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【结 构 式】 
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【分子编号】23800 【品名】Diphenylacetyl chloride; 2,2-diphenylacetyl chloride 【CA登记号】1871-76-7 |
【 分 子 式 】C14H11ClO 【 分 子 量 】230.69344 【元素组成】C 72.89% H 4.81% Cl 15.37% O 6.94% |
合成路线1
该中间体在本合成路线中的序号：(VI)The condensation of (S)-phenylglycine (I) with ethyl chloroformate gave carbamate (II). After activation of (II) as the mixed anhydride with ethyl chloroformate in the presence of N-methylmorpholine, coupling with (S)-3-hydroxypyrrolidine (III) provided amide (IV). Reduction of both amide and carbamate groups of (IV) employing LiAlH4 in refluxing THF yielded diamine (V). This was finally condensed with diphenylacetyl chloride (VI) to furnish the title amide The condensation of (S)-phenylglycine (I) with ethyl chloroformate gave carbamate (II). After activation of (II) as the mixed anhydride with ethyl chloroformate in the presence of N-methylmorpholine, coupling with (S)-3-hydroxypyrrolidine (III) provided amide (IV). Reduction of both amide and carbamate groups of (IV) employing LiAlH4 in refluxing THF yielded diamine (V). This was finally condensed with diphenylacetyl chloride (VI) to furnish the title amide.
| 【1】 Ackermann, K.-A.; Budak, J.; Bathe, A.; Gottschlich, R.; Helfert, B.; Stein, I. (Merck Patent GmbH); Method for producing enantiomer-free N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethyl]-2,2-diphenyl acetamide. DE 19827633; WO 9954298 . |
| 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) | 10716 | (2S)-2-Amino-2-phenylethanoic acid; L-(+)-alpha-Phenylglycine | 2935-35-5 | C8H9NO2 | 详情 | 详情 |
| (II) | 12171 | (2S)-2-[(Ethoxycarbonyl)amino]-2-phenylethanoic acid | C11H13NO4 | 详情 | 详情 | |
| (III) | 14490 | (3R)tetrahydro-1H-pyrrol-3-ol; R-3-hydroxypyrrolidine | 2799-21-5 | C4H9NO | 详情 | 详情 |
| (IV) | 31452 | ethyl (1S)-2-[(3S)-3-hydroxypyrrolidinyl]-2-oxo-1-phenylethylcarbamate | C15H20N2O4 | 详情 | 详情 | |
| (V) | 31453 | (3S)-1-[(2S)-2-(methylamino)-2-phenylethyl]-3-pyrrolidinol | C13H20N2O | 详情 | 详情 | |
| (VI) | 23800 | Diphenylacetyl chloride; 2,2-diphenylacetyl chloride | 1871-76-7 | C14H11ClO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)N-(2,2-Diphenylacetyl)piperazine (IV) was prepared by acylation of N-formylpiperazine (II) with 2,2-diphenylacetyl chloride (I), followed by acid-promoted formyl deprotection of the resulting amide (III). Condensation of 5-hydroxyquinoline (VI) with epichlorohydrin (V) in the presence of potassium tert-butoxide in DMF at 90 C provided 5-(2,3-epoxypropoxy)quinoline (VII), which was subsequently coupled with acylpiperazine (IV) in boiling isopropanol to yield (VIII). This was finally treated with fumaric acid (IX) in MeOH to furnish the title sesquifumarate salt.
| 【1】 Suzuki, T.; et al.; Structure-activity relationship of newly synthesiz. J Med Chem 1997, 40, 13, 2047. |
| 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) | 23800 | Diphenylacetyl chloride; 2,2-diphenylacetyl chloride | 1871-76-7 | C14H11ClO | 详情 | 详情 |
| (II) | 23801 | 1-piperazinecarbaldehyde; N-Formylpiperazine | 7755-92-2 | C5H10N2O | 详情 | 详情 |
| (III) | 23802 | 4-(2,2-diphenylacetyl)-1-piperazinecarbaldehyde | C19H20N2O2 | 详情 | 详情 | |
| (IV) | 23803 | 2,2-diphenyl-1-(1-piperazinyl)-1-ethanone | C18H20N2O | 详情 | 详情 | |
| (V) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (VI) | 23805 | 5-quinolinol | 578-67-6 | C9H7NO | 详情 | 详情 |
| (VII) | 23806 | 5-(2-oxiranylmethoxy)quinoline; 2-oxiranylmethyl 5-quinolinyl ether | C12H11NO2 | 详情 | 详情 | |
| (VIII) | 23807 | 1-[4-[2-hydroxy-3-(5-quinolinyloxy)propyl]-1-piperazinyl]-2,2-diphenyl-1-ethanone | C30H31N3O3 | 详情 | 详情 | |
| (IX) | 23808 | Fumaric acid; (E)-2-butenedioic acid | 110-17-8 | C4H4O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The reaction of Nomega'-nitro-D-arginine (I) with 2,2-diphenylacetyl chloride (II) by means of NaOH in THF/water gives the expected Nalpha-diphenylacetyl derivative (III), which is condensed with 4-(ureidomethyl)benzylamine (IV) by means of TBTU and DIEA in THF to yield the corresponding amide (V). Finally, this compound is hydrogenated with H2 over Pd/C in aqueous acetic acid in order to eliminate the Nomega'-nitro group and treated with trifluoroacetic acid to provide the target compound.
| 【1】 Engel, W.; Eberlein, W.; Rudolf, K.; Doods, H.; Wieland, H.-A.; Willim, K.-D.; Entzeroth, M.; Wienen, W. (Dr. Karl Thomae GmbH); Amino acid derivs., pharmaceutical compsns. containing these cpds. and processes for preparing them. DE 19544687; EP 0885186; WO 9719911 . |
| 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) | 25103 | N-omega'-nitro-D-arginine | C6H13N5O4 | 详情 | 详情 | |
| (II) | 23800 | Diphenylacetyl chloride; 2,2-diphenylacetyl chloride | 1871-76-7 | C14H11ClO | 详情 | 详情 |
| (III) | 25104 | N-alpha-(2,2-diphenylacetyl)-N-omega'-nitro-D-arginine | C20H23N5O5 | 详情 | 详情 | |
| (IV) | 25105 | N-[4-(aminomethyl)benzyl]urea | C9H13N3O | 详情 | 详情 | |
| (V) | 25106 | N-alpha-(2,2-diphenylacetyl)-N-omega'-nitro-N1-[4-(ureidomethyl)benzyl]-D-arginine | C29H34N8O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)The protected (R)-ornithine (I) was converted to the active ester (III) upon coupling with 2-nitrophenol (II) in the presence of DCC and pyridine. Subsequent reaction of the nitrophenyl ester (III) with (R)-4-hydroxy-alpha-methylbenzylamine (IV) produced the corresponding amide (V). After acid cleavage of the Boc protecting group of (V), the resulting amine (VI) was acylated with diphenylacetyl chloride (VII) to give (VIII). Removal of the N-benzyloxycarbonyl group of (VIII) was achieved by catalytic hydrogenation over Pd/C. The resultant amine (IX) was then converted to the protected guanidine (XI) by reaction with N,N'-bis(benzyloxycarbonyl)-S-methylisothiourea (X). The protecting groups of (X) were finally removed by hydrogenation over Pd/C.
| 【1】 Pilling, G.; Bergman, N.-A.; D'Ambra, T. (AstraZeneca plc); New NPY antagonists. EP 1017672; WO 9915498 . |
| 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) | 44215 | (2R)-5-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid | C18H26N2O6 | 详情 | 详情 | |
| (II) | 19106 | 2-nitrophenol | 88-75-5 | C6H5NO3 | 详情 | 详情 |
| (III) | 46848 | 2-nitrophenyl (2R)-5-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoate | C24H29N3O8 | 详情 | 详情 | |
| (IV) | 46849 | 4-[(1R)-1-aminoethyl]phenol | 134855-87-1 | C8H11NO | 详情 | 详情 |
| (V) | 46850 | benzyl (4R)-4-[(tert-butoxycarbonyl)amino]-5-[[(1R)-1-(4-hydroxyphenyl)ethyl]amino]-5-oxopentylcarbamate | C26H35N3O6 | 详情 | 详情 | |
| (VI) | 46851 | benzyl (4R)-4-amino-5-[[(1R)-1-(4-hydroxyphenyl)ethyl]amino]-5-oxopentylcarbamate | C21H27N3O4 | 详情 | 详情 | |
| (VII) | 23800 | Diphenylacetyl chloride; 2,2-diphenylacetyl chloride | 1871-76-7 | C14H11ClO | 详情 | 详情 |
| (VIII) | 46852 | benzyl (4R)-4-[(2,2-diphenylacetyl)amino]-5-[[(1R)-1-(4-hydroxyphenyl)ethyl]amino]-5-oxopentylcarbamate | C35H37N3O5 | 详情 | 详情 | |
| (IX) | 46853 | (2R)-5-amino-2-[(2,2-diphenylacetyl)amino]-N-[(1R)-1-(4-hydroxyphenyl)ethyl]pentanamide | C27H31N3O3 | 详情 | 详情 | |
| (X) | 32861 | benzyl (E)-[[(benzyloxy)carbonyl]amino](methylsulfanyl)methylidenecarbamate | C18H18N2O4S | 详情 | 详情 | |
| (XI) | 46854 | benzyl (E)-[[(benzyloxy)carbonyl]amino][((4R)-4-[(2,2-diphenylacetyl)amino]-5-[[(1R)-1-(4-hydroxyphenyl)ethyl]amino]-5-oxopentyl)amino]methylidenecarbamate | C44H45N5O7 | 详情 | 详情 |