|
【结 构 式】 
|
【药物名称】BILD-1633-SE 【化学名称】1-[1(S)-[5(S)-[N-[3-Cyclohexyl-2(R)-methylpropionyl]-N-methyl-L-valylamino]-6,6-dimethyl-4-oxo-2(R)-(pivaloylmethyl)heptanamido]-1-[N-[1(R)-ethyl-2,2-dimethylpropyl]carbamoyl]methyl]cyclopentane-1-carboxylic acid 【CA登记号】186900-74-3 【 分 子 式 】C46H80N4O8 【 分 子 量 】817.1725 |
【开发单位】Bio-Mega (Originator) 【药理作用】ANTIINFECTIVE THERAPY, Antiviral Drugs, Ribonucleoside-Diphosphate Reductase Inhibitors |
合成路线1
The esterification of N-(tert-butoxycarbonyl)-L-tert-butylglycine (I) with DBU and methyl iodide gives the corresponding methyl ester (II), which is condensed with dimethyl methylphosphonate by means of butyllithium in THF yielding N-(tert-butoxycarbonyl)-L-tert-butylglycylmethylphosphonic acid dimethyl ester (III). The reaction of benzyl glyoxylate (IV) (obtained by IO4H oxidation of dibenzyl L-tartrate (V)) with phosphonic ester (III) by means of triethylamine in acetonitrile affords 5(S)-(tert-butoxycarbonylamino)-6,6-dimethyl-4-oxo-2-heptenoic acid benzyl ester (VI). The condensation of (VI) with allyl 2-pivaloylacetate (VII)(obtained by reaction of pivaloyl chloride (VIII) with allyl acetate (A) by means of LHDMS in THF) by means of NaH in THF provides the intermediate (IX). Selective elimination of the allyloxycarbonyl group of (IX) by means of Pd(PPh3)4 and pyrrolidine in dichloromethane/acetonitrile gives 5(S)-(tert-butoxycarbonylamino)-6,6-dimethyl-4-oxo-2(R)-(pivaloylmethyl)heptanoic acid benzyl ester (X). Hydrogenolysis of the benzyl ester group of (X) with H2 over Pd/C in ethanol gives the heptanoic acid (XI), which is condensed with the amino group of the cyclopentanecarboxylic ester (XII) by means of TBTU and NMM in dichloromethane to afford the corresponding amide (XIII).
| 【1】 Gauthier, J.-A.; Moss, N. (Bio-Mega, Inc.; Boehringer Ingelheim GmbH); Herpes ribonucleotide reductase inhibitors. EP 0837845; JP 1999508246; US 5672586; WO 9700855 . |
| 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) | 27147 | allyl acetate | 591-87-7 | C5H8O2 | 详情 | 详情 |
| (I) | 22251 | (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid;2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid;N-(tert-butoxycarbonyl)-3-methyl-L-valine | 62965-35-9 | C11H21NO4 | 详情 | 详情 |
| (II) | 27141 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoate | C12H23NO4 | 详情 | 详情 | |
| (III) | 27142 | dimethyl (3S)-3-[(tert-butoxycarbonyl)amino]-4,4-dimethyl-2-oxopentylphosphonate | C14H28NO6P | 详情 | 详情 | |
| (IV) | 27143 | benzyl 2-oxoacetate | C9H8O3 | 详情 | 详情 | |
| (V) | 27144 | dibenzyl 2,3-dihydroxysuccinate | C18H18O6 | 详情 | 详情 | |
| (VI) | 27145 | benzyl (E,5S)-5-[(tert-butoxycarbonyl)amino]-6,6-dimethyl-4-oxo-2-heptenoate | C21H29NO5 | 详情 | 详情 | |
| (VII) | 27146 | allyl 4,4-dimethyl-3-oxopentanoate | C10H16O3 | 详情 | 详情 | |
| (VIII) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (IX) | 27148 | 4-allyl 1-benzyl (2S,3S)-2-[(3S)-3-[(tert-butoxycarbonyl)amino]-4,4-dimethyl-2-oxopentyl]-3-(2,2-dimethylpropanoyl)butanedioate | C31H45NO8 | 详情 | 详情 | |
| (X) | 27149 | benzyl (2R,5S)-5-[(tert-butoxycarbonyl)amino]-2-(3,3-dimethyl-2-oxobutyl)-6,6-dimethyl-4-oxoheptanoate | C27H41NO6 | 详情 | 详情 | |
| (XI) | 27150 | (2R,5S)-5-[(tert-butoxycarbonyl)amino]-2-(3,3-dimethyl-2-oxobutyl)-6,6-dimethyl-4-oxoheptanoic acid | C20H35NO6 | 详情 | 详情 | |
| (XII) | 27151 | benzyl 1-((1S)-1-amino-2-[[(1R)-1-ethyl-2,2-dimethylpropyl]amino]-2-oxoethyl)cyclopentanecarboxylate | C22H34N2O3 | 详情 | 详情 | |
| (XIII) | 27152 | benzyl 1-((1S)-1-[[(2R,5S)-5-[(tert-butoxycarbonyl)amino]-2-(3,3-dimethyl-2-oxobutyl)-6,6-dimethyl-4-oxoheptanoyl]amino]-2-[[(1R)-1-ethyl-2,2-dimethylpropyl]amino]-2-oxoethyl)cyclopentanecarboxylate | C42H67N3O8 | 详情 | 详情 |
合成路线2
The reaction of (XIII) with HCl in dioxane eliminates the carbamate protecting group giving (XIV) with a free amino group, which is condensed with N-(tert-butoxycarbonyl)-N-methyl-L-valine (XV) by means of NMM and TBTU in dichloromethane to provide the intermediate (XVI) with four amide groups. Elimination of the ter-butyl carbamate group of (XVI) with HCl in dioxane affords compound (XVII) with a reactive methylamino group, which is finally condensed with 3-cyclohexyl-2(R)-methylpropionyl chloride (XVIII) by means of NMM in dichloromethane to afford the target compound.
| 【1】 Gauthier, J.-A.; Moss, N. (Bio-Mega, Inc.; Boehringer Ingelheim GmbH); Herpes ribonucleotide reductase inhibitors. EP 0837845; JP 1999508246; US 5672586; WO 9700855 . |
| 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) | 27152 | benzyl 1-((1S)-1-[[(2R,5S)-5-[(tert-butoxycarbonyl)amino]-2-(3,3-dimethyl-2-oxobutyl)-6,6-dimethyl-4-oxoheptanoyl]amino]-2-[[(1R)-1-ethyl-2,2-dimethylpropyl]amino]-2-oxoethyl)cyclopentanecarboxylate | C42H67N3O8 | 详情 | 详情 | |
| (XIV) | 27153 | benzyl 1-((1S)-1-[[(2R,5S)-5-amino-2-(3,3-dimethyl-2-oxobutyl)-6,6-dimethyl-4-oxoheptanoyl]amino]-2-[[(1R)-1-ethyl-2,2-dimethylpropyl]amino]-2-oxoethyl)cyclopentanecarboxylate | C37H59N3O6 | 详情 | 详情 | |
| (XV) | 27154 | (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methylbutyric acid | 45170-31-8 | C11H21NO4 | 详情 | 详情 |
| (XVI) | 27155 | benzyl 1-[(1S,4R,7S,10S)-7-(tert-butyl)-4-(3,3-dimethyl-2-oxobutyl)-1-([[(1R)-1-ethyl-2,2-dimethylpropyl]amino]carbonyl)-10-isopropyl-11,14,14-trimethyl-3,6,9,12-tetraoxo-13-oxa-2,8,11-triazapentadec-1-yl]cyclopentanecarboxylate | C48H78N4O9 | 详情 | 详情 | |
| (XVII) | 27156 | 1-((1S)-1-[((2R,5S)-2-(3,3-dimethyl-2-oxobutyl)-6,6-dimethyl-5-[[(2S)-3-methyl-2-(methylamino)butanoyl]amino]-4-oxoheptanoyl)amino]-2-[[(1R)-1-ethyl-2,2-dimethylpropyl]amino]-2-oxoethyl)cyclopentanecarboxylic acid | C36H64N4O7 | 详情 | 详情 | |
| (XVIII) | 27157 | (2R)-3-cyclohexyl-2-methylpropanoyl chloride | C10H17ClO | 详情 | 详情 |
合成路线3
The intermediate cyclopentanecarboxylic ester (XII) has been obtained as follows: The reaction of 2-oxaspiro[4.4]nonane-1,3-dione (XXVI) with the chiral auxiliary 4(S)-isopropyloxazolidin-2-one (XXVII) by means of BuLi in THF gives the addition product (XXVIII), which is protected as the benzyl ester (XXIX) with benzylbromide and DBU. The regioselective azidation of (XXIX) with 2,4,6-triisopropylbenzenesulfonyl azide and potassium bis(trimethylsilyl)amide affords the (S)-azide (XXX), which is treated with H2O2 in THF/water to eliminate chiral auxiliary and providing 2(S)-azido-2-[1-(benzyloxycarbonyl)cyclopentyl]acetic acid (XXXI). Condensation of (XXXI) with 1(R)-ethyl-2,2-dimethylpropylamine (XXXII) by means of HBTU in dichloromethane gives the corresponding amide (XXXIII), which is finally reduced at the azido group with SnCl2 in methanol to afford the target intermediate (XII). The intermediate 1(R)-ethyl-2,2-dimethylpropylamine (XXXII) has been obtained as follows: The reaction of 2,2-dimethyl-3-pentanone (XXXIV) with the chiral auxiliary 1(R)-phenylethylamine (XXXV) by means of TiCl4 in benzene gives N-(1(R)-ethyl-2,2-dimethylpropyl)-N-(1(R)-phenylethyl)amine (XXXVI), which is then hydrogenated with H2 over Pd/C in methanol to eliminate the chiral auxiliary and obtain the target amine (XXXII).
| 【1】 Gauthier, J.-A.; Moss, N. (Bio-Mega, Inc.; Boehringer Ingelheim GmbH); Herpes ribonucleotide reductase inhibitors. EP 0837845; JP 1999508246; US 5672586; WO 9700855 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 27151 | benzyl 1-((1S)-1-amino-2-[[(1R)-1-ethyl-2,2-dimethylpropyl]amino]-2-oxoethyl)cyclopentanecarboxylate | C22H34N2O3 | 详情 | 详情 | |
| (XXVI) | 27158 | 2-oxaspiro[4.4]nonane-1,3-dione | C8H10O3 | 详情 | 详情 | |
| (XXVII) | 12867 | (4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone | 17016-83-0 | C6H11NO2 | 详情 | 详情 |
| (XXVIII) | 27159 | 1-[2-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethyl]cyclopentanecarboxylic acid | C14H21NO5 | 详情 | 详情 | |
| (XXIX) | 27160 | benzyl 1-[2-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethyl]cyclopentanecarboxylate | C21H27NO5 | 详情 | 详情 | |
| (XXX) | 27161 | benzyl 1-[(1S)-1-azido-2-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethyl]cyclopentanecarboxylate | C21H26N4O5 | 详情 | 详情 | |
| (XXXI) | 27162 | (2S)-2-azido-2-[1-[(benzyloxy)carbonyl]cyclopentyl]ethanoic acid | C15H17N3O4 | 详情 | 详情 | |
| (XXXII) | 27163 | (1R)-1-ethyl-2,2-dimethylpropylamine | C7H17N | 详情 | 详情 | |
| (XXXIII) | 27164 | benzyl 1-((1S)-1-azido-2-[[(1R)-1-ethyl-2,2-dimethylpropyl]amino]-2-oxoethyl)cyclopentanecarboxylate | C22H32N4O3 | 详情 | 详情 | |
| (XXXIV) | 27165 | 2,2-dimethyl-3-pentanone | 564-04-5 | C7H14O | 详情 | 详情 |
| (XXXV) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XXXVI) | 27166 | (3R)-2,2-dimethyl-N-[(1R)-1-phenylethyl]-3-pentanamine | C15H25N | 详情 | 详情 |
合成路线4
The intermediate 3-cyclohexyl-2(R)-methylpropionyl chloride (XVIII) has been obtained as follows: The reaction of 4(S)-isopropyloxazolidin-2-one (XIX) with propionyl chloride (XX) by means of BuLi in THF gives 4(S)-isopropyl-3-propionyloxazolidin-2-one (XXI), which is condensed with benzyl bromide (XXII) by means of LHMDS in THF yielding 4(S)-isopropyl-3-(2(R)-methyl-3-phenylpropionyl)oxazolidin-2-one (XXIII). The oxidative cleavage of (XXIII) with H2O2 in THF/water affords 2(R)-methyl-3-phenylpropionic acid (XXIV), which is hydrogenated with H2 over alumina providing 3-cyclohexyl-2(R)-methylpropionic acid (XXV). Finally, this compound is treated with oxalyl chloride in DMF to afford the desired intermediate 3-cyclohexyl-2(R)-methylpropionyl chloride (XVIII).
| 【1】 Gauthier, J.-A.; Moss, N. (Bio-Mega, Inc.; Boehringer Ingelheim GmbH); Herpes ribonucleotide reductase inhibitors. EP 0837845; JP 1999508246; US 5672586; WO 9700855 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 27157 | (2R)-3-cyclohexyl-2-methylpropanoyl chloride | C10H17ClO | 详情 | 详情 | |
| (XIX) | 12867 | (4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone | 17016-83-0 | C6H11NO2 | 详情 | 详情 |
| (XX) | 15967 | propanoyl chloride; propionyl chloride | 79-03-8 | C3H5ClO | 详情 | 详情 |
| (XXI) | 11535 | (4S)-4-Isopropyl-3-propionyl-1,3-oxazolidin-2-one | 77877-19-1 | C9H15NO3 | 详情 | 详情 |
| (XXII) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (XXIII) | 27167 | (4S)-4-isopropyl-3-[(2R)-2-methyl-3-phenylpropanoyl]-1,3-oxazolidin-2-one | C16H21NO3 | 详情 | 详情 | |
| (XXIV) | 27168 | (2R)-2-methyl-3-phenylpropionic acid | C10H12O2 | 详情 | 详情 | |
| (XXV) | 27169 | (2R)-3-cyclohexyl-2-methylpropionic acid | C10H18O2 | 详情 | 详情 |