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【结 构 式】

【分子编号】16605

【品名】4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene

【CA登记号】7693-46-1

【 分 子 式 】C7H4ClNO4

【 分 子 量 】201.5658

【元素组成】C 41.71% H 2% Cl 17.59% N 6.95% O 31.75%
与该中间体有关的原料药合成路线共 34 条
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合成路线1

该中间体在本合成路线中的序号：(II)

Elinogrel potassium is prepared as follows. Condensation of methyl 2-amino-4,5-difluorobenzoate (I) with 4-nitrophenyl chloroformate (II) in refluxing CH2Cl2 gives the 4-nitrophenyl carbamate (III), which is condensed with 4-(Boc-amino)aniline (IV) in the presence of Et3N in THF at 60-70 °C to yield the diaryl urea (V), which, without isolation, is cyclized to the quinazoline-2,4-dione (VI) upon treatment with methanolic NaOMe or DBU. Alternatively, diaryl urea (V) is prepared by treatment of anthranilate (I) with COCl2 in toluene to yield isocyanate (VII) and/or carbamoyl chloride (VIII), which are then condensed with 4-(Boc-amino)aniline (IV) in the presence of Et3N in DMF . Deprotection of the amino group in compound (VI) by removal of the Boc group by means of HCl in dioxane provides 3-(4-aminophenyl)-6,7-difluoroquinazoline-2,4(1H,3H)-dione hydrochloride (IX), which undergoes selective fluoride displacement with methylamine (X) in DMSO at 110 °C to provide 3-(4-aminophenyl)-6-fluoro-7-(methylamino)quinazoline-2,4(1H,3H)-dione (XI). Subsequent carbamoylation of the primary amino group of quinazoline (XI) with ethyl N-(5-chlorothien-2-ylsulfonyl)carbamate (XII) in refluxing DMSO or acetonitrile yields elinogrel (XIII) , which is finally converted to its potassium salt by treatment with KOH in acetonitrile/H2O at 45-55 °C .

参考文献 中间体
合成目标
【1】 Scarborough, R.M., Pandey, A., Yiannikouros, G.P., Cruskie, M., White, D.C., Mehrotra, M. (Portola Pharmaceuticals, Inc.). Substituted-(quinazolinyl)phenyl thiophenyl-sulfonylureas, methods for making and intermediates thereof. US 2007208045, WO 2007056167.
【2】 Huang, W., Mehrotra, M., Zhang, X., Cannon, H., Grant, C.M. (Portola Pharmaceuticals, Inc.). [4-(6-Halo-7-substituted-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureas and forms and methods related thereto. EP 1951254, JP 2009515836, US 2007123547, WO 200705619.
【3】 Sharp, E., Quegan, L.J., Pandey, A., Wang, J., Nieder, M., Huang, W. (Portola Pharmaceuticals, Inc.). [4-(6-Fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea salts, in different crystalline forms, pharmaceutical compositions thereof. EP 2076510, JP 2010526105, WO 2008137809.
【4】 Sharp, E., Quegan, L.J., Pandey, A., Wang, J., Nieder, M., Huang, W. (Portola Pharmaceuticals, Inc.). [4-(6-Fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea salts, forms and methods related thereto. US 2009156620, WO 2010054020.
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) 69088 methyl 2-amino-4,5-difluorobenzoate;2-Amino-4,5-difluorobenzoicacid methyl ester 207346-42-7 C8H7F2NO2 详情 详情
(II) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(III) 69089 methyl 4,5-difluoro-2-(((4-nitrophenoxy)carbonyl)amino)benzoate 　 C15H10F2N2O6 详情 详情
(IV) 43972 4-(N-Boc-aminomethyl)aniline;tert-butyl (4-aminophenyl)carbamate;tert-butyl 4-aminophenylcarbamate C11H16N2O2 详情 详情
(V) 69090 methyl 2-(3-(4-((tert-butoxycarbonyl)amino)phenyl)ureido)-4,5-difluorobenzoate 　 C20H21F2N3O5 详情 详情
(VI) 69091 tert-butyl (4-(6,7-difluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)carbamate 　 C19H17F2N3O4 详情 详情
(VII) 69092 methyl 4,5-difluoro-2-isocyanatobenzoate 　 C9H5F2NO3 详情 详情
(VIII) 69093 methyl 2-((chlorocarbonyl)amino)-4,5-difluorobenzoate 　 C9H6ClF2NO3 详情 详情
(IX) 69094 3-(4-aminophenyl)-6,7-difluoroquinazoline-2,4(1H,3H)-dione hydrochloride 　 C14H9F2N3O2.HCl 详情 详情
(X) 11021 Methanamine; Methylamine 74-89-5 CH5N 详情 详情
(XI) 69095 3-(4-aminophenyl)-6-fluoro-7-(methylamino)quinazoline-2,4(1H,3H)-dione 　 C15H13FN4O2 详情 详情
(XII) 69097 ethyl N-(5-chlorothien-2-ylsulfonyl)carbamate;[(5-Chlorothien-2-yl)sulfonyl]carbamic acid ethyl ester;Ethyl[(5-chlorothiophen-2-yl)sulfonyl]carbamate;N-[(5-chloro-2-thienyl)sulfonyl]- 849793-87-9 C7H8ClNO4S2 详情 详情
(XIII) 69096 5-chloro-N-((4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)carbamoyl)thiophene-2-sulfonamide 　 C20H15ClFN5O5S2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

The title compound has also been obtained by solid phase synthesis. Bromoacetic acid (I) is coupled to hydroxymethyl polystyrene resin by means of DIC/DMAP to produce the bromoacetyl resin (II). Bromide displacement with tert-butyl carbazate (III) leads to the N-Boc hydrazino ester (IV), which is further deprotected to (V) employing trifluoroacetic acid. The hydrazinoacetic acid-bound resin (V) is then condensed with 5-(p-nitrophenyl)furfural (VI) to furnish hydrazone (VII). Acylation of resin (VII) with p-nitrophenyl chloroformate (VIII) produces the p-nitrophenyl carbamate (IX), which upon treatment with ammonia gives rise to the semicarbazone (X). Finally, concomitant intramolecular ring closure and resin cleavage of (X) produces the target aminohydantoin derivative (XI) (4, 5).

参考文献 中间体
合成目标
【1】 Wilson, L.J.; Li, M.; Portlock, D.E.; Solid phase synthesis of 1-aminohydantoin libraries. Tetrahedron Lett 1998, 39, 29, 5135.
【2】 Portlock, D.E.; Li, M.; Wilson, L.J. (The Procter & Gamble Co.); Solid phase synthesis of 1-aminohydantoins. WO 9942450 .
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) 23660 2-Bromoacetic acid 79-08-3 C2H3BrO2 详情 详情
(II) 12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
(III) 12091 1-Methylhydrazine; Monomethyl hydrazine 60-34-4 CH6N2 详情 详情
(IV) 63589 2-[2-(tert-butoxycarbonyl)hydrazino]acetic acid C7H14N2O4 详情 详情
(V) 63590 2-hydrazinoacetic acid C2H6N2O2 详情 详情
(VI) 63583 5-(4-nitrophenyl)-2-furaldehyde C11H7NO4 详情 详情
(VII) 63591 2-(2-{(E)-[5-(4-nitrophenyl)-2-furyl]methylidene}hydrazino)acetic acid C13H11N3O5 详情 详情
(VIII) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(IX) 63592 2-(1-[(4-nitrophenoxy)carbonyl]-2-{(E)-[5-(4-nitrophenyl)-2-furyl]methylidene}hydrazino)acetic acid C20H14N4O9 详情 详情
(X) 63593 2-(1-(aminocarbonyl)-2-{(E)-[5-(4-nitrophenyl)-2-furyl]methylidene}hydrazino)acetic acid C14H12N4O6 详情 详情
(XI) 63586 1-({(E)-[5-(4-nitrophenyl)-2-furyl]methylidene}amino)-2,4-imidazolidinedione C14H10N4O5 详情 详情

合成路线3

该中间体在本合成路线中的序号：(XIII)

The condensation of indoline (I) with methyl acetoacetate (II) by means of Ts-OH in refluxing benzene gives the adduct (III), which is cyclized by means of Pd(OAc)2 in hot DMA to yield the pyrroloindole (IV). The hydrolysis of the acetate group of (IV) by means of K2CO3 in methanol affords the hydroxymethyl compound (V), which is treated with CCl4 and PPh3 to provide the chloromethyl derivative (VI). The cleavage of the benzyl protecting group of (VI) by means of HCOONH4 and Pd/C in THF gives the hydroxy derivative (VII), which is N-deprotected by means of HCl in ethyl acetate to yield the intermediate (VIII). The condensation of (VIII) with 5,6,7-trimethoxy-1H-indole-2-carboxylic acid (IX) by means of EDC in DMF affords the carboxamide (X), which is treated with DBU in acetonitrile to provide the cyclopropapyrroloindole (XI). The reaction of (XI) with HBr in acetonitrile gives the bromomethyl derivative (XII), which is treated with 4-nitrophenyl chloroformate (XIII) to yield the active carbonate ester (XIV). Finally, this compound is treated with 1-methylpiperazine (XV) to provide the target Pibrozelesin.

参考文献 中间体
合成目标
【1】 Fukuda, Y.; et al.; Novel syntheses of optically active CC-1065, U-73,975 (adozelesin), U-80,244 (carzelesin), U-77,779 (bizelesin), KW-2189, and DU-86. Heterocycles 1997, 45, 12, 2303.
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) 59123 tert-butyl (3S)-3-[(acetyloxy)methyl]-5-amino-6-(benzyloxy)-2,3-dihydro-1H-indole-1-carboxylate C23H28N2O5 详情 详情
(II) 11791 methyl 3-oxobutanoate; Methyl acetoacetate 105-45-3 C5H8O3 详情 详情
(III) 61767 tert-butyl (3S)-3-[(acetyloxy)methyl]-6-(benzyloxy)-5-{[(E)-3-methoxy-1-methyl-3-oxo-1-propenyl]amino}-2,3-dihydro-1H-indole-1-carboxylate C28H34N2O7 详情 详情
(IV) 61768 6-(tert-butyl) 1-methyl (8S)-8-[(acetyloxy)methyl]-4-(benzyloxy)-2-methyl-7,8-dihydropyrrolo[3,2-e]indole-1,6(3H)-dicarboxylate C28H32N2O7 详情 详情
(V) 61769 6-(tert-butyl) 1-methyl (8S)-4-(benzyloxy)-8-(hydroxymethyl)-2-methyl-7,8-dihydropyrrolo[3,2-e]indole-1,6(3H)-dicarboxylate C26H30N2O6 详情 详情
(VI) 61770 6-(tert-butyl) 1-methyl (8S)-4-(benzyloxy)-8-(chloromethyl)-2-methyl-7,8-dihydropyrrolo[3,2-e]indole-1,6(3H)-dicarboxylate C26H29ClN2O5 详情 详情
(VII) 61771 6-(tert-butyl) 1-methyl (8S)-8-(chloromethyl)-4-hydroxy-2-methyl-7,8-dihydropyrrolo[3,2-e]indole-1,6(3H)-dicarboxylate C19H23ClN2O5 详情 详情
(VIII) 61772 methyl (8S)-8-(chloromethyl)-4-hydroxy-2-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate C14H15ClN2O3 详情 详情
(IX) 61773 5,6,7-trimethoxy-1H-indole-2-carboxylic acid C12H13NO5 详情 详情
(X) 61774 methyl (8S)-8-(chloromethyl)-4-hydroxy-2-methyl-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate C26H26ClN3O7 详情 详情
(XI) 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
(XII) 61775 methyl (8S)-8-(bromomethyl)-4-hydroxy-2-methyl-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate C26H26BrN3O7 详情 详情
(XIII) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(XIV) 61776 methyl (8S)-8-(bromomethyl)-2-methyl-4-{[(4-nitrophenoxy)carbonyl]oxy}-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate C33H29BrN4O11 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4

该中间体在本合成路线中的序号：(VII)

Ring opening of D-glucuronolactone (I) with NaOMe, followed by peracetylation and bromination of the resulting methyl uronate (II), afforded bromopyranose (III). Coupling of (III) with benzaldehyde (IV) using silver oxide in acetonitrile provided aldehyde (V), which was reduced with NaBH4 in the presence of silica gel in CHCl3-i-PrOH at 0 C to give benzyl alcohol (VI). Subsequent reaction with 4-nitrophenyl chloroformate (VII) in the presence of Et3N formed nitrophenyl carbonate (VIII) which, without purification, was coupled with doxorubicin (IX) in the presence of Et3N in DMF to give (X).

参考文献 中间体
合成目标
【1】 Florent, J.-C.; Dong, X.; Gaudel, G.; Mitaku, S.; Monneret, C.; Gesson, J.P.; Jacquesy, J.C.; Mondon, M.; Renoux, B.; Andrianomenjanahary, S.; Michel, S.; Koch, M.; Tillequin, F.; Gerken, M.; Czech, J.; Straub, R.; Bosslet, K.; Prodrugs of anthracyclines for use in antibody-directed enzyme prodrug therapy. J Med Chem 1998, 41, 19, 3572.
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) 18369 (3S,3aR,6R,6aR)-3,5,6-trihydroxytetrahydrofuro[3,2-b]furan-2(3H)-one 32449-92-6 C6H8O6 详情 详情
(II) 18370 methyl (3S,4R,6S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-carboxylate C7H12O7 详情 详情
(III) 18371 methyl (3S,4R,6R)-3,4,5-tris(acetoxy)-6-bromotetrahydro-2H-pyran-2-carboxylate 21085-72-3 C13H17BrO9 详情 详情
(IV) 18372 4-hydroxy-3-nitrobenzaldehyde 3011-34-5 C7H5NO4 详情 详情
(V) 18373 methyl (3R,4R,6S)-3,4,5-tris(acetoxy)-6-(4-formyl-2-nitrophenoxy)tetrahydro-2H-pyran-2-carboxylate C20H21NO13 详情 详情
(VI) 18374 methyl (3R,4R,6S)-3,4,5-tris(acetoxy)-6-[4-(hydroxymethyl)-2-nitrophenoxy]tetrahydro-2H-pyran-2-carboxylate C20H23NO13 详情 详情
(VII) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(VIII) 18376 methyl (3R,4R,6S)-3,4,5-tris(acetoxy)-6-[2-nitro-4-[([[(4-nitrobenzyl)oxy]carbonyl]oxy)methyl]phenoxy]tetrahydro-2H-pyran-2-carboxylate C28H28N2O17 详情 详情
(IX) 18377 (8S,10S)-10-[[(2R,4S,5S)-4-amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-8-glycoloyl-6,8,11-trihydroxy-1-methoxy-7,8,9,10-tetrahydro-5,12-naphthacenedione C27H29NO11 详情 详情
(X) 18378 methyl (3R,4R,6S)-3,4,5-tris(acetoxy)-6-[4-[([[((3S,4S,6R)-6-[[(1S,3S)-3-glycoloyl-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-1-naphthacenyl]oxy]-3-hydroxy-2-methyltetrahydro-2H-pyran-4-yl)amino]carbonyl]oxy)methyl]-2-nitrophenoxy]tetrahydro-2H-pyran-2-carboxylate C48H50N2O25 详情 详情

合成路线5

该中间体在本合成路线中的序号：(IV)

A new enantioselective synthesis of efavirenz starting from 2-[5-chloro-2-(4-methoxybenzylamino)phenyl]-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2(S)-ol (I), a previously described intermediate [see Drugs Fut 1998 23(2):133], has been reported: The oxidative cyclization of butynol (I) with dichlorodicyanobenzoquinone (DDQ) in toluene gives the benzoxazine (II) which, without isolation, is treated with NaOH and NaBH4 in methanol yielding the aminoalcohol (III). The acylation of (III) with p-nitrophenyl chloroformate (IV) and NaHCO3 in water affords the carbamate (V). Finally, this compound is cyclized by means of lithium tert-butoxide in tert-butyl methyl ether, or KOH in tert-butyl methyl ether/water.

参考文献 中间体
合成目标
【1】 Pierce, M.E.; et al.; Practical asymmetric synthesis of efavirenz (DMP 266), an HIV-1 reverse transcriptase inhibitor. J Org Chem 1998, 63, 23, 8536.
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) 16578 (2S)-2-[5-chloro-2-[(4-methoxybenzyl)amino]phenyl]-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol C21H19ClF3NO2 详情 详情
(II) 21199 (4S)-6-chloro-4-(2-cyclopropylethynyl)-2-(4-methoxyphenyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine; 4-[(4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-yl]phenyl methyl ether C21H17ClF3NO2 详情 详情
(III) 21200 (2S)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol 209414-27-7 C13H11ClF3NO 详情 详情
(IV) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(V) 21203 4-nitrophenyl 4-chloro-2-[(1S)-3-cyclopropyl-1-hydroxy-1-(trifluoromethyl)-2-propynyl]phenylcarbamate C20H14ClF3N2O5 详情 详情

合成路线6

该中间体在本合成路线中的序号：(XXI)

The thiazolyl carbonate (XI) has been synthesized as follows: The reaction of formamide (XIV) with P2S5 in ethyl ether gives thioformamide (XV), which is cyclized with 2-chloro-3-oxopropionic acid ethyl ester (XVI) [obtained by condensation of ethyl chloroacetate (XVII) with ethyl formate (XVIII) by means of t-BuOK in THF] yielding thiazol-5-carboxylic acid ethyl ester (XIX). The reduction of (XIX) with LiAlH4 in THF affords 5-thiazolylmethanol (XX), which is then esterified with 4-nitrophenyl chloroformate (XXI) by means of 4-methylmorpholine (MPH) in dichloromethane to give the desired product (XI).

参考文献 中间体
合成目标
【1】 Graul, A.; Castañer, J.; Ritonavir. Drugs Fut 1996, 21, 7, 700.
【2】 Kempf, D.J.; Norbeck, D.W.; Sham, H.L.; Zhao, C.; Sowin, T.J.; Reno, D.S.; Haight, A.R.; Cooper, A.J. (Abbott Laboratories Inc.); Retroviral protease inhibiting cpds. EP 0674513; EP 0727419; JP 1996505844; JP 1997118679; JP 1998087639; WO 9414436 .
【3】 Al-Razzak, L.; Marsh, K.C.; Manning, L.P.; Kaul, D. (Abbott Laboratories Inc.); Pharmaceutical compsns. containing HIV protease inhibitors. EP 0732923; US 5484801; WO 9520384 .
【4】 Flentge, C.; Kempf, D.; Marsh, K.; et al.; Symmetry-based inhibitors of HIV protease with high oral bioavailability. 207th ACS Natl Meet (March 13-17, San Diego) 1994, Abst MEDI 35.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XI) 16595 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate 144163-97-3 C11H8N2O5S 详情 详情
(XIV) 16598 Formamide 75-12-7 CH3NO 详情 详情
(XV) 16599 Thioformamide CH3NS 详情 详情
(XVI) 16600 ethyl 2-chloro-3-oxopropanoate C5H7ClO3 详情 详情
(XVII) 16601 ethyl chloroacetate; ethyl 2-chloroacetate 105-39-5 C4H7ClO2 详情 详情
(XVIII) 16602 ethyl formate 109-94-4 C3H6O2 详情 详情
(XIX) 16603 ethyl 1,3-thiazole-5-carboxylate 32955-22-9 C6H7NO2S 详情 详情
(XX) 16604 1,3-thiazol-5-ylmethanol;5-thiazolylmethanol;Thiazole-5-methanol 38585-74-9 C4H5NOS 详情 详情
(XXI) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情

合成路线7

该中间体在本合成路线中的序号：(XXI)

The N-substituted valine (XIII) has been synthesized as follows: The reaction of isobutyramide (XXII) with phosphorus pentasulfide (P4S10) in ethyl ether gives the corresponding thioamide (XXIII), which is cyclized with 1,3-dichloroacetone (XXIV) by means of MgSO4 in refluxing acetone yielding 4-(chloromethyl)-2-isopropylthiazole (XXV). The reaction of (XXV) with methylamine in water affords N-(2-isopropylthiazol-4-ylmethyl)-N-methylamine (XXVI), which is condensed with N-(4-nitrophenoxycarbonyl)-L-valine methyl ester (XXVII) by means of 4-(dimethylamino)pyridine (DMAP) and triethylamine in refluxing THF to give the thiazol-substituted L-valine ester (XXVIII). Finally, this compound is converted into the corresponding free acid with LiOH in dioxane/water. The N-(4-nitrophenoxycarbonyl)-L-valine methyl ester (XXVII) has been synthesized by reaction of chloroformate (XXI) with L-valine methyl ester (XXIX) by means of 4-methylmorpholine (MPH) in dichloromethane.

参考文献 中间体
合成目标
【1】 Graul, A.; Castañer, J.; Ritonavir. Drugs Fut 1996, 21, 7, 700.
【2】 Kempf, D.J.; Norbeck, D.W.; Sham, H.L.; Zhao, C.; Sowin, T.J.; Reno, D.S.; Haight, A.R.; Cooper, A.J. (Abbott Laboratories Inc.); Retroviral protease inhibiting cpds. EP 0674513; EP 0727419; JP 1996505844; JP 1997118679; JP 1998087639; WO 9414436 .
【3】 Al-Razzak, L.; Marsh, K.C.; Manning, L.P.; Kaul, D. (Abbott Laboratories Inc.); Pharmaceutical compsns. containing HIV protease inhibitors. EP 0732923; US 5484801; WO 9520384 .
【4】 Flentge, C.; Kempf, D.; Marsh, K.; et al.; Symmetry-based inhibitors of HIV protease with high oral bioavailability. 207th ACS Natl Meet (March 13-17, San Diego) 1994, Abst MEDI 35.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIII) 16597 (2S)-2-([[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl]amino)-3-methylbutyric acid C14H23N3O3S 详情 详情
(XXI) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(XXII) 16606 Isobutyramide; 2-methylpropanamide 563-83-7 C4H9NO 详情 详情
(XXIII) 16607 2-methylpropanethioamide 13515-65-6 C4H9NS 详情 详情
(XXIV) 63907 1,3-dichloroacetone C3H4Cl2O 详情 详情
(XXV) 16609 4-(chloromethyl)-2-isopropyl-1,3-thiazole C7H10ClNS 详情 详情
(XXVI) 16610 (2-isopropyl-1,3-thiazol-4-yl)-N-methylmethanamine; N-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-N-methylamine 154212-60-9 C8H14N2S 详情 详情
(XXVII) 16611 methyl (2S)-3-methyl-2-[[(4-nitrophenoxy)carbonyl]amino]butanoate C13H16N2O6 详情 详情
(XXVIII) 16612 methyl (2S)-2-([[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl]amino)-3-methylbutanoate C15H25N3O3S 详情 详情
(XXIX) 16613 methyl (2S)-2-amino-3-methylbutanoate C6H13NO2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(VI)

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.

参考文献 中间体
合成目标
【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9

该中间体在本合成路线中的序号：(VI)

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.

参考文献 中间体
合成目标
【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10

该中间体在本合成路线中的序号：(VI)

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.

参考文献 中间体
合成目标
【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11

该中间体在本合成路线中的序号：(XI)

Condensation of alpha-methyl tryptophan methyl ester (I) with benzylchloroformate (II) in the presence of Et3N in THF yields urethane (III), which is hydrolyzed with LiOH in THF/MeOH/H2O and then activated with DCCI and pentafluorophenol (IV) to furnish ester (V). Treatment of (V) with alpha-methyl-benzylamine (VI) gives derivative (VII), which is then debenzylated by hydrogenation over Pd(OH)2 in EtOH to afford (VIII). Finally, amine (VIII) reacts in DMF with DMAP and carbonate (IX), which has been previously prepared from 2-benzofuranylmethanol (X), 4-nitrophenylchloroformate (XI) and pyridine in CH2Cl2.

参考文献 中间体
合成目标
【1】 Boyle, S.; et al.; Rational design of high affinity tachykinin NK1 receptor antagonists. Bioorg Med Chem 1994, 2, 5, 357.
【2】 Horwell, D.C.; Howson, W.; Rees, D.C.; Roberts, E.; Pritchard, M.C. (Pfizer Inc.); Tachykinin antagonists. EP 0655055; EP 1000930; US 5594022; WO 9404494 .
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) 44166 methyl (2R)-2-amino-3-(1H-indol-3-yl)-2-methylpropanoate C13H16N2O2 详情 详情
(II) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(III) 44167 methyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropanoate C21H22N2O4 详情 详情
(IV) 22662 2,3,4,5,6-pentafluorophenol 771-61-9 C6HF5O 详情 详情
(V) 44168 2,3,4,5,6-pentafluorophenyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropanoate C26H19F5N2O4 详情 详情
(VI) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(VII) 44169 benzyl (1R)-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[[(1S)-1-phenylethyl]amino]ethylcarbamate C28H29N3O3 详情 详情
(VIII) 44170 (2R)-2-amino-3-(1H-indol-3-yl)-2-methyl-N-[(1S)-1-phenylethyl]propanamide C20H23N3O 详情 详情
(IX) 44171 1-benzofuran-2-ylmethyl 4-nitrophenyl carbonate C16H11NO6 详情 详情
(X) 38335 1-benzofuran-2-ylmethanol C9H8O2 详情 详情
(XI) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情

合成路线12

该中间体在本合成路线中的序号：(VI)

The reaction of methyl acetoacetate (I) with 3,4-difluorobenzaldehyde (II) in hot benzene gives the corresponding benzylidene derivative (III), which is cyclized with O-methylisourea (IV) by means of NaHCO3 in hot DMF yielding the dihydropyrimidine (V). The condensation of (V) with 4-nitrophenyl chloroformate (VI) by means of DMAP in dichloromethane affords the 4-nitrophenyl ester (VII), which is brominated with Br2 in chloroform to the bromomethyl compound (VIII). The cyclization of (VIII) by heating at 130 C affords the furopyrimidine (X), which is treated with propylamine derivative (X) in THF or dichloromethane to furnish the target amide.

参考文献 中间体
合成目标
【1】 Chiu, G.; Tian, D.; Lagu, B.; et al.; Synthesis and evaluation of furo[3,4-d]pyrimidinones as selective alpha1a-adrenergic receptor antagonists. Bioorg Med Chem Lett 2000, 10, 2, 175.
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) 11791 methyl 3-oxobutanoate; Methyl acetoacetate 105-45-3 C5H8O3 详情 详情
(II) 26654 3,4-difluorobenzaldehyde 34036-07-2 C7H4F2O 详情 详情
(III) 38075 methyl (Z)-2-acetyl-3-(3,4-difluorophenyl)-2-propenoate C12H10F2O3 详情 详情
(IV) 26657 O-methyl isourea; [Amino(imino)methoxy]methane 52328-05-9 C2H6N2O 详情 详情
(V) 38076 methyl 6-(3,4-difluorophenyl)-2-methoxy-4-methyl-1,6-dihydro-5-pyrimidinecarboxylate C14H14F2N2O3 详情 详情
(VI) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(VII) 38077 5-methyl 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-2-methoxy-4-methyl-1,5(6H)-pyrimidinedicarboxylate C21H17F2N3O7 详情 详情
(VIII) 38078 5-methyl 1-(4-nitrophenyl) 4-(bromomethyl)-6-(3,4-difluorophenyl)-2-methoxy-1,5(6H)-pyrimidinedicarboxylate C21H16BrF2N3O7 详情 详情
(IX) 38079 4-nitrophenyl 4-(3,4-difluorophenyl)-2-methoxy-5-oxo-5,6-dihydrofuro[2,3-d]pyrimidine-3(4H)-carboxylate C20H13F2N3O7 详情 详情
(X) 25450 methyl 1-(3-aminopropyl)-4-phenyl-4-piperidinecarboxylate C16H24N2O2 详情 详情

合成路线13

该中间体在本合成路线中的序号：(VII)

Reaction of 2,6-dihydroxyacetophenone (I) with acetylated bromoglucose (II) in the presence of CdCO3 in refluxing toluene, with water removal using a Dean Stark apparatus, afforded glycoside (III). Potassium hydroxide-promoted condensation of acetophenone (III) with benzofuran-5-carboxyaldehyde (IV), with concomitant hydrolysis of acetate esters, gave enone (V), which was hydrogenated over Pt/C in the presence of DMAP to provide dihydrochalcone derivative (VI). Treatment of (VI) with 4-nitrophenyl chloroformate (VII) and 2,4,6-collidine gave the intermediate 6-O-(4-nitrophenylcarbonyl) compound, which is cyclized to the cyclic carbonate (VIII) by heating at 50 C. The ring opening reaction of (VIII) with TsOH and methanol afforded the target 4-O-(methoxycarbonyl) compound along with some 6-O-methoxycarbonyl isomer, which is separated by column chromatography.

参考文献 中间体
合成目标
【1】 Hongu, M.; et al.; Na+-Glucose cotransporter inhibitors as antidiabetic agents. II. Synthesis and structure-activity relationships of 4'-dehydroxyphlorizin derivatives. Chem Pharm Bull 1998, 46, 1, 22.
【2】 Tsujihara, K.; et al.; Na+-glucose cotransporter inhibitors as antidiabetics. I. Synthesis and pharmacological properties of 4'-dehydroxyphlorizin derivatives based on a new concept. Chem Pharm Bull 1996, 44, 6, 1174.
【3】 Hongu, M.; Funami, N.; Takahashi, Y.; Saito, K.; Arakawa, K.; Matsumoto, M.; Yamakita, H.; Tsujihara, K.; Na+-glucose cotransporter inhibitors as antidiabetic agents. III. Synthesis and pharmacological properties of 4'-dehydroxyphlorizin derivatives modified at the OH groups of the glucose moiety. Chem Pharm Bull 1998, 46, 10, 1545.
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) 27511 1-(2,6-dihydroxyphenyl)-1-ethanone 699-83-2 C8H8O3 详情 详情
(II) 27260 (2R,3R,4S,5S,6R)-4,5-bis(acetoxy)-6-[(acetoxy)methyl]-2-bromotetrahydro-2H-pyran-3-yl acetate 572-09-8 C14H19BrO9 详情 详情
(III) 27512 (2R,3R,4S,5R,6S)-6-(2-acetyl-3-hydroxyphenoxy)-4,5-bis(acetoxy)-2-[(acetoxy)methyl]tetrahydro-2H-pyran-3-yl acetate C22H26O12 详情 详情
(IV) 27262 1-benzofuran-5-carbaldehyde C9H6O2 详情 详情
(V) 27513 (E)-3-(1-benzofuran-5-yl)-1-(2-hydroxy-6-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]phenyl)-2-propen-1-one C23H22O9 详情 详情
(VI) 27514 3-(1-benzofuran-5-yl)-1-(2-hydroxy-6-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]phenyl)-1-propanone C23H24O9 详情 详情
(VII) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(VIII) 27520 (4aR,6S,7R,8R,8aS)-6-[2-[3-(1-benzofuran-5-yl)propanoyl]-3-hydroxyphenoxy]-7,8-dihydroxyhexahydropyrano[3,2-d][1,3]dioxin-2-one C24H22O10 详情 详情

合成路线14

该中间体在本合成路线中的序号：(XIII)

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.

参考文献 中间体
合成目标
【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15

该中间体在本合成路线中的序号：(II)

The known phenolic antibiotic (I) was treated with p-nitrophenyl chloroformate (II) in the presence of Et3N to give carbonate (III). Then, condensation of (III) with (R)-3-(hydroxymethyl)morpholine (IV) furnished the target carbamate.

参考文献 中间体
合成目标
【1】 Shimazawa, R.; Terashima, S.; Fukuda, Y.; Oomori, Y. (Kyorin Pharmaceutical Co., Ltd.; Sagami Chemical Research Center); Pyrroloindole derivs. and intermediates in producing the same. EP 0972775; JP 1998265473; US 6080859; WO 9832757 .
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) 41328 methyl (8S)-8-(chloromethyl)-4-hydroxy-6-[(5-[[(7-methoxy-1-benzofuran-2-yl)carbonyl]amino]-1H-indol-2-yl)carbonyl]-2-(trifluoromethyl)-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate C33H24ClF3N4O7 详情 详情
(II) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(III) 41329 methyl (8S)-8-(chloromethyl)-6-[(5-[[(7-methoxy-1-benzofuran-2-yl)carbonyl]amino]-1H-indol-2-yl)carbonyl]-4-[[(4-nitrophenoxy)carbonyl]oxy]-2-(trifluoromethyl)-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate C40H27ClF3N5O11 详情 详情
(IV) 41330 (3R)morpholinylmethanol C5H11NO2 详情 详情

合成路线16

该中间体在本合成路线中的序号：(XIII)

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.

参考文献 中间体
合成目标
【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17

该中间体在本合成路线中的序号：(III)

The condensation of 6,7-dimethoxy-4-(1-piperazinyl)quinazoline (I) with 4-bromophenylamine (II) by means of CDI or triphosgene gives the target piperazine-1-carboxamide. Alternatively, the reaction of 4-bromophenylamine (II) with 4-nitrophenyl chloroformate (III) by means of TEA gives the carbamate (IV), which is finally condensed with the quinazoline (I) in hot NMP to yield the target piperazine-1-carboxamide.

参考文献 中间体
合成目标
【1】 Matsuno, K.; Ichimura, M.; Nakajima, T.; Tahara, K.; Fujiwara, S.; Kase, H.; Ushiki, J.; Giese, N.A.; Pandey, A.; Scarborough, R.M.; Lokker, N.A.; Yu, J.C.; Irie, J.; Tsukuda, E.; Ide, S.-i; Oda, S.; Nomoto, Y.; Potent and selective inhibitors of platelet-derived growth factor receptor phosphorylation. 1. Synthesis, structure-activity relationship, and biological effects of a new class of quinazoline derivatives. J Med Chem 2002, 45, 14, 3057.
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) 41610 6,7-dimethoxy-4-(1-piperazinyl)quinazoline; 6-methoxy-4-(1-piperazinyl)-7-quinazolinyl methyl ether C14H18N4O2 详情 详情
(II) 22351 ethyl 3-([2-amino-5-[(4-cyanobenzoyl)amino]benzoyl]amino)propanoate C20H20N4O4 详情 详情
(III) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(IV) 63170 4-nitrophenyl 4-bromophenylcarbamate C13H9BrN2O4 详情 详情

合成路线18

该中间体在本合成路线中的序号：(VI)

The reaction of 3,4-difluorobenzaldehyde (I) with methyl 4-methoxyacetoacetate (II) by means of piperidinium acetate in benzene gives the 3-benzylidene derivative (III), which is cyclized with O-methylisourea (IV) yielding dihydropyrimidine (V). The optical resolution of dihydropyrimidine (V) can also be performed as follows: Dihydropyrimidine (V) is condensed with 4-nitrophenyl chloroformate (VI) by means of DMAP giving the 4-nitrophenyl ester (VII), which is treated with (R)-(+)-alpha-methylbenzylamine [(R)-MBA] yielding amide (VIII) as mixture of diastereomers that is separated by column chromatography. The (+) isomer was then treated with DBU in hot toluene to provide the dihydropyrimidine (+)(IX), already reported. The intermediate 2-(trans-4-cyano-4-phenylcyclohexyl)ethylamine (XII) has been obtained by reductocondensation of 4-cyano-4-phenylcyclohexanone (XIII) with ethylenediamine (XIV) by means of p-toluenesulfonic acid and NaBH4 and separation of the isomers by careful chromatography.

参考文献 中间体
合成目标
【1】 Nagarathnam, D.; et al.; Design, synthesis and evaluation of dihydropyrimidinones as alpha-1A selective antagonists: 7. Modification of the piperidine moiety into 4-aminocyclohexane; identification and structure-activity relationship of SNAP 6991 analogs. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 110.
【2】 Nagarathnam, D.; Wong, W.C.; Miao, S.W.; Patane, M.A.; Gluchowski, C. (Merck & Co., Inc.; Synaptic Pharmaceutical Corp.); Dihydropyrimidines and uses thereof. EP 0866708; JP 2000500470; WO 9717969 .
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) 26654 3,4-difluorobenzaldehyde 34036-07-2 C7H4F2O 详情 详情
(II) 26655 methyl 4-methoxy-3-oxobutanoate;Methyl 4-methoxyacetoacetate;Methyl 4-methoxy-3-oxo-butanoate 41051-15-4 C6H10O4 详情 详情
(III) 26656 methyl (Z)-3-(3,4-difluorophenyl)-2-(2-methoxyacetyl)-2-propenoate C13H12F2O4 详情 详情
(IV) 26657 O-methyl isourea; [Amino(imino)methoxy]methane 52328-05-9 C2H6N2O 详情 详情
(V) 26658 methyl 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,6-dihydro-5-pyrimidinecarboxylate C15H16F2N2O4 详情 详情
(VI) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(VII) 26659 5-methyl 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,5(6H)-pyrimidinedicarboxylate C22H19F2N3O8 详情 详情
(VIII) 26660 methyl 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1-[[(1-phenylethyl)amino]carbonyl]-1,6-dihydro-5-pyrimidinecarboxylate C24H25F2N3O5 详情 详情
(IX) 26658 methyl 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,6-dihydro-5-pyrimidinecarboxylate C15H16F2N2O4 详情 详情
(X) 16606 Isobutyramide; 2-methylpropanamide 563-83-7 C4H9NO 详情 详情
(XI) 26659 5-methyl 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,5(6H)-pyrimidinedicarboxylate C22H19F2N3O8 详情 详情
(XII) 26661 5-methyl 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate C21H17F2N3O8 详情 详情
(XIII) 26662 4-[(2-aminoethyl)amino]-1-phenylcyclohexanecarbonitrile C15H21N3 详情 详情
(XIV) 26663 4-oxo-1-phenylcyclohexanecarbonitrile 25115-74-6 C13H13NO 详情 详情
(XV) 14754 ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine 107-15-3 C2H8N2 详情 详情

合成路线19

该中间体在本合成路线中的序号：(II)

The reaction of L-glutamic acid di tert-butyl ester (I) with 4-nitrophenyl chloroformate (II) by means of triethylamine in dichloromethane gives the corresponding carbamate (III), which is treated with 4-methoxythiophenol (IV) in dichloromethane to afford the thiocarbamate (V). Finally, this compound is treated with HCl.

参考文献 中间体
合成目标
【1】 Browne, P.J.; Burke, P.J.; Eno-Amooquaye, E.A.; Khan, T.H.; Osborn, H.M.I.; Searle, F.; Novel inhibitors of carboxypeptidase G2 (CPG2): Potential use in antibody-directed enzyme prodrug therapy. J Med Chem 1999, 42, 6, 951.
【2】 Khan, T. (Aepact Ltd.); Drug therapy. WO 9720580 .
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) 29471 di(tert-butyl) (2S)-2-aminopentanedioate C13H25NO4 详情 详情
(II) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(III) 29472 di(tert-butyl) (2S)-2-[[(4-nitrophenoxy)carbonyl]amino]pentanedioate C20H28N2O8 详情 详情
(IV) 25639 4-methoxyphenylhydrosulfide; 4-methoxybenzenethiol 34320-82-6 C7H8OS 详情 详情
(V) 29473 di(tert-butyl) (2S)-2-([[(4-methoxyphenyl)sulfanyl]carbonyl]amino)pentanedioate C21H31NO6S 详情 详情

合成路线20

该中间体在本合成路线中的序号：(IV)

Coupling of 4-aminobenzyl alcohol (I) with diallyl L-glutamylisocyanate (II) produced the urea derivative (III). Subsequent activation of the benzylic alcohol group with 4-nitrophenyl chloroformate (IV) afforded carbonate (V). This was then condensed with doxorubicin (VI) to furnish the corresponding carbamate (VII). Finally, palladium-catalyzed cleavage of the allyl esters of (VII) yielded the title compound.

参考文献 中间体
合成目标
【1】 Friedlos, F.; Spooner, R.; Marais, R.; Springer, C.J.; Martin, J.; Niculescu-Duvaz, I.; Niculescu-Duvaz, D.; Self-immolative anthracycline prodrugs for suicide gene therapy. J Med Chem 1999, 42, 13, 2485.
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) 34430 (4-aminophenyl)methanol 623-04-1 C7H9NO 详情 详情
(II) 34431 diallyl (2S)-2-isocyanatopentanedioate C12H15NO5 详情 详情
(III) 34432 diallyl (2S)-2-([[4-(hydroxymethyl)anilino]carbonyl]amino)pentanedioate C19H24N2O6 详情 详情
(IV) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(V) 34433 diallyl (2S)-2-([[4-([[(4-nitrophenoxy)carbonyl]oxy]methyl)anilino]carbonyl]amino)pentanedioate C26H27N3O10 详情 详情
(VI) 11675 (8S,10S)-10-[[(2R,4S,5S,6S)-4-Amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-8-glycoloyl-6,8,11-trihydroxy-1-methoxy-7,8,9,10-tetrahydro-5,12-naphthacenedione C27H29NO11 详情 详情
(VII) 34434 　 C47H51N3O18 详情 详情

合成路线21

该中间体在本合成路线中的序号：

Acylation of (XII) with acetic anhydride and DMAP yielded the 3-acetyl coumarin (XIII). Following desilylation of (XIII) with tetrabutylammonium fluoride to give (XIV), condensation with O-methyl hydroxylamine gave oxime (XV). Treatment of (XV) with p-nitrophenyl chloroformate and DMAP generated carbonate (XVI), which was further coupled with O-propargyl hydroxylamine (XVII) to yield carbamate (XVIII). The tetrahydropyranyl group of (XVIII) was finally deprotected by methanolysis in the presence of p-toluenesulfonic acid.

参考文献 中间体
合成目标
【1】 Periers, A.-M.; Laurin, P.; Klich, M.; Musicki, B.; Haesslein, J.-L. (Aventis Pharma SA); Novel aromatic amides, preparation method and application as medicines. FR 2773369; WO 9935155 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(XII) 38192 4-hydroxy-7-([(7R,8R,9R,10R)-10-methoxy-8-(tetrahydro-2H-pyran-2-yloxy)-9-[(triethylsilyl)oxy]-6-oxaspiro[4.5]dec-7-yl]oxy)-8-methyl-2H-chromen-2-one C31H46O9Si 详情 详情
(XIII) 38193 3-acetyl-4-hydroxy-7-([(7R,8R,9R,10R)-10-methoxy-8-(tetrahydro-2H-pyran-2-yloxy)-9-[(triethylsilyl)oxy]-6-oxaspiro[4.5]dec-7-yl]oxy)-8-methyl-2H-chromen-2-one C33H48O10Si 详情 详情
(XIV) 38194 3-acetyl-4-hydroxy-7-[[(7R,8R,9R,10R)-9-hydroxy-10-methoxy-8-(tetrahydro-2H-pyran-2-yloxy)-6-oxaspiro[4.5]dec-7-yl]oxy]-8-methyl-2H-chromen-2-one C27H34O10 详情 详情
(XV) 38195 3-ethanimidoyl-4-hydroxy-7-[[(7R,8R,9R,10R)-9-hydroxy-10-methoxy-8-(tetrahydro-2H-pyran-2-yloxy)-6-oxaspiro[4.5]dec-7-yl]oxy]-8-methyl-2H-chromen-2-one C28H37NO10 详情 详情
(XVI) 38196 (7R,8R,9R,10R)-7-[(3-ethanimidoyl-4-hydroxy-8-methyl-2-oxo-2H-chromen-7-yl)oxy]-10-methoxy-8-(tetrahydro-2H-pyran-2-yloxy)-6-oxaspiro[4.5]dec-9-yl 4-nitrophenyl carbonate C35H40N2O14 详情 详情
(XVII) 38197 O-(2-propynyl)hydroxylamine; 3-(aminooxy)-1-propyne C3H5NO 详情 详情
(XVIII) 38198 (7R,8R,9R,10R)-7-[(3-ethanimidoyl-4-hydroxy-8-methyl-2-oxo-2H-chromen-7-yl)oxy]-10-methoxy-8-(tetrahydro-2H-pyran-2-yloxy)-6-oxaspiro[4.5]dec-9-yl 2-propynyloxycarbamate C32H40N2O12 详情 详情

合成路线22

该中间体在本合成路线中的序号：

Condensation of 4-methylpentanoyl chloride (I) with (S)-4-benzyl-2-oxazolidinone using n-BuLi afforded the N-acyloxazolidinone (III). Asymmetric alkylation of (III) with tert-butyl bromoacetate and LDA gave (IV), and subsequent removal of the chiral auxiliary by hydrolysis with lithium peroxide yielded (R)-2-isobutylsuccinic acid mono tert-butyl ester (V). This was further alkylated with allyl bromide (VI) and LDA to provide the (R,R)-2,3-disubstituted succinate (VII). Epimerization of (VII) to the required (2R,3S)-isomer (VIII) was accomplished by treatment with LDA and Et2AlCl. Benzyl ester (IX) was then prepared by reaction of (VIII) with benzyl bromide and DBU. Hydroboration of the olefinic double bond of (IX) by means of 9-borabicyclononane, followed by oxidative treatment with H2O2 gave rise to the primary alcohol (X). This was converted to carbonate (XI) upon reaction with p-nitrophenyl chloroformate and N-methylmorpholine (NMM). Coupling of (XI) with lysine derivative (XII) then yielded carbamate (XIII).

参考文献 中间体
合成目标
【1】 Xue, C.-B.; Cherney, R.J.; DeCicco, C.P.; Degrado, W.F.; He, X.; Hodge, C.N.; Jacobson, I.C.; Magolda, R.L.; Arner, E.C.; Duan, J.; Nelson, D.J. (DuPont Pharmaceuticals Co.); Novel macrocyclic cpds. as metalloprotease inhibitors. EP 0863885; JP 2000502050; WO 9718207 .
【2】 Nelson, D.; Magolda, R.L.; Jacobson, I.C.; He, X.; Arner, E.; Cherney, R.J.; Duan, J.; Xue, C.-B.; Decicco, C.P.; Degrado, W.F. (DuPont Pharmaceuticals Co.); Novel macrocyclic cpds. as metalloprotease inhibitors. EP 0981521; WO 9851665 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(I) 25390 4-methylpentanoyl chloride 38136-29-7 C6H11ClO 详情 详情
(II) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(III) 25391 (4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one C16H21NO3 详情 详情
(IV) 25392 tert-butyl (3R)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-5-methylhexanoate C22H31NO5 详情 详情
(V) 25393 (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-4-methylpentanoic acid C12H22O4 详情 详情
(VI) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(VII) 35082 (2R,3R)-3-(tert-butoxycarbonyl)-2-isobutyl-5-hexenoic acid C15H26O4 详情 详情
(VIII) 35083 (2R,3S)-3-(tert-butoxycarbonyl)-2-isobutyl-5-hexenoic acid C15H26O4 详情 详情
(IX) 35084 4-benzyl 1-(tert-butyl) (2S,3R)-2-allyl-3-isobutylbutanedioate C22H32O4 详情 详情
(X) 35085 4-benzyl 1-(tert-butyl) (2S,3R)-2-(3-hydroxypropyl)-3-isobutylbutanedioate C22H34O5 详情 详情
(XI) 35086 1-benzyl 4-(tert-butyl) (2R,3S)-2-isobutyl-3-(3-[[(4-nitrophenoxy)carbonyl]oxy]propyl)butanedioate C29H37NO9 详情 详情
(XII) 35087 methyl (2S)-6-amino-2-[[(benzyloxy)carbonyl]amino]hexanoate C15H22N2O4 详情 详情
(XIII) 35088 17-benzyl 16-(tert-butyl) 5-methyl (5S,16S,17R)-19-methyl-3,11-dioxo-1-phenyl-2,12-dioxa-4,10-diazaicosane-5,16,17-tricarboxylate C38H54N2O10 详情 详情

合成路线23

该中间体在本合成路线中的序号：(VII)

Treatment of (20S)-camptothecin (I) with HOAc and H2O2 followed by light irradiation in H2SO4 yields hydroxy derivative (II), which is then nitrated by means of HNO3 and H2SO4 to afford compound (III). Sulfonation of (III) by reaction with p-TsCl (IV) in the presence of Et3N and DMAP in CH2Cl2 provides sulfonate (V), which is then subjected to reduction by treatment with Pd(OAc)2, PPh3 and triethylammoniumformate (HCOOH·Et3N) to give 9-aminocamptothecin (VI). Reaction of (VI) with nitrophenyl chloroformate (VII) in dioxane, followed by treatment with intermediate (VIII) and DMAP in acetonitrile, provides (IX). Alternatively, (IX) can also be obtained by first treatment of (VI) with triphosgene followed by reaction with intermediate (VIII) in pyridine and chromatographic purification. Finally, (IX) is treated with potassium trimethyl silanate (KOSiMe3) for methyl ester cleavage and acidified with HCl.

参考文献 中间体
合成目标
【1】 Cabri, W.; et al.; A new high yield semisynthetic approach to (20S)-9-NH2-camptothecin based on a sequence of palladium-catalysed reductions. Tetrahedron Lett 1995, 36, 50, 9197.
【2】 Leu, Y.-L.; Roffler, S.R.; Chern, J.-W.; Design and synthesis of water-soluble glucuronide derivatives of camptothecin for cancer prodrug monotherapy and antibody-directed enzyme prodrug therapy (ADEPT). J Med Chem 1999, 42, 18, 3623.
【3】 Chern, J.-W.; Roffler, S.; Leu, Y.-L. (Academia Sinica); Proactive antitumor cpds.. EP 0990661; US 6043367 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 44149 bis(trichloromethyl) carbonate;Triphosgene 32315-10-9 C3Cl6O3 详情 详情
(I) 10816 Camptothecin; (4S)-4-Ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 4-et-4-hydroxy-1,12-dihydro-4h-2-oxa-6,12a-diaza-dibenzo(b,h)fluorene-3,13-dione 7689-03-4 C20H16N2O4 详情 详情
(II) 13340 (4S)-4-Ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 7-Ethyl-10-hydroxycamptothecin 86639-52-3 C20H16N2O5 详情 详情
(III) 43901 (4S)-4-ethyl-4,9-dihydroxy-10-nitro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione C20H15N3O7 详情 详情
(IV) 13975 p-Toluenesulfonyl chloride;p-tosyl chloride;Toluene-4-sulfonyl chloride;4-Toluene sulfochloride;tosyl chloride; 4-Methylbenzenesulfonyl chloride 98-59-9 C7H7ClO2S 详情 详情
(V) 43902 (4S)-4-ethyl-4-hydroxy-10-nitro-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-methylbenzenesulfonate C27H21N3O9S 详情 详情
(VI) 44148 (4S)-10-amino-4-ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione C20H17N3O4 详情 详情
(VII) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(VIII) 44150 methyl 3,4,5-trihydroxy-6-[4-(hydroxymethyl)phenoxy]tetrahydro-2H-pyran-2-carboxylate C14H18O8 详情 详情
(IX) 44151 methyl 6-(4-[[([[(4S)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-yl]amino]carbonyl)oxy]methyl]phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate C35H33N3O13 详情 详情

合成路线24

该中间体在本合成路线中的序号：(XII)

Treatment of 3,4-(methylenedioxy)cinnamic (VII) with SOCl2 and then with EtOH provided ethyl ester (VIII). Subsequent conjugate addition of the chiral amine (IX) to ester (VIII) in the presence of BuLi gave amino ester (X). Cleavage of benzyl and alpha-methylbenzyl protecting groups of (X) was then achieved by catalytic hydrogenolysis over Pd/C. The resulting primary amine (XI) was acylated with 4-nitrophenyl chloroformate (XII) to produce carbamate (XIII), which was condensed with amine (VI) to generate urea (XIV). Finally, basic hydrolysis of the ethyl ester of (XIV) furnished the title carboxylic acid.

参考文献 中间体
合成目标
【1】 Scott, I.L.; et al.; Novel N,N-disubstituted amides that are highly potent VLA-4 antagonists. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 284.
【2】 Raju, B.G.; Scott, I.L.; Biediger, R.J.; Market, R.V.; Grabbe, V.O.; Kassir, J.M.; Kogan, T.P.; Lin, S. (Texas Biotechnology Corp.); N,N-Disubstd. amides that inhibit the binding of integrins to their receptors. US 6096773; WO 9952493; WO 9952898 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 38468 (2S)-2-amino-N,N-bis(2-thienylmethyl)hexanamide C16H22N2OS2 详情 详情
(VII) 11634 (E)-3-(1,3-Benzodioxol-5-yl)-2-propenoic acid; 3,4-(Methylenedioxy)cinnamic acid 2373-80-0 C10H8O4 详情 详情
(VIII) 38469 ethyl (E)-3-(1,3-benzodioxol-5-yl)-2-propenoate C12H12O4 详情 详情
(IX) 38470 (1S)-N-benzyl-1-phenyl-1-ethanamine; N-benzyl-N-[(1S)-1-phenylethyl]amine 38235-77-7 C15H17N 详情 详情
(X) 38471 ethyl (3S)-3-(1,3-benzodioxol-5-yl)-3-[benzyl[(1S)-1-phenylethyl]amino]propanoate C27H29NO4 详情 详情
(XI) 38472 ethyl (3S)-3-amino-3-(1,3-benzodioxol-5-yl)propanoate C12H15NO4 详情 详情
(XII) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(XIII) 38473 ethyl (3S)-3-(1,3-benzodioxol-5-yl)-3-[[(4-nitrophenoxy)carbonyl]amino]propanoate C19H18N2O8 详情 详情
(XIV) 38474 ethyl (3S)-3-(1,3-benzodioxol-5-yl)-3-([[((1S)-1-[[bis(2-thienylmethyl)amino]carbonyl]pentyl)amino]carbonyl]amino)propanoate C29H35N3O6S2 详情 详情

合成路线25

该中间体在本合成路线中的序号：(X)

Treatment of protected derivative (I) with ethyl chloroformate (II) and DMAP in dichloromethane yields (III), which is then protected by Mitsunobu reaction with benzyl alcohol (IV) in the presence of PPh3 and DEAD to provide (V). Coumarin (V) undergoes Mitsunobu reaction with noviose (VI) to afford alpha-glycoside (VII), which is converted into (VIII) by protection in 3'-OH by means of TESCl, imidazole and DIEA in dichloromethane (chromatographic separation of 3'- and 2'-TES-protected regioisomers is needed), followed by protection of the 2'-OH by treatment with DHP and catalytic TsOH in dichloromethane. Hydrogenolysis of (VIII) over Pd/C followed by desilylation with TBAF in THF affords intermediate (IX), which is then converted into N'-alkoxycarbamate (XII) by reaction with (X) and DMAP in dichloromethane to yield the corresponding p-nitrophenylcarbonate activated form, followed by reaction with hydroxylamine (XI) in DMF and catalysis of DMAP. Exchange of the 3-ester group in (XII) by hydroxylamine (XIII) in pyridine gives coumarin-3-hydroxamate derivative (XIV), which is finally deprotected of its THP form in MeOH and catalysis of TsOH.

参考文献 中间体
合成目标
【1】 Haesslein, J.-L.; Dupuis-Hamelin, C.; Periers, A.-M.; Ferroud, D.; Laurin, P.; Bonnefoy, A.; Lassaigne, P.; Misicki, B.; Klich, M.; Mauvais, P.; Coumarin inhibitors of gyrase B with N-propargyloxy-carbamate as an effective pyrrole bioisostere. Bioorg Med Chem Lett 2000, 10, 2, 161.
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) 42325 4-hydroxy-8-methyl-7-(tetrahydro-2H-pyran-2-yloxy)-2H-chromen-2-one C15H16O5 详情 详情
(II) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(III) 42326 ethyl 4-hydroxy-8-methyl-2-oxo-7-(tetrahydro-2H-pyran-2-yloxy)-2H-chromene-3-carboxylate C18H20O7 详情 详情
(IV) 18710 Benzyl alcohol; Phenylmethanol 100-51-6 C7H8O 详情 详情
(V) 42327 ethyl 4-(benzyloxy)-7-hydroxy-8-methyl-2-oxo-2H-chromene-3-carboxylate C20H18O6 详情 详情
(VI) 40547 (3R,4S,5R)-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2,3,4-triol C8H16O5 详情 详情
(VII) 42328 ethyl 4-(benzyloxy)-7-[[(2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-2-oxo-2H-chromene-3-carboxylate C27H30O10 详情 详情
(VIII) 42329 ethyl 4-(benzyloxy)-7-([(2R,3R,4R,5R)-5-methoxy-6,6-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-4-[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]oxy)-2-oxo-2H-chromene-3-carboxylate C38H52O11Si 详情 详情
(IX) 42330 ethyl 4-hydroxy-7-[[(2R,3R,4R,5R)-4-hydroxy-5-methoxy-6,6-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-2-yl]oxy]-2-oxo-2H-chromene-3-carboxylate C25H32O11 详情 详情
(X) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(XI) 38197 O-(2-propynyl)hydroxylamine; 3-(aminooxy)-1-propyne C3H5NO 详情 详情
(XII) 42331 ethyl 4-hydroxy-7-[[(2R,3R,4R,5R)-5-methoxy-6,6-dimethyl-4-([[(2-propynyloxy)amino]carbonyl]oxy)-3-(tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-2-yl]oxy]-2-oxo-2H-chromene-3-carboxylate C29H35NO13 详情 详情
(XIII) 42332 1-(aminooxy)-3-methyl-2-butene; O-(3-methyl-2-butenyl)hydroxylamine C5H11NO 详情 详情
(XIV) 42333 (3R,4R,5R,6R)-6-[[4-hydroxy-3-([[(3-methyl-2-butenyl)oxy]amino]carbonyl)-2-oxo-2H-chromen-7-yl]oxy]-3-methoxy-2,2-dimethyl-5-(tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-4-yl 2-propynyloxycarbamate C32H40N2O13 详情 详情

合成路线26

该中间体在本合成路线中的序号：(I)

The title compound was prepared by solid-phase synthesis. Resin (II) was treated with 4-nitrophenyl chloroformate (I), and the activated nitrophenyl carbonate resin (III) was coupled to (R)-N-[2-(4-aminophenyl)ethyl]-2-hydroxy-2-(pyrid-3-yl)ethylamine (IV) to furnish the resine-bound aniline (V). After protection of the hydroxyl group as the triethylsilyl ether (VI), reaction with 4-cyanobenzenesulfonyl chloride (VII) in the presence of pyridine provided the resine-bound sulfonamide (VIII). Addition of hydroxylamine to the cyano group of (VIII) afforded the corresponding amidoxime (IX). The required oxadiazole (XI) was obtained by acylation of (IX) with 4-(trifluoromethoxy)phenylacetic acid (X) in the presence of EDC, followed by heating in diglyme to effect the cyclization. Cleavage from the resin and simultaneous desilylation was achieved by treatment with trifluoroacetic acid in dichloromethane.

参考文献 中间体
合成目标
【1】 Biftu, T.; Liang, G.-B.; Feng, D.D.; et al.; Synthesis and SAR of benzyl and phenoxymethylene oxadiazole benzenesulfonamides as selective beta3 adrenergic receptor agonist antiobesity agents. Bioorg Med Chem Lett 2000, 10, 13, 1431.
【2】 Biftu, T.; Feng, D.D.; Fisher, M.H.; Kuo, C.-H.; Liang, G.-B.; Weber, A.E.; Naylor, E.M. (Merck & Co., Inc.); Oxadiazole benzenesulfonamides as selective beta3 agonists for the treatment of diabetes and obesity. EP 0906310; US 6034106; WO 9746556 .
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) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(II) 38837 4-nitrophenyl hydrogen carbonate C7H5NO5 详情 详情
(III) 26652 tert-butyl (3S,4S)-1-benzyl-4-methoxypyrrolidinylcarbamate C17H26N2O3 详情 详情
(IV) 42097 4-aminophenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamic acid C16H19N3O3 详情 详情
(V) 42098 4-aminophenethyl[(2R)-2-(3-pyridinyl)-2-[(triethylsilyl)oxy]ethyl]carbamic acid C22H33N3O3Si 详情 详情
(VI) 29284 4-cyanobenzenesulfonyl chloride 49584-26-1 C7H4ClNO2S 详情 详情
(VII) 42099 4-[[(4-cyanophenyl)sulfonyl]amino]phenethyl[(2R)-2-(3-pyridinyl)-2-[(triethylsilyl)oxy]ethyl]carbamic acid C29H36N4O5SSi 详情 详情
(VIII) 42100 4-[([4-[amino(hydroxyimino)methyl]phenyl]sulfonyl)amino]phenethyl[(2R)-2-(3-pyridinyl)-2-[(triethylsilyl)oxy]ethyl]carbamic acid C29H39N5O6SSi 详情 详情
(IX) 29289 2-[4-(trifluoromethoxy)phenyl]acetic acid 4315-07-5 C9H7F3O3 详情 详情
(X) 42101 (2R)-2-(3-pyridinyl)-2-[(triethylsilyl)oxy]ethyl(4-[[(4-[5-[4-(trifluoromethoxy)benzyl]-1,2,4-oxadiazol-3-yl]phenyl)sulfonyl]amino]phenethyl)carbamic acid C38H42F3N5O7SSi 详情 详情

合成路线27

该中间体在本合成路线中的序号：(XI)

The reaction of (S)-(+)-methyl lactate (I) with pyrrolidine (II) gives the corresponding acyl pyrrolidine (III), which is silylated with Tbdms-Cl and imidazole to yield the silyl ether (IV). The condensation of (IV) with 3,4-difluorobromobenzene (V) by means of BuLi in THF affords the chiral propiophenone derivative (VI), which is treated with hydroxylamine and NaOAc in methanol to provide the corresponding oxime (VII). The reduction of (VII) with LiAlH4 in refluxing ethyl ether gives the expected amine (VIII), which is treated with (Boc)2O in chloroform, yielding the carbamate (IX). The cyclization of (IX) by means of NaH in THF gives a mixture of cis- and trans-oxazolidinones, from which the desired trans-(4S,5S)-isomer (X) is separated by flash chromatography. The reaction of (X) with 4-nitrophenyl chloroformate (XI) by means of NaH yields the oxazolidinone-carboxylate (XII), which is finally condensed with 3-[4-(4-fluorophenyl)piperidin-1-yl]propylamine (XIII) in THF to afford the target amide.

参考文献 中间体
合成目标
【1】 Lagu, B.; Wetzel, J.M.; Forray, C.; Patane, M.A.; Bock, M.G.; Determination of the relative and absolute stereochemistry of a potent and alpha1A-selective adrenoceptor antagonist. Bioorg Med Chem Lett 2000, 10, 24, 2705.
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) 17075 propionic acid, 2-hydroxy-, methyl ester, (S)-; methyl (2S)-2-hydroxypropanoate 27871-49-4 C4H8O3 详情 详情
(II) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情
(III) 17099 (2S)-2-hydroxy-1-(1-pyrrolidinyl)-1-propanone C7H13NO2 详情 详情
(IV) 51565 (2S)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-(1-pyrrolidinyl)-1-propanone C13H27NO2Si 详情 详情
(V) 51566 1-Bromo-3,4-difluorobenzene; 3,4-Difluorobromobenzene; 4-Bromo-1,2-difluorobenzene 348-61-8 C6H3BrF2 详情 详情
(VI) 51567 (2S)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-(3,4-difluorophenyl)-1-propanone C15H22F2O2Si 详情 详情
(VII) 51568 (2S)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-(3,4-difluorophenyl)-1-propanone oxime C15H23F2NO2Si 详情 详情
(VIII) 51569 (2S)-1-amino-1-(3,4-difluorophenyl)-2-propanol C9H11F2NO 详情 详情
(IX) 51570 tert-butyl (2S)-1-(3,4-difluorophenyl)-2-hydroxypropylcarbamate C14H19F2NO3 详情 详情
(X) 43324 (4S,5S)-4-(3,4-difluorophenyl)-5-methyl-1,3-oxazolidin-2-one C10H9F2NO2 详情 详情
(XI) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(XII) 43325 3,4-difluorobenzylamine; (3,4-difluorophenyl)methanamine 72235-53-1 C7H7F2N 详情 详情
(XIII) 39302 3-[4-(4-fluorophenyl)-1-piperidinyl]propylamine; 3-[4-(4-fluorophenyl)-1-piperidinyl]-1-propanamine C14H21FN2 详情 详情

合成路线28

该中间体在本合成路线中的序号：

Treatment of 6-nitroindole (I) with aqueous NaNO2 and HCl affords 3-indazolecarboxaldehyde (II), which is then subjected to reductive amination with pyrrolidine (III) by means of NaBH(OAc)3 in dichloroethane/DMF in the presence of acetic acid to provide compound (IV). Alkylation of (IV) with 2,6-dichlorobenzyl bromide (V) by means of KOH in THF yields compound (VI), whose nitro group is reduced with dimethyl hydrazine (Me2NNH2), FeCl3 and charcoal in refluxing MeOH to furnish aminoindazole intermediate (VII). The synthesis of intermediate (XIII) is performed as follows: Coupling of protected diaminobutyric acid (VIII) with benzylamine (IX) by means of DCC and HOBt in acetonitrile, followed by Fmoc removal after treatment with diethylamine, gives derivative (X), which is then condensed with protected difluorophenylalanine (XI) by means of DIC and HOBt in acetonitrile to afford protected dipeptide (XII). Finally, intermediate (XIII) is obtained by Fmoc removal of (XII) by treatment with ethylamine. The desired product is finally obtained by condensation of intermediates (VII) and (XIII) by means of 4-nitrophenyl chloroformate and DIEA in dichloromethane, followed by Boc removal with TFA in dichloromethane.

参考文献 中间体
合成目标
【1】 Andrade-Gordon, P.; Zhang, H.-C.; Derian, C.K.; et al.; Discovery and optimization of a novel series of thrombin receptor (PAR-1) antagonists: Potent, selective peptide mimetics based on indole and indazole templates. J Med Chem 2001, 44, 7, 1021.
【2】 Zhang, H.-C.; Pandey, A.; Scarborough, R.M.; Maryanoff, B.E. (COR Therapeutics, Inc.; Ortho-McNeil Pharmaceutical, Inc.); Novel indazole peptidomimetics as thrombin receptor antagonists. WO 0100656 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(I) 39294 6-Nitroindole; 6-Nnitro-1H-indole 4769-96-4 C8H6N2O2 详情 详情
(II) 48891 6-nitro-1H-indazole-3-carbaldehyde C8H5N3O3 详情 详情
(III) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情
(IV) 48892 6-nitro-3-(1-pyrrolidinylmethyl)-1H-indazole C12H14N4O2 详情 详情
(V) 40793 2-(bromomethyl)-1,3-dichlorobenzene 20443-98-5 C7H5BrCl2 详情 详情
(VI) 48893 1-(2,6-dichlorobenzyl)-6-nitro-3-(1-pyrrolidinylmethyl)-1H-indazole C19H18Cl2N4O2 详情 详情
(VII) 48894 1-(2,6-dichlorobenzyl)-3-(1-pyrrolidinylmethyl)-1H-indazol-6-ylamine; 1-(2,6-dichlorobenzyl)-3-(1-pyrrolidinylmethyl)-1H-indazol-6-amine C19H20Cl2N4 详情 详情
(VIII) 42257 (2S)-4-[(tert-butoxycarbonyl)amino]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]butyric acid 125238-99-5 C24H28N2O6 详情 详情
(IX) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(X) 48895 tert-butyl (3S)-3-amino-4-(benzylamino)-4-oxobutylcarbamate C16H25N3O3 详情 详情
(XI) 42260 (2S)-3-(3,4-difluorophenyl)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid C24H19F2NO4 详情 详情
(XII) 48896 9H-fluoren-9-ylmethyl (1S)-2-([(1S)-1-[(benzylamino)carbonyl]-3-[(tert-butoxycarbonyl)amino]propyl]amino)-1-(3,4-difluorobenzyl)-2-oxoethylcarbamate C40H42F2N4O6 详情 详情
(XIII) 48897 tert-butyl (3S)-3-[[(2S)-2-amino-3-(3,4-difluorophenyl)propanoyl]amino]-4-(benzylamino)-4-oxobutylcarbamate C25H32F2N4O4 详情 详情

合成路线29

该中间体在本合成路线中的序号：(II)

Esterification of the primary hydroxyl group of dexamethasone (I) by treatment with 4-nitrophenyl chloroformate (II) in the presence of N-methylmorpholine afforded the nitrophenyl carbonate (III). Condensation of the active ester (III) with mono-N-Boc-1,6-diaminohexane (IV) produced carbamate (V). After acidic deprotection of the Boc group, the resultant amine (VI) was acylated with succinimidyl 4-maleimidobutyrate (VII), yielding the title amide.

参考文献 中间体
合成目标
【1】 Bernasconi, A.; et al.; Synthesis of a dexamethasone-21-maleimido-linked derivative as a potential molecule for specific gene delivery. Tetrahedron Lett 2001, 42, 37, 6511.
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) 40461 (8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-17-glycoloyl-11,17-dihydroxy-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one C22H29FO5 详情 详情
(II) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(III) 50240 2-[(8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 4-nitrophenyl carbonate C29H32FNO9 详情 详情
(IV) 31638 tert-butyl 6-aminohexylcarbamate 51857-17-1 C11H24N2O2 详情 详情
(V) 50241 2-[(8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 6-[(tert-butoxycarbonyl)amino]hexylcarbamate C34H51FN2O8 详情 详情
(VI) 50242 2-[(8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 6-aminohexylcarbamate C29H43FN2O6 详情 详情
(VII) 50243 4-Maleimidobutyric acid N-hydroxysuccinimide ester; Maleimidobutyric acid N-hydroxysuccinimide ester; N-(4-Maleimidobutyryloxy)succinimide; N-(gamma-Maleimidobutyryloxy)succinimide; N-Succinimidyl 4-Maleimidobutyrate 80307-12-6 C12H12N2O6 详情 详情

合成路线30

该中间体在本合成路线中的序号：(XIII)

Esterification of 3-(4-hydroxyphenyl)propionic acid (I), followed by alkylation of the phenolic hydroxyl, provided methyl 3-(4-benzyloxyphenyl)propionate (II), which was hydrolyzed to the corresponding carboxylic acid (III) by means of LiOH. Coupling of carboxylic acid (III) with the chiral auxiliary (S)-4-benzyl-2-oxazolidinone (IV) gave the oxazolide (V), which was subjected to diastereoselective alkylation with tert-butyl bromoacetate (VI), yielding (VII). Subsequent removal of the chiral auxiliary group of (VII) using lithium hydroperoxide afforded the (R)-acid (VIII). Alkylation of the dianion of acid (VIII) with allyl bromide (IX) and further epimerization in the presence of LDA and Et2AlCl furnished the anti-dialkylated succinate (X). The carboxyl group of (X) was then alkylated using benzyl bromide and DBU to produce the corresponding benzyl ester (XI). Olefin (XI) hydroboration followed by oxidative work-up gave rise to the primary alcohol (XII). This was acylated with 4-nitrophenyl chloroformate (XIII) to provide the activated carbonate (XIV).

参考文献 中间体
合成目标
【1】 Xue, C.-B.; et al.; Discovery of macrocyclic hydroxamic acids containing biphenylmethyl derivatives at P1', a series of selective TNF-alpha converting enzyme inhibitors with potent cellular activity in the inhibition of TNF-alpha release. J Med Chem 2001, 44, 21, 3351.
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) 25691 3-(4-hydroxyphenyl)propionic acid 501-97-3 C9H10O3 详情 详情
(II) 53167 methyl 3-[4-(benzyloxy)phenyl]propanoate n/a C17H18O3 详情 详情
(III) 53168 3-[4-(benzyloxy)phenyl]propanoic acid 50463-48-4 C16H16O3 详情 详情
(IV) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(V) 53169 (4S)-4-benzyl-3-{3-[4-(benzyloxy)phenyl]propanoyl}-1,3-oxazolidin-2-one n/a C26H25NO4 详情 详情
(VI) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(VII) 53170 tert-butyl (3R)-4-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-[4-(benzyloxy)benzyl]-4-oxobutanoate n/a C32H35NO6 详情 详情
(VIII) 53171 (2R)-2-[4-(benzyloxy)benzyl]-4-(tert-butoxy)-4-oxobutanoic acid n/a C22H26O5 详情 详情
(IX) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(X) 53172 (2R,3S)-2-[4-(benzyloxy)benzyl]-3-(tert-butoxycarbonyl)-5-hexenoic acid n/a C25H30O5 详情 详情
(XI) 53173 4-benzyl 1-(tert-butyl) (2S,3R)-2-allyl-3-[4-(benzyloxy)benzyl]butanedioate n/a C32H36O5 详情 详情
(XII) 53174 1-benzyl 4-(tert-butyl) (2R,3S)-2-[4-(benzyloxy)benzyl]-3-(3-hydroxypropyl)butanedioate n/a C32H38O6 详情 详情
(XIII) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(XIV) 53175 1-benzyl 4-(tert-butyl) (2R,3S)-2-[4-(benzyloxy)benzyl]-3-(3-{[(4-nitrophenoxy)carbonyl]oxy}propyl)butanedioate n/a C39H41NO10 详情 详情

合成路线31

该中间体在本合成路线中的序号：(X)

The phenolic hydroxyl group of (IX) is acylated by 4-nitrophenyl chloroformate (X), producing carbonate (XI). Then, displacement of the 4-nitrophenoxy group of (XI) with N-methylpiperazine (XII) yields carbamate (XIII). Finally, nitro group reduction in (XIII) gives rise to the title compound

参考文献 中间体
合成目标
【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
(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
(X) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(XI) 63446 methyl 8-(chloromethyl)-2-methyl-6-[(5-{[(7-nitro-1H-indol-2-yl)carbonyl]amino}-1-benzofuran-2-yl)carbonyl]-4-({[(4-nitrophenyl)oxy]carbonyl}oxy)-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate C39H27ClN6O12 详情 详情
(XII) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(XIII) 63447 methyl 8-(chloromethyl)-2-methyl-4-{[(4-methyl-1-piperazinyl)carbonyl]oxy}-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 C38H34ClN7O9 详情 详情

合成路线32

该中间体在本合成路线中的序号：(X)

The title compound was synthesized within a combinatorial library on a Wang polystyrene resin. Attachment of N-Fmoc-(R)-beta-phenylalanine (I) to the solid support was achieved via activation with 2,6-dichlorobenzoyl chloride to afford the aminoacid-bound resin (II). After conventional Fmoc group deprotection with piperidine in DMF, the resultant amine resin (III) was acylated with 5-bromo-2-methoxybenzenesulfonyl chloride (IV) yielding sulfonamide (V). Mitsunobu coupling between aryl bromide (V) and 3-nitrobenzeneboronic acid (VI) gave rise to the biphenyl derivative (VII). Reduction of the nitro group of (VII) to the corresponding aniline (VIII) was then performed by treatment with stannous chloride in N-methylpyrrolidone. Alternatively, the aminobiphenyl resin (VIII) was directly prepared by coupling between aryl bromide (V) and 3-aminobenzeneboronic acid (IX). Reaction of amine (VIII) with p-nitrophenyl chloroformate (X) produced the nitrophenyl carbamate resin (IX), which was further reacted with 2-aminobenzimidazole (XII) to furnish urea (XIII). Final resin cleavage was effected by treatment with trifluoroacetic acid in CH2Cl2.

参考文献 中间体
合成目标
【1】 Gerdes, C.; Albers, M.; Schmidt, D.; Stelte-Ludwig, B.; Bruggemeier, U.; Vaupel, A.; Harter, M.; Urbahns, K.; Biphenyls as potent vitronectin receptor antagonists. Bioorg Med Chem Lett 2002, 12, 2, 205.
【2】 Schmidt, D.; Urbahns, K.; Gerdes, C.; Keldenich, J.; Härter, M.; Stahl, E.; Albers, M.; Vaupel, A.; Stelte-Ludwig, B.; Brüggemeier, U.; Lustig, K. (Bayer AG); New biphenyl and biphenyl-analogous cpds. as integrin antagonists. EP 1140809; JP 2002532465; US 6420396; WO 0035864 .
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),(II) 56271 Fmoc-(R)-3-amino-3-phenylpropionic acid C24H21NO4 详情 详情
(III) 56272 (3R)-3-amino-3-phenylpropanoic acid C9H11NO2 详情 详情
(IV) 56273 5-Bromo-2-methoxybenzenesulfonyl chloride 23095-05-8 C7H6BrClO3S 详情 详情
(V) 56274 (3R)-3-{[(5-bromo-2-methoxyphenyl)sulfonyl]amino}-3-phenylpropanoic acid C16H16BrNO5S 详情 详情
(VI) 40934 3-nitrophenylboronic acid 13331-27-6 C6H6BNO4 详情 详情
(VII) 56275 (3R)-3-{[(4-methoxy-3'-nitro[1,1'-biphenyl]-3-yl)sulfonyl]amino}-3-phenylpropanoic acid C22H20N2O7S 详情 详情
(VIII) 56276 (3-Aminophenyl)dihydroxyborane; 3-Aminobenzeneboronic acid; 3-Aminophenylboronic acid 30418-59-8 C22H22N2O5S 详情 详情
(IX) 56277 3-aminophenylboronic acid C6H8BNO2 详情 详情
(X) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(XI) 56278 (3R)-3-{[(4-methoxy-3'-{[(4-nitrophenoxy)carbonyl]amino}[1,1'-biphenyl]-3-yl)sulfonyl]amino}-3-phenylpropanoic acid C29H25N3O9S 详情 详情
(XII) 48437 2-Aminobenzimidazole; 2-Amino-1H-benzimidazol; 1H-Benzimidazol-2-amine; 2-Benzimidazolamine 934-32-7 C7H7N3 详情 详情
(XIII) 56279 (3R)-3-{[(3'-{[(1H-benzimidazol-2-ylamino)carbonyl]amino}-4-methoxy[1,1'-biphenyl]-3-yl)sulfonyl]amino}-3-phenylpropanoic acid C30H27N5O6S 详情 详情

合成路线33

该中间体在本合成路线中的序号：(IV)

The target piperazine-1-carboxamide has been obtained by several different methods: 1.- The condensation of 6,7-dimethoxy-4-(1-piperazinyl)quinazoline (I) with 4-chlorophenyl isocyanate (II) in DMF gives the target compound. 2.- The condensation of 6,7-dimethoxy-4-(1-piperazinyl)quinazoline (I) with 4-chlorophenylamine (III) by means of CDI or triphosgene also gives the target piperazine-1-carboxamide. 3.- The reaction of 4-chlorophenylamine (III) with 4-nitrophenyl chloroformate (IV) by means of TEA gives the carbamate (V), which is finally condensed with the quinazoline (I) in hot NMP to yield the target piperazine-1-carboxamide.

参考文献 中间体
合成目标
【1】 Matsuno, K.; Ichimura, M.; Nakajima, T.; Tahara, K.; Fujiwara, S.; Kase, H.; Ushiki, J.; Giese, N.A.; Pandey, A.; Scarborough, R.M.; Lokker, N.A.; Yu, J.C.; Irie, J.; Tsukuda, E.; Ide, S.-i; Oda, S.; Nomoto, Y.; Potent and selective inhibitors of platelet-derived growth factor receptor phosphorylation. 1. Synthesis, structure-activity relationship, and biological effects of a new class of quinazoline derivatives. J Med Chem 2002, 45, 14, 3057.
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) 41610 6,7-dimethoxy-4-(1-piperazinyl)quinazoline; 6-methoxy-4-(1-piperazinyl)-7-quinazolinyl methyl ether C14H18N4O2 详情 详情
(II) 12035 4-chlorophenyl isocyanate; 1-Chloro-4-isocyanatobenzene; p-Chlorophenyl isocyanate 104-12-1 C7H4ClNO 详情 详情
(III) 12034 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline 106-47-8 C6H6ClN 详情 详情
(IV) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(V) 63171 4-nitrophenyl 4-chlorophenylcarbamate C13H9ClN2O4 详情 详情

合成路线34

该中间体在本合成路线中的序号：(IX)

Reaction of tyramine (VIII) with p-nitrophenyl chloroformate (IX) gives rise to the nitrophenyl carbamate (X). Finally, coupling of (X) with aniline (VII) provides the title urea.

参考文献 中间体
合成目标
【1】 Jordan, A.M.; Khan, T.H.; Malkin, H.; Osborn, H.M.I.; Synthesis and analysis of urea and carbamate prodrugs as candidates for melanocyte-directed enzyme prodrug therapy (MDEPT). Bioorg Med Chem 2002, 10, 8, 2625.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 64082 N~1~,N~1~-bis(2-chloroethyl)-1,4-benzenediamine; N-(4-aminophenyl)-N,N-bis(2-chloroethyl)amine C10H14Cl2N2 详情 详情
(VIII) 19988 4-(2-Aminoethyl)phenol; Tyramine 51-67-2 C8H11NO 详情 详情
(IX) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(X) 64083 4-nitrophenyl 4-hydroxyphenethylcarbamate C15H14N2O5 详情 详情
Extended Information