|
【结 构 式】 
|
【分子编号】25718 【品名】2,4,6-trichlorobenzoyl chloride 【CA登记号】4136-95-2 |
【 分 子 式 】C7H2Cl4O 【 分 子 量 】243.90308 【元素组成】C 34.47% H 0.83% Cl 58.14% O 6.56% |
合成路线1
该中间体在本合成路线中的序号：(II)The reaction of rapamycin (III) with chlorotrimethylsilane and imidazole in AcOEt gives 31,42-bis-O-(trimethylsilyl)rapamycin, which, without isolation, is partially deprotected with sulfuric acid to provide 31-O-(trimethylsilyl)rapamycin (V). Coupling ether (V) with either 2,2,5-trimethyl-1,3-dioxane-5-carboxylic acid chloride (VI) by means of DMAP in CH2Cl2/DMF or with carboxylic acid (I) pretreated with 2,4,6-trichlorobenzoyl chloride (II) and DIEA by means of DMAP in CH2Cl2 yields the protected rapamycin 42-ester (VII). Removing the trimethylsilyl group of (VII) by treatment with 0.5N sulfuric acid in acetone affords ester (VIII), which is finally converted into CCI-779 by hydrolysis of the ketal group by means of 2N sulfuric acid in THF.
| 【1】 Sorbera, L.A.; del Fresno, M.; Castaner, J.; CCI-779. Drugs Fut 2002, 27, 1, 7. |
| 【2】 Skotnicki, J.S.; Leone, C.L.; Schiehser, G.A. (American Home Products Corp.); Rapamycin hydroxyesters. EP 0763039; JP 1997512018; US 5362718; WO 9528406 . |
| 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) | 51488 | 2,2,5-trimethyl-1,3-dioxane-5-carboxylic acid | C8H14O4 | 详情 | 详情 | |
| (II) | 25718 | 2,4,6-trichlorobenzoyl chloride | 4136-95-2 | C7H2Cl4O | 详情 | 详情 |
| (III) | 20296 | (1R,9S,12S,15R,18R,19R,21R,23S,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0(4,9)]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone | 53123-88-9 | C51H79NO13 | 详情 | 详情 |
| (V) | 51487 | (1R,9S,12S,15R,18R,19R,21R,23S,30S,32S,35R)-1-hydroxy-12-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-18-[(trimethylsilyl)oxy]-11,36-dioxa-4-azatricyclo[30.3.1.0(4,9)]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone | C54H87NO13Si | 详情 | 详情 | |
| (VI) | 51489 | 2,2,5-trimethyl-1,3-dioxane-5-carbonyl chloride | C8H13ClO3 | 详情 | 详情 | |
| (VII) | 51490 | (1R,2R,4S)-4-((2R)-2-[(1R,9S,12S,15R,18R,19R,21R,23S,30S,32S,35R)-1-hydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-18-[(trimethylsilyl)oxy]-11,36-dioxa-4-azatricyclo[30.3.1.0(4,9)]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl)-2-methoxycyclohexyl 2,2,5-trimethyl-1,3-dioxane-5-carboxylate | C62H99NO16Si | 详情 | 详情 | |
| (VIII) | 51491 | (1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,18R,19R,21R,23S,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0(4,9)]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl 2,2,5-trimethyl-1,3-dioxane-5-carboxylate | C59H91NO16 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)2,2-Bis(hydroxymethyl)propionic acid isopropylidene ketal (I) is activated by treatment with 2,4,6-trichlorobenzoyl chloride (II) and triethylamine in anhydrous THF at 0 C. The resulting activated acid is then coupled with rapamycin (III) by means of DMAP in benzene to provide the protected rapamycin derivative (IV). Finally, CCI-779 is obtained by hydrolysis of the ketal group with HCl in THF.
| 【1】 Sorbera, L.A.; del Fresno, M.; Castaner, J.; CCI-779. Drugs Fut 2002, 27, 1, 7. |
| 【2】 Noureldin, R.; Fortier, G.; Cheal, G.K.; Shaw, C.-C.; Sellstedt, J.H. (American Home Products Corp.); Regioselective synthesis of rapamycin derivs.. WO 0123395 . |
| 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) | 51488 | 2,2,5-trimethyl-1,3-dioxane-5-carboxylic acid | C8H14O4 | 详情 | 详情 | |
| (II) | 25718 | 2,4,6-trichlorobenzoyl chloride | 4136-95-2 | C7H2Cl4O | 详情 | 详情 |
| (III) | 20296 | (1R,9S,12S,15R,18R,19R,21R,23S,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0(4,9)]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone | 53123-88-9 | C51H79NO13 | 详情 | 详情 |
| (IV) | 51491 | (1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,18R,19R,21R,23S,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0(4,9)]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl 2,2,5-trimethyl-1,3-dioxane-5-carboxylate | C59H91NO16 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)Boron enolate obtained from chiral propionyloxazolidinone (I) and dibutylboron triflate (Bu2BOTf) was condensed with n-octanal (II) to produce the syn aldol compound (III), which was protected as the silyl ether (IV) with tert-butyldimethylsilyl triflate. Then, removal of the chiral auxiliary by hydrolysis with lithium peroxide afforded the (2S,3R)-beta-(silyloxy)acid (V). After activation as the mixed anhydride (VII) with 2,4,6-trichlorobenzoyl chloride (VI), esterification with benzyl (S)-2-hydroxy-3-methylbutyrate (VIII) gave diester (IX). Subsequent removal of the silyl group using HF in acetonitrile provided intermediate (X).
| 【1】 Wagner, B.; et al.; Total synthesis and conformational studies of hapalosin, N-desmethylhapalosin and 8-deoxyhapalosin. Bioorg Med Chem 1999, 7, 5, 737. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40666 | tert-butyl(dimethyl)silyl trifluoromethanesulfonoperoxoate | C7H15F3O4SSi | 详情 | 详情 | ||
| (I) | 25713 | (4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (II) | 25714 | octanal | 124-13-0 | C8H16O | 详情 | 详情 |
| (III) | 25715 | (4S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2-methyldecanoyl]-1,3-oxazolidin-2-one | C21H31NO4 | 详情 | 详情 | |
| (IV) | 25716 | (4S)-4-benzyl-3-((2S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyldecanoyl)-1,3-oxazolidin-2-one | C27H45NO4Si | 详情 | 详情 | |
| (V) | 25717 | (2S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyldecanoic acid | C17H36O3Si | 详情 | 详情 | |
| (VI) | 25718 | 2,4,6-trichlorobenzoyl chloride | 4136-95-2 | C7H2Cl4O | 详情 | 详情 |
| (VII) | 25719 | (2S,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methyldecanoic 2,4,6-trichloro-1-benzenecarboxylic anhydride | C24H37Cl3O4Si | 详情 | 详情 | |
| (VIII) | 25720 | benzyl (2S)-2-hydroxy-3-methylbutanoate | C12H16O3 | 详情 | 详情 | |
| (IX) | 25721 | (1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyldecanoate | C29H50O5Si | 详情 | 详情 | |
| (X) | 25722 | (1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2S,3R)-3-hydroxy-2-methyldecanoate | C23H36O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)Treatment of N-Boc-L-phenylalanine (XI) with carbonyl diimidazole, followed by condensation with the lithium enolate of ethyl acetate provided the beta-ketoester (XII). Then, reduction with NaBH4 in EtOH at -78 C furnished the anti aminoalcohol (XIII) as the major isomer. Subsequent reaction with formaldehyde in the presence of p-toluenesulfonic acid in boiling toluene produced the cis oxazolidine (XIV). Basic hydrolis of the ester group yielded carboxylic acid (XV) which, after activation as the mixed anhydride with 2,4,6-trichlorobenzoyl chloride (VI), was coupled to hydroxyester (X) to give triester (XVI). Reduction of the oxazolidine with NaBH3CN in the presence of trifluoroacetic acid afforded the N-methylated derivative (XVII). Then, hydrogenolysis of the benzyl ester in the presence of Pd/C produced acid (XVIII), which was finally cyclized using DPPA.
| 【1】 Wagner, B.; et al.; Total synthesis and conformational studies of hapalosin, N-desmethylhapalosin and 8-deoxyhapalosin. Bioorg Med Chem 1999, 7, 5, 737. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 25718 | 2,4,6-trichlorobenzoyl chloride | 4136-95-2 | C7H2Cl4O | 详情 | 详情 |
| (X) | 25722 | (1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2S,3R)-3-hydroxy-2-methyldecanoate | C23H36O5 | 详情 | 详情 | |
| (XI) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (XII) | 12876 | ethyl (4S)-4-[(tert-butoxycarbonyl)amino]-3-oxo-5-phenylpentanoate | C18H25NO5 | 详情 | 详情 | |
| (XIII) | 25723 | ethyl (3R,4S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-phenylpentanoate | C18H27NO5 | 详情 | 详情 | |
| (XIV) | 25724 | tert-butyl (4S,5R)-4-benzyl-5-(2-ethoxy-2-oxoethyl)-1,3-oxazolidine-3-carboxylate | C19H27NO5 | 详情 | 详情 | |
| (XV) | 25725 | 2-[(4S,5R)-4-benzyl-3-(tert-butoxycarbonyl)-1,3-oxazolidin-5-yl]acetic acid | C17H23NO5 | 详情 | 详情 | |
| (XVI) | 25726 | tert-butyl (4S,5R)-4-benzyl-5-[2-([(1S)-1-[(1S)-2-([(1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl]oxy)-1-methyl-2-oxoethyl]octyl]oxy)-2-oxoethyl]-1,3-oxazolidine-3-carboxylate | C40H57NO9 | 详情 | 详情 | |
| (XVII) | 25727 | (1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2S,3S)-3-[[(3R,4S)-3-hydroxy-4-(methylamino)-5-phenylpentanoyl]oxy]-2-methyldecanoate | C35H51NO7 | 详情 | 详情 | |
| (XVIII) | 25728 | (2S)-2-[((2S,3S)-3-[[(3R,4S)-3-hydroxy-4-(methylamino)-5-phenylpentanoyl]oxy]-2-methyldecanoyl)oxy]-3-methylbutyric acid | C28H45NO7 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XI)Coupling of aniline (X) with 2,4,6-trichlorobenzoyl chloride (XI) generated amide (XII). Subsequent deprotection of the tert-butyl ester group of (XII) by means of trifluoroacetic acid gave acid (XIII). Finally, the methyl ester group of (XIII) was hydrolyzed with LiOH to furnish the title compound.
| 【1】 Rishton, G.; Chrusciel, R.A.; Yamagishi, M.; Polinsky, A.; Thomas, E.W.; Lobl, T.J.; Tanis, S.P.; Teegarden, B.; Fisher, J.F. (Pharmacia Corp.; Tanabe Seiyaku Co., Ltd.); Inhibitors of alpha4beta1 mediated cell adhesion. EP 0991619; WO 9858902 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 32583 | tert-butyl (1R,3S)-3-([[(1S)-1-(4-aminobenzyl)-2-methoxy-2-oxoethyl]amino]carbonyl)-1,2,2-trimethylcyclopentanecarboxylate | C24H36N2O5 | 详情 | 详情 | |
| (XI) | 25718 | 2,4,6-trichlorobenzoyl chloride | 4136-95-2 | C7H2Cl4O | 详情 | 详情 |
| (XII) | 32584 | tert-butyl (1R,3S)-3-[[((1S)-2-methoxy-2-oxo-1-[4-[(2,4,6-trichlorobenzoyl)amino]benzyl]ethyl)amino]carbonyl]-1,2,2-trimethylcyclopentanecarboxylate | C31H37Cl3N2O6 | 详情 | 详情 | |
| (XIII) | 32585 | (1R,3S)-3-[[((1S)-2-methoxy-2-oxo-1-[4-[(2,4,6-trichlorobenzoyl)amino]benzyl]ethyl)amino]carbonyl]-1,2,2-trimethylcyclopentanecarboxylic acid | C27H29Cl3N2O6 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)The reaction of 5-(chlorosulfonyl)-2-propoxybenzoic acid (I) with 2-(1-methylpyrrolidin-2-yl)ethylamine (II) in acetone gives the sulfonamide (III), which is treated with 2,4,6-trichlorobenzozyl chloride (IV) and TEA to afford the active mixed anhydride (V). The condensation of (V) with 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide (VI) in dichloromethane provides the corresponding carboxamide (VII). Finally, this compound is cyclized by means of tBu-OK in refluxing tert-butanol to furnish the target pyrrolo-pyrimidinone.
| 【1】 Kim, S.; Kim, H.; Kim, D.S.; Chang, M.S.; Yoo, M.; Lim, J.I.; Ahn, B.O.; Kim, W.; Kim, I.Y.; Lim, T.K.; Kang, K.K.; Son, M.; Doh, M.; Shim, H.; Oh, T.; Kim, D.G. (Dong-A Pharmaceutical Co., Ltd.); Pyrazolopyrimidinone derivs. for the treatment of impotence. EP 1129093; WO 0027848 . |
| 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) | 53956 | 5-(chlorosulfonyl)-2-propoxybenzoic acid | C10H11ClO5S | 详情 | 详情 | |
| (II) | 53954 | 2-(2-Aminoethyl)-1-methylpyrrolidine | n/a | C7H16N2 | 详情 | 详情 |
| (III) | 53957 | 5-({[2-(1-methyl-2-pyrrolidinyl)ethyl]amino}sulfonyl)-2-propoxybenzoic acid | n/a | C17H26N2O5S | 详情 | 详情 |
| (IV) | 25718 | 2,4,6-trichlorobenzoyl chloride | 4136-95-2 | C7H2Cl4O | 详情 | 详情 |
| (V) | 53958 | 5-({[2-(1-methyl-2-pyrrolidinyl)ethyl]amino}sulfonyl)-2-propoxy-1-benzenecarboxylic 2,4,6-trichloro-1-benzenecarboxylic anhydride | n/a | C24H27Cl3N2O6S | 详情 | 详情 |
| (VI) | 15627 | 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide; 4-amino-1-methyl-3-propyl-5-pyrazolecarboxamide | 139756-02-8 | C8H14N4O | 详情 | 详情 |
| (VII) | 53955 | 1-methyl-4-{[5-({[2-(1-methyl-2-pyrrolidinyl)ethyl]amino}sulfonyl)-2-propoxybenzoyl]amino}-3-propyl-1H-pyrazole-5-carboxamide | C25H38N6O5S | 详情 | 详情 |