1,3-diamino-2-propanol -Drug Synthesis Database

【结构式】

【分子编号】47975

【品名】1,3-diamino-2-propanol

【CA登记号】616-29-5

【分子式】C₃H₁₀N₂O

【分子量】90.12528

【元素组成】C 39.98% H 11.18% N 31.08% O 17.75%

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：

The synthetic pathway is shown in Scheme 19316401a: Treatment of (S)-5-[(2-acetyloxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarbonyldichloride (I) with 2-amino-1,3-propanediol in diglyme yields (S)-3-[(2-acetyloxy-1-oxopropyl)amino]-5-[[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]carbonyl]-2,4,6-triiodobenzenecarbonylchloride (II). Compound (II) is treated with 1,3-diamino-2-propanol to give the dimeric compound [(S)-(R*,R*)]-N,N''-(2-hydroxy-1,3-propanediyl)bis[N'-[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-acetyloxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide] (III). Hydrolysis of compound (III) and desalting of its aqueous solution gives a crude [S-(R*,R*)]-N,N''-(2-hydroxy-1,3-propanediyl)bis[N'-[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide, which is subsequently purified through a bed of adsorbent resin.

参考文献中间体

合成目标

【1】 Heimann, G.; Kollenkirchen, U.; Miklautz, H.; Krause, W.; Physicochemical parameters of X-ray contrast media. Invest Radiol 1994, 29, 72-80.
【2】 Renaa, T.; Jakobsen, T.; Contrast media research. An investment for the future. Acta Radiol 1987, Suppl. 370, 9-11.
【3】 Luzzani, F.L.; Haen, C.; Iofratol. Drugs Fut 1995, 20, 11, 1120.
【4】 Uggeri, F.; Brocchetta, M. (Bracco SpA); 1,3-Bis[3-(mono- or poly-hydroxy)acylamino-5-(mono- or poly-hydroxyalkyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-hydroxy-or hydroxyalkyl-propanes, their methods of preparation and X-ray contrast media containing them. EP 0557345; JP 1994504268; WO 9208691 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	23333	2-amino-1,3-propanediol; serinol	534-03-2	C₃H₉NO₂	详情	详情
	47975	1,3-diamino-2-propanol	616-29-5	C₃H₁₀N₂O	详情	详情
(I)	16006	(1S)-2-[3,5-bis(chlorocarbonyl)-2,4,6-triiodoanilino]-1-methyl-2-oxoethyl acetate		C₁₃H₈Cl₂I₃NO₅	详情	详情
(II)	16007	(1S)-2-[3-(chlorocarbonyl)-5-([[2-hydroxy-1-(hydroxymethyl)ethyl]amino]carbonyl)-2,4,6-triiodoanilino]-1-methyl-2-oxoethyl acetate		C₁₆H₁₆ClI₃N₂O₇	详情	详情
(III)	16008	(1S)-2-[3-[[(3-[[3-[[(2S)-2-(acetoxy)propanoyl]amino]-5-([[2-hydroxy-1-(hydroxymethyl)ethyl]amino]carbonyl)-2,4,6-triiodobenzoyl]amino]-2-hydroxypropyl)amino]carbonyl]-5-([[2-hydroxy-1-(hydroxymethyl)ethyl]amino]carbonyl)-2,4,6-triiodoanilino]-1-methyl-2-oxoethyl acetate		C₃₅H₄₀I₆N₆O₁₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIII)

The condensation of 1,3-diamino-2-propanol (XIII) with carbon disulfide produced 5-hydroxytetrahydropyrimidine-2-thione (XIV). Alkylation of thione (XIV) with iodomethane gave the cyclic S-methylisothiourea (XV), which was further protected as the N-Boc derivative (XVI). 3-Amino-5-hydroxybenzoic acid (XVIII) was prepared from 3,5-dihydroxybenzoic acid (XVII) by treatment with ammonia and ammonium chloride. Coupling of thioether (XVI) with amino acid (XVIII) in hot DMA furnished the guanidine adduct (XIX). This was then condensed with the intermediate (XII) via activation as the mixed anhydride with isobutyl chloroformate, producing amide (XX). Acid cleavage of the Boc group of (XX) gave (XXI). The ethyl ester of (XXI) was then hydrolyzed using NaOH in aqueous dioxan. The title compound was finally isolated as the hydrochloride salt after lyophilization from an HCl solution.

参考文献中间体

合成目标

【2】 Ruminski, P.G.; Rogers, T.E. (Pharmacia Corp.); Meta-azacyclic amino benzoic acid cpds. and derivs. thereof being integrin antagonists. EP 1060164; WO 9944994 .
【3】 Gordon, G.B.; Ruminski, P.G.; Nickols, G.A.; Westlin, W.F.; Rogers, T.E.; Cunningham, J. (Pharmacia Corp.); Use of integrin antagonist and a chemotherapeutic agent in the treatment of neoplasia. WO 0051686 .
【1】 Ruminski, P.G.; Clare, M.; Collins, P.W.; Desai, B.N.; Lindmark, R.J.; Rico, J.G.; Rogers, T.E.; Russell, M.A. (Pharmacia Corp.); Meta-guanidine, urea, thiourea or azacyclic amino benzoic acid derivs. as integrin antagonists. EP 0850221; JP 1999510814; US 6013651; WO 9708145 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XII)	47974	ethyl (3S)-3-[(2-aminoacetyl)amino]-3-(3,5-dichloro-2-hydroxyphenyl)propanoate		C₁₃H₁₆Cl₂N₂O₄	详情	详情
(XIII)	47975	1,3-diamino-2-propanol	616-29-5	C₃H₁₀N₂O	详情	详情
(XIV)	47976	5-hydroxytetrahydro-2(1H)-pyrimidinethione		C₄H₈N₂OS	详情	详情
(XV)	47977	2-(methylsulfanyl)-1,4,5,6-tetrahydro-5-pyrimidinol		C₅H₁₀N₂OS	详情	详情
(XVI)	47978	tert-butyl 5-hydroxy-2-(methylsulfanyl)-5,6-dihydro-1(4H)-pyrimidinecarboxylate		C₁₀H₁₈N₂O₃S	详情	详情
(XVII)	16230	resorcylic acid; 3,5-dihydroxybenzoic acid	99-10-5	C₇H₆O₄	详情	详情
(XVIII)	47979	3-amino-5-hydroxybenzoic acid		C₇H₇NO₃	详情	详情
(XIX)	47980	3-[[1-(tert-butoxycarbonyl)-5-hydroxy-1,4,5,6-tetrahydro-2-pyrimidinyl]amino]-5-hydroxybenzoic acid		C₁₆H₂₁N₃O₆	详情	详情
(XX)	47981	tert-butyl 2-(3-[[(2-[[(1S)-1-(3,5-dichloro-2-hydroxyphenyl)-3-ethoxy-3-oxopropyl]amino]-2-oxoethyl)amino]carbonyl]-5-hydroxyanilino)-5-hydroxy-5,6-dihydro-1(4H)-pyrimidinecarboxylate		C₂₉H₃₅Cl₂N₅O₉	详情	详情
(XXI)	47982	ethyl (3S)-3-(3,5-dichloro-2-hydroxyphenyl)-3-[[2-([3-hydroxy-5-[(5-hydroxy-1,4,5,6-tetrahydro-2-pyrimidinyl)amino]benzoyl]amino)acetyl]amino]propanoate		C₂₄H₂₇Cl₂N₅O₇	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XV)

5-Aminonicotinic acid (XII) is condensed with benzoyl isothiocyanate to form the benzoyl thiourea (XIII). Removal of the benzoyl group of (XIII) with NaOMe in MeOH, followed by alkylation with iodomethane, furnishes the S-methyl isothiourea (XIV). This is then condensed with 1,3-diamino-2-propanol (XV) in hot DMF, producing the tetrahydropyrimidine derivative (XVI). The carboxyl group of (XVI) is then activated as the mixed anhydride (XVII) employing isobutyl chloroformate and NMM. Coupling between anhydride (XVII) and amine (XI) in the presence of NMM leads to the diamide (XVIII). The ethyl ester group of (XVIII) is finally hydrolyzed by means of LiOH to the corresponding carboxylic acid.

参考文献中间体

合成目标

【1】 Miyashiro, J.M.; Gasiecki, A.F.; Khanna, I.K.; Chandrakumar, N.S.; Desai, B.N.; Russell, M.A.; Devadas, B.; Rico, J.G.; Rogers, T.E.; Rao, S.N.; Malecha, J.W.; Ruminski, P.G.; Yu, Y.; Huff, R. (Pfizer Inc.); Heterocyclic glycyl beta-alanine derivs. as vitronectin antagonists. EP 1070060; JP 2002511462; WO 9952896 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	47974	ethyl (3S)-3-[(2-aminoacetyl)amino]-3-(3,5-dichloro-2-hydroxyphenyl)propanoate		C₁₃H₁₆Cl₂N₂O₄	详情	详情
(XII)	65053	5-aminonicotinic acid		C₆H₆N₂O₂	详情	详情
(XIII)	65054	5-{[(benzoylamino)carbothioyl]amino}nicotinic acid		C₁₄H₁₁N₃O₃S	详情	详情
(XIV)	65055	5-{[imino(methylsulfanyl)methyl]amino}nicotinic acid		C₈H₉N₃O₂S	详情	详情
(XV)	47975	1,3-diamino-2-propanol	616-29-5	C₃H₁₀N₂O	详情	详情
(XVI)	65056	5-[(5-hydroxy-1,4,5,6-tetrahydro-2-pyrimidinyl)amino]nicotinic acid		C₁₀H₁₂N₄O₃	详情	详情
(XVII)	65057			C₁₅H₂₀N₄O₅	详情	详情
(XVIII)	65058	ethyl (3S)-3-(3,5-dichloro-2-hydroxyphenyl)-3-({2-[({5-[(5-hydroxy-1,4,5,6-tetrahydro-2-pyrimidinyl)amino]-3-pyridinyl}carbonyl)amino]acetyl}amino)propanoate		C₂₃H₂₆Cl₂N₆O₆	详情	详情

Extended Information