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【结 构 式】

【分子编号】59316

【品名】5-amino-N~1~,N~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide

【CA登记号】

【 分 子 式 】C14H18I3N3O6

【 分 子 量 】705.02695

【元素组成】C 23.85% H 2.57% I 54% N 5.96% O 13.62%
与该中间体有关的原料药合成路线共 6 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6

合成路线1

该中间体在本合成路线中的序号：(I)

Acetylation of 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (I) in refluxing acetic anhydride in the presence of p-toluenesulfonic acid affords acetamide (II). The title compound is then obtained by alkylation of acetamide (II) with 1-chloro-3-methoxy-2-propanol (III). The selectivity in the alkylation at the acetamide N has been improved with the addition of several metallic cations, the best results being obtained with calcium ions.

参考文献 中间体
合成目标
【1】 Bjoersvik, H.-R.; et al.; An observation of cationic influence on the N/O alkylation selectivity in the alkylation of a compound containing several nucleophilic sites. Acta Chem Scand 1994, 48, 7, 582.
【2】 Wille, K. (Amersham plc); X-Ray contrast agents. EP 0105752 .
【3】 Cockbain, J.R.M.; Gulbrandsen, T.; Ingvoldstad, O.E.; Holmaas, L.T. (Amersham plc); Process for the preparation of contrast agents. WO 9808805 .
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) 59316 5-amino-N~1~,N~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide C14H18I3N3O6 详情 详情
(II) 59311 5-(acetylamino)-N~1~,N~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide C16H20I3N3O7 详情 详情
(III) 34214 1-chloro-3-methoxy-2-propanol 4151-97-7 C4H9ClO2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(IV)

Chlorination of 5-amino-2,4,6-triiodoisophthalic acid (I) with SOCl2 in EtOAc or toluene affords acid chloride (II). Yields have been improved with the addition of benzyltriethylammonium chloride as a catalyst. Acid chloride (II) is then condensed with 3-amino-1,2-propanediol (III) to produce diamide (IV). Compound (IV) is converted to the tetraacetate ester (V) employing acetic anhydride in pyridine. Subsequent acylation of the amino group of (V) with acetoxyacetyl chloride (VI) gives amide (VII). After saponification of the ester groups of (VII), the resultant hydroxy acetamide (VIII) is alkylated by 2-chloroethanol (IX) to furnish the title compound. Alternatively, amide (VIII) is alkylated by bromoethyl acetate (X), producing (XI). Hexa-ester (XI) is finally hydrolyzed with aqueous sulfuric acid. An improved procedure for this final hydrolysis step uses 1,1,2-trichloroethane as co-solvent.

参考文献 中间体
合成目标
【1】 Lin, Y. (Mallinckrodt Medical Inc.); Cpds. suitable for X-ray visualisation methods. EP 0083964; US 4396598 .
【2】 Dunn, T.J.; White, D.H.; Kneller, M.T.; Jones, M.M.; Doran, N.O. III; Bailey, A.R. (Mallinckrodt Medical Inc.); Process for producing ioversol. WO 9727172 .
【3】 Kneller, M.T.; Bailey, A.R.; Sathe, S.S.; Spears, A.T.; Wisneski, R.C. (Mallinckrodt Medical Inc.); Improved synthesis of ioversol. WO 9323365 .
【4】 Villa, M.; Castaldi, G.; Pozzoli, C.; Russo, L. (Zambon Group SpA); Process for the preparation of 5-amino-2,4,6-triiodoisophthalic acid dichloride by chlorination with thionyl chloride in the presence of a catalyst. WO 9636590 .
【5】 Lin, Y.; Dean, R.T.; Kneller, M.; Wallace, R.A.; McCarthy, W.Z.; White, D.H. (Mallinckrodt Medical Inc.); Process for production of ioversol. WO 9111431 .
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) 22006 5-amino-2,4,6-triiodoisophthalic acid 35453-19-1 C8H4I3NO4 详情 详情
(II) 31194 5-amino-2,4,6-triiodoisophthaloyl dichloride 37441-29-5 C8H2Cl2I3NO2 详情 详情
(III) 12979 3-Amino-1,2-propanediol；3-aminopropane-1,2-diol 616-30-8 C3H9NO2 详情 详情
(IV) 59316 5-amino-N~1~,N~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide C14H18I3N3O6 详情 详情
(V) 59322 2-(acetyloxy)-1-({[3-amino-5-({[2,3-bis(acetyloxy)propyl]amino}carbonyl)-2,4,6-triiodobenzoyl]amino}methyl)ethyl acetate C22H26I3N3O10 详情 详情
(VI) 10456 Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate 13831-31-7 C4H5ClO3 详情 详情
(VII) 59323 2-(acetyloxy)-1-({[3-{[2-(acetyloxy)acetyl]amino}-5-({[2,3-bis(acetyloxy)propyl]amino}carbonyl)-2,4,6-triiodobenzoyl]amino}methyl)ethyl acetate C26H30I3N3O13 详情 详情
(VIII) 59324 N~1~,N~3~-bis(2,3-dihydroxypropyl)-5-(glycoloylamino)-2,4,6-triiodoisophthalamide C16H20I3N3O8 详情 详情
(IX) 33463 2-bromoethyl acetate 927-68-4 C4H7BrO2 详情 详情
(X) 10384 2-Chloro-1-ethanol; Ethylene chlorohydrin 107-07-3 C2H5ClO 详情 详情
(XI) 59325 2-[[2-(acetyloxy)acetyl]-3,5-bis({[2,3-bis(acetyloxy)propyl]amino}carbonyl)-2,4,6-triiodoanilino]ethyl acetate C30H36I3N3O15 详情 详情

合成路线3

该中间体在本合成路线中的序号：(I)

In a related method, the intermediate tetrahydroxy amine (I) is acylated by chloroacetyl chloride (II) to produce the penta(chloroacetyl) derivative (III). The chloroacetate ester groups are then hydrolyzed under basic conditions to afford the tetra-hydroxy chloroacetamide (IV). Conversion of (IV) to the hydroxy acetamide (V) is accomplished by treatment with sodium acetate and NaOH. Amide (V) is finally alkylated with either chloroetanol (VI) or with ethylene oxide (VII) to furnish the title N-(hydroxyethyl) amide.

参考文献 中间体
合成目标
【1】 Dunn, T.J.; Kneller, M.T.; White, D.H.; Jones, M.M.; Doran, N.O. (Mallinckrodt Medical Inc.); Process for producing ioversol. WO 9640286 .
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) 59316 5-amino-N~1~,N~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide C14H18I3N3O6 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 59326 2-({3-[({2,3-bis[(2-chloroacetyl)oxy]propyl}amino)carbonyl]-5-[(2-chloroacetyl)amino]-2,4,6-triiodobenzoyl}amino)-1-{[(2-chloroacetyl)oxy]methyl}ethyl 2-chloroacetate C24H23Cl5I3N3O11 详情 详情
(IV) 59327 5-[(2-chloroacetyl)amino]-N~1~,N~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide C16H19ClI3N3O7 详情 详情
(V) 59324 N~1~,N~3~-bis(2,3-dihydroxypropyl)-5-(glycoloylamino)-2,4,6-triiodoisophthalamide C16H20I3N3O8 详情 详情
(VI) 10384 2-Chloro-1-ethanol; Ethylene chlorohydrin 107-07-3 C2H5ClO 详情 详情
(VII) 10393 Oxirane; Ethylene oxide 75-21-8 C2H4O 详情 详情

合成路线4

该中间体在本合成路线中的序号：(I)

Similarly, the tetrahydroxy amine (I) is acylated by chloroacetyl chloride (II) to produce the tetraester amide (III). After amide alkylation with bromoethyl acetate (IV), the resultant penta-ester (V) is hydrolyzed to the title compound using aqueous sulfuric acid.

参考文献 中间体
合成目标
【1】 McCarthy, W.Z.; Kneller, M.T.; Lin, Y.; White, D.H. (Mallinckrodt Medical Inc.); Synthesis of ioversol using chloroacetyl chloride. WO 9301840 .
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) 59316 5-amino-N~1~,N~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide C14H18I3N3O6 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 59326 2-({3-[({2,3-bis[(2-chloroacetyl)oxy]propyl}amino)carbonyl]-5-[(2-chloroacetyl)amino]-2,4,6-triiodobenzoyl}amino)-1-{[(2-chloroacetyl)oxy]methyl}ethyl 2-chloroacetate C24H23Cl5I3N3O11 详情 详情
(IV) 33463 2-bromoethyl acetate 927-68-4 C4H7BrO2 详情 详情
(V) 59330 2-({3-[[2-(acetyloxy)ethyl](2-chloroacetyl)amino]-5-[({2,3-bis[(2-chloroacetyl)oxy]propyl}amino)carbonyl]-2,4,6-triiodobenzoyl}amino)-1-{[(2-chloroacetyl)oxy]methyl}ethyl 2-chloroacetate C28H29Cl5I3N3O13 详情 详情

合成路线5

该中间体在本合成路线中的序号：(I)

A further synthetic variation for the title compound is based on the acylation of intermediate (I) with acetoxyacetyl chloride (II) to afford (III). Amide alkylation with bromoethyl acetate (IV) furnishes (V). The ester groups of (V) are finally hydrolyzed in aqueous sulfuric acid.

参考文献 中间体
合成目标
【1】 Lin, Y.; Wallace, R.A.; McCarthy, W.Z.; Kneller, M.T.; White, D.H. (Mallinckrodt Medical Inc.); Synthesis of ioversol using a minimal excessof acetoxyacetylchloride. US 5371278 .
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) 59316 5-amino-N~1~,N~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide C14H18I3N3O6 详情 详情
(II) 10456 Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate 13831-31-7 C4H5ClO3 详情 详情
(III) 59331 2-[(3-{[2-(acetyloxy)acetyl]amino}-5-{[(2,3-bis{[2-(acetyloxy)acetyl]oxy}propyl)amino]carbonyl}-2,4,6-triiodobenzoyl)amino]-1-({[2-(acetyloxy)acetyl]oxy}methyl)ethyl 2-(acetyloxy)acetate C34H38I3N3O21 详情 详情
(IV) 33463 2-bromoethyl acetate 927-68-4 C4H7BrO2 详情 详情
(V) 59332 2-[(3-{[2-(acetyloxy)acetyl][2-(acetyloxy)ethyl]amino}-5-{[(2,3-bis{[2-(acetyloxy)acetyl]oxy}propyl)amino]carbonyl}-2,4,6-triiodobenzoyl)amino]-1-({[2-(acetyloxy)acetyl]oxy}methyl)ethyl 2-(acetyloxy)acetate C38H44I3N3O23 详情 详情

合成路线6

该中间体在本合成路线中的序号：(II)

An improved method for the preparation of the iodinated precursor (II) has been reported. Thus, iodination of the amino isophthalamide (I) with iodine monochloride is performed with co-addition of phosphoric acid, to yield a higher purity triiodo derivative (II).

参考文献 中间体
合成目标
【1】 Leibner, J.E. (Mallinckrodt Medical Inc.); Improved synthesis of ioversol using phosphoric acid modified co-addition. WO 9535122 .
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) 59333 5-amino-N~1~,N~3~-bis(2,3-dihydroxypropyl)isophthalamide C14H21N3O6 详情 详情
(II) 59316 5-amino-N~1~,N~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide C14H18I3N3O6 详情 详情
Extended Information