5-amino-2,4,6-triiodoisophthaloyl dichloride -Drug Synthesis Database

【结构式】

【分子编号】31194

【品名】5-amino-2,4,6-triiodoisophthaloyl dichloride

【CA登记号】37441-29-5

【分子式】C₈H₂Cl₂I₃NO₂

【分子量】595.72823

【元素组成】C 16.13% H 0.34% Cl 11.9% I 63.91% N 2.35% O 5.37%

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：(II)

Treatment of 5-amino-2,4,6-triiodo-1,3-benzenedicarboxylic acid (I) with thionyl chloride yields the dichloride (II). Compound (II) is treated with acetoxyacetyl chloride to give compound (III), which is methylated with iodomethane. Condensation with 3-amino-1,2-propanediol of the N-methyl derivative (IV) thus obtained, followed by deacetylation with alkali metal hydroxide, yields iomeprol.

参考文献中间体

合成目标

【1】 Felder, E.; Musu, C.; Fumagalli, L.; Uggeri, F. (Bracco SpA); Preparation of 5-acylamino-2,4,6-triiodo- or tribromo-benzoic acid derivs.. WO 8809328 .
【2】 Davies, A.; Felder, E.; Tirone, P.; IOMEPROL < Rec INN; BAN; USAN >. Drugs Fut 1990, 15, 11, 1074.
【3】 Musu, C.; Felder, E.; Fumagalli, L.; Piva, R.; Uggeri, F.; Smiles rearrangement, a new synthetic pathway to the synthesis of 5-(hydroxyacyl)-amino-2,4,6-triiodoisophthalamides. Invest Radiol 1990, 25, Suppl. 1, S100-1.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	12979	3-Amino-1,2-propanediol；3-aminopropane-1,2-diol	616-30-8	C₃H₉NO₂	详情	详情
(A)	16601	ethyl chloroacetate; ethyl 2-chloroacetate	105-39-5	C₄H₇ClO₂	详情	详情
(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)	31195	2-[3,5-bis(chlorocarbonyl)-2,4,6-triiodoanilino]-2-oxoethyl acetate		C₁₂H₆Cl₂I₃NO₅	详情	详情
(IV)	31196	2-[3,5-bis(chlorocarbonyl)-2,4,6-triiodomethylanilino]-2-oxoethyl acetate		C₁₃H₈Cl₂I₃NO₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

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)

Acylation of 5-amino-2,4,6-triiodoisophthaloyl chloride (I) with 2-isopropyl-1,3-dioxane-5-carbonyl chloride (II) provided the amido isophthaloyl chloride (III). Acid chloride (III) was then condensed with 3-(methylamino)-1,2-propanediol (IV) to furnish the triamide compound (V). The acetal protecting group was finally removed under acidic conditions.

参考文献中间体

合成目标

【1】 Schaefer, M.; Dugast-Zrihen, M.; Guillemot, M.; Doucet, D.; Meyer, D. (Guerbet SA); Non-ionic iodinated cpds., procedure for their preparation and contrast agents containing them. EP 0437144; WO 9109836 .
【2】 Meyer, D.; Doucet, D.; Guillemot, M.; Dugast-Zrihen, M.; Schaefer, M. (Guerbet SA); Iodinated non-ionic triiodobenzene cpds. and contrast media containing them. US 5043152 .

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)	31194	5-amino-2,4,6-triiodoisophthaloyl dichloride	37441-29-5	C₈H₂Cl₂I₃NO₂	详情	详情
(II)	59590	2-isopropyl-1,3-dioxane-5-carbonyl chloride		C₈H₁₃ClO₃	详情	详情
(III)	59591	2,4,6-triiodo-5-{[(2-isopropyl-1,3-dioxan-5-yl)carbonyl]amino}isophthaloyl dichloride		C₁₆H₁₄Cl₂I₃NO₅	详情	详情
(IV)	59592	2,3-Dihydroxy-N-methylpropylamine; N-Methyl-3-amino-1,2-propanediol; 3-Methylamino-1,2-propanediol	40137-22-2	C₄H₁₁NO₂	详情	详情
(V)	59593	N~1~,N~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-{[(2-isopropyl-1,3-dioxan-5-yl)carbonyl]amino}-N~1~,N~3~-dimethylisophthalamide		C₂₄H₃₄I₃N₃O₉	详情	详情

Extended Information