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【结 构 式】 
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【分子编号】38365 【品名】methyl (3bR,4aS)-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate 【CA登记号】 |
【 分 子 式 】C14H14N2O3 【 分 子 量 】258.27684 【元素组成】C 65.11% H 5.46% N 10.85% O 18.58% |
合成路线1
该中间体在本合成路线中的序号：(II)The hydrolysis of DU-86 (I) with NaOMe gives tetracyclic compound (II), which is acylated with the 4-nitrophenyl cinnamate (III) and NaH yielding the adduct (IV). The opening of the cyclopropane ring of (IV) with HBr in acetonitrile affords the aromatic phenol (V), which is activated with 4-nitrophenyl chloroformate (VI) and TEA to provide the activated anhydride (VII). Finally, this compound is condensed with 4-methylpiperazine-1-amine (VIII), and treated with HBr to furnish the target dihydrobromide.
| 【1】 Amishiro, N.; Nagamura, S.; Saito, H.; Kobayashi, E.; Okamoto, A.; Gomi, K. (Kyowa Hakko Kogyo Co., Ltd.); DC-89 deriv.. EP 0702014; US 5670492; WO 9526964 . |
| 【2】 Nagamura, S.; Murakata, C.; Amishiro, N.; et al.; Synthesis and antitumor activity of duocarmycin derivatives: Modification at C-8 position of A-ring pyrrole compounds bearing the simplified DNA-binding groups. Bioorg Med Chem 2000, 8, 2, 381. |
| 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) | 40881 | methyl (3bR,4aS)-2-methyl-8-oxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C26H25N3O7 | 详情 | 详情 | |
| (II) | 38365 | methyl (3bR,4aS)-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C14H14N2O3 | 详情 | 详情 | |
| (III) | 40887 | 4-nitrophenyl (E)-3-[3-(dimethylamino)-4-methoxyphenyl]-2-propenoate | C18H18N2O5 | 详情 | 详情 | |
| (IV) | 40888 | methyl (3bR,4aS)-6-[(E)-3-[3-(dimethylamino)-4-methoxyphenyl]-2-propenoyl]-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C26H27N3O5 | 详情 | 详情 | |
| (V) | 40889 | methyl (8S)-8-(bromomethyl)-6-[(E)-3-[3-(dimethylamino)-4-methoxyphenyl]-2-propenoyl]-4-hydroxy-2-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C26H28BrN3O5 | 详情 | 详情 | |
| (VI) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (VII) | 40890 | methyl (8S)-8-(bromomethyl)-6-[(E)-3-[3-(dimethylamino)-4-methoxyphenyl]-2-propenoyl]-2-methyl-4-[[(4-nitrophenoxy)carbonyl]oxy]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C33H31BrN4O9 | 详情 | 详情 | |
| (VIII) | 40886 | 4-methyl-1-piperidinamine; 4-methyl-1-piperidinylamine | 19107-42-7 | C6H14N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The hydrolysis of DU-86 (I) with NaOMe gives tetracyclic compound (II), which is acylated with the 4-nitrophenyl cinnamate (III) and NaH yielding the adduct (IV). The opening of the cyclopropane ring of (IV) with HBr in acetonitrile affords the aromatic phenol (V), which is activated with 4-nitrophenyl chloroformate (VI) and TEA to provide the activated anhydride (VII). Finally, this compound is condensed with 4-(1-piperidinyl)piperidine-1-amine (VIII), and treated with HBr to furnish the target hydrobromide.
| 【1】 Amishiro, N.; Nagamura, S.; Saito, H.; Kobayashi, E.; Okamoto, A.; Gomi, K. (Kyowa Hakko Kogyo Co., Ltd.); DC-89 deriv.. EP 0702014; US 5670492; WO 9526964 . |
| 【2】 Nagamura, S.; Murakata, C.; Amishiro, N.; et al.; Synthesis and antitumor activity of duocarmycin derivatives: Modification at C-8 position of A-ring pyrrole compounds bearing the simplified DNA-binding groups. Bioorg Med Chem 2000, 8, 2, 381. |
| 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) | 40881 | methyl (3bR,4aS)-2-methyl-8-oxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C26H25N3O7 | 详情 | 详情 | |
| (II) | 38365 | methyl (3bR,4aS)-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C14H14N2O3 | 详情 | 详情 | |
| (III) | 33752 | 4-nitrophenyl (E)-3-(4-methoxyphenyl)-2-propenoate | C16H13NO5 | 详情 | 详情 | |
| (IV) | 40882 | methyl (3bR,4aS)-6-[(E)-3-(4-methoxyphenyl)-2-propenoyl]-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C24H22N2O5 | 详情 | 详情 | |
| (V) | 40883 | methyl (8S)-8-(bromomethyl)-4-hydroxy-6-[(E)-3-(4-methoxyphenyl)-2-propenoyl]-2-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C24H23BrN2O5 | 详情 | 详情 | |
| (VI) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (VII) | 40884 | methyl (8S)-8-(bromomethyl)-6-[(E)-3-(4-methoxyphenyl)-2-propenoyl]-2-methyl-4-[[(4-nitrophenoxy)carbonyl]oxy]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C31H26BrN3O9 | 详情 | 详情 | |
| (VIII) | 40885 | C10H21N3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The hydrolysis of DU-86 (I) with NaOMe gives tetracyclic compound (II), which is acylated with the 4-nitrophenyl cinnamate (III) and NaH yielding the adduct (IV). The opening of the cyclopropane ring of (IV) with HBr in acetonitrile affords the aromatic phenol (V), which is activated with 4-nitrophenyl chloroformate (VI) and TEA to provide the activated anhydride (VII). Finally, this compound is condensed with 4-methylpiperazine-1-amine (VIII), and treated with HBr to furnish the target hydrobromide.
| 【1】 Amishiro, N.; Nagamura, S.; Saito, H.; Kobayashi, E.; Okamoto, A.; Gomi, K. (Kyowa Hakko Kogyo Co., Ltd.); DC-89 deriv.. EP 0702014; US 5670492; WO 9526964 . |
| 【2】 Nagamura, S.; Murakata, C.; Amishiro, N.; et al.; Synthesis and antitumor activity of duocarmycin derivatives: Modification at C-8 position of A-ring pyrrole compounds bearing the simplified DNA-binding groups. Bioorg Med Chem 2000, 8, 2, 381. |
| 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) | 40881 | methyl (3bR,4aS)-2-methyl-8-oxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C26H25N3O7 | 详情 | 详情 | |
| (II) | 38365 | methyl (3bR,4aS)-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C14H14N2O3 | 详情 | 详情 | |
| (III) | 33752 | 4-nitrophenyl (E)-3-(4-methoxyphenyl)-2-propenoate | C16H13NO5 | 详情 | 详情 | |
| (IV) | 40882 | methyl (3bR,4aS)-6-[(E)-3-(4-methoxyphenyl)-2-propenoyl]-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C24H22N2O5 | 详情 | 详情 | |
| (V) | 40883 | methyl (8S)-8-(bromomethyl)-4-hydroxy-6-[(E)-3-(4-methoxyphenyl)-2-propenoyl]-2-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C24H23BrN2O5 | 详情 | 详情 | |
| (VI) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (VII) | 40884 | methyl (8S)-8-(bromomethyl)-6-[(E)-3-(4-methoxyphenyl)-2-propenoyl]-2-methyl-4-[[(4-nitrophenoxy)carbonyl]oxy]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C31H26BrN3O9 | 详情 | 详情 | |
| (VIII) | 40886 | 4-methyl-1-piperidinamine; 4-methyl-1-piperidinylamine | 19107-42-7 | C6H14N2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)The reaction of 4-bromothiophene-2-carbaldehyde (I) with triethyl orthoformate gives the corresponding acetal (II), which is treated with NaOMe, CuO and KI in hot methanol yielding 5-methoxythiophene-2-carbaldehyde diethylacetal (III). The hydrolysis of (III) with HCl in methanol affords the carbaldehyde (IV), which is condensed with the phosphonate (V) by means of NaH in THF to provide the ethyl acrylate (VI). The hydrolysis of (VI) with KOH in methanol gives the acrylic acid (VII), which is esterified with 4-nitrophenol, TEA and 2-chloro-1-methylpyridinium iodide in dichloromethane yielding the activate ester (VIII). The condensation of (VIII) with the tetracyclic ketone (IX) (obtained by treatment of the dimeric ketonic compound (X) with NaOMe in methanol) affords the adduct (XI), which is treated with HBr in acetonitrile to open the cyclopropane ring and provide the bromomethyl compound (XII). The aromatization of (XII) with p-nitrophenyl chloroformate (XIII) and TEA in dichloromethane affords the activated carbonate ester (XIV), which is finally treated with 1-methylpiperazine (XV) to furnish the target carbamate.
| 【1】 Saito, H.; Kobayashi, E.; Gomi, K.; Okamoto, A.; Nagamura, S.; Amishiro, N.; Synthesis and antitumor activity of duocarmycin derivatives: A-ring pyrrole compounds bearing 5-membered heteroarylacryloyl groups. Chem Pharm Bull 1999, 47, 10, 1393. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11236 | 4-Nitrophenol; p-Nitrophenol | 100-02-7 | C6H5NO3 | 详情 | 详情 | |
| (I) | 24142 | 4-bromo-2-thiophenecarbaldehyde | 18791-75-8 | C5H3BrOS | 详情 | 详情 |
| (II) | 38358 | (4-bromo-2-thienyl)(ethoxy)methyl ethyl ether; 4-bromo-2-(diethoxymethyl)thiophene | C9H13BrO2S | 详情 | 详情 | |
| (III) | 38359 | 5-(diethoxymethyl)-3-thienyl methyl ether; 2-(diethoxymethyl)-4-methoxythiophene | C10H16O3S | 详情 | 详情 | |
| (IV) | 35360 | C47H75N3O14 | 详情 | 详情 | ||
| (V) | 38361 | ethyl 2-(dimethoxyphosphoryl)acetate | C6H13O5P | 详情 | 详情 | |
| (VI) | 38362 | ethyl (E)-3-(4-methoxy-2-thienyl)-2-propenoate | C10H12O3S | 详情 | 详情 | |
| (VII) | 38363 | (E)-3-(4-methoxy-2-thienyl)-2-propenoic acid | C8H8O3S | 详情 | 详情 | |
| (VIII) | 38364 | 4-nitrophenyl (E)-3-(4-methoxy-2-thienyl)-2-propenoate | C14H11NO5S | 详情 | 详情 | |
| (IX) | 38365 | methyl (3bR,4aS)-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C14H14N2O3 | 详情 | 详情 | |
| (X) | 38366 | methyl (2R,3bR,4aS)-2-methyl-3,8-dioxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,4,4a,5,6,8-octahydrocyclopropa[c]pyrrolo[3,2-e]indole-2-carboxylate | C26H25N3O8 | 详情 | 详情 | |
| (XI) | 38367 | methyl (3bR,4aS)-6-[(E)-3-(4-methoxy-2-thienyl)-2-propenoyl]-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C22H20N2O5S | 详情 | 详情 | |
| (XII) | 38368 | methyl (8S)-8-(bromomethyl)-6-[(E)-3-(4-methoxy-2-thienyl)-2-propenoyl]-2-methyl-4-oxo-3,4,6,7,8,8a-hexahydropyrrolo[3,2-e]indole-1-carboxylate | C22H21BrN2O5S | 详情 | 详情 | |
| (XIII) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (XIV) | 38369 | methyl (8S)-8-(bromomethyl)-6-[(E)-3-(4-methoxy-2-thienyl)-2-propenoyl]-2-methyl-4-[[(4-nitrophenoxy)carbonyl]oxy]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C29H24BrN3O9S | 详情 | 详情 | |
| (XV) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IX)The reaction of 2-chloropyrimidine (I) with NaOMe in methanol gives 2-methoxypyrimidine (II), which is iodinated with N-iodosuccinimide (NIS) and trifluoroacetic anhydride in refluxing THF to yield 5-iodo-2-methoxypyrimidine (III). The condensation of (III) with methyl acrylate (IV) by means of Pd(OAc)2, K2CO3 and Bu4NCl at 120 C affords 3-(2-methoxypyrimidin-5-yl)acrylic acid methyl ester (V), which is hydrolyzed with KOH in methanol to provide the free acid (VI). The esterification of (VI) with p-nitrophenol (VII) by means of DCC and DMAP in dichloromethane gives the activate ester (VIII). The condensation of (VIII) with the tetracyclic ketone (IX) (obtained by treatment of the dimeric ketonic compound (X) with NaOMe in methanol) affords the adduct (XI), which is treated with HBr in acetonitrile to open the cyclopropane ring and provide the bromomethyl compound (XII). The aromatization of (XII) with p-nitrophenyl chloroformate (XIII) and TEA in dichloromethane affords the activated carbonate ester (XIV), which is finally treated with 1-methylpiperazine (XV) to furnish the target carbamate.
| 【1】 Nagamura, S.; et al.; Synthesis and antitumor activity of duocarmycin derivatives: Modification of affinity moiety to DNA minor groove. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 206. |
| 【2】 Saito, H.; Nagamura, S.; Amishiro, N.; Kobayashi, E.; Gomi, K.; New water-soluble duocarmycin derivatives: Synthesis and antitumor activity of A-ring pyrrole compounds bearing beta-heteroarylacryloyl groups. J Med Chem 1999, 42, 4, 669. |
| 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) | 11191 | 2-Chloropyrimidine | 1722-12-9 | C4H3ClN2 | 详情 | 详情 |
| (II) | 38398 | methyl 2-pyrimidinyl ether; 2-methoxypyrimidine | C5H6N2O | 详情 | 详情 | |
| (III) | 38394 | 5-iodo-2-methoxypyrimidine; 5-iodo-2-pyrimidinyl methyl ether | C5H5IN2O | 详情 | 详情 | |
| (IV) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (V) | 38395 | methyl (E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoate | C9H10N2O3 | 详情 | 详情 | |
| (VI) | 38396 | (E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoic acid | C8H8N2O3 | 详情 | 详情 | |
| (VII) | 11236 | 4-Nitrophenol; p-Nitrophenol | 100-02-7 | C6H5NO3 | 详情 | 详情 |
| (VIII) | 38397 | 4-nitrophenyl (E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoate | C14H11N3O5 | 详情 | 详情 | |
| (IX) | 38365 | methyl (3bR,4aS)-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C14H14N2O3 | 详情 | 详情 | |
| (X) | 38366 | methyl (2R,3bR,4aS)-2-methyl-3,8-dioxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,4,4a,5,6,8-octahydrocyclopropa[c]pyrrolo[3,2-e]indole-2-carboxylate | C26H25N3O8 | 详情 | 详情 | |
| (XI) | 38399 | methyl (3bR,4aS)-6-[(E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoyl]-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C22H20N4O5 | 详情 | 详情 | |
| (XII) | 38400 | methyl (8S)-8-(bromomethyl)-6-[(E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoyl]-2-methyl-4-oxo-3,4,6,7,8,8a-hexahydropyrrolo[3,2-e]indole-1-carboxylate | C22H21BrN4O5 | 详情 | 详情 | |
| (XIII) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (XIV) | 38401 | methyl (8S)-8-(bromomethyl)-6-[(E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoyl]-2-methyl-4-[[(4-nitrophenoxy)carbonyl]oxy]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C29H24BrN5O9 | 详情 | 详情 | |
| (XV) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IX)The reaction of 2-chloropyrimidine (I) with NaOMe in methanol gives 2-methoxypyrimidine (II), which is iodinated with N-iodosuccinimide (NIS) and trifluoroacetic anhydride in refluxing THF to yield 5-iodo-2-methoxypyrimidine (III). The condensation of (III) with methyl acrylate (IV) by means of Pd(OAc)2, K2CO3 and Bu4NCl at 120 C affords 3-(2-methoxypyrimidin-5-yl)acrylic acid methyl ester (V), which is hydrolyzed with KOH in methanol to provide the free acid (VI). The esterification of (VI) with p-nitrophenol (VII) by means of DCC and DMAP in dichloromethane gives the activate ester (VIII). Finally, the condensation of (VIII) with the tetracyclic ketone (IX) (obtained by treatment of the dimeric ketonic compound (X) with NaOMe in methanol) affords the target compound.
| 【1】 Saito, H.; Nagamura, S.; Amishiro, N.; Kobayashi, E.; Gomi, K.; New water-soluble duocarmycin derivatives: Synthesis and antitumor activity of A-ring pyrrole compounds bearing beta-heteroarylacryloyl groups. J Med Chem 1999, 42, 4, 669. |
| 【2】 Nagamura, S.; et al.; Synthesis and antitumor activity of duocarmycin derivatives: Modification of affinity moiety to DNA minor groove. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 206. |
| 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) | 11191 | 2-Chloropyrimidine | 1722-12-9 | C4H3ClN2 | 详情 | 详情 |
| (II) | 38398 | methyl 2-pyrimidinyl ether; 2-methoxypyrimidine | C5H6N2O | 详情 | 详情 | |
| (III) | 38394 | 5-iodo-2-methoxypyrimidine; 5-iodo-2-pyrimidinyl methyl ether | C5H5IN2O | 详情 | 详情 | |
| (IV) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (V) | 38395 | methyl (E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoate | C9H10N2O3 | 详情 | 详情 | |
| (VI) | 38396 | (E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoic acid | C8H8N2O3 | 详情 | 详情 | |
| (VII) | 11236 | 4-Nitrophenol; p-Nitrophenol | 100-02-7 | C6H5NO3 | 详情 | 详情 |
| (VIII) | 38397 | 4-nitrophenyl (E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoate | C14H11N3O5 | 详情 | 详情 | |
| (IX) | 38365 | methyl (3bR,4aS)-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C14H14N2O3 | 详情 | 详情 | |
| (X) | 38366 | methyl (2R,3bR,4aS)-2-methyl-3,8-dioxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,4,4a,5,6,8-octahydrocyclopropa[c]pyrrolo[3,2-e]indole-2-carboxylate | C26H25N3O8 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VII)The pyrrolecarboxylic acid derivative (I) was treated with BOP reagent, and the resulting hydroxybenzotriazolyl ester was reduced in situ with NaBH4 to furnish alcohol (II). Oxidation of (II) by means of activated MnO2 produced aldehyde (III). Wadsworth-Emmons reaction of aldehyde (III) with triethylphosphonoacetate gave rise to the unsaturated ester (IV). After basic hydrolysis of the ester group of (IV), the resultant carboxylic acid (V) was activated as the imidazolide (VI) upon treatment with carbonyldiimidazole. This was finally coupled with the segment A of DU86 (VII) in the presence of NaH in DMF at low temperature to yield the target amide.
| 【1】 Tao, Z.-F.; et al.; Highly cooperative DNA dialkylation by the homodimer of imidazole - Pyrrole diamide - CPI conjugate with vinyl linker. J Am Chem Soc 2000, 122, 8, 1602. |
| 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) | 50160 | 4-([[4-(acetamido)-1-methyl-1H-imidazol-2-yl]carbonyl]amino)-1-methyl-1H-pyrrole-2-carboxylic acid | C13H15N5O4 | 详情 | 详情 | |
| (II) | 50161 | 4-(acetamido)-N-[5-(hydroxymethyl)-1-methyl-1H-pyrrol-3-yl]-1-methyl-1H-imidazole-2-carboxamide | C13H17N5O3 | 详情 | 详情 | |
| (III) | 50162 | 4-(acetamido)-N-(5-formyl-1-methyl-1H-pyrrol-3-yl)-1-methyl-1H-imidazole-2-carboxamide | C13H15N5O3 | 详情 | 详情 | |
| (IV) | 50163 | ethyl (E)-3-[4-([[4-(acetamido)-1-methyl-1H-imidazol-2-yl]carbonyl]amino)-1-methyl-1H-pyrrol-2-yl]-2-propenoate | C17H21N5O4 | 详情 | 详情 | |
| (V) | 50164 | (E)-3-[4-([[4-(acetamido)-1-methyl-1H-imidazol-2-yl]carbonyl]amino)-1-methyl-1H-pyrrol-2-yl]-2-propenoic acid | C15H17N5O4 | 详情 | 详情 | |
| (VI) | 50165 | 4-(acetamido)-N-[5-[(E)-3-(1H-imidazol-1-yl)-3-oxo-1-propenyl]-1-methyl-1H-pyrrol-3-yl]-1-methyl-1H-imidazole-2-carboxamide | C18H19N7O3 | 详情 | 详情 | |
| (VII) | 38365 | methyl (3bR,4aS)-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C14H14N2O3 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)The segment-A moiety of duocarmycin analogue (I) was formylated with dichloromethyl methyl ether in the presence of TiCl4 to produce aldehyde (II). Opening of the cyclopropane ring of (II) by means of HCl in EtOAc gave rise to chloromethyl compound (III), which was subsequently coupled with 4-methoxycinnamic acid (IV) by means of EDC to furnish the title amide.
| 【1】 Okamoto, A.; Okabe, M.; Saito, H.; Amishiro, N.; Synthesis and antitumor activity of duocarmycin derivatives: Modification at the C-7 position of segement-A of A-ring pyrrole compounds. Bioorg Med Chem 2000, 8, 5, 1195. |
| 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) | 38365 | methyl (3bR,4aS)-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C14H14N2O3 | 详情 | 详情 | |
| (II) | 42106 | methyl (3bR,4aS)-7-formyl-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C15H14N2O4 | 详情 | 详情 | |
| (III) | 42107 | methyl (8S)-8-(chloromethyl)-5-formyl-4-hydroxy-2-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C15H15ClN2O4 | 详情 | 详情 | |
| (IV) | 42108 | (E)-3-(4-methoxyphenyl)-2-propenoic acid | 830-09-1 | C10H10O3 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XIII)The protection of the OH group of 4-hydroxy-3,5-dimethoxybenzaldehyde (I) with benzyl bromide and K2CO3 DMF gives the benzyl ether (II), which is condensed with ethyl 2-azidoacetate (III) by means of NaOMe in methanol to yield the 2-azido acrylic acid derivative (IV). The cyclization of (IV) in refluxing xylene affords the indole carboxylate (V), which is deprotected by hydrogenation with H2 over PtO2 in THF/methanol to provide 6-hydroxy-5,7-dimethoxy-1H-indole-2-carboxylic acid methyl ester (I). The condensation of (VI) with 1,2-dibromoethane (VII) by means of K2CO3 in DMF gives the 2-bromoethoxy derivative (VIII), which is treated with sodium azide in DMF to yield the 2-azidoethoxy compound (IX). The hydrolysis of the ester group of (IX) with NaOH in THF/water affords the carboxylic acid (X), which is esterified with 4-nitrophenol (XI) by means of DCC and DMAP in dichloromethane to provide the activated ester (XII). The condensation of (XII) with the tetracyclic compound (XIII) by means of NaH in DMF gives the adduct (XIV), which is finally reduced at the azido group with H2 over Pd/C in THF/HOAc to yield the target compound.
| 【1】 Suzawa, T.; et al.; Synthesis of a novel duocarmycin derivative DU-257 and its application to immunoconjugate using poly(ethylene glycol-dipeptidyl linker capable of tumor specific activation. Bioorg Med Chem 2000, 8, 8, 2175. |
| 【2】 Saito, H.; Nagamura, S.; Suzawa, T.; Yamasaki, M.; Ohta, S.; Hanai, N. (Kyowa Hakko Kogyo Co., Ltd.); Toxin conjugates. US 6103236; WO 9635451 . |
| 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) | 49243 | 3,5-Dimethoxy-4-hydroxybenzaldehyde; 4-Hydroxy-3,5-dimethoxybenzaldehyde; Syringaldehyde | 134-96-3 | C9H10O4 | 详情 | 详情 |
| (II) | 49244 | 4-Benzyloxy-3,5-dimethoxybenzaldehyde | C16H16O4 | 详情 | 详情 | |
| (III) | 49245 | alpha-azido acetic acid methyl ester | C3H5N3O2 | 详情 | 详情 | |
| (IV) | 49246 | methyl (Z)-2-azido-3-[4-(benzyloxy)-3,5-dimethoxyphenyl]-2-propenoate | C19H19N3O5 | 详情 | 详情 | |
| (V) | 49247 | methyl 6-(benzyloxy)-5,7-dimethoxy-1H-indole-2-carboxylate | C19H19NO5 | 详情 | 详情 | |
| (VI) | 49248 | methyl 6-hydroxy-5,7-dimethoxy-1H-indole-2-carboxylate | C12H13NO5 | 详情 | 详情 | |
| (VII) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (VIII) | 49249 | methyl 6-(2-bromoethoxy)-5,7-dimethoxy-1H-indole-2-carboxylate | C14H16BrNO5 | 详情 | 详情 | |
| (IX) | 49250 | methyl 6-(2-azidoethoxy)-5,7-dimethoxy-1H-indole-2-carboxylate | C14H16N4O5 | 详情 | 详情 | |
| (X) | 49251 | 6-(2-azidoethoxy)-5,7-dimethoxy-1H-indole-2-carboxylic acid | C13H14N4O5 | 详情 | 详情 | |
| (XI) | 11236 | 4-Nitrophenol; p-Nitrophenol | 100-02-7 | C6H5NO3 | 详情 | 详情 |
| (XII) | 49252 | 4-nitrophenyl 6-(2-azidoethoxy)-5,7-dimethoxy-1H-indole-2-carboxylate | C19H17N5O7 | 详情 | 详情 | |
| (XIII) | 38365 | methyl (3bR,4aS)-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C14H14N2O3 | 详情 | 详情 | |
| (XIV) | 49253 | methyl (3bR,4aS)-6-[[6-(2-azidoethoxy)-5,7-dimethoxy-1H-indol-2-yl]carbonyl]-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C27H26N6O7 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(IV)5-Nitrobenzofuran-2-carboxylic acid (I) is coupled to 4-nitrophenol (II) in the presence of EDC to produce the p-nitrophenyl ester (III). Subsequent acylation of the duocarmycin derivative (IV) with active ester (III) leads to amide (V). Cyclopropane ring opening in (V) with HCl in DMF furnishes the chloromethyl derivative (VI). The nitro group of (VI) is then reduced by catalytic hydrogenation, yielding amine (VII). Acylation of (VII) with 7-nitroindole-2-carboxylic acid (VIII) affords the corresponding amide (IX)
| 【1】 McGee, D.P.C.; Saunders, O.L.; Martichonok, V.; Wu, G.; Ng, H.P.; Li, Z.; Yarranton, G.T. (Medarex, Inc.); Cytotoxic agents. US 2003050331; WO 0296910 . |
| 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) | 63365 | 5-nitro-1-benzofuran-2-carboxylic acid | 10242-12-3 | C9H5NO5 | 详情 | 详情 |
| (II) | 11236 | 4-Nitrophenol; p-Nitrophenol | 100-02-7 | C6H5NO3 | 详情 | 详情 |
| (III) | 63440 | 4-nitrophenyl 5-nitro-1-benzofuran-2-carboxylate | C15H8N2O7 | 详情 | 详情 | |
| (IV) | 38365 | methyl (3bR,4aS)-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C14H14N2O3 | 详情 | 详情 | |
| (V) | 63441 | methyl 2-methyl-6-[(5-nitro-1-benzofuran-2-yl)carbonyl]-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C23H17N3O7 | 详情 | 详情 | |
| (VI) | 63442 | methyl 8-(chloromethyl)-4-hydroxy-2-methyl-6-[(5-nitro-1-benzofuran-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C23H18ClN3O7 | 详情 | 详情 | |
| (VII) | 63443 | methyl 6-[(5-amino-1-benzofuran-2-yl)carbonyl]-8-(chloromethyl)-4-hydroxy-2-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C23H20ClN3O5 | 详情 | 详情 | |
| (VIII) | 63444 | 7-nitro-1H-indole-2-carboxylic acid | C9H6N2O4 | 详情 | 详情 | |
| (IX) | 63445 | methyl 8-(chloromethyl)-4-hydroxy-2-methyl-6-[(5-{[(7-nitro-1H-indol-2-yl)carbonyl]amino}-1-benzofuran-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C32H24ClN5O8 | 详情 | 详情 |