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【结 构 式】 
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【分子编号】23333 【品名】2-amino-1,3-propanediol; serinol 【CA登记号】534-03-2 |
【 分 子 式 】C3H9NO2 【 分 子 量 】91.11 【元素组成】C 39.55% H 9.96% N 15.37% O 35.12% |
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.
| 【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：(I)Serinol (I) was protected with triphenylmethyl chloride giving the N-trityl derivative (II), which was O-methylated using CH3I and NaH to afford the bis(methyl ether) (III). Subsequent acid deprotection of the trityl group of (III) provided 1,3-dimethoxy-2-aminopropane (IV). The hydroxypyridone (V) was converted to the salt with cyclohexylamine (VI), and then treated with phosphoryl chloride to produce the 4-chloropyridone (VII), which was condensed with amine (IV) to yield the aminopyridone (VIII). Further treatment of (VIII) with phosphoryl chloride gave 2-chloropyridine (IX). The nitro group of (IX) was then reduced with iron powder and AcOH, and the resulting diamino pyridine (X) was treated with NaNO2 and AcOH to produce the triazolopyridine (XI). Finally, coupling of (XI) with 2-chloro-4,6-dimethylaniline (XII) in the presence of p-TsOH provided the title compound, which was isolated as the mesylate salt.
| 【1】 Bakthavatchalam, R.; Arvanitis, A.G.; Beck, J.P.; Cain, G.A.; Chorvat, R.J.; Gilligan, P.J.; Olson, R.E. (DuPont Pharmaceuticals Co.); Arylamino fused pyridines and pyrimidines. EP 0935601; WO 9735539 . |
| 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) | 23333 | 2-amino-1,3-propanediol; serinol | 534-03-2 | C3H9NO2 | 详情 | 详情 |
| (II) | 23334 | 2-(tritylamino)-1,3-propanediol | C22H23NO2 | 详情 | 详情 | |
| (III) | 23335 | 1,3-dimethoxy-N-trityl-2-propanamine | C24H27NO2 | 详情 | 详情 | |
| (IV) | 23336 | 1,3-dimethoxy-2-propanamine | C5H13NO2 | 详情 | 详情 | |
| (V) | 23337 | 4-hydroxy-6-methyl-3-nitro-2(1H)-pyridinone | 4966-90-9 | C6H6N2O4 | 详情 | 详情 |
| (VI) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (VII) | 23339 | 4-chloro-6-methyl-3-nitro-2(1H)-pyridinone | C6H5ClN2O3 | 详情 | 详情 | |
| (VIII) | 23340 | 4-[[2-methoxy-1-(methoxymethyl)ethyl]amino]-6-methyl-3-nitro-2(1H)-pyridinone | C11H17N3O5 | 详情 | 详情 | |
| (IX) | 23341 | 2-chloro-N-[2-methoxy-1-(methoxymethyl)ethyl]-6-methyl-3-nitro-4-pyridinamine | C11H16ClN3O4 | 详情 | 详情 | |
| (X) | 23342 | 2-chloro-N(4)-[2-methoxy-1-(methoxymethyl)ethyl]-6-methyl-3,4-pyridinediamine | C11H18ClN3O2 | 详情 | 详情 | |
| (XI) | 23343 | 2-(4-chloro-6-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)-3-methoxypropyl methyl ether | C11H15ClN4O2 | 详情 | 详情 | |
| (XII) | 23344 | 2-chloro-4,6-dimethylaniline | C8H10ClN | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)2-Amino-1,3-propanediol (I) was reacted with in situ generated trifluoromethanesulfonyl azide, and the resulting 2-azido compound was purified by chromatography after conversion to the diacetate ester (II). Deacetylation of (II) with sodium methoxide gave 2-azido-1,3-propanediol (III), which was condensed with tosylate (IV) in the presence of NaH to produce the dihydroxyether (V). The primary alcohol group of (V) was then protected as the mono-silyl derivative (VI) employing tert-butyldiphenylsilyl chloride. After acylation of the free hydroxyl group of (VI) with the unsaturated acid (VII), the resulting ester (VIII) was desilylated by using HF in acetonitrile to yield alcohol (IX). The phosphorylating reagent (XII) was prepared by treatment of allyl phosphorodiamidite (X) with N-Boc-ethanolamine (XI). Phosphitylation of alcohol (IX) with phosphoramidite (XII), followed by oxidation of the intermediate phosphite ester with oxone , furnished phosphate (XIII). The azido group of (XIII) was then reduced to the corresponding amine (XIV) by employing (PhS)2Sn.
| 【1】 Rossignol, D.P.; Ishizaka, S.T.; Nault, A.; Lewis, M.; Rose, J.; McGuiness, P.; Hawkins, L.D. (Eisai Co., Ltd.); Immunological adjuvant cpd.. EP 1147117; US 6290973; WO 0044758 . |
| 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) | 23333 | 2-amino-1,3-propanediol; serinol | 534-03-2 | C3H9NO2 | 详情 | 详情 |
| (II) | 49119 | 3-(acetoxy)-2-azidopropyl acetate | C7H11N3O4 | 详情 | 详情 | |
| (III) | 49120 | 2-azido-1,3-propanediol | C3H7N3O2 | 详情 | 详情 | |
| (IV) | 49121 | (3R)-3-hydroxydecyl 4-methylbenzenesulfonate | C17H28O4S | 详情 | 详情 | |
| (V) | 49122 | (3R)-1-(2-azido-3-hydroxypropoxy)-3-decanol | C13H27N3O3 | 详情 | 详情 | |
| (VI) | 49123 | (3R)-1-(2-azido-3-[[tert-butyl(diphenyl)silyl]oxy]propoxy)-3-decanol | C29H45N3O3Si | 详情 | 详情 | |
| (VII) | 49124 | (Z)-5-dodecenoic acid | C12H22O2 | 详情 | 详情 | |
| (VIII) | 49125 | (1R)-1-[2-(2-azido-3-[[tert-butyl(diphenyl)silyl]oxy]propoxy)ethyl]octyl (Z)-5-dodecenoate | C41H65N3O4Si | 详情 | 详情 | |
| (IX) | 49126 | (1R)-1-[2-(2-azido-3-hydroxypropoxy)ethyl]octyl (Z)-5-dodecenoate | C25H47N3O4 | 详情 | 详情 | |
| (X) | 49127 | C15H33N2OP | 详情 | 详情 | ||
| (XI) | 32500 | tert-butyl 2-hydroxyethylcarbamate | 26690-80-2 | C7H15NO3 | 详情 | 详情 |
| (XII) | 49128 | C16H33N2O4P | 详情 | 详情 | ||
| (XIII) | 49129 | (1R)-9-(allyloxy)-6-azido-1-heptyl-16,16-dimethyl-9,14-dioxo-4,8,10,15-tetraoxa-13-aza-9lambda(5)-phosphaheptadec-1-yl (Z)-5-dodecenoate | C35H65N4O9P | 详情 | 详情 | |
| (XIV) | 49130 | (1R)-9-(allyloxy)-6-amino-1-heptyl-16,16-dimethyl-9,14-dioxo-4,8,10,15-tetraoxa-13-aza-9lambda(5)-phosphaheptadec-1-yl (Z)-5-dodecenoate | C35H67N2O9P | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XI)Substitution of 1-bromo-3,3-dimethyl-2-butanone (I) with NaN3 affords the azido ketone (II), which is reduced to amino ketone (III) by either catalytic hydrogenation or with triphenylphosphine. Acylation of (III) with chloroacetyl chloride affords amide (IV). Cyclization of the keto amide (IV) in hot POCl3 or in the presence of Burgess' reagent leads to the chloromethyl oxazole (V). Displacement of the chlorine atom of (V) with thiourea provides the S-alkyl isothiourea (VI). Hydrolysis of (VI), followed by condensation with 2-amino-5-bromothiazole (VII) under phase-transfer conditions furnishes thioether (VIII). The amino thiazole (VIII) is then coupled with 4-(bromomethyl)phenylacetic acid (IX), yielding amide (X). Finally, the bromide group of (X) is displaced with 2-amino-1,3-propanediol (XI) to produce the title compound.
| 【1】 Kim, K.S.; Misra, R.N.; Hunt, J.T.; Kimball, S.D.; Poss, M.A.; Han, W.-C.; Webster, K.R.; Cai, Z.-W.; Rawlins, D.B. (Bristol-Myers Squibb Co.); N-[5-[[[5-Alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases. EP 1240165; WO 0144241 . |
| 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) | 30809 | 1-bromo-3,3-dimethyl-2-butanone | 5469-26-1 | C6H11BrO | 详情 | 详情 |
| (II) | 58414 | 1-azido-3,3-dimethyl-2-butanone | 76779-98-1 | C6H11N3O | 详情 | 详情 |
| (III) | 58415 | 1-amino-3,3-dimethyl-2-butanone | 82962-91-2 | C6H13NO | 详情 | 详情 |
| (IV) | 58416 | 2-chloro-N-(3,3-dimethyl-2-oxobutyl)acetamide | C8H14ClNO2 | 详情 | 详情 | |
| (V) | 58417 | 5-(tert-butyl)-2-(chloromethyl)-1,3-oxazole | 224441-73-0 | C8H12ClNO | 详情 | 详情 |
| (VI) | 58418 | 2-({[amino(imino)methyl]sulfanyl}methyl)-5-(tert-butyl)-1,3-oxazole | 345629-22-3 | C9H15N3OS | 详情 | 详情 |
| (VII) | 58419 | 5-bromo-1,3-thiazol-2-ylamine; 5-bromo-1,3-thiazol-2-amine | C3H3BrN2S | 详情 | 详情 | |
| (VIII) | 58420 | 5-({[5-(tert-butyl)-1,3-oxazol-2-yl]methyl}sulfanyl)-1,3-thiazol-2-amine; 5-({[5-(tert-butyl)-1,3-oxazol-2-yl]methyl}sulfanyl)-1,3-thiazol-2-ylamine | 224436-97-9 | C11H15N3OS2 | 详情 | 详情 |
| (IX) | 58421 | 2-[4-(bromomethyl)phenyl]acetic acid; 4-(Bromomethyl)phenyl acetic acid; 4-Carboxymethylbenzyl bromide | 13737-36-5 | C9H9BrO2 | 详情 | 详情 |
| (X) | 58422 | 2-[4-(bromomethyl)phenyl]-N-[5-({[5-(tert-butyl)-1,3-oxazol-2-yl]methyl}sulfanyl)-1,3-thiazol-2-yl]acetamide | C20H22BrN3O2S2 | 详情 | 详情 | |
| (XI) | 23333 | 2-amino-1,3-propanediol; serinol | 534-03-2 | C3H9NO2 | 详情 | 详情 |