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【结 构 式】 
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【分子编号】16364 【品名】tert-butyl N-[2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-2-oxoethyl]carbamate; N-T-BOC-glycine N-hydroxysuccinimide ester 【CA登记号】3392-07-2 |
【 分 子 式 】C11H16N2O6 【 分 子 量 】272.25792 【元素组成】C 48.53% H 5.92% N 10.29% O 35.26% |
合成路线1
该中间体在本合成路线中的序号：(V)This compound can be obtained by two related ways:1) The nitration of minocycline (I) by means of NaNO3 and H2SO4 gives the 9-nitro derivative (II), which is hydrogenated with H2 over Pd/C in 2-methoxyethanol to yield the 9-amino derivative (III). Finally, this compound is acylated with sarcosyl chloride (IV) by means of Na2CO3 in acetonitrile/dimethylpropylenurea.2) The acylation of the 9-amino derivative (III) with N-(succinimidyloxycarbonyl)carbamic acid tert-butyl ester (V) by means of sodium acetate in THF gives the 9-(tert-butoxycarbonyl)glycylamino substituted compound (VI), which is deprotected with trifluoroacetic acid to afford the 9-glycylamino compound (VII). Finally, this compound is methylated with formaldehyde and simultaneous hydrogenation with H2 over Pd/C in 2-methoxyethanol.
| 【1】 Hlavka, J.J.; Gluzman, Y.; Tally, F.P.; Bloom, J.D.; Testa, R.T.; Ellestad, G.A.; Lee, V.J.; Sum, P.-E.; The discovery of a new generation of tetracycline antibacterial agents, the "glycylcyclines". 33rd Intersci Conf Antimicrob Agents Chemother (Oct 17-20, New Orleans) 1993, Abst 431. |
| 【2】 Fromtling, R.A.; Castañer, J.; DMG-MINO. Drugs Fut 1995, 20, 11, 1116. |
| 【3】 Hlavka, J.J.; Sum, P.-E.; Gluzman, Y.; Lee, V.J.; Ross, A.A. (American Cyanamid Co.); Novel 7-substd.-9-substd. amino-6-demethyl-6-deoxytetracyclines. EP 0536515; JP 1993255219; US 5494903 . |
| 【4】 Sum, P.-E.; Lee, V.J.; Testa, R.T.; Hlavka, J.J.; Ellestad, G.A.; Bloom, J.D.; Gluzman, Y.; Tally, F.P.; Glycylcyclines. 1. A new generation of potent antibacterial agents through modification of 9-aminotetracyclines. J Med Chem 1994, 37, 1, 184-8. |
| 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) | 16360 | (4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamide | 10118-90-8 | C23H27N3O7 | 详情 | 详情 |
| (II) | 16361 | (4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-9-nitro-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamide | C23H26N4O9 | 详情 | 详情 | |
| (III) | 16362 | (4S,4aS,5aR,12aS)-9-amino-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamide | C23H28N4O7 | 详情 | 详情 | |
| (IV) | 16359 | 2-(dimethylamino)acetyl chloride | C4H8ClNO | 详情 | 详情 | |
| (V) | 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 |
| (VI) | 16365 | tert-butyl 2-[[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1,8,10a,11-tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydro-2-naphthacenyl]amino]-2-oxoethylcarbamate | C30H39N5O10 | 详情 | 详情 | |
| (VII) | 16366 | (4S,4aS,5aR,12aS)-9-[(2-aminoacetyl)amino]-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamide | C25H31N5O8 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The reaction of 3,5-dichlorobenzaldehyde (I) with malonic acid and ammonium acetate in refluxing isopropanol gives 3-amino-3-(3,5-dichlorophenyl)propionic acid (II), which is esterified with ethanol and HCl yielding the ethyl ester (III), The condensation of (III) with N-(tert-butoxycarbonyl)glycine succinimidyl ester (IV) by means of TEA in THF affords the glycinamide (V), which is deprotected with HCl in dioxane to afford intermediate (VI). The free amino group of (VI) is then acylated with 3-guanidinobenzoic acid by means of isobutyl chloroformate and NMM in DMF yielding the ethyl ester (VIII) of the target product, which is finally hydrolyzed with LiOH in water.
| 【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) | 24169 | 3,5-dichlorobenzaldehyde | 10203-08-4 | C7H4Cl2O | 详情 | 详情 |
| (II) | 28352 | 3-(3,5-dichlorophenyl)-beta-alanine | C9H9Cl2NO2 | 详情 | 详情 | |
| (III) | 28353 | ethyl 3-amino-3-(3,5-dichlorophenyl)propanoate | C11H13Cl2NO2 | 详情 | 详情 | |
| (IV) | 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 |
| (V) | 28354 | ethyl 3-([2-[(tert-butoxycarbonyl)amino]acetyl]amino)-3-(3,5-dichlorophenyl)propanoate | C18H24Cl2N2O5 | 详情 | 详情 | |
| (VI) | 28355 | ethyl 3-[(2-aminoacetyl)amino]-3-(3,5-dichlorophenyl)propanoate | C13H16Cl2N2O3 | 详情 | 详情 | |
| (VII) | 28356 | 3-[[amino(imino)methyl]amino]benzoic acid | C8H9N3O2 | 详情 | 详情 | |
| (VIII) | 28357 | ethyl 3-([2-[(3-[[amino(imino)methyl]amino]benzoyl)amino]acetyl]amino)-3-(3,5-dichlorophenyl)propanoate | C21H23Cl2N5O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)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4
该中间体在本合成路线中的序号：(II)Condensation of N-heptylhydroxylamine (I) with the protected glycine succinimidyl ester (II) produced the O-acyl intermediate (III), which spontaneously rearranged to the N-acyl analogue (IV). Then, cleavage of the amino protecting group of (IV) furnished the title N-hydroxy glycinamide.
| 【1】 Pietra, C.; Delcanale, M.; Merlini, L.; Bergamaschi, M.; Ventura, P.; Servadio, V.; Villetti, G.; Redenti, E.; Ghidini, E.; Synthesis of a new series of N-hydroxy, N-alkylamides of aminoacids as ligands of NMDA glycine site. Eur J Med Chem 1999, 34, 9, 711. |
| 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) | 51331 | N-heptylhydroxylamine; 1-(hydroxyamino)heptane | C7H17NO | 详情 | 详情 | |
| (II) | 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 |
| (III) | 51332 | tert-butyl 2-[(heptylamino)oxy]-2-oxoethylcarbamate | C14H28N2O4 | 详情 | 详情 | |
| (IV) | 51333 | tert-butyl 2-[heptyl(hydroxy)amino]-2-oxoethylcarbamate | C14H28N2O4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IX)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 |