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【结 构 式】 
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【分子编号】20417 【品名】1-([[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]oxy)-2,5-pyrrolidinedione 【CA登记号】74124-79-1 |
【 分 子 式 】C9H8N2O7 【 分 子 量 】256.1718 【元素组成】C 42.2% H 3.15% N 10.94% O 43.72% |
合成路线1
该中间体在本合成路线中的序号：(XII)Treatment of D-tryptophan methyl ester (XI) with N,N'-disuccinimidyl carbonate (XII) gave the intermediate succinimidyl carbamate (XIII), which was subsequently converted to urea (XV) upon reaction with spiro(indene-1,4'-piperidine) (XIV). Saponification of the ester function of (XV) with LiOH afforded the carboxylic acid (XVI), and this was then coupled with the Boc-protected chiral diamine (X) using EDC and HOBt. The resulting precursor (XVII) was finally deprotected with HCl in EtOAc to provide the title compound.
| 【1】 Yang, L.; et al.; Spiro[1H-indene-1,4'-piperidine] derivatives as potent and selective non-peptide human somatostatin receptor subtype 2 (sst2) agonists. J Med Chem 1998, 41, 13, 2175. |
| 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) | 20415 | tert-butyl [(1S,3R)-3-(aminomethyl)cyclohexyl]methylcarbamate | C13H26N2O2 | 详情 | 详情 | |
| (XI) | 20416 | methyl (2R)-2-amino-3-(1H-indol-3-yl)propanoate | C12H14N2O2 | 详情 | 详情 | |
| (XII) | 20417 | 1-([[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]oxy)-2,5-pyrrolidinedione | 74124-79-1 | C9H8N2O7 | 详情 | 详情 |
| (XIII) | 20418 | methyl (2R)-2-([[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]amino)-3-(1H-indol-3-yl)propanoate | C17H17N3O6 | 详情 | 详情 | |
| (XIV) | 20419 | Spiro[indene-1,4'-piperidine] | C13H15N | 详情 | 详情 | |
| (XV) | 20420 | N-[Spiro[indene-1,4'-piperidin]-1'-ylcarbonyl]-D-tryptophan methyl ester | C26H27N3O3 | 详情 | 详情 | |
| (XVI) | 20421 | N-[Spiro[indene-1,4'-piperidin]-1'-ylcarbonyl]-D-tryptophan | C25H25N3O3 | 详情 | 详情 | |
| (XVII) | 20422 | N-[3(R)-[N-alpha-[Spiro[indene-1,4'-piperidin]-1'-ylcarbonyl]-D-tryptophanamidomethyl]cyclohex-1(S)-ylmethyl]carbamic acid tert-butyl ester | C38H49N5O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)Condensation of beta-methyl-D-tryptophan methyl ester (VI) with disuccinimidyl carbonate (VIII) and then with 4-(2-oxo-1-benzimidazolinyl) piperidine (VII) furnished urea (IX). Basic hydrolysis of the methyl ester of (IX), followed by coupling of the resulting carboxylic acid (X) with the intermediate amine (V) in the presence of EDC and HOBt yielded the corresponding amide (XI). The Boc protecting group of (XI) was finally cleaved with trifluoroacetic acid to give the title compound.
| 【1】 Pasternak, A.; Chapman, K.; Guo, L.; Patchett, A.A.; Tata, J.R.; Yang, L. (Merck & Co., Inc.); Somatostatin agonists. EP 0977751; WO 9845285 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 29400 | tert-butyl [2-(aminomethyl)-4-pyridinyl]methylcarbamate | C12H19N3O2 | 详情 | 详情 | |
| (VI) | 29274 | methyl (2R,3S)-2-amino-3-(1H-indol-3-yl)butanoate | C13H16N2O2 | 详情 | 详情 | |
| (VII) | 12138 | 1-(4-Piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one; 4-(2-Keto-1-benzimidazolinyl)piperidine | 20662-53-7 | C12H15N3O | 详情 | 详情 |
| (VIII) | 20417 | 1-([[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]oxy)-2,5-pyrrolidinedione | 74124-79-1 | C9H8N2O7 | 详情 | 详情 |
| (IX) | 29401 | methyl (2R,3S)-3-(1H-indol-3-yl)-2-([[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl]carbonyl]amino)butanoate | C26H29N5O4 | 详情 | 详情 | |
| (X) | 29402 | (2R,3S)-3-(1H-indol-3-yl)-2-([[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl]carbonyl]amino)butyric acid | C25H27N5O4 | 详情 | 详情 | |
| (XI) | 29403 | tert-butyl [2-([[(2R,3S)-3-(1H-indol-3-yl)-2-([[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl]carbonyl]amino)butanoyl]amino]methyl)-4-pyridinyl]methylcarbamate | C37H44N8O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)The oxidation of the chiral 2(R)-(benzyloxymethyl-4-phenyl-1-butanol (I) with (COCl)2 and TEA in DMSO/dichloromethane gives the corresponding aldehyde (II) , which by a pinacol coupling promoted by VCl3, Zn and 1,3-dimethylimidazolidin-2-one (DMI) in dichloromethane yields the glycol (III) as a mixture of all the possible enantiomers. The protection of the glycol function of (III) by means of 2,2-dimethoxypropane (IV), 2-methoxypropene and CSA in acetone affords the isopropylidene ketal (V), which is debenzylated by hydrogenation with H2 over Pd/C in aq. NaHCO3/EtOAc to provide the hexane-1,6-diol (VI). The oxidation of diol (VI) with RuCl3 and NaIO4 in acetonitrile/water/dichloromethane gives the adipic acid derivative (VII), which is treated with disuccinimidyl carbonate (VIII) to yield the corresponding enantiomeric mixture of activated esters, which is resolved by column chromatography to isolate the (R,R)-activated ester (IX). The reaction of (IX) with (1S,2R)-1-amino-2-indanol (X) in hot dichloroethane (DCE) affords the diamide (XI), which is finally deprotected (elimination of the isopropylidene group) by means of FeCl3.6H2O in dichloromethane to provide the target (R,R,R,R)-dihydroxydiamide.
| 【1】 Muhlman, A.; et al.; Synthesis of novel potent, diol-based HIV-1 protease inhibitors via intermolecular pinacol homocoupling of (2S)-2-benzyloxymethyl-4-phenylbutanal. J Med Chem 2001, 44, 21, 3407. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (R,R)-(III) | 52454 | 1,8-diphenyl-3,6-bis{[(phenylmethyl)oxy]methyl}-4,5-octanediol | C36H42O4 | 详情 | 详情 | |
| (R,S)-(III) | 52455 | 1,8-diphenyl-3,6-bis{[(phenylmethyl)oxy]methyl}-4,5-octanediol | C36H42O4 | 详情 | 详情 | |
| (S,S)-(III) | 52456 | 1,8-diphenyl-3,6-bis{[(phenylmethyl)oxy]methyl}-4,5-octanediol | C36H42O4 | 详情 | 详情 | |
| (I) | 52452 | 4-phenyl-2-{[(phenylmethyl)oxy]methyl}-1-butanol | C18H22O2 | 详情 | 详情 | |
| (II) | 52453 | 4-phenyl-2-{[(phenylmethyl)oxy]methyl}butanal | C18H20O2 | 详情 | 详情 | |
| (IV) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (V) | 52457 | 2,2-dimethyl-4,5-bis(3-phenyl-1-{[(phenylmethyl)oxy]methyl}propyl)-1,3-dioxolane; 2-[2,2-dimethyl-5-(3-phenyl-1-{[(phenylmethyl)oxy]methyl}propyl)-1,3-dioxolan-4-yl]-4-phenylbutyl phenylmethyl ether | C39H46O4 | 详情 | 详情 | |
| (VI) | 52458 | C25H34O4 | 详情 | 详情 | ||
| (VII) | 52459 | C25H30O6 | 详情 | 详情 | ||
| (VIII) | 20417 | 1-([[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]oxy)-2,5-pyrrolidinedione | 74124-79-1 | C9H8N2O7 | 详情 | 详情 |
| (IX) | 52460 | 1-({2-[5-(1-{[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl}-3-phenylpropyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-phenylbutanoyl}oxy)-2,5-pyrrolidinedione | C33H36N2O10 | 详情 | 详情 | |
| (X) | 16239 | (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol; Cis-(1S)-1-amino-2,3-dihydro-1H-inden-2-ol | 126456-43-7 | C9H11NO | 详情 | 详情 |
| (XI) | 52461 | C43H48N2O6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)The mixed carbonate ester intermediate (X) has been obtained as follows: The reaction of dihydrofuran (I) with propargyl alcohol (II) and N-iodosuccinimide (NIS) gives the propargyl ether (III), which is cyclized by means of tributyltin hydride and AIBN in refluxing toluene to yield the perhydrofuro[2,3-b]furan (IV). The oxidation of the methylene group of (IV) with ozone in methanol/dichloromethane affords the bicyclic ketone (V), which is reduced with NaBH4 in ethanol to provide racemic (VI). The digestion of (rac)-(VI) with immobilized lipase 30 and acetic anhydride in DME provides a mixture of the (3R)-alcohol (VII) and the (3S)-acetoxy derivative (VIII) that is separated by chromatography. Finally, the (3R)-(VII) alcohol is condensed with disuccinimidyl carbonate (IX) and TEA in acetonitrile to give the target mixed carbonate ester intermediate (X).
| 【1】 Hussain, K.A.; Gulnik, S.V.; Ghosh, A.K.; Erickson, J.W. (University of Illinois; US Department of Health & Human Services); Multi-drug resistant retroviral protease inhibitors and associated methods. WO 9967254 . |
| 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),(VII) | 32815 | (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol | C6H10O3 | 详情 | 详情 | |
| (I) | 22766 | 2,3-dihydrofuran | 1191-99-7 | C4H6O | 详情 | 详情 |
| (II) | 16664 | Propargyl Alcohol; 2-propyn-1-ol | 107-19-7 | C3H4O | 详情 | 详情 |
| (III) | 32813 | (2R,3S)-3-iodo-2-(2-propynyloxy)tetrahydrofuran; (2R,3S)-3-iodotetrahydro-2-furanyl 2-propynyl ether | C7H9IO2 | 详情 | 详情 | |
| (IV) | 32814 | (3aS,6aR)-3-methylenehexahydrofuro[2,3-b]furan | C7H10O2 | 详情 | 详情 | |
| (V) | 53547 | (3aR,6aR)tetrahydrofuro[2,3-b]furan-3(2H)-one | n/a | C6H8O3 | 详情 | 详情 |
| (VIII) | 53548 | (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl acetate | n/a | C8H12O4 | 详情 | 详情 |
| (IX) | 20417 | 1-([[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]oxy)-2,5-pyrrolidinedione | 74124-79-1 | C9H8N2O7 | 详情 | 详情 |
| (X) | 32812 | 1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione | C11H13NO7 | 详情 | 详情 |