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【结 构 式】 
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【分子编号】18168 【品名】1-iodo-2-methylpropane 【CA登记号】513-38-2 |
【 分 子 式 】C4H9I 【 分 子 量 】184.01993 【元素组成】C 26.11% H 4.93% I 68.96% |
合成路线1
该中间体在本合成路线中的序号：(X)An alternative synthesis has been reported employing pure (2R,3S)-aminoalcohol (XVII). Treatment of isobutyl iodide (X) with sodium nitrite in the presence of urea in DMF afforded 2-methyl-1-nitropropane (XI). Further condensation of fluoral hydrate (XII) with this nitrocompound using K2CO3 provided a diastereomeric mixture of nitroalcohols (XIII). Fractional crystallization from pentane yielded the racemic threo-nitroalcohol (XIV), which was converted to the alredy reported racemic threo-aminoalcohol (VII) by catalytic hydrogenation. This compound (VII) was treated with triphosgene and NaOH to produce oxazolidone (XV). After conversion of (XV) to the corresponding lithium salt with BuLi at -70 C, its condensation with (-)-menthyl chloroformate gave a diastereomeric mixture of carbamates, from which the desired isomer (XVI) was isolated by fractional crystallization from ether/hexane. The chiral auxiliary and the oxazolidone ring were then cleaved by hydrolysis with KOH yielding the (2R,3S)-aminoalcohol (XVII)(1). The coupling of (XVII) with the amino protected dipeptide (XVIII) (obtained by treatment of peptide (I) with trifluoroacetic acid) afforded dipeptide amide (XIX), The N-(benzyloxycarbonyl) protecting group of (XIX) was subsequently removed by catalytic hydrogenation, and the resulting amino compound was condensed with anisoyl chloride (III) to furnish the anisoyl dipeptide (XX). Finally, oxidation of the alcohol group of (XX) using the modified Pfitner-Moffat procedure produced some epimerization of the resulting ketone, the oxidation with KMnO4 in the presence of NaOH yielded the target S,S,S-peptide.
| 【1】 Bohnert, C.M.; Bernstein, P.R.; Veale, C.A.; et al.; Orally active trifluoromethyl ketone inhibitors of. J Med Chem 1997, 40, 20, 3173. |
| 【2】 Pegg, S.J.; Sependa, G.J.; Davies, E.P.; Veale, C.A. (AstraZeneca plc); Diastereomeric pure trifluoromethyl ketone peptide. EP 0743953; JP 1997508902; US 5739157; US 6037363; WO 9521855 . |
| 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) | 22770 | tert-butyl (2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylate | C22H32N2O5 | 详情 | 详情 | |
| (III) | 22671 | 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride | 100-07-2 | C8H7ClO2 | 详情 | 详情 |
| (VII) | 22776 | (2R,3S)-3-amino-1,1,1-trifluoro-4-methyl-2-pentanol | C6H12F3NO | 详情 | 详情 | |
| (X) | 18168 | 1-iodo-2-methylpropane | 513-38-2 | C4H9I | 详情 | 详情 |
| (XI) | 11782 | 2-Methyl-1-nitropropane | C4H9NO2 | 详情 | 详情 | |
| (XII) | 22781 | 2,2,2-trifluoro-1,1-ethanediol | 421-53-4 | C2H3F3O2 | 详情 | 详情 |
| (XIII) | 11783 | 1,1,1-Trifluoro-4-methyl-3-nitro-2-pentanol | C6H10F3NO3 | 详情 | 详情 | |
| (XIV) | 22783 | (2R,3S)-1,1,1-trifluoro-4-methyl-3-nitro-2-pentanol | C6H10F3NO3 | 详情 | 详情 | |
| (XV) | 22784 | (4S,5R)-4-isopropyl-5-(trifluoromethyl)-1,3-oxazolidin-2-one | C7H10F3NO2 | 详情 | 详情 | |
| (XVI) | 22785 | (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (4S,5R)-4-isopropyl-2-oxo-5-(trifluoromethyl)-1,3-oxazolidine-3-carboxylate | C18H28F3NO4 | 详情 | 详情 | |
| (XVII) | 22776 | (2R,3S)-3-amino-1,1,1-trifluoro-4-methyl-2-pentanol | C6H12F3NO | 详情 | 详情 | |
| (XVIII) | 22787 | (2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylic acid | C18H24N2O5 | 详情 | 详情 | |
| (XIX) | 22788 | benzyl (1S)-2-methyl-1-[[(2S)-2-([[(1S,2R)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]amino]carbonyl)pyrrolidinyl]carbonyl]propylcarbamate | C24H34F3N3O5 | 详情 | 详情 | |
| (XX) | 22789 | (2S)-1-[(2S)-2-[(4-methoxybenzoyl)amino]-3-methylbutanoyl]-N-[(1S,2R)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]-2-pyrrolidinecarboxamide | C24H34F3N3O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)2-Naphtalenethiol (I) was treated with ethyl 4-bromobutyrate (II) and NaH to give thioether (III). Alkylation of (III) with isobutyl iodide (IV) in the presence of LDA afforded racemic (V), which was then hydrolyzed to the acid (VI) on treatment with litium hydroxide. Coupling of racemic acid (VI) with (S)-leucinol (VII) yielded a mixture of diastereomeric amides, which were separated by column chromatography. Diastereoisomer (VIII) was oxidized with m-chloroperbenzoic acid to give sulfone (IX), and was further oxidized with DMSO and sulfur trioxide-pyridine complex to produce the target aldehyde.
| 【1】 Chatterjee, S.; et al.; Nonpeptidic inhibitors of recombinant human calpain; I. Bioorg Med Chem Lett 1997, 7, 3, 287-290. |
| 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) | 15234 | 2-Naphthalenethiol; 2-Naphthylhydrosulfide | 91-60-1 | C10H8S | 详情 | 详情 |
| (II) | 11263 | ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate | 2969-81-5 | C6H11BrO2 | 详情 | 详情 |
| (III) | 18167 | ethyl 4-(2-naphthylsulfanyl)butanoate | C16H18O2S | 详情 | 详情 | |
| (IV) | 18168 | 1-iodo-2-methylpropane | 513-38-2 | C4H9I | 详情 | 详情 |
| (V) | 18169 | ethyl 4-methyl-2-[2-(2-naphthylsulfanyl)ethyl]pentanoate | C20H26O2S | 详情 | 详情 | |
| (VI) | 18170 | 4-methyl-2-[2-(2-naphthylsulfanyl)ethyl]pentanoic acid | C18H22O2S | 详情 | 详情 | |
| (VII) | 18171 | L-(+)-leucinol; (S)-2-amino-4-methyl-1-pentanol; (2S)-2-amino-4-methyl-1-pentanol | 7533-40-6 | C6H15NO | 详情 | 详情 |
| (VIII) | 18172 | (2R)-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]-4-methyl-2-[2-(2-naphthylsulfanyl)ethyl]pentanamide | C24H35NO2S | 详情 | 详情 | |
| (IX) | 18173 | (2R)-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]-4-methyl-2-[2-(2-naphthylsulfonyl)ethyl]pentanamide | C24H35NO4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)The condensation of gamma-butyrolactone (I) with phenethyl amine (II) at high temperatures afforded phenethylpyrrolidinone (III). This was alkylated with isobutyl iodide (IV) in the presence of lithium diisopropylamide in cold THF yielding the 3-isobutyl pyrrolidinone (V), and further alkylated with tert-butyl bromoacetate (VI) to give (VII). Subsequent alkylation of (VII) at the alpha-position of carboxylate group with allyl bromide provided (VIII). Ozonolysis of the double bond of (VIII), followed by reductive treatment with NaBH4 produced alcohol (IX), which was coupled with dibenzyl iminodicarboxylate (X) under Mitsunobu conditions giving (XI). The biscarbamate (XI) was deprotected by hydrogenolysis over Pd/C, and the resulting primary amine (XII) was condensed with 3,4-difluorobenzoyl chloride (XIII) to furnish amide (XIV). Then, trifluoroacetic acid-promoted cleavage of the tert-butyl ester of (XIV) provided the corresponding carboxylic acid, which was finally coupled with hydroxylamine by means of EDC and HOBt to afford the target hydroxamic acid
| 【1】 Jacobsen, E.J. (Pharmacia & Upjohn AB); Hydroxamic acid derivs. for use with the treatment of diseases related to connective tissue degradation. EP 0898562; JP 2000506163; US 5712300; WO 9732846 . |
| 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) | 20576 | dihydro-2(3H)-furanone | 96-48-0 | C4H6O2 | 详情 | 详情 |
| (II) | 18333 | Phenethylamine; 2-Phenyl-1-ethanamine | 64-04-0 | C8H11N | 详情 | 详情 |
| (III) | 28259 | 1-phenethyl-2-pyrrolidinone | C12H15NO | 详情 | 详情 | |
| (IV) | 18168 | 1-iodo-2-methylpropane | 513-38-2 | C4H9I | 详情 | 详情 |
| (V) | 28267 | 3-isobutyl-1-phenethyl-2-pyrrolidinone | C16H23NO | 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) | 28260 | tert-butyl 2-(3-isobutyl-2-oxo-1-phenethyl-3-pyrrolidinyl)acetate | C22H33NO3 | 详情 | 详情 | |
| (VIII) | 28261 | tert-butyl 2-(3-isobutyl-2-oxo-1-phenethyl-3-pyrrolidinyl)-4-pentenoate | C25H37NO3 | 详情 | 详情 | |
| (IX) | 28268 | tert-butyl 4-hydroxy-2-(3-isobutyl-2-oxo-1-phenethyl-3-pyrrolidinyl)butanoate | C24H37NO4 | 详情 | 详情 | |
| (X) | 28262 | 1-[[([[(benzyloxy)carbonyl]amino]carbonyl)oxy]methyl]benzene | C16H15NO4 | 详情 | 详情 | |
| (XI) | 28263 | tert-butyl 4-[bis[(benzyloxy)carbonyl]amino]-2-(3-isobutyl-2-oxo-1-phenethyl-3-pyrrolidinyl)butanoate | C40H50N2O7 | 详情 | 详情 | |
| (XII) | 28264 | tert-butyl 4-amino-2-(3-isobutyl-2-oxo-1-phenethyl-3-pyrrolidinyl)butanoate | C24H38N2O3 | 详情 | 详情 | |
| (XIII) | 28265 | 3,4-difluorobenzoyl chloride | 76903-88-3 | C7H3ClF2O | 详情 | 详情 |
| (XIV) | 28266 | tert-butyl 4-[(3,4-difluorobenzoyl)amino]-2-(3-isobutyl-2-oxo-1-phenethyl-3-pyrrolidinyl)butanoate | C31H40F2N2O4 | 详情 | 详情 |