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【结 构 式】

【分子编号】10309

【品名】ethyl 2-aminoacetate; Glycine ethyl ester

【CA登记号】459-73-4

【 分 子 式 】C4H9NO2

【 分 子 量 】103.121

【元素组成】C 46.59% H 8.8% N 13.58% O 31.03%
与该中间体有关的原料药合成路线共 25 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20合成路线21合成路线22合成路线23合成路线24合成路线25

合成路线1

该中间体在本合成路线中的序号：(XVIII)

The reaction of 3-chloroaniline (X) with choral hydrate (XI) and hydroxylamine gives isonitroso-3-chloroacetanilide (XII), which is cyclized by means of H2SO4 to 4-chloroisatin (XIII). Chlorination of (XIII) with SO2Cl2 affords 4,5-dichloroisatin (XIV), which is oxidized with H2O2 yielding 5,6-dichloroanthranilic acid (XV). The reduction of (XV) with borane in THF gives 6-amino-2,3-dichlorobenzyl alcohol (XVI), which by reaction with SOCl2 in benzene is converted to 6-amino-2,3-dichlorobenzyl chloride (XVII). This compound is condensed with ethyl glycinate (XVIII) by means of triethylamine in refluxing methylene chloride to give ethyl N-(6-amino-2,3-dichlorobenzyl)glycinate (VII), which is cyclized with cyanogen bromide (VIII) in toluene affording ethyl 5,6-dichloro-3,4-dihydro-2-(1H)-iminoquinazoline-3-acetate (IX). Finally, this compound is submitted to a new cyclization by means of triethylamine in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Jenks, T.A.; Beverung, W.N.Jr.; Partyka, R.A. (Bristol-Myers Squibb Co.); Preparation of 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one. CA 1137474 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 29087 ethyl 2-[(6-amino-2,3-dichlorobenzyl)amino]acetate C11H14Cl2N2O2 详情 详情
(VIII) 28017 cyanic bromide；cyanogen bromide 506-68-3 CBrN 详情 详情
(IX) 29088 ethyl 2-[5,6-dichloro-2-imino-1,4-dihydro-3(2H)-quinazolinyl]acetate C12H13Cl2N3O2 详情 详情
(X) 25239 3-chloroaniline; 3-chlorophenylamine 108-42-9 C6H6ClN 详情 详情
(XI) 14018 2,2,2-Trichloro-1,1-ethanediol; Chloral hydrate 302-17-0 C2H3Cl3O2 详情 详情
(XII) 29089 N-(3-chlorophenyl)-2-(hydroxyimino)acetamide C8H7ClN2O2 详情 详情
(XIII) 29090 4-chloro-1H-indole-2,3-dione C8H4ClNO2 详情 详情
(XIV) 29091 4,5-dichloro-1H-indole-2,3-dione C8H3Cl2NO2 详情 详情
(XV) 29092 6-amino-2,3-dichlorobenzoic acid C7H5Cl2NO2 详情 详情
(XVI) 29093 (6-amino-2,3-dichlorophenyl)methanol C7H7Cl2NO 详情 详情
(XVII) 29094 3,4-dichloro-2-(chloromethyl)aniline C7H6Cl3N 详情 详情
(XVIII) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

The condensation of 2-nitro-6-chlorobenzyl chloride (I) with ethyl glycinate (II) by means of triethylamine in refluxing ethanol gives ethyl N-(2-nitro-6-chlorobenzyl)glycinate (III), which is reduced with H2 over Pd/C in ethanol yielding ethyl N-(2-amino-6-chlorobenzyl)glycinate (IV). The cyclization of (IV) with cyanogen bromide (A) in refluxing ethanol affords 6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one (V), which is finally chlorinated with Cl2 and FeCl3 in hot nitromethane.

参考文献 中间体
合成目标
【1】 Beverung, W.N.Jr.; Partyka, A.; Optionally substituted 1,2,3,5-tetrahydroimidezo(2,1-b)-quinazolin-2-ones and 6(H)-1,2,3,4-tetrahydropyimido(2,1-b)quinazolin-2-ones. US 3932407 .
【2】 Castaner, J.; Serradell, M.N.; Hillier, K.; Blancafort, P.; Anagrelide hydrochloride. Drugs Fut 1980, 5, 3, 117.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 28017 cyanic bromide；cyanogen bromide 506-68-3 CBrN 详情 详情
(I) 32683 1-Chloro-2-(chloromethyl)-3-nitrobenzene 15258-72-7 C7H5Cl2NO2 详情 详情
(II) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(III) 32684 ethyl 2-[(2-chloro-6-nitrobenzyl)amino]acetate 50608-25-8 C11H13ClN2O4 详情 详情
(IV) 32685 ethyl 2-[(2-amino-6-chlorobenzyl)amino]acetate C11H15ClN2O2 详情 详情
(V) 32686 6-chloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one 61834-95-5 C10H8ClN3O 详情 详情

合成路线3

该中间体在本合成路线中的序号：(V)

The nitration of 2,3-dichlorobenzaldehyde (I) with HNO3/H2SO4 gives 2,3-dichloro-6-nitrobenzaldehyde (II), which is reduced with NaBH4 in methanol, yielding 2,3-dichloro-6-nitrobenzyl alcohol (III). The reaction of (III) with SOCl2 and TEA affords the benzyl chloride (IV), which is condensed with glycine ethyl ester (V) by means of TEA to provide the adduct (VI). The reduction of the nitro group of (VI) with SnCl2 in aq. HCl or H2 over PtO2/C in ethanol gives the expected amino derivative (VII), which is cyclized with CN-Br in toluene to yield the iminoquinazoline (VIII). Finally, this compound is further cyclized by means of TEA in water to afford the target imidazoquinazolinone.

参考文献 中间体
合成目标
【1】 Lang, P.C.; Spencer, R.P.; Yeh, W.-L.; Roth, M.J. (Shire Richwood Inc.); Method for the manufacture of anagrelide. WO 0208228 .
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) 14742 2,3-dichlorobenzaldehyde 6334-18-5 C7H4Cl2O 详情 详情
(II) 52800 2,3-dichloro-6-nitrobenzaldehyde C7H3Cl2NO3 详情 详情
(III) 52801 (2,3-dichloro-6-nitrophenyl)methanol C7H5Cl2NO3 详情 详情
(IV) 52802 1,2-dichloro-3-(chloromethyl)-4-nitrobenzene C7H4Cl3NO2 详情 详情
(V) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(VI) 29086 ethyl 2-[(2,3-dichloro-6-nitrobenzyl)amino]acetate C11H12Cl2N2O4 详情 详情
(VII) 29087 ethyl 2-[(6-amino-2,3-dichlorobenzyl)amino]acetate C11H14Cl2N2O2 详情 详情
(VIII) 29088 ethyl 2-[5,6-dichloro-2-imino-1,4-dihydro-3(2H)-quinazolinyl]acetate C12H13Cl2N3O2 详情 详情

合成路线4

该中间体在本合成路线中的序号：(I)

The reductocondensation of ethyl glycinate (I) with 2-indanone (II) by means of sodium cyanoborohydride in methanol gives ethyl N-(2-indanyl)glycinate (III), which is condensed with N-benzyloxycarbonyl-L-alanine (IV) by means of isobutyl chlorocarbonate and triethylamine in THF yielding N-(N-benzyloxycarbonyl-L-alanyl)-N-(2-indanyl)glycine ethyl ester (V). The partial hydrolysis of (V) with NaOH in methanol affords N-(N-benzyloxycarbonyl-L-alanyl)-N-(2-indanyl)glycine (VI), which is deprotected by hydrogenolysis with H2 over Pd/C in ethanol giving N-(L-alanyl)-N-(2-indanyl)glycine (VII). Finally, this compound is reductocondensed with ethyl 2-oxo-4-phenylbutanoate (VIII) by means of sodium cyanoborohydride in ethanol.

参考文献 中间体
合成目标
【1】 Oka, Y.; Nishikawa, K.; Miyake, A. (Takeda Chemical Industries, Ltd.); Bicyclic compounds, their production and use. EP 0051391; GB 2086393; JP 82179141; JP 8277651; US 4385051 .
【2】 Serradell, M.N.; Castaner, J.; CV-3317. Drugs Fut 1984, 9, 5, 324.
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) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(II) 30550 1,3-dihydro-2H-inden-2-one 615-13-4 C9H8O 详情 详情
(III) 30551 ethyl 2-(2,3-dihydro-1H-inden-2-ylamino)acetate C13H17NO2 详情 详情
(IV) 61209 CBZ-L-Alanine; (2S)-2-[[(Benzyloxy)carbonyl]amino]propionic acid; N-((Phenylmethoxy)carbonyl)-alanine; Carbobenzyloxy-L-alanine C11H13NO4 详情 详情
(V) 30552 ethyl 2-[((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)(2,3-dihydro-1H-inden-2-yl)amino]acetate C24H28N2O5 详情 详情
(VI) 30553 2-[((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)(2,3-dihydro-1H-inden-2-yl)amino]acetic acid C22H24N2O5 详情 详情
(VII) 30554 2-[[(2S)-2-aminopropanoyl](2,3-dihydro-1H-inden-2-yl)amino]acetic acid C14H18N2O3 详情 详情
(VIII) 20896 Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester 64920-29-2 C12H14O3 详情 详情

合成路线5

该中间体在本合成路线中的序号：(IV)

The reaction of 7-fluoro-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2,5-dione (I) with POCl3 and N,N-dimethyl-p-toluidine in hot toluene gives 2-chloro-7-fluoro-4-methyl-4,5-dihydro-3H-1,4-benzodiazepin-5 one (II), which is condensed with N-(dimethylaminomethylene)glycine ethyl ester (III) (obtained by condensation of glycine ethyl ester (IV) with dimethylformamide (V) and TEA in dichloromethane) to yield a mixture of intermediates (VI) and (VII). Finally, these compounds are cyclized in refluxing AcOH to provide the target flumazenil.

参考文献 中间体
合成目标
【1】 Rogers-Evans, M.; Spurr, P.; Hennig, M.; The isolation and use of a benzodiazepine iminochloride for the efficient construction of flumazenil. Tetrahedron Lett 2003, 44, 11, 2425.
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) 31965 7-Fluoro-4-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione; 7-Fluoro-4-methyl-3,4-dihydro-2H-1,4-benzodiazepin-2,5(1H)-dione C10H9FN2O2 详情 详情
(II) 64506 2-chloro-7-fluoro-4-methyl-3,4-dihydro-5H-1,4-benzodiazepin-5-one C10H8ClFN2O 详情 详情
(III) 64507 ethyl 2-{[(E)-(dimethylamino)methylidene]amino}acetate C7H14N2O2 详情 详情
(IV) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(V) 33491 Dimethylformamide 68-12-2 C3H7NO 详情 详情
(VI) 64508 ethyl 2-{[(E)-(dimethylamino)methylidene]amino}-2-(7-fluoro-4-methyl-5-oxo-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-ylidene)acetate C17H21FN4O3 详情 详情
(VII) 64509 ethyl 2-{[(E)-(dimethylamino)methylidene]amino}-2-(7-fluoro-4-methyl-5-oxo-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-ylidene)acetate C17H21FN4O3 详情 详情

合成路线6

该中间体在本合成路线中的序号：(II)

Two new syntheses of labeled azamianserin have been described: 1) [13C]-Labeled: The reaction of 2-chloropyridine-3-carbonitrile (I) with glycine ethyl ester (II) by means of Na2CO3 in DMSO gives N-(3-cyanopyridin-2-yl)glycine ethyl ester (III), which by reaction with methylamine in toluene is converted into the corresponding amide (IV). The treatment of (IV) with sodium hypophosphite and RaNi in water-acetic acid-pyridine affords N-(3-formylpyridin-2-yl)glycine methylamide (V), which is reduced with NaBH4 in methanol to the corresponding alcohol (VI). Further reduction of (VI) with LiAlH4 in refluxing dioxane gives 2-[2-(methylamino)ethylamino]-3-pyridinemethanol (VII), which is condensed with [13C]-labeled alpha-bromoacetophenone (VIII) [prepared from labeled benzene (IX) submitted to a Friedel-Crafts condensation with AlCl3 and acetic anhydride to acetophenone (X) and bromination with Br2 in ether] by means of triethylamine in dioxane to afford the substituted acetophenone (XI). The cyclization of (XI) by heating at 120 C yields the tricyclic compound (XII), which is reduced with LiAlH4 - AlCl3 in ethyl ether to give 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol (XIII). Finally, this compound is cyclized in hot H2SO4.

参考文献 中间体
合成目标
【1】 Wieringa, J.H.; Kaspersen, F.M.; van Rooij, F.A.M.; Sperling, E.G.M.; The synthesis of ORG 3770 labelled with 3H, 13C and 14C. J Label Compd Radiopharm 1989, 27, 9, 1055.
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) 10308 2-Chloronicotinonitrile; 2-Chloro-3-cyanopyridine 6602-54-6 C6H3ClN2 详情 详情
(II) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(III) 10310 ethyl 2-[(3-cyano-2-pyridinyl)amino]acetate C10H11N3O2 详情 详情
(IV) 10311 2-[(3-Cyano-2-pyridinyl)amino]-N-methylacetamide C9H10N4O 详情 详情
(V) 10312 2-[(3-Formyl-2-pyridinyl)amino]-N-methylacetamide C9H11N3O2 详情 详情
(VI) 10313 2-[[3-(Hydroxymethyl)-2-pyridinyl]amino]-N-methylacetamide C9H13N3O2 详情 详情
(VII) 10314 (2-[[2-(Methylamino)ethyl]amino]-3-pyridinyl)methanol C9H15N3O 详情 详情
(VIII) 10315 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone 70-11-1 C8H7BrO 详情 详情
(VIII) 44642 2-bromo-1-phenyl-1-ethanone C8H7BrO 详情 详情
(IX) 13364 Benzene 71-43-2 C6H6 详情 详情
(IX) 44640 benzene C6H6 详情 详情
(X) 10317 Acetophenone 98-86-2 C8H8O 详情 详情
(X) 44641 acetophenone C8H8O 详情 详情
(XI) 10318 2-[(2-[[3-(Hydroxymethyl)-2-pyridinyl]amino]ethyl)(methyl)amino]-1-phenyl-1-ethanone C17H21N3O2 详情 详情
(XI) 44643 2-[(2-[[3-(hydroxymethyl)-2-pyridinyl]amino]ethyl)(methyl)amino]-1-phenyl-1-ethanone C17H21N3O2 详情 详情
(XII) 10319 8-Methyl-6a-phenyl-7,8,9,10-tetrahydro-5H,6aH-pyrazino[2,1-b]pyrido[2,3-d][1,3]oxazine C17H19N3O 详情 详情
(XII) 44644 8-methyl-6a-phenyl-7,8,9,10-tetrahydro-5H,6aH-pyrazino[2,1-b]pyrido[2,3-d][1,3]oxazine C17H19N3O 详情 详情
(XIII) 10320 [2-(4-Methyl-2-phenylpiperazino)-3-pyridinyl]methanol 61337-89-1 C17H21N3O 详情 详情
(XIII) 44645 [2-(4-methyl-2-phenyl-1-piperazinyl)-3-pyridinyl]methanol C17H21N3O 详情 详情

合成路线7

该中间体在本合成路线中的序号：(VII)

4) The reaction of amine (I) with phenyl cyanate (V) and KH in THF gives N-(5-bromoquinoxalin-6-yl)cyanamide (VI), which is cyclized with ethyl glycinate (VII) in refluxing ethanol to yield 2-(5-bromoquinoxalin-6-imino)imidazolidin-4-one (AGN-192119). 5) The reaction of cyanamide (VI) with 2-aminoacetaldehyde diethyl acetal (VIII) affords N1-(5-bromoquinoxalin-6-yl)-N3-(2,2-diethoxyethyl)guanidine (IX), which is cyclized by means of HCl to the hydroxyimidazoline (X). Finally, this compound is treated with NaOH to afford 5-bromo-6-(2-imidazolylamino)quinoxaline (AGN-192076).

参考文献 中间体
合成目标
【1】 Tang-Liu, D.; Burke, J.; Garst, M.; Harcourt, D.; Acheampong, A.; Breau, A.; Munk, S.A.; Wong, H.; Lai, R.; Wheeler, L.; Synthesis and characterization of degradation products and metabolites of brimonidine - A potent alpha2 adrenergic agonist. 211th ACS Natl Meet (March 24-28, New Orleans) 1996, Abst MEDI 021.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
AGN-192119 62987 2-[(5-bromo-6-quinoxalinyl)imino]-4-imidazolidinone C11H8BrN5O 详情 详情
AGN-192076 62988 5-bromo-N-(1H-imidazol-2-yl)-6-quinoxalinamine; N-(5-bromo-6-quinoxalinyl)-N-(1H-imidazol-2-yl)amine C11H8BrN5 详情 详情
(I) 10328 5-Bromo-6-quinoxalinamine; 5-Bromo-6-quinoxalinylamine C8H6BrN3 详情 详情
(V) 62986 phenyl cyanate C7H5NO 详情 详情
(VI) 10330 N-(5-Bromo-6-quinoxalinyl)cyanamide C9H5BrN4 详情 详情
(VII) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(VIII) 10331 2,2-Diethoxy-1-ethanamine; 2,2-Diethoxyethylamine; Aminoacetaldehyde diethyl acetal 645-36-3 C6H15NO2 详情 详情
(IX) 10332 N-(5-Bromo-6-quinoxalinyl)-N'-(2,2-diethoxyethyl)guanidine C15H20BrN5O2 详情 详情
(X) 10333 2-[(5-Bromo-6-quinoxalinyl)amino]-4,5-dihydro-1H-imidazol-5-ol C11H10BrN5O 详情 详情

合成路线8

该中间体在本合成路线中的序号：(A)

1) The alkylation of 2-amino-5-chlorobenzophenone (I) with 2,2,2-trifluoroethyl trichloromethansulfonate (II) in refluxing xylene gives the N-trifluoroethyl derivative (III), which is then cyclized with glycine ethyl ester (A) in refluxing pyridine. 2) Compound (III) can also be bromoacetylated with bromoacetyl bromide (B) in refluxing benzene yielding the N-bromoacetyl compound (IV), which is then cyclized with ammonia in CHCl3. 3) By alkylation of 7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IX) with NaOMe and 2,2,2-trifluoroethyl iodide in MeOH.

参考文献 中间体
合成目标
【1】 Topliss, J.G.; 2-Polyfluoroweralkyl benzophenones. US 3641147 .
【2】 Topliss, J.G.; 1-Polyhalogenoalkyl-2-oxo-1,3-dihydro-2H-14-benzodiazepines. US 3429874 .
【3】 Topliss, J.G.; Verfahren zur Herstellung von neuen 1,4-benzodiazepinen bzw. ihren 4-Oxyden. CH 505842; DE 1793682; FR 1518382; GB 1179125 .
【4】 Castaner, J.; Thorpe, P.; Halazepam. Drugs Fut 1978, 3, 2, 109.
【5】 Topliss, J.G.; Steinman, M.; Alekel, R.; Wong, Y.S.; York, E.E.; 1-Polyfluoroalkylbenzodiazepines. J Med Chem 1973, 16, 12, 1354-60.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
18806 1,1,1-trifluoro-2-iodoethane 353-83-3 C2H2F3I 详情 详情
(A) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(B) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(I) 10279 (2-Amino-5-chlorophenyl)(phenyl)methanone; 2-Amino-5-chlorobenzophenone 719-59-5 C13H10ClNO 详情 详情
(II) 33474 2,2,2-Trifluoroethyl trichloromethanesulfonate; 2,2,2-Trifluoroethyl trichloromethylsulfonate 23199-56-6 C3H2Cl3F3O3S 详情 详情
(III) 33848 [5-chloro-2-[(2,2,2-trifluoroethyl)amino]phenyl](phenyl)methanone C15H11ClF3NO 详情 详情
(IV) 33849 N-(2-benzoyl-4-chlorophenyl)-2-bromo-N-(2,2,2-trifluoroethyl)acetamide C17H12BrClF3NO2 详情 详情
(IX) 10281 7-Chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one; 1,4-benzdiazepin-2-one-5-phenyl-7-chloro 1088-11-5 C15H11ClN2O 详情 详情

合成路线9

该中间体在本合成路线中的序号：(II)

The condensation of 1-methyl-5-(4-methylbenzoyl)pyrrole-2-acetic acid (I) with glycine ethyl ester (II) by means of carbonyldiimidazole (CDI) and triethylamine in THF gives the corresponding acetamidoacetate (III), which is hydrolyzed with NaOH in THF-water yielding 2-[2-[1-methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetamido]acetic acid (IV). Finally, this compound is esterified with 2-methoxyphenol (guayacol) (V) by means of CDI in hot THF.

参考文献 中间体
合成目标
【1】 Baglioni, A. (Medosan; Sigma-Tau); Pyrroleacetic acid amides, their preparation and use. BE 0896018 .
【2】 Serradell, M.N.; Castaner, J.; Castaner, R.M.; Arrigoni-Martelli, E.; ST-679. Drugs Fut 1989, 14, 10, 963.
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) 11352 2-[1-Methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetic acid C15H15NO3 详情 详情
(II) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(III) 21363 ethyl 2-([2-[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetyl]amino)acetate C19H22N2O4 详情 详情
(IV) 21364 2-([2-[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetyl]amino)acetic acid C17H18N2O4 详情 详情
(V) 13182 Guaiacol; 2-Methoxyphenol 90-05-1 C7H8O2 详情 详情

合成路线10

该中间体在本合成路线中的序号：(IX)

The syntheses of the metabolites of grepafloxacin, 7-(2-aminoethylamino)-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro quinoline-3-carboxylic acid (III), 7-(2-aminopropylamino)-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydr oquinoline-3-carboxylic acid (V), 7-amino-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-ca rboxylic acid (VIII), 7-(carboxymethylamino)-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydr oquinoline-3-carboxylic acid (XI), 1-cyclopropyl-6-fluoro-5-(hydroxymethyl)-7-(3-methylpiperazin-1-yl)-4-o xo-1,4-dihydroquinoline-3-carboxylic acid (XVIII) and 7-amino-1-cyclopropyl-6-fluoro-5-(hydroxymethyl)-4-oxo-1,4-dihydroquino line-3-carboxylic acid (XX) have been reported: 1) Compound (III): By condensation of 7-bromo-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-ca rboxylic acid diacetoxyborane ester (I) with 2-(tert-butoxycarbonylamino)ethylamine (II) by heating at 110 C followed by a treatment with HCl in ethanol/water. 2) Compound (V): By condensation of quinolone (I) with 2-(tert-butoxycarbonylamino)ethylamine (IV) by heating at 110 C, followed by hydrolysis with HCl as before. 3) Compound (VIII): The condensation of quinolone (I) with 4-methoxybenzylamine (VII) by heating at 110 C gives 1-cyclopropyl-6-fluoro-7-(4-methoxybenzylamino)-5-methyl-4-oxo-1,4-dihy droquinoline-3-carboxylic acid (VII), which is then debenzylated by treatment with a mixture of trifluoroacetic acid and concentrated sulfuric acid. 4) Compound (XI): The condensation of quinolone (I) with glycine ethyl ester (IX) by heating at 110 C gives 1-cyclopropyl-7-(ethoxycarbonylmethylamino)-6-fluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (X), which is then saponified with NaOH in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Otsubo, K.; Kawano, Y.; Ohguro, K.; Uchida, M.; Ohtani, T.; Ohmori, K.; Matsubara, J.; Morita, S.; Synthesis of possible metabolites of 1-cyclopropyl-1,4-dihydro-6-fluoro-5-methyl-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (grepafloxacin, OPC-17116). Chem Pharm Bull 1995, 43, 12, 2246.
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) 15093 diacetyl (7-bromo-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinyl)carbonyl borate C18H16BBrFNO7 详情 详情
(II) 13241 N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate 57260-73-8 C7H16N2O2 详情 详情
(III) 15095 7-[(2-aminoethyl)amino]-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C16H18FN3O3 详情 详情
(IV) 15096 tert-butyl N-(2-amino-1-methylethyl)carbamate C8H18N2O2 详情 详情
(V) 15097 7-[(2-aminopropyl)amino]-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C17H20FN3O3 详情 详情
(VI) 15098 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine 2393-23-9 C8H11NO 详情 详情
(VII) 15099 1-cyclopropyl-6-fluoro-7-[(4-methoxybenzyl)amino]-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C22H21FN2O4 详情 详情
(VIII) 15100 7-amino-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C14H13FN2O3 详情 详情
(IX) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(X) 15102 1-cyclopropyl-7-[(2-ethoxy-2-oxoethyl)amino]-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C18H19FN2O5 详情 详情
(XI) 15103 7-[(carboxymethyl)amino]-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C16H15FN2O5 详情 详情

合成路线11

该中间体在本合成路线中的序号：(II)

Condensation of imidate (I) with glycine ethyl ester (II) in refluxing acetone yielded imidazolone (III). Subsequent alkylation with N-triphenylmethyl-5-[4'-bromomethyl)biphenyl-2-yl]tetrazole (IV) in the presence of potassium tert-butoxide in cold DMF provided (V), which was finally deprotected by refluxing in a methanolic solution of AcOH to afford the title compound.

参考文献 中间体
合成目标
【1】 Okazaki, T.; et al.; Studies of nonpeptide angiotensin II receptor antagonists. III. Synthesis and biological evaluation of 5-alkylidine-3,5-dihydro-4H-imidazol-4-one derivatives. Chem Pharm Bull 1998, 46, 5, 777.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
23199 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether 67-64-1 C3H6O 详情 详情
(I) 18737 ethyl butanimidoate C6H13NO 详情 详情
(II) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(III) 18739 5-(1-methylethylidene)-2-propyl-3,5-dihydro-4H-imidazol-4-one C9H14N2O 详情 详情
(IV) 15538 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-2-trityl-2H-1,2,3,4-tetraazole 124750-51-2 C33H25BrN4 详情 详情
(V) 18741 5-(1-methylethylidene)-2-propyl-3-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3,5-dihydro-4H-imidazol-4-one C42H38N6O 详情 详情

合成路线12

该中间体在本合成路线中的序号：(III)

The reaction of ethyl valerimidate hydrochloride (I) with cyanamide in ethanol yielded cyanoimidate (II), which was converted into the cyanoimidoylglycine (IV) on treatment with glycine ethyl ester (III) and triethylamine. Alkylation of (IV) with the biphenyl derivative (V) in the presence of 1 mole of NaH in DMF gave the intermediate cyanoamidine (VI), which, by further addition of half an equivalent of sodium hydride was cyclized to the imidazole (VII). Acylation of (VII) with 3,3-dimethylacryloyl chloride (VIII) in cold pyridine yielded amide (IX), and then N-alkylation with iodomethane and sodium hydride in DMF provided (X). Acidic treatment with acetic acid in refluxing ethanol removed the trityl group to give (XI).

参考文献 中间体
合成目标
【1】 Okazaki, T.; et al.; Studies on nonpeptide angiotensin II receptor antagonists. IV. Synthesis and biological evaluation of 4-acrylamide-1H-imidazole derivatives. Chem Pharm Bull 1998, 46, 6, 973.
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) 15120 ethyl pentanimidoate C7H15NO 详情 详情
(II) 17804 ethyl N-cyanopentanimidoate C8H14N2O 详情 详情
(III) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(IV) 17806 ethyl 2-(pentanimidoylamino)acetate C10H17N3O2 详情 详情
(V) 65045 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-1-trityl-1H-1,2,3,4-tetraazole C33H25BrN4 详情 详情
(VI) 17808 ethyl 2-(pentanimidoyl[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)acetate C43H41N7O2 详情 详情
(VII) 17809 ethyl 4-amino-2-butyl-1-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylate C43H41N7O2 详情 详情
(VIII) 17810 3-methyl-2-butenoyl chloride; 3,3-Dimethylacryloyl chloride 3350-78-5 C5H7ClO 详情 详情
(IX) 17811 ethyl 2-butyl-4-[(3-methyl-2-butenoyl)amino]-1-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylate C48H47N7O3 详情 详情
(X) 17812 ethyl 2-butyl-4-[methyl(3-methyl-2-butenoyl)amino]-1-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylate C49H49N7O3 详情 详情
(XI) 17813 ethyl 2-butyl-4-[methyl(3-methyl-2-butenoyl)amino]-1-[[2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylate C30H35N7O3 详情 详情

合成路线13

该中间体在本合成路线中的序号：(II)

The reaction of isatoic anhydride (I) with glycine ethyl ester (II) gives N-(2-aminobenzoyl)glycine ethyl ester (III), which is cyclized with carbonyldiimidazole (CDI) to yield 2-(2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl)acetic acid ethyl ester (IV). The alkylation of (IV) with 3,4-dichlorobenzyl bromide (V) affords 2-[1-(3,4-dichlorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl]acetic acid ethyl ester (VI), which is finally hydrolyzed in basic medium.

参考文献 中间体
合成目标
【1】 Itoh, Y.; Hashimoto, M.; Ao, S.; Notsu, Y.; Novel aldose reductase inhibitors: Synthesis and structure-activity studies of (3-benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl)acetic acids. Drugs Fut 1992, 17, 1, 31.
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) 29797 2H-3,1-benzoxazine-2,4(1H)-dione；Isatoic anhydride;4H-3,1-Benzoxazine-2,4(1H)-dione；1,2-Dihydro-4H-3,1-benzoxazine-2,4-dione;1H-benzo[d][1,3]oxazine-2,4-dione 118-48-9 C8H5NO3 详情 详情
(II) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(III) 42909 ethyl 2-[(2-aminobenzoyl)amino]acetate C11H14N2O3 详情 详情
(IV) 42910 ethyl 2-[2,4-dioxo-1,4-dihydro-3(2H)-quinazolinyl]acetate C12H12N2O4 详情 详情
(V) 42911 4-(bromomethyl)-1,2-dichlorobenzene 18880-04-1 C7H5BrCl2 详情 详情
(VI) 42912 ethyl 2-[1-(3,4-dichlorobenzyl)-2,4-dioxo-1,4-dihydro-3(2H)-quinazolinyl]acetate C19H16Cl2N2O4 详情 详情

合成路线14

该中间体在本合成路线中的序号：(I)

The addition of glycine ethyl ester (I) to 2-propenenitrile (II) by means of KOH in water gives N-(2-cyanoethyl)glycine ethyl ester (III), which is cyclized by means of di-tert-butyl dicarbonate yielding the protected pyrrolidinone (IV). The reduction of (IV) with NaBH4 in ethanol affords the pyrrolidinol (V), which is further reduced with LiAlH4 in THF and protected with di-tert-butyl dicarbonate to give the fully N-protected compound (VI). The oxidation of (VI) with pyridine/SO3 complex yields the pyrrolidinone (VII), which is treated with O-methylhydroxylamine (VIII) to afford the correponding oxime (IX). The deprotection of (IX) with acetyl chloride in cool methanol gives 4-(aminomethyl)pyrrolidin-3-one O-methyloxime (X), which is finally condensed with 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (XI) by means of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetonitrile.

参考文献 中间体
合成目标
【1】 Kim, Y.K.; Chang, J.H.; Choi, H.; Hong, C.Y.; Nam, D.H.; Kim, Y.Z.; Kim, S.H.; Kwak, J.H.; Novel fluoroquinolone antibacterial agents containing oxime-substituted (aminomethyl)pyrrolidines: Synthesis and antibacterial activity of LB20304. J Med Chem 1997, 40, 22, 3584-93.
【2】 Graul, A.; Castañer, J.; SB-265805/LB-20304a. Drugs Fut 1998, 23, 11, 1199-1204.
【3】 Kwak, J.H.; Jeong, Y.N.; Oh, J.I. (LG Chem Ltd.); Novel quinoline carboxylic acid derivs. having 7-(4-amino-methyl-3-oxime)pyrrolidine substituents and processes for their preparation. CA 2151890; EP 0688772; JP 1996041050; US 5633262; US 5698570; US 5776944 .
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) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(II) 10847 Acrylonitrile 107-13-1 C3H3N 详情 详情
(III) 17731 ethyl 2-[(2-cyanoethyl)amino]acetate C7H12N2O2 详情 详情
(IV) 17732 tert-butyl 3-cyano-4-oxo-1-pyrrolidinecarboxylate C10H14N2O3 详情 详情
(V) 17733 tert-butyl 3-cyano-4-hydroxy-1-pyrrolidinecarboxylate C10H16N2O3 详情 详情
(VI) 17734 tert-butyl 3-[[(tert-butoxycarbonyl)amino]methyl]-4-hydroxy-1-pyrrolidinecarboxylate C15H28N2O5 详情 详情
(VII) 17735 tert-butyl 3-[[(tert-butoxycarbonyl)amino]methyl]-4-oxo-1-pyrrolidinecarboxylate C15H26N2O5 详情 详情
(VIII) 15455 (aminooxy)methane; O-methylhydroxylamine 67-62-9 CH5NO 详情 详情
(IX) 17737 tert-butyl 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(methoxyimino)-1-pyrrolidinecarboxylate C16H29N3O5 详情 详情
(X) 17738 4-(aminomethyl)-3-pyrrolidinone O-methyloxime C6H13N3O 详情 详情
(XI) 17034 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid 100361-18-0 C12H8ClFN2O3 详情 详情

合成路线15

该中间体在本合成路线中的序号：(II)

The title compound has been obtained by two related ways: Condensation of glycine ethyl ester (II) with 2,4-difluoronirobenzene (I) provided the N-arylglycine (III), which was further reduced to the phenylenediamine derivative (IV) by catalytic hydrogenation. Acylation of diamine (IV) with ethyl chloroglyoxylate, followed by ring closure in refluxing ethanol, yielded the quinoxalinedione (V). Subsequent electrophyllic nitration of (V) furnished the 6-nitroquinoxaline (VI). The fluoride group of (III) was then displaced with imidazole (VII) in hot DMF yielding the imidazolyl quinoxaline (VIII). Finally, basic hydrolysis of the ethyl ester function of (VIII) gave the target carboxylic acid.

参考文献 中间体
合成目标
【1】 Shishikura, J.; Inami, H.; Sakamoto, S.; Tsukamoto, S.; Sasamata, M.; Okada, M.; Fujii, M. (Yamanouchi Pharmaceutical Co., Ltd.); 1,2,3,4-Tetrahydroquinoxalindione deriv.. EP 0784054; US 6096743; WO 9610023 .
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) 32036 2,4-difluoro-1-nitrobenzene 446-35-5 C6H3F2NO2 详情 详情
(II) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(III) 58528 ethyl 2-(5-fluoro-2-nitroanilino)acetate C10H11FN2O4 详情 详情
(IV) 58529 ethyl 2-(2-amino-5-fluoroanilino)acetate C10H13FN2O2 详情 详情
(V) 58530 ethyl 2-[7-fluoro-2,3-dioxo-3,4-dihydro-1(2H)-quinoxalinyl]acetate C12H11FN2O4 详情 详情
(VI) 58531 ethyl 2-[7-fluoro-6-nitro-2,3-dioxo-3,4-dihydro-1(2H)-quinoxalinyl]acetate C12H10FN3O6 详情 详情
(VII) 10255 Imidazole; 1H-Imidazole 288-32-4 C3H4N2 详情 详情
(VIII) 58532 ethyl 2-[7-(1H-imidazol-1-yl)-6-nitro-2,3-dioxo-3,4-dihydro-1(2H)-quinoxalinyl]acetate C15H13N5O6 详情 详情

合成路线16

该中间体在本合成路线中的序号：(I)

Ethyl glycinate (I) was converted to the 2-aminoacetohydroxamic acid (II) by reaction with hydroxylamine in the presence of KOH in aqueous MeOH. Subsequent cyclization of (II) upon treatment with formaldehyde provided the target 3-hydroxyimidazolin-4-one.

参考文献 中间体
合成目标
【1】 Audinot, V.; Millan, M.; Cordi, A.; Lacoste, J.-M.; Design, synthesis and structure-activity relationships of novel strychnine-insensitive glycine receptor ligands. Bioorg Med Chem Lett 1999, 9, 10, 1409.
【2】 Cordi, A.; Lacoste, J.-M.; Millan, M.; Audinot, V. (ADIR et Cie.); 4-Imidazolidinone cpds.. EP 0780379; US 5677325 .
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) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(II) 24602 2-amino-N-hydroxyacetamide C2H6N2O2 详情 详情

合成路线17

该中间体在本合成路线中的序号：(V)

The hydrogenation of 5-methoxy-1H-indole (I) by means of NaCNBH3 in acetic acid gives 5-methoxyindoline (II), which is benzoylated with benzonitrile (III) by means of BCl3/AlCl3 in dichloroethane yielding 7-benzoyl-5-methoxyindoline (IV). The cyclization of (IV) with glycine ethyl ester (V) in pyridine affords the pyrrolo[1,4]benzodiazepine (VI), which is treated with amyl nitrite in toluene/THF to provide the oxime (VII). The reduction of (VII) with H2 over Ru/C in methanol gives the racemic amine (VIII), which is submitted to optical resolution with di-p-toluoyl-D-tartaric acid yielding the corresponding (R)-isomer (IX). Finally, this compound is condensed with 1H-indole-2-carboxylic acid (X) by means of TOTU and DIEA in dichloromethane.

参考文献 中间体
合成目标
【1】 Feru, F.; et al.; Synthesis and structure-activity relationships of 9-methoxy-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indolines: Novel PDE 4 inhibitors. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 049.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
40665 cyclopentyl nitrite C5H9NO2 详情 详情
(I) 25902 1H-Indol-5-yl methyl ether; 5-Methoxy-1H-indole; 5-Methoxyindole 1006-94-6 C9H9NO 详情 详情
(II) 25903 5-methoxyindoline; 2,3-dihydro-1H-indol-5-yl methyl ether C9H11NO 详情 详情
(III) 25904 benzonitrile 100-47-0 C7H5N 详情 详情
(IV) 25905 (5-methoxy-2,3-dihydro-1H-indol-7-yl)(phenyl)methanone C16H15NO2 详情 详情
(V) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(VI) 25906 9-methoxy-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one C18H16N2O2 详情 详情
(VII) 25907 9-methoxy-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indole-3,4-dione 3-oxime C18H15N3O3 详情 详情
(VIII) 25908 3-amino-9-methoxy-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one C18H17N3O2 详情 详情
(IX) 25909 (3R)-3-amino-9-methoxy-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one C18H17N3O2 详情 详情
(X) 25226 1H-Indole-2-carboxylic acid; Indole-2-carboxylic acid 1477-50-5 C9H7NO2 详情 详情

合成路线18

该中间体在本合成路线中的序号：(III)

Nalpha-(Benzyloxycarbonyl)-1,4-diaminobutyric acid (I) was protected as the Nomega-Boc derivative (II) and then coupled to glycine ethyl ester (III) by means of EDC and HOBt to produce dipeptide (IV). Hydrogenolysis of the benzyloxycarbonyl group of (IV) to give (V), followed by condensation with alpha-toluenesulfonyl chloride (VI) gave sulfonamide (VII). Side-chain deprotection of (VII) with HCl liberated amine (VIII), which was acylated with 2-pyrazinecarboxylic acid (IX) to afford amide (X). Saponification of the ethyl ester of (X) with LiOH gave carboxylic acid (XI).

参考文献 中间体
合成目标
【1】 Ho, J.Z.; et al.; Exploration solid-phase synthesis of factor Xa inhibitors: Discovery and application of P3-heterocyclic amides as novel types of non-basic arginine surrogates. Bioorg Med Chem Lett 1999, 9, 24, 3459.
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) 37250 (2R)-4-amino-2-[[(benzyloxy)carbonyl]amino]butyric acid 62234-40-6 C12H16N2O4 详情 详情
(II) 37251 (2R)-2-[[(benzyloxy)carbonyl]amino]-4-[(tert-butoxycarbonyl)amino]butyric acid C17H24N2O6 详情 详情
(III) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(IV) 37252 ethyl 2-([(2R)-2-[[(benzyloxy)carbonyl]amino]-4-[(tert-butoxycarbonyl)amino]butanoyl]amino)acetate C21H31N3O7 详情 详情
(V) 37253 ethyl 2-([(2R)-2-amino-4-[(tert-butoxycarbonyl)amino]butanoyl]amino)acetate C13H25N3O5 详情 详情
(VI) 25151 phenylmethanesulfonyl chloride 1939-99-7 C7H7ClO2S 详情 详情
(VII) 37254 ethyl 2-([(2R)-2-[(benzylsulfonyl)amino]-4-[(tert-butoxycarbonyl)amino]butanoyl]amino)acetate C20H31N3O7S 详情 详情
(VIII) 37255 ethyl 2-([(2R)-4-amino-2-[(benzylsulfonyl)amino]butanoyl]amino)acetate C15H23N3O5S 详情 详情
(IX) 37256 2-pyrazinecarboxylic acid; Pyrazinoic acid 98-97-5 C5H4N2O2 详情 详情
(X) 37257 ethyl 2-([(2R)-2-[(benzylsulfonyl)amino]-4-[(2-pyrazinylcarbonyl)amino]butanoyl]amino)acetate C20H25N5O6S 详情 详情
(XI) 37258 2-([(2R)-2-[(benzylsulfonyl)amino]-4-[(2-pyrazinylcarbonyl)amino]butanoyl]amino)acetic acid C18H21N5O6S 详情 详情

合成路线19

该中间体在本合成路线中的序号：(XXI)

The synthesis of the intermediate carboxylic acid (XV) has been reported by an alternative procedure. The cyclic anhydride (III) was condensed with glycine ethyl ester (XXI) in refluxing Ac2O, yielding the cyclic imide (XXII). Reduction of the imide (XXII) with NaBH4 produced the aminal (XXIII), which was subsequently converted to the more reactive acetoxyamide (XXIV). Boron trifluoride-catalyzed addition of propargyl trimethylsilane (XXV) to the acetoxyamide (XXIV) gave rise to allene (XXVI). This underwent smooth ozonolysis to the aldehyde (XXVII). After protection of the aldehyde (XXVII) as the dimethyl acetal (XIV), hydrolysis of the ethyl ester group gave the intermediate carboxylic acid (XV).

参考文献 中间体
合成目标
【1】 Reich, S.; Guo, C.X.; Villafranca, E.; Showalter, R.; Dong, L.; A concise synthesis of AG5473/5507 utilizing N-acyliminium ion chemistry. Tetrahedron Lett 2000, 41, 28, 5307.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 43292 benzyl 2,4-dioxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate C15H15NO5 详情 详情
(XIV) 43302 benzyl 2-(dimethoxymethyl)-3-(2-ethoxy-2-oxoethyl)-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate C22H30N2O7 详情 详情
(XV) 43303 2-[9-[(benzyloxy)carbonyl]-2-(dimethoxymethyl)-4-oxo-3,9-diazabicyclo[3.3.1]non-3-yl]acetic acid C20H26N2O7 详情 详情
(XXI) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(XXII) 43307 benzyl 3-(2-ethoxy-2-oxoethyl)-2,4-dioxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate C19H22N2O6 详情 详情
(XXIII) 43308 benzyl 3-(2-ethoxy-2-oxoethyl)-2-hydroxy-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate C19H24N2O6 详情 详情
(XXIV) 43309 benzyl 2-(acetoxy)-3-(2-ethoxy-2-oxoethyl)-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate C21H26N2O7 详情 详情
(XXV) 43310 trimethyl(2-propynyl)silane 13361-64-3 C6H12Si 详情 详情
(XXVI) 43311 benzyl 3-(2-ethoxy-2-oxoethyl)-2-oxo-4-(1,2-propadienyl)-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate C22H26N2O5 详情 详情
(XXVII) 43312 benzyl 3-(2-ethoxy-2-oxoethyl)-2-formyl-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate C20H24N2O6 详情 详情

合成路线20

该中间体在本合成路线中的序号：(XXI)

The synthesis of the intermediate carboxylic acid (XV) has been reported by an alternative procedure. The cyclic anhydride (III) was condensed with glycine ethyl ester (XXI) in refluxing Ac2O, yielding the cyclic imide (XXII). Reduction of the imide (XXII) with NaBH4 produced the aminal (XXIII), which was subsequently converted to the more reactive acetoxyamide (XXIV). Boron trifluoride-catalyzed addition of propargyl trimethylsilane (XXV) to the acetoxyamide (XXIV) gave rise to allene (XXVI). This underwent smooth ozonolysis to the aldehyde (XXVII). After protection of the aldehyde (XXVII) as the dimethyl acetal (XIV), hydrolysis of the ethyl ester group gave the intermediate carboxylic acid (XV).

参考文献 中间体
合成目标
【1】 Reich, S.; Guo, C.X.; Villafranca, E.; Showalter, R.; Dong, L.; A concise synthesis of AG5473/5507 utilizing N-acyliminium ion chemistry. Tetrahedron Lett 2000, 41, 28, 5307.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 43292 benzyl 2,4-dioxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate C15H15NO5 详情 详情
(XIV) 43302 benzyl 2-(dimethoxymethyl)-3-(2-ethoxy-2-oxoethyl)-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate C22H30N2O7 详情 详情
(XV) 43303 2-[9-[(benzyloxy)carbonyl]-2-(dimethoxymethyl)-4-oxo-3,9-diazabicyclo[3.3.1]non-3-yl]acetic acid C20H26N2O7 详情 详情
(XXI) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(XXII) 43307 benzyl 3-(2-ethoxy-2-oxoethyl)-2,4-dioxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate C19H22N2O6 详情 详情
(XXIII) 43308 benzyl 3-(2-ethoxy-2-oxoethyl)-2-hydroxy-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate C19H24N2O6 详情 详情
(XXIV) 43309 benzyl 2-(acetoxy)-3-(2-ethoxy-2-oxoethyl)-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate C21H26N2O7 详情 详情
(XXV) 43310 trimethyl(2-propynyl)silane 13361-64-3 C6H12Si 详情 详情
(XXVI) 43311 benzyl 3-(2-ethoxy-2-oxoethyl)-2-oxo-4-(1,2-propadienyl)-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate C22H26N2O5 详情 详情
(XXVII) 43312 benzyl 3-(2-ethoxy-2-oxoethyl)-2-formyl-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate C20H24N2O6 详情 详情

合成路线21

该中间体在本合成路线中的序号：(A)

By cyclocondensation of 2-methylamino-3-(o-chlorobenzoyl)-5-ethylthiophene (I) with ethyl glycinate hydrochloride (A) in pyridine.

参考文献 中间体
合成目标
【1】 Castaner, J.; Chartterjee, S.S.; Clotiazepan. Drugs Fut 1976, 1, 8, 363.
【2】 Nakanishi, M.; et al. (Yoshitomi Pharmaceutical Industries Ltd.); DE 2107356 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(I) 60743 (2-chlorophenyl)[5-ethyl-2-(methylamino)-3-thienyl]methanone C14H14ClNOS 详情 详情

合成路线22

该中间体在本合成路线中的序号：(IV)

Friedel-Crafts condensation of indoline (I) with benzonitrile (II) in the presence of BCl3 and AlCl3 produced ketone (III), which was subsequently cyclized to (V) by treatment with ethyl glycinate (IV) in refluxing pyridine. The primary amino group was then introduced by conversion of (V) into oxime (VI) with isoamyl nitrite and potassium tert-butoxide, followed by catalytic hydrogenation over Ru/C to produce amine (VII) (1). The racemic amine was resolved by recrystallization as the corresponding salt with N-acetyl-L-phenylalanine to yield the desired (R)-isomer (VIII). Nitration of (VIII) with KNO3 in H2SO4 gave (IX), which was reduced to the diamino derivative (X) using stannous chloride. Finally, regioselective coupling of (X) at the aliphatic amino group with nicotinic acid (XI) by means of O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU) provided the target amide.

参考文献 中间体
合成目标
【2】 Pascal, Y.; Jacobelli, H.; Calvet, A.; Payne, A.; Dahl, S.G. (Institut de Recherche Jouveinal); Diazepino-indoles as phosphodiesterase IV inhibitors. EP 0828742; US 5972927; WO 9736905 .
【1】 Burnouf, C.; Auclair, E.; Avenel, N.; et al.; Synthesis, structure-activity relationships, and pharmacological profile of 9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[]1,4]diazepino[6,7,1-]indoles: Discovery of potent, selective phosphodiesterase type 4 inhibitors. J Med Chem 2000, 43, 25, 4850.
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) 19652 indoline 496-15-1 C8H9N 详情 详情
(II) 25904 benzonitrile 100-47-0 C7H5N 详情 详情
(III) 47455 2,3-dihydro-1H-indol-7-yl(phenyl)methanone C15H13NO 详情 详情
(IV) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(V) 47456 1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one C17H14N2O 详情 详情
(VI) 47457 1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indole-3,4-dione 3-oxime C17H13N3O2 详情 详情
(VII) 47458 3-amino-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one C17H15N3O 详情 详情
(VIII) 47459 (3R)-3-amino-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one C17H15N3O 详情 详情
(IX) 47460 (3R)-3-amino-9-nitro-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one C17H14N4O3 详情 详情
(X) 47461 (3R)-3,9-diamino-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one C17H16N4O 详情 详情
(XI) 10752 Nicotinic acid; Niacin 59-67-6 C6H5NO2 详情 详情

合成路线23

该中间体在本合成路线中的序号：(II)

Michael addition of ethyl acrylate (I) to glycine ethyl ester (II) produces the amino diester (III), which is protected as the allyl carbamate (IV) by treatment with allyl chloroformate. Dieckmann cyclization of diester (IV) in the presence of NaH leads to pyrrolidinone (V). After reduction of (V) to the corresponding alcohol (VI) with NaBH4, dehydration by means of methanesulfonyl chloride and pyridine furnishes the conjugated ester (VII). Acid (VIII), obtained by alkaline hydrolysis of (VII), is then condensed with magnesium tert-butyl malonate in the presence of CDI to produce keto ester (IX). Chlorination of (IX) with sulfuryl chloride, followed by acidic decarboxylation gives rise to chloro ketone (X). This is then condensed with ammonium dithiocarbamate to generate the 2-mercapto thiazole (XI)

参考文献 中间体
合成目标
【1】 Sunagawa, M.; Itoh, M.; Kubota, K.; et al.; New anti-MRSA and anti-VRE carbapenems; synthesis and structure-activity relationships of 1beta-methyl-2-(thiazol-2-ylthio)carbapenems. J. Antibiot. 2002, 55, 8, 722.
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) 10164 ethyl acrylate 140-88-5 C5H8O2 详情 详情
(II) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(III) 61451 ethyl 3-[(2-ethoxy-2-oxoethyl)amino]propanoate C9H17NO4 详情 详情
(IV) 61452 ethyl 3-[[(allyloxy)carbonyl](2-ethoxy-2-oxoethyl)amino]propanoate C13H21NO6 详情 详情
(V) 61453 1-allyl 3-ethyl 4-oxo-1,3-pyrrolidinedicarboxylate C11H15NO5 详情 详情
(VI) 61454 1-allyl 3-ethyl 4-hydroxy-1,3-pyrrolidinedicarboxylate C11H17NO5 详情 详情
(VII) 61455 1-allyl 3-ethyl 2,5-dihydro-1H-pyrrole-1,3-dicarboxylate C11H15NO4 详情 详情
(VIII) 61456 1-[(allyloxy)carbonyl]-2,5-dihydro-1H-pyrrole-3-carboxylic acid C9H11NO4 详情 详情
(IX) 61457 allyl 3-[3-(tert-butoxy)-3-oxopropanoyl]-2,5-dihydro-1H-pyrrole-1-carboxylate C15H21NO5 详情 详情
(X) 61458 allyl 3-(2-chloroacetyl)-2,5-dihydro-1H-pyrrole-1-carboxylate C10H12ClNO3 详情 详情
(XI) 61459 allyl 3-(2-sulfanyl-1,3-thiazol-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate C11H12N2O2S2 详情 详情

合成路线24

该中间体在本合成路线中的序号：(X)

Acylation of glycine ethyl ester (X) with ethyl oxalyl chloride (XI) provides the oxalic acid mono-amide (XII). Subsequent condensation of (XII) with aminoacetaldehyde dimethylacetal (XIII) affords the diamide (XIV). Cyclization of (XIV) under acetal hydrolysis conditions leads to pyrazinone (XV). This is then brominated to (XVI) employing POBr3 in refluxing dichloroethane. Condensation of the bromopyrazinone (XVI) with amine (IX) at 120 C in a sealed vessel furnishes the aminopyrazinone (XVII). After chlorination of (XVII) with N-chlorosuccinimide, the resultant chloropyrazine ester (XVIII) is hydrolyzed to acid (XIX) under alkaline conditions

参考文献 中间体
合成目标
【1】 Selnick, H.G.; Rittle, K.E.; Barrow, J.C.; Morrissette, M.M.; Nantermet, P.G.; Staas, D. (Merck & Co., Inc.); Thrombin inhibitors. WO 0257225 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 63218 2-(2-amino-1,1-difluoroethyl)-1-pyridiniumolate C7H8F2N2O 详情 详情
(X) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(XI) 11043 Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride 4755-77-5 C4H5ClO3 详情 详情
(XII) 63556 ethyl 2-[(2-ethoxy-2-oxoethyl)amino]-2-oxoacetate C8H13NO5 详情 详情
(XIII) 34158 aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine 22483-09-6 C4H11NO2 详情 详情
(XIV) 63557 ethyl 2-({2-[(2,2-dimethoxyethyl)amino]-2-oxoacetyl}amino)acetate C10H18N2O6 详情 详情
(XV) 63558 ethyl 2-[2,3-dioxo-3,4-dihydro-1(2H)-pyrazinyl]acetate C8H10N2O4 详情 详情
(XVI) 63219 ethyl 2-[3-bromo-2-oxo-1(2H)-pyrazinyl]acetate C8H9BrN2O3 详情 详情
(XVII) 63220 2-(2-{[4-(2-ethoxy-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}-1,1-difluoroethyl)-1-pyridiniumolate C15H16F2N4O4 详情 详情
(XVIII) 63221 2-(2-{[5-chloro-4-(2-ethoxy-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}-1,1-difluoroethyl)-1-pyridiniumolate C15H15ClF2N4O4 详情 详情
(XIX) 63222 2-(2-{[4-(carboxymethyl)-5-chloro-3-oxo-3,4-dihydro-2-pyrazinyl]amino}-1,1-difluoroethyl)-1-pyridiniumolate C13H11ClF2N4O4 详情 详情

合成路线25

该中间体在本合成路线中的序号：(I)

Acylation of glycine ethyl ester (I) with ethyl oxalyl chloride (II) affords amide (III). Subsequent reaction of (III) with aminoacetaldehyde dimethyl acetal (IV) produces the oxalic acid diamide (V). Cyclization of (V) under acidic conditions furnishes the pyrazine dione (VI), which is further brominated to (VII) employing phosphorus oxybromide.

参考文献 中间体
合成目标
【1】 Selnick, H.G.; Newton, R.C.; Newton, C.L.; Barrow, J.C.; Nantermet, P.G. (Merck & Co., Inc.); Thrombin inhibitors. WO 0311222 .
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) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(II) 11043 Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride 4755-77-5 C4H5ClO3 详情 详情
(III) 63556 ethyl 2-[(2-ethoxy-2-oxoethyl)amino]-2-oxoacetate C8H13NO5 详情 详情
(IV) 34158 aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine 22483-09-6 C4H11NO2 详情 详情
(V) 63557 ethyl 2-({2-[(2,2-dimethoxyethyl)amino]-2-oxoacetyl}amino)acetate C10H18N2O6 详情 详情
(VI) 63558 ethyl 2-[2,3-dioxo-3,4-dihydro-1(2H)-pyrazinyl]acetate C8H10N2O4 详情 详情
(VII) 63219 ethyl 2-[3-bromo-2-oxo-1(2H)-pyrazinyl]acetate C8H9BrN2O3 详情 详情
Extended Information