NSC-694501, UP-2001, NSC-D694501, SJG-136, SP-2001, -Drug Synthesis Database

【结构式】

【药物名称】NSC-694501, UP-2001, NSC-D694501, SJG-136, SP-2001

【化学名称】(11aS,11'aS)-8,8'-(1,3-Propanediyl)bis(oxy)bis(7-methoxy-2-methylene-1,2,3,11a-tetrahydro-5H-pyrrolo[ 2,1-c][1,4]benzodiazepin-5-one)

【CA登记号】232931-57-6

【分子式】C₃₁H₃₂N₄O₆

【分子量】556.62389

【开发单位】Spirogen (Originator), Ipsen (Licensee), Cancer Research UK (Codevelopment), National Cancer Institute (Codevelopment)

【药理作用】Oncolytic Drugs, DNA-Intercalating Drugs

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1

The pyrrolidine intermediate (VIII) has been obtained as follows: Protection of trans-4-hydroxy-L-proline (I) with allyl chloroformate gave carbamate (II). Following esterification of (II) with MeOH and H2SO4, the methyl ester (III) was reduced to diol (IV) by using LiBH4 in THF. Selective silylation of the primary alcohol of (IV) was achieved with TBDMS chloride the presence of DBU to furnish the silyl ether (V). Oxidation of (V) to ketone (VI) was carried out either under Swern conditions or by means of tetrapropylammonium perruthenate (TPAP) in the presence of N-methylmorpholine-N-oxide. Subsequent Wittig reaction of ketone (VI) with methylene triphenylphosphorane provided olefin (VII). The allyloxycarbonyl protecting group of (VII) was then removed by palladium-catalyzed hydrostannolysis with tributyltin hydride to yield the pyrrolidine intermediate (VIII).

参考文献中间体

【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
(I)	14489	(2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline	51-35-4	C₅H₉NO₃	详情	详情
(II)	47730	(2S,4R)-1-[(allyloxy)carbonyl]-4-hydroxy-2-pyrrolidinecarboxylic acid		C₉H₁₃NO₅	详情	详情
(III)	42200	1-allyl 2-methyl (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate		C₁₀H₁₅NO₅	详情	详情
(IV)	47731	allyl (2S,4R)-4-hydroxy-2-(hydroxymethyl)-1-pyrrolidinecarboxylate		C₉H₁₅NO₄	详情	详情
(V)	47732	allyl (2S,4R)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-hydroxy-1-pyrrolidinecarboxylate		C₁₅H₂₉NO₄Si	详情	详情
(VI)	47733	allyl (2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-oxo-1-pyrrolidinecarboxylate		C₁₅H₂₇NO₄Si	详情	详情
(VII)	47734	allyl (2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methylene-1-pyrrolidinecarboxylate		C₁₆H₂₉NO₃Si	详情	详情
(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

合成路线2

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

【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3

Diamine (XVI) was protected as the bis-carbamate (XVII) by treatment with allyl chloroformate. Oxidation of the alcohol functionalities of (XVII) followed by spontaneous ring closure in the presence of tetrapropylammonium perruthenate and N-methylmorpholine-N-oxide produced the bis-pyrrolobenzodiazepine compound (XVIII). Finally, cleavage of the carbamate groups of (XVIII) with concomitant dehydration gave rise to the title compound.

参考文献中间体

【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	分子式	供应商	用于合成
(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
(XVII)	47742	allyl 5-[3-(5-[[(allyloxy)carbonyl]amino]-4-[[(2S)-2-(hydroxymethyl)-4-methylenepyrrolidinyl]carbonyl]-2-methoxyphenoxy)propoxy]-2-[[(2S)-2-(hydroxymethyl)-4-methylenepyrrolidinyl]carbonyl]-4-methoxyphenylcarbamate	C₃₉H₄₈N₄O₁₂	详情	详情
(XVIII)	47743	allyl (11S,11aS)-8-[3-([(11S,11aS)-10-[(allyloxy)carbonyl]-11-hydroxy-7-methoxy-2-methylene-5-oxo-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl]oxy)propoxy]-11-hydroxy-7-methoxy-2-methylene-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate	C₃₉H₄₄N₄O₁₂	详情	详情

合成路线4

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

【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

合成路线5

The desilylation of (XI) with HF and pyridine in THF gives the bis hydroxyethyl derivative (XII), which is submitted to an oxidative cyclization by means of oxalyl chloride and TEA in DMSO/dichloromethane, yielding the bis pyrrolobenzodiazepinone (XIII). Finally, this compound is treated with Pd(PPh3)4 and PPh3 in pyrrolidine/dichloromethane to cleave the allyloxycarbonyl protecting group and simultaneously promote the elimination of the OH groups affording the target pyrrolobenzodiazepinone.

参考文献中间体

【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	分子式	供应商	用于合成
(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
(XII)	47742	allyl 5-[3-(5-[[(allyloxy)carbonyl]amino]-4-[[(2S)-2-(hydroxymethyl)-4-methylenepyrrolidinyl]carbonyl]-2-methoxyphenoxy)propoxy]-2-[[(2S)-2-(hydroxymethyl)-4-methylenepyrrolidinyl]carbonyl]-4-methoxyphenylcarbamate	C₃₉H₄₈N₄O₁₂	详情	详情
(XIII)	47743	allyl (11S,11aS)-8-[3-([(11S,11aS)-10-[(allyloxy)carbonyl]-11-hydroxy-7-methoxy-2-methylene-5-oxo-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl]oxy)propoxy]-11-hydroxy-7-methoxy-2-methylene-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate	C₃₉H₄₄N₄O₁₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)