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【结 构 式】 
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【分子编号】21323 【品名】3,5-dichloro-2-hydroxybenzaldehyde; 3,5-Dichlorosalicylaldehyde 【CA登记号】90-60-8 |
【 分 子 式 】C7H4Cl2O2 【 分 子 量 】191.01296 【元素组成】C 44.02% H 2.11% Cl 37.12% O 16.75% |
合成路线1
该中间体在本合成路线中的序号：(VI)2-Aminobenzophenone (I) is acylated with bromoacetyl bromide followed by reaction with ammonia to form the [1,4]benzodiazepine. N1-Methylation produces 1,3-dihydro-1-methyl-5-phenyl-2H-[1,4]benzodiazepin-2-one (II). Treatment with isoamyl nitrate and t-BuOK gives an oxime, which is reduced by catalytic hydrogenation to racemic 3-amino-benzodiazepine (III), which is isolated as the crystalline benzenesulfonic acid salt. Crystallization-induced asymmetric transformation yields 3(S)-(-)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-[1,4]benzodiazepin-2-one (IV). Acylation with indole-2-carbonylimidazolide produces MK-329.
| 【1】 Reider, P.J.; Davis, P.; Grabowski, E.J.J.; Hughes, D.L.; Crystallization-induced asymmetric transformation: Stereospecific synthesis of a potent peripheral CCK antagonis. J Org Chem 1987, 52, 955. |
| 【2】 Freidinger, R.M.; Berlin, R.G.; MK-329. Drugs Fut 1989, 14, 9, 862. |
| 【3】 Veber, D.F.; Freidinger, R.M.; Hirshfield, J.; Rittle, K.E.; Springer, J.P.; DiPardo, R.M.; Bock, M.G.; Evans, B.E.; Synthesis and resolution of 3-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-ones. J Org Chem 1987, 52, 3232. |
| 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) | 21101 | (2-aminophenyl)(phenyl)methanone; 2-Aminobenzophenone | 2835-77-0 | C13H11NO | 详情 | 详情 |
| (II) | 21319 | 1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one | C16H14N2O | 详情 | 详情 | |
| (III) | 21320 | 3-Amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one benzenesulfonate | C22H21N3O4S | 详情 | 详情 | |
| (IV) | 21321 | (3S)-3-amino-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one | C16H15N3O | 详情 | 详情 | |
| (V) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (VI) | 21323 | 3,5-dichloro-2-hydroxybenzaldehyde; 3,5-Dichlorosalicylaldehyde | 90-60-8 | C7H4Cl2O2 | 详情 | 详情 |
| (VII) | 21324 | 1H-imidazol-1-yl(1H-indol-2-yl)methanone | C12H9N3O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)3,5-Dichlorosalicylaldehyde (I) was protected by treatment with methoxyethoxymethyl chloride (II) in the presence of K2CO3 in DMF. The protected aldehyde (III) was then condensed with (S)-phenylglycinol (IV) to give the chiral imine (V). Addition of the Reformatskii reagent (VI) to the imine function gave rise to aminoester (VII) as a single diastereoisomer. Dealkylation of (VII) with lead tetraacetate furnished the chiral primary amine (VIII). Subsequent acidic treatment of (VIII) cleaved the methoxyethoxy protecting group and the tert-butyl ester to afford (IX). Amine (IX) was then coupled with N-Boc-glycine N-hydroxysuccinimidyl ester (X), producing amide (XI). Acid cleavage of the N-Boc group of (XI) then yielded the intermediate (XII).
| 【2】 Ruminski, P.G.; Rogers, T.E. (Pharmacia Corp.); Meta-azacyclic amino benzoic acid cpds. and derivs. thereof being integrin antagonists. EP 1060164; WO 9944994 . |
| 【3】 Gordon, G.B.; Ruminski, P.G.; Nickols, G.A.; Westlin, W.F.; Rogers, T.E.; Cunningham, J. (Pharmacia Corp.); Use of integrin antagonist and a chemotherapeutic agent in the treatment of neoplasia. WO 0051686 . |
| 【1】 Ruminski, P.G.; Clare, M.; Collins, P.W.; Desai, B.N.; Lindmark, R.J.; Rico, J.G.; Rogers, T.E.; Russell, M.A. (Pharmacia Corp.); Meta-guanidine, urea, thiourea or azacyclic amino benzoic acid derivs. as integrin antagonists. EP 0850221; JP 1999510814; US 6013651; WO 9708145 . |
| 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) | 21323 | 3,5-dichloro-2-hydroxybenzaldehyde; 3,5-Dichlorosalicylaldehyde | 90-60-8 | C7H4Cl2O2 | 详情 | 详情 |
| (II) | 40670 | 2-(chloromethoxy)ethyl methyl ether; 1-(chloromethoxy)-2-methoxyethane; (2-methoxyethoxy)methyl chloride | 3970-21-6 | C4H9ClO2 | 详情 | 详情 |
| (III) | 47968 | 3,5-dichloro-2-[(2-methoxyethoxy)methoxy]benzaldehyde | C11H12Cl2O4 | 详情 | 详情 | |
| (IV) | 10973 | (2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol | 20989-17-7 | C8H11NO | 详情 | 详情 |
| (V) | 47969 | (2R)-2-[((E)-[3,5-dichloro-2-[(2-methoxyethoxy)methoxy]phenyl]methylidene)amino]-2-phenyl-1-ethanol | C19H21Cl2NO4 | 详情 | 详情 | |
| (VI) | 40586 | bromo[2-(tert-butoxy)-2-oxoethyl]zinc | C6H11BrO2Zn | 详情 | 详情 | |
| (VII) | 47970 | tert-butyl (3S)-3-[3,5-dichloro-2-[(2-methoxyethoxy)methoxy]phenyl]-3-[[(1R)-2-hydroxy-1-phenylethyl]amino]propanoate | C25H33Cl2NO6 | 详情 | 详情 | |
| (VIII) | 47971 | tert-butyl (3S)-3-amino-3-[3,5-dichloro-2-[(2-methoxyethoxy)methoxy]phenyl]propanoate | C17H25Cl2NO5 | 详情 | 详情 | |
| (IX) | 47972 | ethyl (3S)-3-amino-3-(3,5-dichloro-2-hydroxyphenyl)propanoate | C11H13Cl2NO3 | 详情 | 详情 | |
| (X) | 16364 | tert-butyl N-[2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-2-oxoethyl]carbamate; N-T-BOC-glycine N-hydroxysuccinimide ester | 3392-07-2 | C11H16N2O6 | 详情 | 详情 |
| (XI) | 47973 | ethyl (3S)-3-([2-[(tert-butoxycarbonyl)amino]acetyl]amino)-3-(3,5-dichloro-2-hydroxyphenyl)propanoate | C18H24Cl2N2O6 | 详情 | 详情 | |
| (XII) | 47974 | ethyl (3S)-3-[(2-aminoacetyl)amino]-3-(3,5-dichloro-2-hydroxyphenyl)propanoate | C13H16Cl2N2O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The hydroxyl group of 3,5-dichlorosalicylaldehyde (I) is protected as the methoxyethoxymethyl (MEM) ether (II) with MEM chloride in DMF. Condensation of the protected salicylaldehyde (II) with (S)-phenylglycinol (III) yields the chiral aldimine (IV). This is then reacted with the Reformatski reagent (VI), prepared from t-butyl bromoacetate (V), to provide adduct (VII). Oxidative removal of the chiral auxiliary group of (VII) with lead tetraacetate, followed by acidic cleavage of the t-butyl and MEM groups, leads to amino ester (VIII). Coupling of (VIII) with the succinimidyl ester of N-Boc-glycine (IX) furnishes amide (X). The N-Boc protecting group of (X) is then removed under acidic conditions to yield amine (XI) (1).
| 【1】 Miyashiro, J.M.; Gasiecki, A.F.; Khanna, I.K.; Chandrakumar, N.S.; Desai, B.N.; Russell, M.A.; Devadas, B.; Rico, J.G.; Rogers, T.E.; Rao, S.N.; Malecha, J.W.; Ruminski, P.G.; Yu, Y.; Huff, R. (Pfizer Inc.); Heterocyclic glycyl beta-alanine derivs. as vitronectin antagonists. EP 1070060; JP 2002511462; WO 9952896 . |
| 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) | 21323 | 3,5-dichloro-2-hydroxybenzaldehyde; 3,5-Dichlorosalicylaldehyde | 90-60-8 | C7H4Cl2O2 | 详情 | 详情 |
| (II) | 47968 | 3,5-dichloro-2-[(2-methoxyethoxy)methoxy]benzaldehyde | C11H12Cl2O4 | 详情 | 详情 | |
| (III) | 10973 | (2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol | 20989-17-7 | C8H11NO | 详情 | 详情 |
| (IV) | 47969 | (2R)-2-[((E)-[3,5-dichloro-2-[(2-methoxyethoxy)methoxy]phenyl]methylidene)amino]-2-phenyl-1-ethanol | C19H21Cl2NO4 | 详情 | 详情 | |
| (V) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (VI) | 40586 | bromo[2-(tert-butoxy)-2-oxoethyl]zinc | C6H11BrO2Zn | 详情 | 详情 | |
| (VII) | 47970 | tert-butyl (3S)-3-[3,5-dichloro-2-[(2-methoxyethoxy)methoxy]phenyl]-3-[[(1R)-2-hydroxy-1-phenylethyl]amino]propanoate | C25H33Cl2NO6 | 详情 | 详情 | |
| (VIII) | 47972 | ethyl (3S)-3-amino-3-(3,5-dichloro-2-hydroxyphenyl)propanoate | C11H13Cl2NO3 | 详情 | 详情 | |
| (IX) | 16364 | tert-butyl N-[2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-2-oxoethyl]carbamate; N-T-BOC-glycine N-hydroxysuccinimide ester | 3392-07-2 | C11H16N2O6 | 详情 | 详情 |
| (X) | 47973 | ethyl (3S)-3-([2-[(tert-butoxycarbonyl)amino]acetyl]amino)-3-(3,5-dichloro-2-hydroxyphenyl)propanoate | C18H24Cl2N2O6 | 详情 | 详情 | |
| (XI) | 47974 | ethyl (3S)-3-[(2-aminoacetyl)amino]-3-(3,5-dichloro-2-hydroxyphenyl)propanoate | C13H16Cl2N2O4 | 详情 | 详情 |