4-[3-(4-carboxy-2-methoxyphenoxy)propoxy]-3-methoxybenzoic acid -Drug Synthesis Database

【结构式】

【分子编号】47736

【品名】4-[3-(4-carboxy-2-methoxyphenoxy)propoxy]-3-methoxybenzoic acid

【CA登记号】

【分子式】C₁₉H₂₀O₈

【分子量】376.363

【元素组成】C 60.64% H 5.36% O 34.01%

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：(XI)

Reaction of 1,3-diiodopropane (X) with two equivalents of vanillic acid (IX) in the presence of NaOH produced diacid (XI). Nitration of (XI) to give (XII) was carried out with concentrated HNO3 at -10 C. Dinitro diacid (XII) was then converted to the corresponding acid chloride (XIII) by treatment with oxalyl chloride. Coupling of acid chloride (XIII) with pyrrolidine (VIII) gave the bis-amide (XIV). After desilylation of (XIV) with tetrabutylammonium fluoride, the resultant bis-nitro-alcohol (XV) was reduced by means of SnCl2 to the diamine (XVI).

参考文献中间体

合成目标

【2】 Thurston, D.E.; Howard, P.W. (University of Portsmouth); Compounds. EP 1109812; WO 0012508 .
【1】 Kelland, L.R.; Gregson, S.J.; Brooks, N.A.; Jenkins, T.C.; Thurston, D.E.; Hartley, J.A.; Howard, P.W.; Adams, L.J.; Design, synthesis, and evaluation of a novel pyrrolobenzodiazepine DNA-interactive agent with highly efficient cross-linking ability and potent cytotoxicity. J Med Chem 2001, 44, 5, 737.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	47735	(2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methylenepyrrolidine; tert-butyl(dimethyl)silyl [(2S)-4-methylenepyrrolidinyl]methyl ether		C₁₂H₂₅NOSi	详情	详情
(IX)	17786	4-hydroxy-3-methoxybenzoic acid; Vanillic acid	121-34-6	C₈H₈O₄	详情	详情
(X)	42364	1,3-diiodopropane	627-31-6	C₃H₆I₂	详情	详情
(XI)	47736	4-[3-(4-carboxy-2-methoxyphenoxy)propoxy]-3-methoxybenzoic acid		C₁₉H₂₀O₈	详情	详情
(XII)	47737	4-[3-(4-carboxy-2-methoxy-5-nitrophenoxy)propoxy]-5-methoxy-2-nitrobenzoic acid		C₁₉H₁₈N₂O₁₂	详情	详情
(XIII)	47738	4-[3-[4-(chlorocarbonyl)-2-methoxy-5-nitrophenoxy]propoxy]-5-methoxy-2-nitrobenzoyl chloride		C₁₉H₁₆Cl₂N₂O₁₀	详情	详情
(XIV)	47739	[(2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methylenepyrrolidinyl][4-[3-(4-[[(2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methylenepyrrolidinyl]carbonyl]-2-methoxy-5-nitrophenoxy)propoxy]-5-methoxy-2-nitrophenyl]methanone		C₄₃H₆₄N₄O₁₂Si₂	详情	详情
(XV)	47740	[(2S)-2-(hydroxymethyl)-4-methylenepyrrolidinyl][4-[3-(4-[[(2S)-2-(hydroxymethyl)-4-methylenepyrrolidinyl]carbonyl]-2-methoxy-5-nitrophenoxy)propoxy]-5-methoxy-2-nitrophenyl]methanone		C₃₁H₃₆N₄O₁₂	详情	详情
(XVI)	47741	[2-amino-4-[3-(5-amino-4-[[(2S)-2-(hydroxymethyl)-4-methylenepyrrolidinyl]carbonyl]-2-methoxyphenoxy)propoxy]-5-methoxyphenyl][(2S)-2-(hydroxymethyl)-4-methylenepyrrolidinyl]methanone		C₃₁H₄₀N₄O₈	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The nitration of the dimeric benzoic acid (I) with 70% HNO3 gives the dimeric nitrobenzoic acid (II), which is treated with oxalyl chloride in THF to yield the acid chloride (III). The reaction of (III) with the pyrrolidine (IV) by means of TEA in the same solvent affords the diamide (V). The reduction of the nitro groups of (V) with RaNI and hydrazine in methanol provides the diamino compound (VI), which is protected with allyloxycarbonyl chloride (VII) and pyridine in dichloromethane to give the bis carbamate (VIII). The oxidation of the OH groups of (VIII) with oxalyl chloride and TEA in DMSO/dichloromethane yields the bis-pyrrolidinone (IX), which is allowed to react with methyl triphenylphosphonium bromide (X) and tBu-OK in THF to afford the bis exomethylene derivative (XI).

参考文献中间体

合成目标

【1】 Gregson, S.J.; Howard, P.W.; Corcoran, K.E.; Jenkins, T.C.; Kelland, L.R.; Thurston, D.E.; Synthesis of the first example of a C2-C3/C2'-C3'-endo unsaturated pyrrolo[2,1-c][1,4]benzodiazepine dimer. Bioorg Med Chem Lett 2001, 11, 21, 2859.

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)	47736	4-[3-(4-carboxy-2-methoxyphenoxy)propoxy]-3-methoxybenzoic acid		C₁₉H₂₀O₈	详情	详情
(II)	47737	4-[3-(4-carboxy-2-methoxy-5-nitrophenoxy)propoxy]-5-methoxy-2-nitrobenzoic acid		C₁₉H₁₈N₂O₁₂	详情	详情
(III)	47738	4-[3-[4-(chlorocarbonyl)-2-methoxy-5-nitrophenoxy]propoxy]-5-methoxy-2-nitrobenzoyl chloride		C₁₉H₁₆Cl₂N₂O₁₀	详情	详情
(IV)	62872	(3R,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-pyrrolidinol		C₁₁H₂₅NO₂Si	详情	详情
(V)	62873	[(2S,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-hydroxypyrrolidinyl]{4-[3-(4-{[(2S,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-hydroxypyrrolidinyl]carbonyl}-2-methoxy-5-nitrophenoxy)propoxy]-5-methoxy-2-nitrophenyl}methanone		C₄₁H₆₄N₄O₁₄Si₂	详情	详情
(VI)	62874	{2-amino-4-[3-(5-amino-4-{[(2S,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-hydroxypyrrolidinyl]carbonyl}-2-methoxyphenoxy)propoxy]-5-methoxyphenyl}[(2S,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-hydroxypyrrolidinyl]methanone		C₄₁H₆₈N₄O₁₀Si₂	详情	详情
(VII)	38115	3-[(chlorocarbonyl)oxy]-1-propene	2937-50-0	C₄H₅ClO₂	详情	详情
(VIII)	62875	allyl 5-[3-(5-{[(allyloxy)carbonyl]amino}-4-{[(2S,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-hydroxypyrrolidinyl]carbonyl}-2-methoxyphenoxy)propoxy]-2-{[(2S,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-hydroxypyrrolidinyl]carbonyl}-4-metho		C₄₉H₇₆N₄O₁₄Si₂	详情	详情
(IX)	62876	allyl 5-[3-(5-{[(allyloxy)carbonyl]amino}-4-{[(2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-oxopyrrolidinyl]carbonyl}-2-methoxyphenoxy)propoxy]-2-{[(2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-oxopyrrolidinyl]carbonyl}-4-methoxyphenylcarbam		C₄₉H₇₂N₄O₁₄Si₂	详情	详情
(X)	30484	Methyl(triphenyl)phosphonium bromide	1779-49-3	C₁₉H₁₈BrP	详情	详情
(XI)	62877	allyl 5-[3-(5-{[(allyloxy)carbonyl]amino}-4-{[(2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methylenepyrrolidinyl]carbonyl}-2-methoxyphenoxy)propoxy]-2-{[(2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methylenepyrrolidinyl]carbonyl}-4-methoxy		C₅₁H₇₆N₄O₁₂Si₂	详情	详情

Extended Information