline and pyrazoline factor Xa inhibitors. EP 0874629; US 5939418; WO 9723212 .

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)	13245	3-Formylbenzonitrile; 3-Cyanobenzaldehyde	24964-64-5	C₈H₅NO	详情	详情
(II)	23357	3-[(hydroxyimino)methyl]benzonitrile		C₈H₆N₂O	详情	详情
(III)	34820	2-(2-methoxy-2-oxoethyl)acrylic acid	7338-27-4	C₆H₈O₄	详情	详情
(IV)	26630	3-(3-cyanophenyl)-5-(2-methoxy-2-oxoethyl)-4,5-dihydro-5-isoxazolecarboxylic acid		C₁₄H₁₂N₂O₅	详情	详情
(V)	34821	methyl 2-[5-(chlorocarbonyl)-3-(3-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate		C₁₄H₁₁ClN₂O₄	详情	详情
(VI)	26626	N-(tert-butyl)benzenesulfonamide		C₁₀H₁₅NO₂S	详情	详情
(VII)	26627	2-[(tert-butylamino)sulfonyl]phenylboronic acid		C₁₀H₁₆BNO₄S	详情	详情
(VIII)	34822	5-bromo-2-pyrimidinamine; 5-bromo-2-pyrimidinylamine	7752-82-1	C₄H₄BrN₃	详情	详情
(IX)	34823	2-(2-amino-5-pyrimidinyl)-N-(tert-butyl)benzenesulfonamide		C₁₄H₁₈N₄O₂S	详情	详情
(X)	34824	methyl 2-[5-[[(5-[2-[(tert-butylamino)sulfonyl]phenyl]-2-pyrimidinyl)amino]carbonyl]-3-(3-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate		C₂₈H₂₈N₆O₆S	详情	详情
(XI)	34825	methyl 2-[5-[([5-[2-(aminosulfonyl)phenyl]-2-pyrimidinyl]amino)carbonyl]-3-(3-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate		C₂₄H₂₀N₆O₆S	详情	详情
(XII)	34826	methyl 2-(5-[([5-[2-(aminosulfonyl)phenyl]-2-pyrimidinyl]amino)carbonyl]-3-[3-[imino(methoxy)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetate		C₂₅H₂₄N₆O₇S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XVI)

The key intermediate (XIII) is prepared by N-protection of 5-bromopyrimidin-2-amine (XVI) with Boc2o by means of DMAP in DMF to give N,N-di-Boc-5-bromopyrimidin-2-amine (XVII), which by metalation with BuLi in THF, followed by borylation with (i-Pro)3B provides the pyrimidin-5-ylboronic acid derivative (XVIII). Hydrolysis of protected amine (XVIII) with methanolic HCl affords 2-aminopyrimidin-5-ylboronic acid (IV), which is finally cyclized with pinacol (XX) in refluxing toluene or xylene .

参考文献中间体

合成目标

【1】 Xu, J., Lai, W., Yang, B., Gu, S. (Jiangsu ChemFuture Pharma Tech. Co., Ltd.). Synthesis method of 2-amino-5-pyridineboronic acid pinacol ester. Cn 102399235

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIII)	68102	5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine	402960-38-7	C₁₀H₁₆BN₃O₂	详情	详情
(XVI)	34822	5-bromo-2-pyrimidinamine; 5-bromo-2-pyrimidinylamine	7752-82-1	C₄H₄BrN₃	详情	详情
(XVII)	68105	N,N-di-Boc-5-bromopyrimidin-2-amine;Imidodicarbonicacid, 2-(5-bromo-2-pyrimidinyl)-, 1,3-bis(1,1-dimethylethyl) ester;Imidodicarbonicacid, (5-bromo-2-pyrimidinyl)-, bis(1,1-dimethylethyl) ester (9CI);(5-Bromopyrimidin-2-yl)bis(tert-butoxycarbonyl)amine	209959-33-1	C₁₄H₂₀BrN₃O₄	详情	详情
(XVIII)	68106			C₁₄H₂₂BN₃O₆	详情	详情
(XIX)	68107	(2-aminopyrimidin-5-yl)boronic acid		C₄H₆BN₃O₂	详情	详情
(XX)	68108	2,3-Dimethyl-2,3-butanediol;2,3-Dimethylbutane-2,3-diol;Tetramethylethylene glycol;pinacol	76-09-5	C₆H₁₄O₂	详情	详情

Extended Information