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【结 构 式】

【分子编号】17430

【品名】2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate

【CA登记号】5292-43-3

【 分 子 式 】C6H11BrO2

【 分 子 量 】195.05614

【元素组成】C 36.95% H 5.68% Br 40.96% O 16.4%
与该中间体有关的原料药合成路线共 53 条
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合成路线1

该中间体在本合成路线中的序号：(VI)

The Wittig condensation of protected bicyclic aldehyde (I) with methyl triphenyl phosphonium bromide and potassium tert-butoxide in THF gives the diene (II), which by hydroboration with disiamyl borane followed by oxidative hydrolysis with NaOH and H2O2 is converted into the alcohol (III). Oxidation of (III) with Collins' reagent followed by treatment with acetic anhydride yields the dienol acetate (IV), which is submitted to a 1,4-catalytic hydrogenation with naphthalene Cr(CO)3-H2 in THF and hydrolysis with K2CO3 to afford the allyl alcohol (V). The condensation of (V) with tert-butyl bromoacetate (VI) by means of tetrabutylammonium bisulfate, followed by partial deprotection with tetrabutylammonium fluoride gives the alcohol (VII), which is oxidized with the SO3-pyridine complex to the aldehyde (VIII). The condensation of (VIII) with 1,1-dibromo-3-methyl-5-octyn-2-one (IX) by means of Zn, diethylaluminum chloride and CuBr in THF yields the B-bromoenone (X), which is reduced stereoselectively with (S)-(-)-2,2'-dihydroxy-1,1'-binaphthyl and LiAlH4 in THF to afford the a bromodienol (XI). Finally, this compound is dehydrominated and saponified with tetrabutylammonium bisulfate and NaOH in ether toluene-water.

参考文献 中间体
合成目标
【1】 Gillum, A.M.; Klem, R.E.; Klasa, R.J.; Frankel, S.R.; Oblimersen Bcl-2 antisense: facilitating apoptosis in anticancer treatment. J Org Chem 1988, 53, 6, 1227.
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) 13776 (3aS,5R,6R,6aS)-6-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenecarbaldehyde C22H38O4Si 详情 详情
(II) 23382 [(2R,3R,3aS,6aS)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-vinyl-1,2,3,3a,4,6a-hexahydro-2-pentalenyl]methyl tetrahydro-2H-pyran-2-yl ether; ([(1R,2R,3aS,6aS)-2-[(tetrahydro-2H-pyran-2-yloxy)methyl]-5-vinyl-1,2,3,3a,6,6a-hexahydro-1-pentalenyl]methoxy)(tert-butyl)dimethylsilane C23H40O3Si 详情 详情
(III) 23383 2-[(3aS,5R,6R,6aS)-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]-1-ethanol C23H42O4Si 详情 详情
(IV) 23384 (E)-2-[(3aS,5R,6R,6aS)-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]ethenyl acetate C25H42O5Si 详情 详情
(V) 23385 2-[(3aS,4R,5R,6aR)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]-1-ethanol C23H42O4Si 详情 详情
(VI) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(VII) 23387 tert-butyl 2-[2-[(3aS,4R,5R,6aR)-4-(hydroxymethyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]ethoxy]acetate C23H38O6 详情 详情
(VIII) 23388 tert-butyl 2-[2-[(3aS,4R,5R,6aR)-4-formyl-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]ethoxy]acetate C23H36O6 详情 详情
(IX) 23389 tert-butyl 2-[2-[(3aS,4R,5R,6aR)-4-[(Z,4S)-2-bromo-4-methyl-3-oxo-1-nonen-6-ynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]ethoxy]acetate C32H47BrO6 详情 详情
(X) 23390 tert-butyl 2-[2-[(3aS,4R,5R,6aR)-4-[(Z,4S)-2-bromo-4-methyl-3-oxo-1-nonen-6-ynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]ethoxy]acetate C32H47BrO6 详情 详情
(XI) 23391 tert-butyl 2-[2-[(3aS,4S,5R,6aS)-4-[(Z,3S,4S)-2-bromo-3-hydroxy-4-methyl-1-nonen-6-ynyl]-5-hydroxyhexahydro-2(1H)-pentalenylidene]ethoxy]acetate C26H39BrO5 详情 详情

合成路线2

该中间体在本合成路线中的序号：(XIII)

2) The reduction of (III) with NaBH4 followed by debenzoylation with NaOH and deprotection with acetic acid gives the dihydroxy ketone (X), which by silviation with dimethyl-tert-butylsilyl chloride in DMF is converted to the disilylated ketone (XI). A Horner Wittig reaction of ketone (XI) with phosphonate (VI), followed by reduction with LiAlH4 as before affords the pentalenylideneethanol (XII), which is etherified with ten butyl bromoacetate (XIII) in aqueous NaOH - toluene and tetrabutylammonium sulfate with simultaneous hydrolysis of the tert-butyl group yielding the silylated prostaglandin (XIV). Finally, this compound is deprotected with tetrabutylammonium fluoride in THF.

参考文献 中间体
合成目标
【1】 Skuballa, W.; et al.; Synthesis of a new chemically and metabolically stable prostacyclin analogue with high and long-lasting oral activity. J Med Chem 1986, 29, 3, 313.
【2】 Castaner, J.; Prous, J.; Cicaprost. Drugs Fut 1986, 11, 11, 913.
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) 24200 Benzoic acid (1'R,2'R,3'aR,6'aS)-1'-formylspiro[1,3-dioxolane-2,5'-perhydropentalen]-2'-yl ester C18H20O5 详情 详情
(II) 24201 dimethyl 3-methyl-2-oxo-5-octynylphosphonate C11H19O4P 详情 详情
(III) 24202 Benzoic acid (2'R,3'aR,6'aS)-1'-(2-Bromo-4(S)-methyl-3-oxonon-1(E)-en-6-yn-1-yl)-spiro[1,3-dioxolane-2,5'-perhydropentalen]-2'-yl ester C27H31BrO5 详情 详情
(VI) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(X) 24212 (3aS,5R,6aR)-5-hydroxy-4-[(3S,4S)-3-hydroxy-4-methyl-1,6-nonadiynyl]hexahydro-2(1H)-pentalenone C18H24O3 详情 详情
(XI) 24213 (3aS,5R,6aR)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-((3S,4S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-1,6-nonadiynyl)hexahydro-2(1H)-pentalenone C30H52O3Si2 详情 详情
(XII) 24215 2-[(3aS,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-((3S,4S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-1,6-nonadiynyl)hexahydro-2(1H)-pentalenylidene]-1-ethanol C32H56O3Si2 详情 详情
(XIII) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(XIV) 24216 2-[2-[(3aS,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-((3S,4S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-1,6-nonadiynyl)hexahydro-2(1H)-pentalenylidene]ethoxy]acetic acid C34H58O5Si2 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 cyclopentylamine (I) with tertbutyl bromoacetate (II) by means of NH3 in acetonitrile gives N-cyclopentylglycine tert-butyl ester (III), which is condensed with 3-(acetylthio)-2-methylpropionyl chloride (IV) [prepared from the corresponding acid (V) with SOCl2] by means of triethylamine in dioxane to yield the acylated glycine (VI). Deacetylation of (VI) with dry ammonia in methanol affords the mercapto derivative (VII), which is acylated with pivaloyl chloride (VIII) in the usual way giving the corresponding thio ester (IX). Finally, this compound is hydrolyzed partially with trimethylsilyl iodide in methylene chloride.

参考文献 中间体
合成目标
【1】 Suh, J.T.; et al.; Angiotensin-converting enzyme inhibitors. New orraly active antihypertensive (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycine derivatives. J Med Chem 1985, 28, 1, 57-66.
【2】 Castaner, J.; Serradell, M.N.; Pivopril. Drugs Fut 1986, 11, 2, 116.
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) 28850 cyclopentanamine 1003-03-8 C5H11N 详情 详情
(II) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(III) 28851 tert-butyl 2-(cyclopentylamino)acetate C11H21NO2 详情 详情
(IV) 28852 (2R)-3-Acetylthio-2-methylpropionyl chloride;L-3-(Acetylthio)-2-methylpropanoyl chloride ;S-[(2R)-3-chloro-2-methyl-3-oxopropyl] ethanethioate 74345-73-6 C6H9ClO2S 详情 详情
(V) 28853 (2R)-3-(acetylsulfanyl)-2-methylpropionic acid;(R)-3-(acetylthio)-2-methylpropanoic acid 74431-52-0 C6H10O3S 详情 详情
(VI) 28854 tert-butyl 2-[[(2S)-3-(acetylsulfanyl)-2-methylpropanoyl](cyclopentyl)amino]acetate C17H29NO4S 详情 详情
(VII) 28855 tert-butyl 2-[cyclopentyl[(2S)-2-methyl-3-sulfanylpropanoyl]amino]acetate C15H27NO3S 详情 详情
(VIII) 13597 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride 3282-30-2 C5H9ClO 详情 详情
(IX) 28856 tert-butyl 2-(cyclopentyl[(2S)-3-[(2,2-dimethylpropanoyl)sulfanyl]-2-methylpropanoyl]amino)acetate C20H35NO4S 详情 详情

合成路线4

该中间体在本合成路线中的序号：(VII)

Alkylation of the sodium salt of diclofenac (I) with benzyl bromoacetate (II) in hot DMF yielded the (arylacetoxy)acetate (III). Subsequent hydrogenolysis of the benzyl ester of (III) in the presence of Pd/C gave the title carboxylic acid. Alternatively, the benzyl ester group of (III) was cleaved by means of the combination of chlorotrimethylsilane and sodium iodide. This method of selective ester hydrolysis with in situ generated iodotrimethylsilane was also applied to the corresponding methyl (IV) and tert-butyl (V) esters. In a related procedure, tert-butyl ester (V) was prepared by alkylation of diclofenac (VI) with tert-butyl bromoacetate (VII) in the presence of tertiary amines. Selective cleavage of the tert-butyl ester group of (V) was then performed by treatment with either trifluoroacetic or formic acid.

参考文献 中间体
合成目标
【1】 Casas, A.V. (Almirall Prodesfarma, SA); 2-[(2,6-Dichlorophenyl)amino]phenylacetoxyacetyl derivs. and therapeutic compsns. containing same. EP 0119932; US 4548952 .
【2】 Ginebreda Martí, A.; Agustí Cruz, A. (Almirall Prodesfarma, SA); Process for obtaining 2-[(2,6-dichlorophenyl)amino]phenylacetoxyacetic acid. ES 2020146 .
【3】 Schickaneder, H.; Nikolopoulos, A.; Murphy, T.; Process for the preparation of aceclofenac. WO 9955660 .
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) 56535 sodium 2-[2-(2,6-dichloroanilino)phenyl]acetate C14H10Cl2NNaO2 详情 详情
(II) 12869 benzyl 2-bromoacetate 5437-45-6 C9H9BrO2 详情 详情
(III) 56536 2-(benzyloxy)-2-oxoethyl 2-[2-(2,6-dichloroanilino)phenyl]acetate C23H19Cl2NO4 详情 详情
(IV) 56537 2-methoxy-2-oxoethyl 2-[2-(2,6-dichloroanilino)phenyl]acetate C17H15Cl2NO4 详情 详情
(V) 56538 2-(tert-butoxy)-2-oxoethyl 2-[2-(2,6-dichloroanilino)phenyl]acetate C20H21Cl2NO4 详情 详情
(VI) 33701 Diclofenac; 2-[2-(2,6-Dichloroanilino)phenyl]acetic acid C14H11Cl2NO2 详情 详情
(VII) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情

合成路线5

该中间体在本合成路线中的序号：(IX)

1) The reduction of 2-thiophenecarboxaldehyde cyanohydrin (I) with LiAlH4 gives 2-amino-1-(2-thienyl)ethanol (II), which is N-protected with di-tert-butyl pyrocarbonate yielding 2-(tert-butoxycarbonylamino)-1-(2-thienyl)ethanol (III). The reaction of (III) with PCl5 in dichloromethane affords 2-(tert-butoxycarbonylamino)-1-chloro-1-(2-thienyl)ethane (IV), which is condensed with benzhydryl N-phthaloylcysteinate (V) by means of Na2CO3 in hot DMF giving the S-substituted cysteinate (VI). The deprotection of (VI) with trifluoroacetic acid in anisole yields S-[2-amino-1-(2-thienyl)ethyl]-N-phthaloylcysteine (VII), which is cyclized by means of diphenylphosphoryl azide (DPA) in DMF giving 6-phthalimido-2-(2-thienyl)perhydro-1,4-thiazepin-5-one (VIII). The condensation of (VIII) with tert-butyl bromoacetate (IX) by means of NaH in DMF affords tert-butyl 2-[6-phthalimido-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate (X), which is treated with methylhydrazine in methanol-dichloromethane yielding the 6-amino derivative (XI). The condensation of (XI) with ethyl 2-bromo-4-phenylbutyrate (XII) by means of Na2CO3 in hot DMF gives the tert-butyl ester of the desired product (XIII), which is finally deprotected with trifluoroacetic acid in anisole.

参考文献 中间体
合成目标
【1】 Yanagisawa, H.; Ishihara, S.; Ando, A.; Kanazaki, T.; Koike, H.; Tsujita, Y. (Sankyo Co., Ltd.); Perhydrothiazepine derivatives, their preparation and their therapeutical use. AU 8541058; EP 0161801; ES 8702388; ES 8801229; JP 85215678; JP 86267579 .
【2】 Prous, J.; Castaner, J.; RS-5142. Drugs Fut 1989, 14, 4, 336.
【3】 Ishihara, S.; Ando, A.; Miyamoto, S.; Kanazaki, T.; Hata, T.; Oizumi, K.; Matsushita, Y.; Koike, H.; Yanagisawa, H.; Iijima, Y.; Angiotensin-converting enzyme inhibitors: Perhydro-1,4-thiazepin-5-one derivatives. J Med Chem 1987, 30, 11, 1984.
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) 20799 2-hydroxy-2-(2-thienyl)acetonitrile C6H5NOS 详情 详情
(II) 20800 2-amino-1-(2-thienyl)-1-ethanol C6H9NOS 详情 详情
(III) 20801 tert-butyl 2-hydroxy-2-(2-thienyl)ethylcarbamate C11H17NO3S 详情 详情
(IV) 20802 tert-butyl 2-chloro-2-(2-thienyl)ethylcarbamate C11H16ClNO2S 详情 详情
(V) 20803 benzhydryl 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-sulfanylpropanoate C24H19NO4S 详情 详情
(VI) 20804 benzhydryl 3-[[2-[(tert-butoxycarbonyl)amino]-1-(2-thienyl)ethyl]sulfanyl]-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoate C35H34N2O6S2 详情 详情
(VII) 20805 3-[[2-amino-1-(2-thienyl)ethyl]sulfanyl]-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propionic acid C17H16N2O4S2 详情 详情
(VIII) 20806 2-[5-oxo-2-(2-thienyl)-1,4-thiazepan-6-yl]-1H-isoindole-1,3(2H)-dione C17H14N2O3S2 详情 详情
(IX) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(X) 20808 tert-butyl 2-[6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxo-2-(2-thienyl)-1,4-thiazepan-4-yl]acetate C23H24N2O5S2 详情 详情
(XI) 20809 tert-butyl 2-[6-amino-5-oxo-2-(2-thienyl)-1,4-thiazepan-4-yl]acetate 112968-38-4 C15H22N2O3S2 详情 详情
(XII) 20810 ethyl 2-bromo-4-phenylbutanoate C12H15BrO2 详情 详情
(XIII) 20811 ethyl 2-[[4-[2-(tert-butoxy)-2-oxoethyl]-5-oxo-2-(2-thienyl)-1,4-thiazepan-6-yl]amino]-4-phenylbutanoate C27H36N2O5S2 详情 详情

合成路线6

该中间体在本合成路线中的序号：(XXII)

2) The addition of tert-butoxycarbonyl)-L-cysteine (XIV) to 2-(2-nitroethenyl)thiophene (XV) by means of N-methylmorpholine in toluene gives S-[2-nitro-1-(2-thienyl)ethyl-N-(tert-butoxycarbonyl-L-cysteine (XVI), which is reduced with H2 over Pd/C in acetic acid yielding the corresponding amine (XVII). The cyclization of (XVII) by means of diphenyl phosphorazidate (DPN) and N-methylmorpholine in DMF affords (2RS,6R)-6-(tert-butoxycarbonylamino)-2-(2-thienyl)perhydro-1,4-thiazepine (XVIII), which by hydrolysis and fractional crystallization gives (2S,6R)-6-amino-2-(2-thienyl)perhydro-1,4-thiazepine (XIX). The condensation of (XIX) with ethyl 2(R)-(trifluoromethylsulfonyloxy)-4-phenylbutanoate (XX) by means of triethylamine in dichloromethane yields (2S,2R)-6-[1(S)-(ethoxycarbonyl)-3-phenylpropylamino]-2-(2-thienyl)- perhydro-1,4-thiazepin-5-one (XXI), which is condensed with tert-butyl bromoacetate (XXII) by means of NaH in DMF to give the precursor (XXIII). Finally, this compound is hydrolyzed with 4N-HCl-dioxane at room temperature.

参考文献 中间体
合成目标
【1】 Yanagisawa, H.; Ishihara, S.; Ando, A.; Kanazaki, T.; Koike, H.; Tsujita, Y. (Sankyo Co., Ltd.); Perhydrothiazepine derivatives, their preparation and their therapeutical use. AU 8541058; EP 0161801; ES 8702388; ES 8801229; JP 85215678; JP 86267579 .
【2】 Ishihara, S.; Ando, A.; Miyamoto, S.; Kanazaki, T.; Hata, T.; Oizumi, K.; Matsushita, Y.; Koike, H.; Yanagisawa, H.; Iijima, Y.; Angiotensin-converting enzyme inhibitors: Perhydro-1,4-thiazepin-5-one derivatives. J Med Chem 1987, 30, 11, 1984.
【3】 Prous, J.; Castaner, J.; RS-5142. Drugs Fut 1989, 14, 4, 336.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIV) 20812 (2R)-2-[(tert-butoxycarbonyl)amino]-3-sulfanylpropionic acid 20887-95-0 C8H15NO4S 详情 详情
(XV) 20813 2-[(Z)-2-nitroethenyl]thiophene C6H5NO2S 详情 详情
(XVI) 20814 (2R)-2-[(tert-butoxycarbonyl)amino]-3-[[2-nitro-1-(2-thienyl)ethyl]sulfanyl]propionic acid C14H20N2O6S2 详情 详情
(XVII) 20815 (2R)-3-[[2-amino-1-(2-thienyl)ethyl]sulfanyl]-2-[(tert-butoxycarbonyl)amino]propionic acid C14H22N2O4S2 详情 详情
(XVIII) 20816 tert-butyl (6R)-5-oxo-2-(2-thienyl)-1,4-thiazepan-6-ylcarbamate C14H20N2O3S2 详情 详情
(XIX) 20817 (2S,6R)-6-amino-2-(2-thienyl)-1,4-thiazepan-5-one 110221-26-6 C9H12N2OS2 详情 详情
(XX) 20818 ethyl (2R)-4-phenyl-2-[[(trifluoromethyl)sulfonyl]oxy]butanoate C13H15F3O5S 详情 详情
(XXI) 20819 ethyl (2S)-2-[[(2S,6R)-5-oxo-2-(2-thienyl)-1,4-thiazepan-6-yl]amino]-4-phenylbutanoate C21H26N2O3S2 详情 详情
(XXII) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(XXIII) 20821 ethyl (2S)-2-[[(2S,6R)-4-[2-(tert-butoxy)-2-oxoethyl]-5-oxo-2-(2-thienyl)-1,4-thiazepan-6-yl]amino]-4-phenylbutanoate C27H36N2O5S2 详情 详情

合成路线7

该中间体在本合成路线中的序号：(XII)

The methylation of ethyl 2-(hydroxyimino)-3-oxobutyrate (I) with dimethyl sulfate and Na2CO3 in methanol gives ethyl 2-(methoxyimino)-3-oxobutyrate (II), which is brominated with Br2 in CHCl3 yielding ethyl 4-bromo-2-(methoxyimino)-3-oxobutyrate (III). The cyclization of (III) with thiourea (IV) in refluxing ethanol affords ethyl 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetate (V), which is acylated with chloroacetyl chloride (VI) in DMA to give the corresponding N-chloroacetyl derivative (VII). The hydrolysis of (VII) with KOH in ethanol-water affords 2-(2-chloroacetamidothiazol-4-yl)-2-(methoxyimino)acetic acid (VIII), which is condensed with desacetoxycephalosporanic acid (IX) by means of N-hydroxysuccinimide (NOHS) and dicyclohexylcarbodiimide (DCC) in THF yielding 7beta-[2-(2-chloroacetamidothiazol-4-yl)-2(Z)-(methoxyimino)acetamido]desacetoxycephalosporanic acid (X). The deprotection of (X) with sodium acetate in THF gives the free acid (XI), which is finally esterified with pivaloyloxymethyl bromide (XII) by means of NaHCO3 in ethyl acetate-DMSO.

参考文献 中间体
合成目标
【1】 Ochiai, M.; Morimoto, A.; Matsushita, Y. (Takeda Chemical Industries, Ltd.); Cephalosporin derivatives, process for their preparation and medicines containing them. DE 2715385 .
【2】 Nakao, H.; Sugawara, S. (Sankyo Co., Ltd.); Cephalosporin derivatives for oral administration. DE 3020625 .
【3】 Prous, J.; Castaner, J.; CEFETAMET PIVOXIL < Prop INNM >. Drugs Fut 1989, 14, 5, 420.
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) 20853 ethyl 2-(hydroxyimino)-3-oxobutanoate；(Z)-ethyl 2-(hydroxyimino)-3-oxobutanoate C6H9NO4 详情 详情
(II) 20854 ethyl 2-(methoxyimino)-3-oxobutanoate C7H11NO4 详情 详情
(III) 10181 ethyl 4-bromo-2-(methoxyimino)-3-oxobutanoate 60845-87-6 C7H10BrNO4 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 10182 Ethyl 2-(2-aminothiazole-4-yl)-2-methoxyiminoacetate; ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetate; 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic acid ethyl ester 64485-88-7 C8H11N3O3S 详情 详情
(VI) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(VII) 20859 ethyl 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetate C10H12ClN3O4S 详情 详情
(VIII) 20860 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetic acid 64486-18-6 C8H8ClN3O4S 详情 详情
(IX) 20861 (6R,7R)-7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; 7-ADCA 22252-43-3 C8H10N2O3S 详情 详情
(X) 20862 (6R,7R)-7-[[2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C16H16ClN5O6S2 详情 详情
(XI) 20863 (6R,7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C14H15N5O5S2 详情 详情
(XII) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(IV)

The acylation of 4-hydroxypiperidine (I) with benzyl chloroformate (II) by means of triethylamine in dichloromethane gives 4-hydroxypiperidine-1-carboxylic acid benzyl ester (III), which is condensed with tert-butyl bromoacetate (IV) by means of tetrabutylammonium hydrogensulfate and NaOH in toluene/water, affording 2-[1-(benzyloxycarbonyl)piperidin-4-yloxy]acetic acid tert-butyl ester (V). The deprotection of (V) by hydrogenation with H2 over Pd/C in ethanol gives the piperidine (VI), which is condensed with N-(benzyloxycarbonyl)-4-O-tert-butyl-L-tyrosine (VII) by means of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methylmorpholine (NMM) in dichloromethane, yielding the expected condensation product (VIII). The deprotection of the amino group of (VIII) by hydrogenation as before affords (IX), which is N-acylated with 4-amidinobenzoyl chloride (X), prepared by reaction of 4-amidinobenzoic acid (XI) with SOCl2, giving the bis-tert-butylated product (XII). Finally, this compound is deprotected by means of trifluoroacetic acid in dichloromethane.

参考文献 中间体
合成目标
【1】 Weller, T.; Hadvary, P.; Trzeciak, A.; Knopp, D.; Steiner, B.; Edenhofer, A.; Muller, M.; Hurzeler, M.; Alig, L.; Low molecular weight, non-peptide fibrinogen receptor antagonists. J Med Chem 1992, 35, 23, 4393.
【2】 Castaner, J.; Merlos, M.; Cases, A.; Rabasseda, X.; Lamifiban. Drugs Fut 1999, 24, 3, 261.
【3】 Alig, L.; Hadvary, P.; Huzeler, M.; Muller, M.; Steiner, B.; Weller, T. (F. Hoffmann-La Roche AG); N-acyl-alpha-aminoacids derivs.. EP 0505868; JP 1993148204; US 5378712; US 5545658; US 5658928; US 5670515; US 5747522 .
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) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情
(II) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(III) 19284 benzyl 4-hydroxy-1-piperidinecarboxylate C13H17NO3 详情 详情
(IV) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(V) 19286 benzyl 4-[2-(tert-butoxy)-2-oxoethoxy]-1-piperidinecarboxylate C19H27NO5 详情 详情
(VI) 19287 tert-butyl 2-(4-piperidinyloxy)acetate C11H21NO3 详情 详情
(VII) 22478 (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[4-(tert-butoxy)phenyl]propionic acid C21H25NO5 详情 详情
(VIII) 22479 tert-butyl 2-[(1-[(2S)-2-[[(benzyloxy)carbonyl]amino]-3-[4-(tert-butoxy)phenyl]propanoyl]-4-piperidinyl)oxy]acetate C32H44N2O7 详情 详情
(IX) 22480 tert-butyl 2-[(1-[(2S)-2-amino-3-[4-(tert-butoxy)phenyl]propanoyl]-4-piperidinyl)oxy]acetate C24H38N2O5 详情 详情
(X) 22481 4-[amino(imino)methyl]benzoyl chloride C8H7ClN2O 详情 详情
(XI) 22482 4-Amidinobenzic acid; 4-[amino(imino)methyl]benzoic acid 15535-95-2 C8H8N2O2 详情 详情
(XII) 22483 tert-butyl 2-[(1-[(2S)-2-([4-[amino(imino)methyl]benzoyl]amino)-3-[4-(tert-butoxy)phenyl]propanoyl]-4-piperidinyl)oxy]acetate C32H44N4O6 详情 详情

合成路线9

该中间体在本合成路线中的序号：(XVI)

2) Lactone form: The regioselective opening of (R)-2-(tert-butyldimethylsilylethynyl)oxirane (XIV) with KCN in ethanol gives 3(S)-hydroxy-5-(tert-butyldimethylsilyl)-4-pentynenitrile (XV), which is condensed with tert-butyl bromoacetate (XVI) by means of Zn in refluxing THF to afford the 5(S)-hydroxyketoester (XVII). The controlled reduction of (XVII) with NaBH4/diethylmethoxyborane yields the 3(R),5(S)-dihydroxy ester (XVIII), which is deprotected with 2,2-dimethoxypropane and p-toluenesulfonic acid in THF/methanol to the protected heptynoic ester (XIX). The desilylation of (XIX) with tetrabutylammonium fluoride (TBAF) in THF affords the protected heptynoic ester (XX), which is condensed with 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline (XXI, see Scheme 5) to give the protected NK-104 tert-butyl ester (XXII). Finally, this compound is treated with trifluoroacetic acid in dichloromethane.

参考文献 中间体
合成目标
【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; NK-104. Drugs Fut 1998, 23, 8, 847-859.
【2】 Minami, T.; Hiyama, T.; Takahashi, K.; Ohara, Y.; Synthesis of an artificial HMG-CoA reductase inhibitor NK-104 via a hydrosilylation-cross-coupling reaction. Bull Chem Soc Jpn 1995, 68, 5, 2649-56.
【3】 Takahashi, K.; Minami, T.; Ohara, Y.; Hiyama, T.; A new synthesis of HMG-CoA reductase inhibitor NK-104 through hydrosilylation-cross coupling reaction. Tetrahedron Lett 1993, 34, 51, 8263-6.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIV) 17428 tert-butyl(dimethyl)[2-[(2R)oxiranyl]ethynyl]silane C10H18OSi 详情 详情
(XV) 17429 (3S)-5-[tert-butyl(dimethyl)silyl]-3-hydroxy-4-pentynenitrile C11H19NOSi 详情 详情
(XVI) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(XVII) 17431 tert-butyl (5S)-7-[tert-butyl(dimethyl)silyl]-5-hydroxy-3-oxo-6-heptynoate C17H30O4Si 详情 详情
(XVIII) 17432 tert-butyl (3R,5S)-7-[tert-butyl(dimethyl)silyl]-3,5-dihydroxy-6-heptynoate C17H32O4Si 详情 详情
(XIX) 17433 tert-butyl 2-((4R,6S)-6-[2-[tert-butyl(dimethyl)silyl]ethynyl]-2,2-dimethyl-1,3-dioxan-4-yl)acetate C20H36O4Si 详情 详情
(XX) 17434 tert-butyl 2-[(4R,6S)-6-ethynyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate C14H22O4 详情 详情
(XXI) 17435 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline C18H13FIN 详情 详情
(XXII) 17436 tert-butyl 2-((4R,6S)-6-[(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl]-2,2-dimethyl-1,3-dioxan-4-yl)acetate C32H36FNO4 详情 详情
(XLIV) 64696 (4R,6S)-6-{(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl}-4-hydroxytetrahydro-2H-pyran-2-one C25H22FNO3 详情 详情

合成路线10

该中间体在本合成路线中的序号：(XI)

2) The reaction of 4-methylpentanoic acid (I) with SOCl2 in refluxing chloroform gives the acyl chloride (II), which is condensed with the chiral oxazolidinone (III) by means of BuLi in THF, yielding the corresponding N-acyl derivative (IV). The regioselective alkylation of (IV) with tert-butyl bromoacetate (XI) by means of LDA in THF affords the (S)-adduct (XII). The elimination of the chiral auxiliary with LiOH and H2O2 gives the glutaric acid monoester (XIII), which is reduced with BH3/SMe2 in THF, yielding compound (XIV). The reaction of (XIV) with tosyl chloride in pyridine yields the tosylate (XV), which is treated with sodium azide in DMSO, affording the azide (XVI). The hydrolysis of the tert-butyl group of (XVI) affords the free acid (XVII), which is reduced with H2 over Pd/C.

参考文献 中间体
合成目标
【1】 Newhouse, B.J.; Ibrahim, P.; Burgess, L.E.; et al.; Potent selective nonpeptidic inhibitors of human lung tryptase. Proc Natl Acad Sci USA 1999, 96, 15, 8348.
【2】 Sobieray, D.M.; Hoekstra, M.S.; Schwindt, M.A.; et al.; Chemical development of CI-1008, an enantiomerically pure anticonvulsant. Org Process Res Dev 1997, 1, 1, 26.
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) 25389 4-methylpentanoic acid 646-07-1 C6H12O2 详情 详情
(II) 25390 4-methylpentanoyl chloride 38136-29-7 C6H11ClO 详情 详情
(III) 26040 (4R,5S)-4-methyl-5-phenyl-1,3-oxazolidin-2-one C10H11NO2 详情 详情
(IV) 26041 (4R,5S)-4-methyl-3-(4-methylpentanoyl)-5-phenyl-1,3-oxazolidin-2-one C16H21NO3 详情 详情
(XI) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(XII) 26047 tert-butyl (3S)-5-methyl-3-[[(4R,5S)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]carbonyl]hexanoate C22H31NO5 详情 详情
(XIII) 25393 (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-4-methylpentanoic acid C12H22O4 详情 详情
(XIV) 26048 tert-butyl (3S)-3-(hydroxymethyl)-5-methylhexanoate C12H24O3 详情 详情
(XV) 26049 tert-butyl (3S)-5-methyl-3-([[(4-methylphenyl)sulfonyl]oxy]methyl)hexanoate C19H30O5S 详情 详情
(XVI) 26050 tert-butyl (3S)-3-(azidomethyl)-5-methylhexanoate C12H23N3O2 详情 详情
(XVII) 26051 (3S)-3-(azidomethyl)-5-methylhexanoic acid C8H15N3O2 详情 详情

合成路线11

该中间体在本合成路线中的序号：(VIII)

The acylation of O-benzyltyrosine (I) with ethyl trifluoroacetate in methanol gives O-benzyl-N-trifluroacetyltyrosine (II), which is condensed with N-(2-aminoethyl)carbamic acid benzyl ester (III) by means of ethyl chloroformate in THF, yielding the tyrosinamide (IV). The deacylation of (IV) by means of NaBH4 in ethanol affords the N-deprotected tyrosinamide (V), which is submitted to hydrogenolysis with H2 over Pd/C in methanol to provide tyrosine 2-aminoethylamide (VI). The reduction of (VI) with diborane gives 3-aza-1-(4-hydroxybenzyl)pentane-1,5-diamine (VII), which is alkylated with bromoacetic acid tert-butyl ester (VIII) and NaHCO3 to yield the 1-(4-hydroxybenzyl)-3-azapentane-1,5-diamine N,N,N'.N'',N''-pentaacetate penta-tert-butyl ester (IX) (1). The alkylation of the OH group of (IX) with ethyl iodide and NaH in THF affords the corresponding ethoxybenzyl derivative (X), which is treated with TFA to provide the pentaacetic acid derivative (XI). Finally, this compound is complexed with Gd2O3 and NaOH in hot water to furnish the target gadolinium complex.

参考文献 中间体
合成目标
【1】 Schmitt-Willich, H.; Platzek, J.; Gries, H.; Schuhmann-Giampieri, G.; Vogler, H.; Weinmann, H.-J. (Schering AG); DTPA-complexes derivs., pharmaceutical compsns. containing them, their use and process for their preparation. AU 9058024; DE 3922005; EP 0405704; JP 1991215457; US 5695739; US 6039931 .
【2】 Deutsch, J.; Gries, H.; Klieger, E.; Niedballa, U.; Renneke, F.J.; Conrad, J.; Mützel, W. (Schering AG); Substd. complex-builders, complexes and complex salts, process for their preparation and pharmaceutical compsns. containing them. DE 3710730; WO 8807521 .
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) 26716 (2S)-2-amino-3-[4-(benzyloxy)phenyl]propionic acid 16652-64-5 C16H17NO3 详情 详情
(II) 53319 (2S)-3-[4-(benzyloxy)phenyl]-2-[(2,2,2-trifluoroacetyl)amino]propanoic acid n/a C18H16F3NO4 详情 详情
(III) 51002 benzyl 2-aminoethylcarbamate C10H14N2O2 详情 详情
(IV) 53320 benzyl 2-({(2S)-3-[4-(benzyloxy)phenyl]-2-[(2,2,2-trifluoroacetyl)amino]propanoyl}amino)ethylcarbamate n/a C28H28F3N3O5 详情 详情
(V) 53321 benzyl 2-({(2S)-2-amino-3-[4-(benzyloxy)phenyl]propanoyl}amino)ethylcarbamate n/a C26H29N3O4 详情 详情
(VI) 53322 (2S)-2-amino-N-(2-aminoethyl)-3-(4-hydroxyphenyl)propanamide n/a C11H17N3O2 详情 详情
(VII) 53323 4-{(2S)-2-amino-3-[(2-aminoethyl)amino]propyl}phenol n/a C11H19N3O 详情 详情
(VIII) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(IX) 53324 tert-butyl (7S)-6,9,12-tris[2-(tert-butoxy)-2-oxoethyl]-7-(4-hydroxybenzyl)-2,2-dimethyl-4-oxo-3-oxa-6,9,12-triazatetradecan-14-oate n/a C41H69N3O11 详情 详情
(X) 53325 tert-butyl (7S)-6,9,12-tris[2-(tert-butoxy)-2-oxoethyl]-7-(4-ethoxybenzyl)-2,2-dimethyl-4-oxo-3-oxa-6,9,12-triazatetradecan-14-oate n/a C43H73N3O11 详情 详情
(XI) 53326 2-([(2S)-2-[bis(carboxymethyl)amino]-3-(4-ethoxyphenyl)propyl]{2-[bis(carboxymethyl)amino]ethyl}amino)acetic acid n/a C23H33N3O11 详情 详情

合成路线12

该中间体在本合成路线中的序号：(XXV)

Reaction of 2-(1,3-dioxol-5-yl)acetic acid (XXI) with pivaloyl chloride and TEA gives the corresponding anhydride (XXII), which is condensed with the chiral oxazolidinone (XXIII) by means of n-BuLi in THF to yield the amide (XXIV). Condensation of (XXIV) with 2-bromoacetic acid tert-butyl ester (XXV) by means of NaHMDS in THF affords the adduct (XXVI). Elimination of the chiral auxiliary of (XXVI) by means of LiOOH in THF/water provides the chiral succinic acid hemiester (XXVII) (93% ee), which is selectively reduced with BH3­THF complex to give the 4-hydroxysuccinate (XXVIII). Reaction of succinate (XXVIII) with 4-chlorophenylsulfonyl chloride, TEA and DMAP in dichloromethane yields the sulfonate (XXIX), which is condensed with 4-methoxybenzaldoxime (XXX) by means of Cs2CO3 in hot acetonitrile to afford the oxime ether (XXXI). Transesterification of the tert-butyl ester of (XXXI) with trimethyl orthoformate and p-toluenesulfonic acid in hot methanol provides the methyl ester (XXXII), which is cyclized by means of trimethylsilyl triflate and tributylamine in dichloroethane to afford a 9:1 diastereomeric mixture of perhydro-1,2-oxazines (XXXIII) and (XXXIV) which is easily separated. The reductive N-O-bond cleavage of the major oxazine diastereomer (XXXIII) by means of Zn/HOAc or H2 over Pd/C gives the trisubstituted 4-aminobutanol (XXXV), which is cyclized by means of CBr4, PPh3 and TEA to yield chiral pyrrolidine (XXXVI) (4). Finally, pyrrolidine (XXXVI) is alkylated with N,N-dibutyl-2-bromoacetamide (XIII) followed by ester hydrolysis as before.

参考文献 中间体
合成目标
【1】 Leeson, P.; Castañer, R.M.; Sorbera, L.A.; Castañer, J.; Atrasentan. Drugs Fut 2001, 26, 10, 939.
【2】 McLaughlin, M.A.; Wittenberger, S.J.; Preparation of endothelin antagonist ABT-627. Tetrahedron Lett 1999, 40, 7175.
【3】 Winn, M.; et al.; 2,4-Diarylpyrrolidine-3-carboxylic acids-potent ETA selective endothelin receptor antagonists. 1. Discovery of A-127722. J Med Chem 1996, 39, 5, 1039.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
15787 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride 98-60-2 C6H4Cl2O2S 详情 详情
(XIII) 20685 2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide C10H20BrNO 详情 详情
(XXI) 18117 2-(1,3-benzodioxol-5-yl)acetic acid; 3,4-(Methylenedioxy)phenylacetic acid 2861-28-1 C9H8O4 详情 详情
(XXII) 48688 1,3-benzodioxol-5-ylacetic 1,1-dimethylpropionic anhydride C14H16O5 详情 详情
(XXIII) 12867 (4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone 17016-83-0 C6H11NO2 详情 详情
(XXIV) 48689 (4S)-3-[2-(1,3-benzodioxol-5-yl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one C15H17NO5 详情 详情
(XXV) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(XXVI) 48690 tert-butyl (3S)-3-(1,3-benzodioxol-5-yl)-4-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxobutanoate C21H27NO7 详情 详情
(XXVII) 48691 (2S)-2-(1,3-benzodioxol-5-yl)-4-(tert-butoxy)-4-oxobutyric acid C15H18O6 详情 详情
(XXVIII) 48692 tert-butyl (3S)-3-(1,3-benzodioxol-5-yl)-4-hydroxybutanoate C15H20O5 详情 详情
(XXIX) 48693 tert-butyl (3S)-3-(1,3-benzodioxol-5-yl)-4-[[(4-chlorophenyl)sulfonyl]oxy]butanoate C21H23ClO7S 详情 详情
(XXX) 48694 4-methoxybenzaldehyde oxime C8H9NO2 详情 详情
(XXXI) 48695 tert-butyl (3S)-3-(1,3-benzodioxol-5-yl)-4-([[(E)-(4-methoxyphenyl)methylidene]amino]oxy)butanoate C23H27NO6 详情 详情
(XXXII) 48696 methyl (3S)-3-(1,3-benzodioxol-5-yl)-4-([[(E)-(4-methoxyphenyl)methylidene]amino]oxy)butanoate C20H21NO6 详情 详情
(XXXIII) 48697 methyl (3R,4R,5S)-5-(1,3-benzodioxol-5-yl)-3-(4-methoxyphenyl)-1,2-oxazinane-4-carboxylate C20H21NO6 详情 详情
(XXXIV) 48698 methyl (3S,5S)-5-(1,3-benzodioxol-5-yl)-3-(4-methoxyphenyl)-1,2-oxazinane-4-carboxylate C20H21NO6 详情 详情
(XXXV) 48699 methyl (2R,3S)-2-[(R)-amino(4-methoxyphenyl)methyl]-3-(1,3-benzodioxol-5-yl)-4-hydroxybutanoate C20H23NO6 详情 详情
(XXXVI) 48700 methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate C20H21NO5 详情 详情

合成路线13

该中间体在本合成路线中的序号：(X)

2) The reaction of 4-hydroxypiperidine (VII) with benzyl chloroformate (VIII) by means of triethylamine in dichloromethane gives the expected benzyloxycarbonyl derivative (IX), which is condensed with tert-butyl 2-bromoacetate (X) by means of tetrabutylammonium bisulfate and NaOH, yielding 2-[1-(benzyloxycarbonyl)piperidin-4-yloxy]acetic acid tert-butyl ester (XI). The deprotection of (XI) as ususal affords 2-(4-piperidinyloxy)acetic acid tert-butyl ester (XII), which is condensed with N-(benzyloxycarbonyl)-L-alanine (XIII) by means of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methyl-morpholine (NMM) in dichloromethane to yield the acylated piperidine (XIV). The deprotection of (XIV) as usual affords compound (XV), which is acylated at the free amino group with 4-cyanobenzoyl chloride (V) and tetrabutylammonium bisulfate to give 2-[1-[N-(4-cyanobenzoyl)-L-alanyl]piperidin-4-yloxy]acetic acid tert-butyl ester (XVI). The reaction of the cyano group of (XVI) with hydroxylamine affords compound (XVII) with a hydroxyamidino substituent. Finally, the tert-butyl ester group of (XVII) is converted in ethyl ester by hydrolysis with hot fomic acid to the corresponding acetic acid (XVIII) and subsequent esterification with ethanol/H2SO4.

参考文献 中间体
合成目标
【1】 Alig, L.; Beresini, M.; Weller, T.; et al.; Orally active fibrinogen receptor antagonists. 2. Amidoximes as prodrugs of amidines. J Med Chem 1996, 39, 16, 3139.
【2】 Weller, T.; Hadvary, P.; Trzeciak, A.; Knopp, D.; Steiner, B.; Edenhofer, A.; Muller, M.; Hurzeler, M.; Alig, L.; Low molecular weight, non-peptide fibrinogen receptor antagonists. J Med Chem 1992, 35, 23, 4393.
【3】 Castañer, J.; Graul, A.; Merlos, M.; Sibrafiban . Drugs Fut 1998, 23, 12, 1297.
【4】 Alig, L.; Hadvary, P.; Hurzeler Muller, M.; Muller, M.; Steiner, B.; Weller, T. (F. Hoffmann-La Roche AG); Acetic acid derivs. as medicaments. EP 0656348; JP 1995196592; US 5726185 .
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) 19280 4-cyanobenzoyl chloride 6068-72-0 C8H4ClNO 详情 详情
(VII) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情
(VIII) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(IX) 19284 benzyl 4-hydroxy-1-piperidinecarboxylate C13H17NO3 详情 详情
(X) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(XI) 19286 benzyl 4-[2-(tert-butoxy)-2-oxoethoxy]-1-piperidinecarboxylate C19H27NO5 详情 详情
(XII) 19287 tert-butyl 2-(4-piperidinyloxy)acetate C11H21NO3 详情 详情
(XIII) 61209 CBZ-L-Alanine; (2S)-2-[[(Benzyloxy)carbonyl]amino]propionic acid; N-((Phenylmethoxy)carbonyl)-alanine; Carbobenzyloxy-L-alanine C11H13NO4 详情 详情
(XIV) 19289 tert-butyl 2-[[1-((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)-4-piperidinyl]oxy]acetate C22H32N2O6 详情 详情
(XV) 19290 tert-butyl 2-([1-[(2S)-2-aminopropanoyl]-4-piperidinyl]oxy)acetate C14H26N2O4 详情 详情
(XVI) 19291 tert-butyl 2-[(1-[(2S)-2-[(4-cyanobenzoyl)amino]propanoyl]-4-piperidinyl)oxy]acetate C22H29N3O5 详情 详情
(XVII) 19292 tert-butyl 2-([1-[(2S)-2-([4-[amino(hydroxyimino)methyl]benzoyl]amino)propanoyl]-4-piperidinyl]oxy)acetate C22H32N4O6 详情 详情
(XVIII) 19293 2-([1-[(2S)-2-([4-[amino(hydroxyimino)methyl]benzoyl]amino)propanoyl]-4-piperidinyl]oxy)acetic acid C18H24N4O6 详情 详情

合成路线14

该中间体在本合成路线中的序号：(III)

Acylation of the chiral oxazolidinone (I) with undecanoyl chloride furnished the N-acyl oxazolidinone (II). The lithium enolate of (II) was diastereoselectively alkylated with tert-butyl bromoacetate (III) producing (IV) as the major isomer. Then, removal of the chiral auxiliary of (IV) with lithium benzyloxide yielded benzyl ester (V). Acidic cleavage of the tert-butyl ester group of (V) provided carboxylic acid (VI), which was subsequently converted to the trichloroethyl ester (VII) via formation of the corresponding acid chloride, followed by treatment with trichloroethanol. After removal of the benzyl ester group of (VII) by hydrogenolysis, chlorination by means of oxalyl chloride gave acid chloride (VIII). This was then coupled with the protected (S)-perhydropyrazine-3-carboxylic acid (IX) to afford amide (X).

参考文献 中间体
合成目标
【1】 Tamaki, K.; et al.; Synthesis and structure-activity relationships of gelatinase inhibitors derived from Matlystatins. Chem Pharm Bull 1995, 43, 11, 1883.
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) 12867 (4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone 17016-83-0 C6H11NO2 详情 详情
(II) 56879 (4S)-4-isopropyl-3-undecanoyl-1,3-oxazolidin-2-one C17H31NO3 详情 详情
(III) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(IV) 56880 tert-butyl (3R)-3-{[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}dodecanoate C23H41NO5 详情 详情
(V) 56881 1-benzyl 4-(tert-butyl) (2R)-2-nonylbutanedioate C24H38O4 详情 详情
(VI) 56882 (3R)-3-[(benzyloxy)carbonyl]dodecanoic acid C20H30O4 详情 详情
(VII) 56883 1-benzyl 4-(2,2,2-trichloroethyl) (2R)-2-nonylbutanedioate C22H31Cl3O4 详情 详情
(VIII) 56884 2,2,2-trichloroethyl (3R)-3-(chlorocarbonyl)dodecanoate C15H24Cl4O3 详情 详情
(IX) 56885 1-benzyl 3-(tert-butyl) (3S)tetrahydro-1,3(2H)-pyridazinedicarboxylate C17H24N2O4 详情 详情
(X) 56886 1-benzyl 3-(tert-butyl) (3S)-2-{(2R)-2-[2-oxo-2-(2,2,2-trichloroethoxy)ethyl]undecanoyl}tetrahydro-1,3(2H)-pyridazinedicarboxylate C32H47Cl3N2O7 详情 详情

合成路线15

该中间体在本合成路线中的序号：(V)

The amidation of L-serine methyl ester (I) with ethylenediamine (II) gives the amide (III), which is reduced with borane/THF to 2(R)-(hydroxymethyl)diethylenetriamine (IV). The reaction of (IV) with bromoacetic acid tert-butyl ester (V) by means of DIEA in DMF affords the penta tert-butyl acetate (VI), which is condensed with the chlorophosphoramidite (VII) by means of DIEA in dichloromethane giving the phosphoramidite intermediate (VIII). The condensation of (VIII) with 4,4-diphenylcyclohexanol (IX) (see scheme 23537901b) by means of tetrazole in acetonitile, with simultaneous oxidation with tert-butyl hydroperoxide yields the phosphate (X), which is selectively hydrolyzed at the 2-cyanoethyl ester group with ammonia in methanol affording the ammonium phosphate (XI). Finally, the hydrolysis of (XI) with HCl in ether/water eliminates the tert-butyl groups affording the desired chelating ligand (XII)

参考文献 中间体
合成目标
【1】 Scott, D.M.; Sajiki, H.; McMurray, T.J.; Lauffer, R.B. (Epix Medical, Inc.); Diagnostic imaging contrast agents with extended blood retention. WO 9623526 .
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) 20915 methyl (2S)-2-amino-3-hydroxypropanoate 5680-80-8 C4H9NO3 详情 详情
(II) 14754 ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine 107-15-3 C2H8N2 详情 详情
(III) 30315 (2S)-2-amino-N-(2-aminoethyl)-3-hydroxypropanamide C5H13N3O2 详情 详情
(IV) 30316 (2R)-2-amino-3-[(2-aminoethyl)amino]-1-propanol C5H15N3O 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) 30317 3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-(hydroxymethyl)-3,6,9-triazaundecanedioic acid di-tert-butyl ester C35H65N3O11 详情 详情
(VII) 22791 2-Cyanoethyl N,N-diisopropylphosphoramidochloridite 89992-70-1 C9H18ClN2OP 详情 详情
(VIII) 30318 3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-[2-cyanoethoxy(diisopropylamino)phosphinyloxymethyl]-3,6,9-triazaundecanedioic acid di-tert-butyl ester C44H82N5O12P 详情 详情
(IX) 30319 4,4-diphenylcyclohexanol C18H20O 详情 详情
(X) 30320 3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-[2-cyanoethoxy(4,4-diphenylcyclohexyloxy)phosphoryloxymethyl]-3,6,9-triazaundecanedioic acid di-tert-butyl ester C56H87N4O14P 详情 详情
(XI) 30321 3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-[4,4-diphenylcyclohexyloxy(hydroxy)phosphoryloxymethyl]-3,6,9-triazaundecanedioic acid di-tert-butyl ester ammonium salt C53H87N4O14P 详情 详情
(XII) 30322 3,6,9-Tris(carboxymethyl)-4(R)-[4,4-diphenylcyclohexyloxy(hydroxy)phosphoryloxymethyl]-3,6,9-triazaundecanedioic acid C33H44N3O14P 详情 详情

合成路线16

该中间体在本合成路线中的序号：

Selective O-alkylation of trans-4-aminocyclohexanol (I) was effected by protection of the amino group as the triazinone (III) upon treatment with N,N-dimethylurea and formaldehyde. Subsequent alkylation of (III) with tert-butyl bromoacetate under phase-transfer conditions afforded ether (IV). The protecting group of (IV) was then removed by treatment with ammonium chloride.

参考文献 中间体
合成目标
【1】 Ono, S.; Yoshida, T.; Ashimori, A.; Kosaka, K.; Okada, T.; Maeda, K.; Eda, M.; Mori, F.; Inoue, Y.; Ebisu, H.; Imada, T.; Ikegawa, R.; Wang, F.; Nakamura, N. (Welfide Corporation); Novel fused-ring carboxylic acid cpds. or salt thereof,and medicinal use thereof. EP 0712844; JP 1996053398; JP 1996231548; US 5635527; US 5753670; WO 9533720 .
【2】 Nakamura, N.; Imada, T.; Inoue, Y.; Kosaka, K.; Yoshida, T.; Ono, S.; Fukaya, C.; Maeda, K.; Preparation and pharmacological evaluation of novel glycoprotein (Gp) IIb/IIIa antagonists. 2. Condensed heterocyclic derivatives. Chem Pharm Bull 1999, 47, 12, 1694.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(I) 19581 trans-4-Aminocyclohexanol；trans-4-Amino-1-cyclohexanol;trans-4-Amino-1-cyclohexanol; 27489-62-9 C6H13NO 详情 详情
(II) 21488 N,N'-dimethylurea 96-31-1 C3H8N2O 详情 详情
(III) 37350 5-(4-hydroxycyclohexyl)-1,3-dimethyl-1,3,5-triazinan-2-one C11H21N3O2 详情 详情
(IV) 37351 tert-butyl 2-[[4-(3,5-dimethyl-4-oxo-1,3,5-triazinan-1-yl)cyclohexyl]oxy]acetate C17H31N3O4 详情 详情
(V) 37352 tert-butyl 2-[(4-aminocyclohexyl)oxy]acetate C12H23NO3 详情 详情

合成路线17

该中间体在本合成路线中的序号：(X)

2) The chiral intermediates the amine (I) and the acid (II) have been obtained as follows: 2a) The bromination of 1-tetralone (IV) with Br2 in methanol gives the 2-bromotetralone (V), which is treated with hydroxylamine yielding the corresponding oximae (VI). The isomerization of (V) with polyphosphoric acid (PPA) at 80 C affords the benzazepinone (VII), which is treated with potassium phthalimide (VIII) in DMF to give the corresponding phthalimido derivative (IX). The reaction of (IX) with tert-butyl bromoacetate (X) by means of potassium tert-butoxide in DMF yields the benzazepinoacetic ester (XI), which is treated with hot ethanolamine to eliminate the phthalimido group yielding racemic (I). Finally, this racemate is submitted to optical resolution with L-(+)-tartaric acid to afford the chiral (S)-intermediate (I).

参考文献 中间体
合成目标
【1】 Waldeck, H.; Höltje, D.; Messinger, J.; Antel, J.; Wurl, M.; Thormählen, D. (Kali-Chemie AG); Benzazepin-, benzoxazepin- and benzothiazepin-N-acetic acid-derivs., their preparation and their pharmaceutical compsns.. CA 2172354; EP 0733642; JP 1996269011; US 5677297 .
【2】 Rozsa, S.; Gy Papp, J.; Thormahlen, D.; Waldeck, H. (Solvay SA); Drugs for increasing gastrointestinal blood supply. DE 19638020; EP 0830863; JP 1998101565 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
rac-(I) 20728 tert-butyl 2-(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate C16H22N2O3 详情 详情
(I) 20717 tert-butyl 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate C16H22N2O3 详情 详情
(IV) 20720 3,4-dihydro-1(2H)-naphthalenone 529-34-0 C10H10O 详情 详情
(V) 20721 2-bromo-3,4-dihydro-1(2H)-naphthalenone C10H9BrO 详情 详情
(VI) 20722 2-bromo-3,4-dihydro-1(2H)-naphthalenone oxime C10H10BrNO 详情 详情
(VII) 20723 3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one C10H10BrNO 详情 详情
(VIII) 10926 (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium C8H4KNO2 详情 详情
(IX) 20725 2-(2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-1H-isoindole-1,3(2H)-dione C18H14N2O3 详情 详情
(X) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(XI) 20727 tert-butyl 2-[3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate C25H26N2O5 详情 详情

合成路线18

该中间体在本合成路线中的序号：(X)

2a) The chiral intermediate amine (I) has been obtained as follows: The bromination of 1-tetralone (IV) with Br2 in methanol gives the 2-bromotetralone (V), which is treated with hydroxylamine yielding the corresponding oximae (VI). The isomerization of (V) with polyphosphoric acid (PPA) at 80 C affords the benzazepinone (VII), which is treated with potassium phthalimide (VIII) in DMF to give the corresponding phthalimido derivative (IX). The reaction of (IX) with tert-butyl bromoacetate (X) by means of potassium tert-butoxide in DMF yields the benzazepinoacetic ester (XI), which is treated with hot ethanolamine to eliminate the phthalimido group yielding racemic (I). Finally, this racemate is submitted to optical resolution with L-(+)-tartaric acid to afford the chiral (S)-intermediate (I).

参考文献 中间体
合成目标
【1】 Sorbera, L.A.; Leeson, P.A.; Castañer, J.; SLV-306. Drugs Fut 2002, 27, 1, 27.
【2】 Waldeck, H.; Höltje, D.; Messinger, J.; Antel, J.; Wurl, M.; Thormählen, D. (Kali-Chemie AG); Benzazepin-, benzoxazepin- and benzothiazepin-N-acetic acid-derivs., their preparation and their pharmaceutical compsns.. CA 2172354; EP 0733642; JP 1996269011; US 5677297 .
【3】 Rozsa, S.; Gy Papp, J.; Thormahlen, D.; Waldeck, H. (Solvay SA); Drugs for increasing gastrointestinal blood supply. DE 19638020; EP 0830863; JP 1998101565 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
rac-(I) 20728 tert-butyl 2-(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate C16H22N2O3 详情 详情
(I) 20717 tert-butyl 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate C16H22N2O3 详情 详情
(IV) 20720 3,4-dihydro-1(2H)-naphthalenone 529-34-0 C10H10O 详情 详情
(V) 20721 2-bromo-3,4-dihydro-1(2H)-naphthalenone C10H9BrO 详情 详情
(VI) 20722 2-bromo-3,4-dihydro-1(2H)-naphthalenone oxime C10H10BrNO 详情 详情
(VII) 20723 3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one C10H10BrNO 详情 详情
(VIII) 10926 (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium C8H4KNO2 详情 详情
(IX) 20725 2-(2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-1H-isoindole-1,3(2H)-dione C18H14N2O3 详情 详情
(X) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(XI) 20727 tert-butyl 2-[3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate C25H26N2O5 详情 详情

合成路线19

该中间体在本合成路线中的序号：(II)

Condensation of 2-(4-methylphenyl)ethanol (I) with t-Bu-bromoacetate (II) in toluene in the presence of NaOH and tetrabutylammonium bromide (TBAB) provides ethoxyacetic acid derivative (III), which is converted into acetamide (V) by reaction with oxalyl chloride (IV) in toluene/DMF followed by treatment with NH4OH. Reduction of (V) by reaction with borane-tetrahydrofuran (BH3·THF) in THF yields ethanamine (VI), which is then coupled to chlorosulfonyl derivative (VII) in CH2Cl2 in the presence of TEA to afford compound (VIII). Reduction of the ester group of (VIII) by treatment with diisobutylaluminium hydride (DIBAL) in toluene furnishes aldehyde (IX), which is finally subjected to a reductive amination with benzothiazol derivative (X) by means of NaCNBH3 in MeOH/HOAc.

参考文献 中间体
合成目标
【1】 Bonnert, R.; et al.; The discovery of dual D2-receptor and beta2-adrenoceptor agonists for the treatment of airway diseases. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Poster PC161.
【2】 Bonnert, R.V.; Brown, R.C.; Cage, P.A.; Ince, F.; Pairaudeau, G. (AstraZeneca plc); Benzothiazolone derivs.. JP 1999512422; US 5846989; WO 9710227 .
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) 45458 2-(4-methylphenyl)-1-ethanol 699-02-5 C9H12O 详情 详情
(II) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(III) 45459 2-[(4-methylphenethyl)oxy]acetic acid C11H14O3 详情 详情
(IV) 29841 Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride 79-37-8 C2Cl2O2 详情 详情
(V) 45460 2-[(4-methylphenethyl)oxy]acetamide C11H15NO2 详情 详情
(VI) 45461 2-[(4-methylphenethyl)oxy]ethylamine; 2-[(4-methylphenethyl)oxy]-1-ethanamine C11H17NO 详情 详情
(VII) 45462 Methyl 3-(chlorosulfonyl)propanoate; 3-(Chlorosulfonyl)propionic acid methylester 15441-07-3 C4H7ClO4S 详情 详情
(VIII) 45463 methyl 3-[([2-[(4-methylphenethyl)oxy]ethyl]amino)sulfonyl]propanoate C15H23NO5S 详情 详情
(IX) 45464 N-[2-[(4-methylphenethyl)oxy]ethyl]-3-oxo-1-propanesulfonamide C14H21NO4S 详情 详情
(X) 25944 7-(2-aminoethyl)-4-hydroxy-1,3-benzothiazol-2(3H)-one C9H10N2O2S 详情 详情

合成路线20

该中间体在本合成路线中的序号：(V)

A new strategy for the synthesis of a key intermediate in the preparation of LY-333531 has been described: Condensation of indole (I) with the tosylate (II) by means of NaH in DMF gives 4-(1-indolyl)butane-1,2-diol (III), which is monotritylated with trityl bromide yielding ether (IV). Alkylation of compound (IV) with tert-butyl bromoacetate (V) and NaH in THF affords the hydroxyacetic derivative (VI), which is reduced with LiBH4 in THF/EtOH to provide the carbinol (VII). Reaction of compound (VII) with Ms2O and pyridine in THF gives the mesylate (VIII), which is condensed with oxalyl chloride (IX) in ethyl ether to yield the oxoacetyl chloride (X). The alcoholysis of (X) with NaOMe in methanol affords the oxoacetate (XI), which is finally cyclized with 2-(3-indolyl)acetamide (XII) by means of NaH in DMF to provide the target intermediate (XIII).

参考文献 中间体
合成目标
【1】 Faul, M.M.; Kumrich, C.A.; Cyclization strategies for the synthesis of macrocyclic bisindolylmaleimides. J Org Chem 2001, 66, 6, 2024.
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) 15292 Indole; 1H-indole 120-72-9 C8H7N 详情 详情
(II) 48674 2-(2,2-diethyl-1,3-dioxolan-4-yl)ethyl 4-methylbenzenesulfonate C16H24O5S 详情 详情
(III) 48675 4-(1H-indol-1-yl)-1,2-butanediol C12H15NO2 详情 详情
(IV) 48676 4-(1H-indol-1-yl)-1-(trityloxy)-2-butanol C31H29NO2 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) 48677 tert-butyl 2-[3-(1H-indol-1-yl)-1-[(trityloxy)methyl]propoxy]acetate C37H39NO4 详情 详情
(VII) 48678 2-[3-(1H-indol-1-yl)-1-[(trityloxy)methyl]propoxy]-1-ethanol C33H33NO3 详情 详情
(VIII) 48679 2-[3-(1H-indol-1-yl)-1-[(trityloxy)methyl]propoxy]ethyl methanesulfonate C34H35NO5S 详情 详情
(IX) 29841 Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride 79-37-8 C2Cl2O2 详情 详情
(X) 48680 2-[3-[3-(2-chloro-2-oxoacetyl)-1H-indol-1-yl]-1-[(trityloxy)methyl]propoxy]ethyl methanesulfonate C36H34ClNO7S 详情 详情
(XI) 48681 methyl 2-[1-[3-[2-[(methylsulfonyl)oxy]ethoxy]-4-(trityloxy)butyl]-1H-indol-3-yl]-2-oxoacetate C37H37NO8S 详情 详情
(XII) 48682 Indole-3-acetamide;3-Indoleacetamide;2-(1H-indol-3-yl) 879-37-8 C10H10N2O 详情 详情
(XIII) 48683 18-[(trityloxy)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.1(7,14).0(2,6).0(8,13).0(22,27)]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione C45H37N3O4 详情 详情

合成路线21

该中间体在本合成路线中的序号：

A further route to benzyl ester (X) is shown in the next scheme: Protection of 2,4,6-trimethylaniline (XI) with Boc2O gave carbamate (XII). Condensation of (XII) with diethyl oxalate in the presence of sec-butyllithium produced the intermediate ketoester (XIII), which was deprotected and cyclized under acidic conditions to yield indole (V). Hydrolysis, followed by alkylation with benzyl bromide as above provided the corresponding benzyl ester (X). An alternative and more direct procedure consisted in the condensation of protected aniline (XII) with dibenzyl oxalate, and then cyclization upon treatment with trifluoroacetic acid. The intermediate indole (X) was N-alkylated with tert-butyl bromoacetate and NaH to give the indole diester (XIV). Subsequent deprotection of the benzyl ester group by hydrogenation over Pd/C gave rise to diacid mono tert-butyl ester (XV). Optionally, the analogous methyl ester (XVII) was prepared by alkylation of indole (X) with methyl bromoacetate, followed by benzyl group hydrogenolysis.

参考文献 中间体
合成目标
【1】 Brodin, R.; Boigegrain, R.; Molimard, J.-C.; Bignon, E.; Olliero, D. (Sanofi-Synthelabo ); Carboxamidothiazole derivs., preparation, pharmaceutical compsns. containing them. EP 1017693; FR 2768737; FR 2777887; WO 9915525 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
40591 benzyl 2-(benzyloxy)-2-oxoacetate C16H14O4 详情 详情
(V) 32914 ethyl 5,7-dimethyl-1H-indole-2-carboxylate C13H15NO2 详情 详情
(X) 32919 benzyl 5,7-dimethyl-1H-indole-2-carboxylate C18H17NO2 详情 详情
(XI) 28804 2,4,6-trimethylaniline 88-05-1 C9H13N 详情 详情
(XII) 32920 tert-butyl mesitylcarbamate C14H21NO2 详情 详情
(XIII) 32921 ethyl 3-[2-[(tert-butoxycarbonyl)amino]-3,5-dimethylphenyl]-2-oxopropanoate C18H25NO5 详情 详情
(XIV) 32922 benzyl 1-[2-(tert-butoxy)-2-oxoethyl]-5,7-dimethyl-1H-indole-2-carboxylate C24H27NO4 详情 详情
(XV) 32923 1-[2-(tert-butoxy)-2-oxoethyl]-5,7-dimethyl-1H-indole-2-carboxylic acid C17H21NO4 详情 详情
(XVI) 32924 benzyl 1-(2-methoxy-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylate C21H21NO4 详情 详情
(XVII) 32925 1-(2-methoxy-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylic acid C14H15NO4 详情 详情

合成路线22

该中间体在本合成路线中的序号：(II)

Nitrophenoxyacetate (III) (prepared from 2-nitrophenol (I) and tert-butyl bromoacetate), was reduced with H2 in the presence of Pd/C to give aniline (IV). This was condensed with Z-D-Phe (V) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (EDC) and 1-hydroxybenzotriazole (HOBt) to yield amide (VI), which was deprotected to amine (VII) by hydrogenolysis in the presence of Pd/C. Subsequent coupling with Z-Pro (VIII), followed by hydrogenolytic deprotection produced (IX). This was coupled with methyl oxalyl chloride (X) to afford (XI). Then, treatment with trifluoroacetic acid in CH2Cl2 gave acid (XII). Finally, dipeptide (XV) (obtained by coupling of protected 3-amino-2-hydroxy-4-phenylbutyric acid (XIII) with tert-butyl prolinamide (XIV)), was condensed with acid (XII) to produce the title compound.

参考文献 中间体
合成目标
【1】 Asagarasu, A.; et al.; Synthesis of dipeptide-type human immunodeficiency virus (HIV) protease inhibitors with a binding unit to GP120. Chem Pharm Bull 1998, 46, 5, 867.
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) 19106 2-nitrophenol 88-75-5 C6H5NO3 详情 详情
(II) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(III) 19108 tert-butyl 2-(2-nitrophenoxy)acetate C12H15NO5 详情 详情
(IV) 19109 tert-butyl 2-(2-aminophenoxy)acetate C12H17NO3 详情 详情
(V) 19110 (2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropionic acid C17H17NO4 详情 详情
(VI) 19111 tert-butyl 2-[2-[((2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropanoyl)amino]phenoxy]acetate C29H32N2O6 详情 详情
(VII) 19112 tert-butyl 2-(2-[[(2R)-2-amino-3-phenylpropanoyl]amino]phenoxy)acetate C21H26N2O4 详情 详情
(VIII) 19113 (2S)-1-[(benzyloxy)carbonyl]-2-pyrrolidinecarboxylic acid 1148-11-4 C13H15NO4 详情 详情
(IX) 19114 tert-butyl 2-[2-[((2R)-3-phenyl-2-[[(2S)pyrrolidinylcarbonyl]amino]propanoyl)amino]phenoxy]acetate C26H33N3O5 详情 详情
(X) 19115 [(chlorocarbonyl)oxy](methoxy)methane C3H5ClO3 详情 详情
(XI) 19116 methyl 2-((2S)-2-[[((1R)-1-benzyl-2-[2-[2-(tert-butoxy)-2-oxoethoxy]anilino]-2-oxoethyl)amino]carbonyl]pyrrolidinyl)-2-oxoacetate C29H35N3O8 详情 详情
(XII) 19117 2-(2-[[(2R)-2-([[(2S)-1-(2-methoxy-2-oxoacetyl)pyrrolidinyl]carbonyl]amino)-3-phenylpropanoyl]amino]phenoxy)acetic acid C25H27N3O8 详情 详情
(XIII) 19118 (2S,3S)-3-[[(benzyloxy)carbonyl]amino]-2-hydroxy-4-phenylbutyric acid C18H19NO5 详情 详情
(XIV) 19119 (2S)-N-(tert-butyl)-2-pyrrolidinecarboxamide C9H18N2O 详情 详情
(XV) 19120 (2S)-1-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutanoyl]-N-(tert-butyl)-2-pyrrolidinecarboxamide C19H29N3O3 详情 详情

合成路线23

该中间体在本合成路线中的序号：(VII)

The cyclization of acetyl cyclopropane (I) with 2-nitroacetamide (II) and formamide dimethylacetal (III) by means of p-tolulenesulfonic acid gives the nitro-pyridinone (IV) (1), which is reduced with H2 over Pd/C affording 3-amino-6-propylpyridin-2(1H)-one (V). The protection of the amino group of (V) with benzyl chloroformate affords the carbamate (VI), which is condensed with tert-butyl bromoacetate (VII) by means of NaH in THF giving substituted acetate ester (VIII). The deprotection of (VIII) by hydrogenolysis with H2 over Pd/C in ethyl acetate yields intermediate (IX) with a free amino group, which is treated with benzylsulfonyl chloride (X) and pyridine to afford the sulfonamide (XI). Hydrolysis of the ester group of (XI) with HCl in ethyl acetate gives the carboxylic acid (XII), which is condensed with the pyridylmethylamine (XIII) by means of EDC and HOBT to afford the carboxamide (XIV). Finally, this compound is deprotected with HCl as usual.

参考文献 中间体
合成目标
【1】 C6 modification of the pyridinone core of thrombin inhibitor L-374,087 as a means of enhancing its oral absorption. Bioorg Med Chem Lett 1998, 8, 13, 1719.
【2】 Sanderson, P.E.; Naylor-Olsen, A.M.; Dyer, D.L.; Vacca, J.P.; Isaacs, R.C.A.; Dorsey, B.D.; Fraley, M.E. (Merck & Co., Inc.); Pyridinone-thrombin inhibitors. EP 0835109; JP 1999508558; WO 9701338 .
【3】 Dorsey, B.D.; Isaacs, R.C.A.; Sanderson, P.E.; Dyer, D.L.; Naylor-Olsen, A.M.; Fraley, M.E.; Vacca, J.P. (Merck & Co., Inc.); Pyridinone thrombin inhibitors. US 5668289 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(I) 12435 Acetylcyclopropane; 1-Cyclopropyl-1-ethanone; Cyclopropylmethylketone 765-43-5 C5H8O 详情 详情
(II) 27209 2-nitroacetamide C2H4N2O3 详情 详情
(III) 11984 N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal 4637-24-5 C5H13NO2 详情 详情
(IV) 27210 6-cyclopropyl-3-nitro-2(1H)-pyridinone C8H8N2O3 详情 详情
(V) 27211 3-amino-6-propyl-2(1H)-pyridinone C8H12N2O 详情 详情
(VI) 27212 benzyl 2-oxo-6-propyl-1,2-dihydro-3-pyridinylcarbamate C16H18N2O3 详情 详情
(VII) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(VIII) 27213 tert-butyl 2-[3-[[(benzyloxy)carbonyl]amino]-2-oxo-6-propyl-1(2H)-pyridinyl]acetate C22H28N2O5 详情 详情
(IX) 27214 tert-butyl 2-[3-amino-2-oxo-6-propyl-1(2H)-pyridinyl]acetate C14H22N2O3 详情 详情
(X) 27215 phenylmethanesulfenyl chloride C7H7ClS 详情 详情
(XI) 27216 tert-butyl 2-[3-[(benzylsulfonyl)amino]-2-oxo-6-propyl-1(2H)-pyridinyl]acetate C21H28N2O5S 详情 详情
(XII) 27217 2-[3-[(benzylsulfonyl)amino]-2-oxo-6-propyl-1(2H)-pyridinyl]acetic acid C17H20N2O5S 详情 详情
(XIII) 27218 tert-butyl 5-(aminomethyl)-6-methyl-2-pyridinylcarbamate C12H19N3O2 详情 详情
(XIV) 27219 tert-butyl 5-[([2-[3-[(benzylsulfonyl)amino]-2-oxo-6-propyl-1(2H)-pyridinyl]acetyl]amino)methyl]-6-methyl-2-pyridinylcarbamate C29H37N5O6S 详情 详情

合成路线24

该中间体在本合成路线中的序号：(VII)

The reaction of succinic anhydride (I) with the lithium salt of the chiral oxazolidinone (II) in THF gives 3-(hydroxysucccinyl)-4(S)-isopropyloxazolidin-2-one (III), which is treated successively with oxalyl chloride, CH2N2 and HBr to yield the bromomethyl derivative (IV). The cyclization of (IV) with thiourea in refluxing isopropanol affords the 2-aminothiazol derivative (V), which is protected with 2,2,2-trichloroethyl chloroformate by means of DIEA and DMAP in dichloromethane giving the carbamate (VI). The reaction of (VI) with tert-butyl 2-bromoacetate (VII) by means of sodium hexamethyldisilazane (NaHMDS) in THF yields the chiral butyrate (VIII), which is hydrolyzed with TFA in dichloromethane to the chiral butyric acid (IX). The condensation of (IX) with the intermediate amine (X) by means of BOP-PF6 and DIEA in DMF affords the corresponding amide (XI), which is treated with magnesium methoxide in methanol to eliminate the oxazolidinone group (the chiral inductor) providing the methyl ester (XII). The hydrolysis of (XII) with NaOH, followed by condensation with amine (XIII) (J Org Chem 1988, 53: 6109; J Med Chem 1993, 36: 449) gives the protected intermediate (XIV), which is finally deprotected by reaction with Zn/HCl in aqueous dioxane.

参考文献 中间体
合成目标
【1】 Simoneau, B.; Lavallee, P.; Anderson, P.C.; et al.; Discovery of non-peptidic P2-P3 butanediamide renin inhibitors with high oral efficacy. Bioorg Med Chem 1999, 7, 3, 489.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10180 Thiourea 62-56-6 CH4N2S 详情 详情
13664 1,1,1-Trichloro-2-[(chlorocarbonyl)oxy]ethane; 2,2,2-Trichloroethyl chloroformate 17341-93-4 C3H2Cl4O2 详情 详情
(I) 11291 Dihydro-2,5-furandione; Succinic anhydride 108-30-5 C4H4O3 详情 详情
(II) 29533 [(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]lithium C6H10LiNO2 详情 详情
(III) 29534 4-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxobutyric acid C10H15NO5 详情 详情
(IV) 29535 5-bromo-1-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-1,4-pentanedione C11H16BrNO4 详情 详情
(V) 29536 (4S)-3-[3-(2-amino-1,3-thiazol-4-yl)propanoyl]-4-isopropyl-1,3-oxazolidin-2-one C12H17N3O3S 详情 详情
(VI) 29537 2,2,2-trichloroethyl 4-[3-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxopropyl]-1,3-thiazol-2-ylcarbamate C15H18Cl3N3O5S 详情 详情
(VII) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(VIII) 29538 tert-butyl (3R)-4-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxo-3-[(2-[[(2,2,2-trichloroethoxy)carbonyl]amino]-1,3-thiazol-4-yl)methyl]butanoate C21H28Cl3N3O7S 详情 详情
(IX) 29539 (3R)-4-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxo-3-[(2-[[(2,2,2-trichloroethoxy)carbonyl]amino]-1,3-thiazol-4-yl)methyl]butyric acid C17H20Cl3N3O7S 详情 详情
(X) 29540 2-[(cyclohexylmethyl)amino]-N-methyl-N-[2-(2-pyridinyl)ethyl]acetamide C17H27N3O 详情 详情
(XI) 29541 2,2,2-trichloroethyl 4-((2R)-4-[(cyclohexylmethyl)(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)amino]-2-[[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-4-oxobutyl)-1,3-thiazol-2-ylcarbamate C34H45Cl3N6O7S 详情 详情
(XII) 29542 methyl (2R)-4-[(cyclohexylmethyl)(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)amino]-4-oxo-2-[(2-[[(2,2,2-trichloroethoxy)carbonyl]amino]-1,3-thiazol-4-yl)methyl]butanoate C29H38Cl3N5O6S 详情 详情
(XIII) 29543 (2S,3R,4S)-2-amino-1-cyclohexyl-6-methyl-3,4-heptanediol C14H29NO2 详情 详情
(XIV) 29544 2,2,2-trichloroethyl 4-[(2R)-2-([[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]amino]carbonyl)-4-[(cyclohexylmethyl)(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)amino]-4-oxobutyl]-1,3-thiazol-2-ylcarbamate C42H63Cl3N6O7S 详情 详情

合成路线25

该中间体在本合成路线中的序号：(IV)

The condensation of dimethyl malonate (I) with 2-cloroallyl chloride (II) by means of sodium methoxide in hot methanol gives the alkylmalonate (III), which is treated with tert-butyl bromoacetate (IV), NaOH and benzyltriethylammonium chloride to yield the tricarboxylic ester (V). Partial decarboxylation of (V) with KOH in hot methanol/water affords the succinic acid derivative (VI), which is submitted to enzymatic hydrolysis with Alcalase 2.4L to provide the chiral monoester (VII). The condensation of monoacid (VII) with amine (VIII) by means of HOBT, DCC, and DIEA in THF gives the amide (IX), which is treated with TFA to eliminate the tert-butyl protecting group yielding the acid (X). The condensation of (X) with amine (XI) by means of NMM and pivaloyl chloride affords the amide (XII), which is treated with 2-methoxypropene (XIII) and TsOH in dichloromethane to protect the vicinal hydroxy groups giving the dioxolane (XIV). The bromination of the allyl double bond of (XIV) with NBS in tert-butyl methyl ether/water gives 3-bromo-2-oxopropyl derivative (XV).

参考文献 中间体
合成目标
【1】 Beaulieu, P.L.; et al.; Practical synthesis of BILA 2157 BS, a potent and orally active renin inhibitor: Use of an enzayme-catalyzed hydrolysis for the preparation of homochiral succinic acid derivatives. J Org Chem 1999, 64, 18, 6622.
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) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(II) 31608 2,3-dichloro-1-propene 78-88-6 C3H4Cl2 详情 详情
(III) 31609 dimethyl 2-(2-chloro-2-propenyl)malonate C8H11ClO4 详情 详情
(IV) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(V) 31610 1-(tert-butyl) 2,2-dimethyl 4-chloro-4-pentene-1,2,2-tricarboxylate C14H21ClO6 详情 详情
(VI) 31611 4-(tert-butyl) 1-methyl 2-(2-chloro-2-propenyl)succinate C12H19ClO4 详情 详情
(VII) 31612 (2S)-2-[2-(tert-butoxy)-2-oxoethyl]-4-chloro-4-pentenoic acid C11H17ClO4 详情 详情
(VIII) 29543 (2S,3R,4S)-2-amino-1-cyclohexyl-6-methyl-3,4-heptanediol C14H29NO2 详情 详情
(IX) 31613 tert-butyl (3S)-5-chloro-3-([[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]amino]carbonyl)-5-hexenoate C25H44ClNO5 详情 详情
(X) 31614 (3S)-5-chloro-3-([[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]amino]carbonyl)-5-hexenoic acid C21H36ClNO5 详情 详情
(XI) 29540 2-[(cyclohexylmethyl)amino]-N-methyl-N-[2-(2-pyridinyl)ethyl]acetamide C17H27N3O 详情 详情
(XII) 31615 (2S)-2-(2-chloro-2-propenyl)-N(4)-(cyclohexylmethyl)-N(1)-[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide C38H61ClN4O5 详情 详情
(XIII) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(XIV) 31616 (2S)-2-(2-chloro-2-propenyl)-N(1)-[(1S)-2-cyclohexyl-1-[(4R,5S)-5-isobutyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]-N(4)-(cyclohexylmethyl)-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide C41H65ClN4O5 详情 详情
(XV) 31617 (2R)-2-(3-bromo-2-oxopropyl)-N(1)-[(1S)-2-cyclohexyl-1-[(4R,5S)-5-isobutyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]-N(4)-(cyclohexylmethyl)-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide C41H65BrN4O6 详情 详情

合成路线26

该中间体在本合成路线中的序号：(VI)

The condensation of gamma-butyrolactone (I) with phenethyl amine (II) at high temperatures afforded phenethylpyrrolidinone (III). This was alkylated with isobutyl iodide (IV) in the presence of lithium diisopropylamide in cold THF yielding the 3-isobutyl pyrrolidinone (V), and further alkylated with tert-butyl bromoacetate (VI) to give (VII). Subsequent alkylation of (VII) at the alpha-position of carboxylate group with allyl bromide provided (VIII). Ozonolysis of the double bond of (VIII), followed by reductive treatment with NaBH4 produced alcohol (IX), which was coupled with dibenzyl iminodicarboxylate (X) under Mitsunobu conditions giving (XI). The biscarbamate (XI) was deprotected by hydrogenolysis over Pd/C, and the resulting primary amine (XII) was condensed with 3,4-difluorobenzoyl chloride (XIII) to furnish amide (XIV). Then, trifluoroacetic acid-promoted cleavage of the tert-butyl ester of (XIV) provided the corresponding carboxylic acid, which was finally coupled with hydroxylamine by means of EDC and HOBt to afford the target hydroxamic acid

参考文献 中间体
合成目标
【1】 Jacobsen, E.J. (Pharmacia & Upjohn AB); Hydroxamic acid derivs. for use with the treatment of diseases related to connective tissue degradation. EP 0898562; JP 2000506163; US 5712300; WO 9732846 .
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) 20576 dihydro-2(3H)-furanone 96-48-0 C4H6O2 详情 详情
(II) 18333 Phenethylamine; 2-Phenyl-1-ethanamine 64-04-0 C8H11N 详情 详情
(III) 28259 1-phenethyl-2-pyrrolidinone C12H15NO 详情 详情
(IV) 18168 1-iodo-2-methylpropane 513-38-2 C4H9I 详情 详情
(V) 28267 3-isobutyl-1-phenethyl-2-pyrrolidinone C16H23NO 详情 详情
(VI) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(VII) 28260 tert-butyl 2-(3-isobutyl-2-oxo-1-phenethyl-3-pyrrolidinyl)acetate C22H33NO3 详情 详情
(VIII) 28261 tert-butyl 2-(3-isobutyl-2-oxo-1-phenethyl-3-pyrrolidinyl)-4-pentenoate C25H37NO3 详情 详情
(IX) 28268 tert-butyl 4-hydroxy-2-(3-isobutyl-2-oxo-1-phenethyl-3-pyrrolidinyl)butanoate C24H37NO4 详情 详情
(X) 28262 1-[[([[(benzyloxy)carbonyl]amino]carbonyl)oxy]methyl]benzene C16H15NO4 详情 详情
(XI) 28263 tert-butyl 4-[bis[(benzyloxy)carbonyl]amino]-2-(3-isobutyl-2-oxo-1-phenethyl-3-pyrrolidinyl)butanoate C40H50N2O7 详情 详情
(XII) 28264 tert-butyl 4-amino-2-(3-isobutyl-2-oxo-1-phenethyl-3-pyrrolidinyl)butanoate C24H38N2O3 详情 详情
(XIII) 28265 3,4-difluorobenzoyl chloride 76903-88-3 C7H3ClF2O 详情 详情
(XIV) 28266 tert-butyl 4-[(3,4-difluorobenzoyl)amino]-2-(3-isobutyl-2-oxo-1-phenethyl-3-pyrrolidinyl)butanoate C31H40F2N2O4 详情 详情

合成路线27

该中间体在本合成路线中的序号：(VIII)

The reaction of 4-ethyl-3,5-dimethoxybenzaldehyde (I) with (ethoxycarbonylmethyl)triphenylphosphonium bromide (II) by means o butyllithium in THF gives the acrylate (III), which is allowed to react with nitromethane/triton B in hot methanol yielding the 4-nitrobutyrate (IV). The reduction of (IV) with H2 over RaNi in ethanol affords the 4-aminobutyrate (V), which is cyclized to the pyrrolidinone (VI) by means of p-toluenesulfonic acid in refluxing ethanol. The methylation of (VI) with NaH/methyl iodide in THF gives the corresponding N-methylpyrrolidinone (VII), which is condensed with tert-butyl bromoacetate (VIII) by means of butyllithium/diisopropylamine in THF yielding the intermediate (IX). The reduction of the ketonic grupof (IX) with the complex borane/THF in THF affords the pyrrolidineacetate ester (X), which is cyclized by means of polyphosphoric acid (PPA) at 120 C giving the benzisoindole (XI). Finally, this compound is selectively demethylate by menas of BBr3 in dichloromethane.

参考文献 中间体
合成目标
【1】 Stadler, H.; Bos, M.; Wichmann, J. (F. Hoffmann-La Roche AG); Tricyclic benzo[e]isoindoles and benzo[h]isoquinolines . EP 0958285; JP 2000507965; WO 9830546 .
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) 20754 4-ethyl-3,5-dimethoxybenzaldehyde C11H14O3 详情 详情
(II) 20755 (2-ethoxy-2-oxoethyl)(triphenyl)phosphonium bromide 1530-45-6 C22H22BrO2P 详情 详情
(III) 20756 ethyl (E)-3-(4-ethyl-3,5-dimethoxyphenyl)-2-propenoate C15H20O4 详情 详情
(IV) 20757 ethyl 3-(4-ethyl-3,5-dimethoxyphenyl)-4-nitrobutanoate C16H23NO6 详情 详情
(V) 20758 ethyl 4-amino-3-(4-ethyl-3,5-dimethoxyphenyl)butanoate C16H25NO4 详情 详情
(VI) 20759 4-(4-ethyl-3,5-dimethoxyphenyl)-2-pyrrolidinone C14H19NO3 详情 详情
(VII) 20760 4-(4-ethyl-3,5-dimethoxyphenyl)-1-methyl-2-pyrrolidinone C15H21NO3 详情 详情
(VIII) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(IX) 20762 tert-butyl 2-[4-(4-ethyl-3,5-dimethoxyphenyl)-1-methyl-2-oxo-3-pyrrolidinyl]acetate C21H31NO5 详情 详情
(X) 20763 tert-butyl 2-[4-(4-ethyl-3,5-dimethoxyphenyl)-1-methyl-3-pyrrolidinyl]acetate C21H33NO4 详情 详情
(XI) 20764 (3aS,9bS)-7-ethyl-6,8-dimethoxy-2-methyl-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]isoindol-5-one C17H23NO3 详情 详情

合成路线28

该中间体在本合成路线中的序号：(V)

4-Methylvaleric acid (I) was converted to acid chloride (II) and then condensed with (S)-4-benzyl-2-oxazolidinone (III) to give (IV). Subsequent alkylation of (IV) with tert-butyl bromoacetate (V) in the presence of sodium bis(trimethylsilyl)amide produced the chiral intermediate (VI), which was hydrolyzed with lithium peroxide to yield (R)-2-isobutylsuccinic acid 4-tert-butyl ester (VII). Further alkylation of (VII) with 4-bromo-1-butene (VIII) afforded a 6:1 mixture of syn/anti isobutenyl compounds (IX), which upon isomerization with LDA in THF at -20 C, followed by quenching with MeOH, provided a 1:1.5 mixture of isomers. Condensation of N-Boc-L-tyrosine (X) with methylamine in the presence of EDC and HOBt gave amide (XI). Then, removal of the Boc protecting group with HCl in dioxan yielded tyrosinamide (XII). This was coupled to succinic acid derivative (IX) using EDC and HOBt to afford the corresponding amide (XIII) as an epimeric mixture. Hydroboration of the butenyl double bond, followed by oxidative treatment with H2O2 produced alcohol (XIV).

参考文献 中间体
合成目标
【1】 Sheppard, G.S.; Guo, Y.; Siummers, J.B.; Holms, J.H.; Steinman, D.H.; Michaelides, M.R.; Florjancic, A.S.; Xu, L.; Davidsen, S.K. (Abbott Laboratories Inc.); Macrocyclic inhibitors of matrix metalloproteinases and TNFalpha secretion. EP 1021423; WO 9830551 .
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) 25389 4-methylpentanoic acid 646-07-1 C6H12O2 详情 详情
(II) 25390 4-methylpentanoyl chloride 38136-29-7 C6H11ClO 详情 详情
(III) 25351 (4R)-4-benzyl-1,3-oxazolidin-2-one; (R)-(+)-4-benzyl-2-oxazolidinone 102029-44-7 C10H11NO2 详情 详情
(IV) 25391 (4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one C16H21NO3 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) 25392 tert-butyl (3R)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-5-methylhexanoate C22H31NO5 详情 详情
(VII) 25393 (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-4-methylpentanoic acid C12H22O4 详情 详情
(VIII) 11720 4-Bromo-1-butene 5162-44-7 C4H7Br 详情 详情
(IX) 25394 (2R)-3-(tert-butoxycarbonyl)-2-isobutyl-6-heptenoic acid C16H28O4 详情 详情
(X) 25395 (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propionic acid 3978-80-1 C14H19NO5 详情 详情
(XI) 25396 tert-butyl (1S)-1-(4-hydroxybenzyl)-2-(methylamino)-2-oxoethylcarbamate C15H22N2O4 详情 详情
(XII) 25397 (2S)-2-amino-3-(4-hydroxyphenyl)-N-methylpropanamide C10H14N2O2 详情 详情
(XIII) 25398 tert-butyl 2-[(1R)-1-([[(1S)-1-(4-hydroxybenzyl)-2-(methylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-5-hexenoate C26H40N2O5 详情 详情
(XIV) 25399 tert-butyl (3R)-3-([[(1S)-1-(4-hydroxybenzyl)-2-(methylamino)-2-oxoethyl]amino]carbonyl)-2-(4-hydroxybutyl)-5-methylhexanoate C26H42N2O6 详情 详情

合成路线29

该中间体在本合成路线中的序号：(V)

The intermediate alcohol (VIII) was prepared as shown in Scheme 27060901a: Aldol condensation of 3,4-dimethoxybenzaldehyde (I) with 3-hydroxyacetophenone (II) in the presence of KOH provided chalcone (III), which was hydrogenated over Pd/C to yield the corresponding diarylpropanone (IV). Subsequent alkylation of the phenolic hydroxyl group of (IV) with tert-butyl bromoacetate (V) using NaH in DMF gave ether (VI). Then, enantioselective reduction of ketone by means of (+)-beta-chlorodiisopinocampheylborane (VII) at -20 C furnished the (R)-alcohol (VIII).

参考文献 中间体
合成目标
【1】 Yang, W.; Guo, T.; Keenan, T.P.; Laborde, E.; Holt, D.A. (Ariad Pharmaceuticals Inc.); Synthetic derivs. of rapamycin as multimerizing agents for chimeric proteins with immunophilin-derived domains. JP 2000505475; WO 9731898 .
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) 18304 3,4-Dimethoxybenzaldehyde; Veratraldehyde 120-14-9 C9H10O3 详情 详情
(II) 25331 3-hydroxyacetophenone; 1-(3-hydroxyphenyl)-1-ethanone 121-71-1 C8H8O2 详情 详情
(III) 25332 (E)-3-(3,4-dimethoxyphenyl)-1-(3-hydroxyphenyl)-2-propen-1-one C17H16O4 详情 详情
(IV) 25341 3-(3,4-dimethoxyphenyl)-1-(3-hydroxyphenyl)-1-propanone C17H18O4 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) 25342 tert-butyl 2-[3-[3-(3,4-dimethoxyphenyl)propanoyl]phenoxy]acetate C23H28O6 详情 详情
(VII) 25343 chloro[bis[(1S,2R,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane 112246-73-8 C20H34BCl 详情 详情
(VIII) 25348 tert-butyl 2-[3-[(1R)-3-(3,4-dimethoxyphenyl)-1-hydroxypropyl]phenoxy]acetate C23H30O6 详情 详情

合成路线30

该中间体在本合成路线中的序号：

2-Chloro-4-propionylpyridine (I) was protected as the cyclic ketal (II) with 1,3-propanediol and p-toluenesulfonic acid in refluxing toluene with azeotropical removal of water. Subsequent halogen displacement in (II) with sodium methoxide in boiling acetonitrile gave methoxypyridine (III). Lithiation of (III) with mesityllithium, followed by condensation with dimethylformamide provided formylpyridine (IV), which was reduced to alcohol (V) using NaBH4 in MeOH. The hydroxyl group of (V) was protected as the benzyl ether (VI), and the ketal group was then hydrolyzed to ketone (VII) with aqueous trifluoroacetic acid. Reformatskii reaction of (VII) with tert-butyl bromoacetate and zinc afforded the beta-hydroxyester (VIII). Further hydrogenolysis of benzyl ether of (VIII) over Pd/C gave alcohol (IX). Then, treatment of (IX) with trifluoroacetic acid produced lactone (X), and hydrolysis of the methoxy group of (X) with aqueous HCl furnished pyridone (XI). Condensation of 3,4-difluoroacetanilide (XII) with Vilsmeier reagent yielded quinolinecarboxaldehyde (XIII), which was reduced to alcohol (XIV) with NaBH4. This was then coupled with pyridone (XI) under Mitsunobu conditions to give (XV). Finally, Heck reaction of (XV) with palladium acetate and triphenyl phosphine generated the target pentacyclic compound.

参考文献 中间体
合成目标
【1】 Lavergne, O.; Lesuer-Ginot, L.; Pla Rodas, F.; Kasprzyk, P.G.; Pommier, J.; Demarquay, D.; Prevost, G.; Ulibarri, G.; Rolland, A.; Schiano-Liberatore, A.M.; Harnett, J.; Pons, D.; Camara, J.; Bigg, D.C.; Homocamptothecins: Synthesis and antitumor activity of novel E-ring-modified camptothecin analogues. J Med Chem 1998, 41, 27, 5410.
【2】 Bigg, D.; Lavergne, O.; Pla Rodas, F.; Pommier, J.; Ulibarri, G. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Novel camptothecin analogues, preparation methods therefor, use thereof as drugs, and pharmaceutical compsns. containing said analogues. EP 0835258; JP 1999508249; US 5981542; WO 9700876 .
【3】 Lanco, C.; Rolland, A.; Bigg, D.; Lavergne, O.; Harnett, J.; Liberatore, A.-M. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Pro-drugs and counterparts of camptothecin, their application as medicines . EP 0946566; WO 9828304 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
14685 1,3-propanediol; Trimethylene Glycol 504-63-2 C3H8O2 详情 详情
17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(I) 25461 1-(2-chloro-4-pyridinyl)-1-propanone C8H8ClNO 详情 详情
(II) 25462 2-chloro-4-(2-ethyl-1,3-dioxan-2-yl)pyridine C11H14ClNO2 详情 详情
(III) 25463 4-(2-ethyl-1,3-dioxan-2-yl)-2-pyridinyl methyl ether; 4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxypyridine C12H17NO3 详情 详情
(IV) 25464 4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxynicotinaldehyde C13H17NO4 详情 详情
(V) 25465 [4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxy-3-pyridinyl]methanol C13H19NO4 详情 详情
(VI) 25466 3-[(benzyloxy)methyl]-4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxypyridine; benzyl [4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxy-3-pyridinyl]methyl ether C20H25NO4 详情 详情
(VII) 25467 1-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-1-propanone C17H19NO3 详情 详情
(VIII) 25468 tert-butyl 3-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-3-hydroxypentanoate C23H31NO5 详情 详情
(IX) 25469 tert-butyl 3-hydroxy-3-[3-(hydroxymethyl)-2-methoxy-4-pyridinyl]pentanoate C16H25NO5 详情 详情
(X) 25470 5-ethyl-5-hydroxy-9-methoxy-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one C12H15NO4 详情 详情
(XI) 25471 5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione C11H13NO4 详情 详情
(XII) 25472 N-(3,4-difluorophenyl)acetamide 458-11-7 C8H7F2NO 详情 详情
(XIII) 25473 2-chloro-6,7-difluoro-3-quinolinecarbaldehyde C10H4ClF2NO 详情 详情
(XIV) 25474 (2-chloro-6,7-difluoro-3-quinolinyl)methanol C10H6ClF2NO 详情 详情
(XV) 25475 8-[(2-chloro-6,7-difluoro-3-quinolinyl)methyl]-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione C21H17ClF2N2O4 详情 详情

合成路线31

该中间体在本合成路线中的序号：(II)

The condensation of 5-(hydroxymethyl)-4-methyl-1H-imidazole (I) with tert-butyl bromoacetate (II) by means of K2CO3 in DMF gives the imidazolylacetic ester (III), which is treated with diphenylphosphoryl azide and DBU in DMF yielding the azidomethyl compound (IV). The reduction of (IV) with H2 over Pd/C in ethyl acetate affords the aminomethyl compound (V), which is acylated with 2-[3-(benzylsulfonamido)-6-methyl-2-oxo-1,2-dihydropyridin-1-yl]acetic acid (VI) by means of EDC and HOBT in DMF providing the carboxamide (VII). Elimination of the tert-butyl group of (VII) with HCl in ethyl acetate gives the free carboxylic acid (VIII), which is finally amidated with tert-butylamine by means of EDC and HOBT in DMF.

参考文献 中间体
合成目标
【1】 Naylor-Olsen, A.M.; Newton, C.L.; Isaacs, R.C.A.; Dorsey, B.D. (Merck & Co., Inc.); Thrombin inhibitors. EP 0969840; US 5932606; WO 9842342 .
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) 26595 (4-methyl-1H-imidazol-5-yl)methanol 38585-62-5 C5H8N2O 详情 详情
(II) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(III) 26596 tert-butyl 2-[5-(hydroxymethyl)-4-methyl-1H-imidazol-1-yl]acetate C11H18N2O3 详情 详情
(IV) 26597 tert-butyl 2-[5-(azidomethyl)-4-methyl-1H-imidazol-1-yl]acetate C11H17N5O2 详情 详情
(V) 26598 tert-butyl 2-[5-(aminomethyl)-4-methyl-1H-imidazol-1-yl]acetate C11H19N3O2 详情 详情
(VI) 26599 2-[3-[(benzylsulfonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetic acid C15H16N2O5S 详情 详情
(VII) 26600 tert-butyl 2-[5-[([2-[3-[(benzylsulfonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetyl]amino)methyl]-4-methyl-1H-imidazol-1-yl]acetate C26H33N5O6S 详情 详情
(VIII) 26601 2-[5-[([2-[3-[(benzylsulfonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetyl]amino)methyl]-4-methyl-1H-imidazol-1-yl]acetic acid C22H25N5O6S 详情 详情

合成路线32

该中间体在本合成路线中的序号：(X)

The intermediate 2-(2(S)-amino-3-phenylpropoxy)ethanol (VII) has been obtained as follows: The condensation of 2(S)-(dibenzylamino)-3-phenyl-1-propanol (IX) with tert-butyl 2-bromoacetate (X) by means of tetrabutylammonium hydrogen sulfate and NaOH in dichloromethane/water gives 2-[2(S)-(dibenzylamino)-3-phenylpropoxy]acetic acid tert-butyl ester (XI), which is reduced with LiAlH4 in THF yielding 2-[2(S)-(dibenzylamino)-3-phenylpropoxy]ethanol (XII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in methanol/acetic acid affording the target intermediate (VII).

参考文献 中间体
合成目标
【1】 Brundish, D.E.; Brown, L.N.; Le Grand, D.M.; Menear, K.A.; Smith, G.P.; Allen, M.C.; Butler, P.I.; Cockroft, X.-L.; Matthews, I.T.W.; Walker, C.V.; Wathey, W.B. (Novartis AG); Thrombin inhibitors. WO 9746553 .
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) 30455 2-[[(2S)-2-amino-3-phenylpropyl]oxy]-1-ethanol C11H17NO2 详情 详情
(IX) 30457 (2S)-2-(dibenzylamino)-3-phenyl-1-propanol 111060-52-7 C23H25NO 详情 详情
(X) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(XI) 30458 tert-butyl 2-[[(2S)-2-(dibenzylamino)-3-phenylpropyl]oxy]acetate C29H35NO3 详情 详情
(XII) 30459 2-[[(2S)-2-(dibenzylamino)-3-phenylpropyl]oxy]-1-ethanol C25H29NO2 详情 详情

合成路线33

该中间体在本合成路线中的序号：(VI)

The condensation of 4-benzyloxy-2-hydroxy-6-methoxyacetophenone (I) with 3,4-dimethoxybenzaldehyde (II) by means of KOH in ethanol/water gives the chalcone (III), which is cyclized by means of SeO2 in refluxing isoamyl alcohol to yield the benzopyran (IV). The hydrogenolysis of the benzyl group of (IV) with H2 over Pd/C in chloroform affords the 7-hydroxybenzopyran (V), which is condensed with tert-butyl bromoacetate (VII) by means of CaCO3 in DMF to provide the benzopyranyloxy acetate (VIII). Finally, this compound is deprotected by reaction with p-toluenesulfonic acid in refluxing benzene.

参考文献 中间体
合成目标
【1】 Yoo, M.; Son, M.W.; Kin, I.Y.; Kin, W.B.; Kin, S.H.; Lee, S.D.; Lim, G.J.; Lim, J.I.; Ahn, B.O.; Baik, N.G.; Kin, D.S.; Oh, T.Y.; Ryu, B.K.; Yang, J.S.; Shin, H.C. (Dong-A Pharmaceutical Co., Ltd.); Gastroprotective flavone/flavone cpds. with therapeutic effect on inflammatory bowel disease. JP 1999514015; US 6025387; WO 9804541 .
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) 27802 1-[4-(benzyloxy)-2-hydroxy-6-methoxyphenyl]-1-ethanone C16H16O4 详情 详情
(II) 18304 3,4-Dimethoxybenzaldehyde; Veratraldehyde 120-14-9 C9H10O3 详情 详情
(III) 27803 (E)-1-[4-(benzyloxy)-2-hydroxy-6-methoxyphenyl]-3-(3,4-dimethoxyphenyl)-2-propen-1-one C25H24O6 详情 详情
(IV) 27804 7-(benzyloxy)-2-(3,4-dimethoxyphenyl)-5-methoxy-4H-chromen-4-one C25H22O6 详情 详情
(V) 27805 2-(3,4-dimethoxyphenyl)-7-hydroxy-5-methoxy-4H-chromen-4-one C18H16O6 详情 详情
(VI) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(VII) 27806 tert-butyl 2-[[2-(3,4-dimethoxyphenyl)-5-methoxy-4-oxo-4H-chromen-7-yl]oxy]acetate C24H26O8 详情 详情

合成路线34

该中间体在本合成路线中的序号：

Condensation of 4-methylpentanoyl chloride (I) with (S)-4-benzyl-2-oxazolidinone using n-BuLi afforded the N-acyloxazolidinone (III). Asymmetric alkylation of (III) with tert-butyl bromoacetate and LDA gave (IV), and subsequent removal of the chiral auxiliary by hydrolysis with lithium peroxide yielded (R)-2-isobutylsuccinic acid mono tert-butyl ester (V). This was further alkylated with allyl bromide (VI) and LDA to provide the (R,R)-2,3-disubstituted succinate (VII). Epimerization of (VII) to the required (2R,3S)-isomer (VIII) was accomplished by treatment with LDA and Et2AlCl. Benzyl ester (IX) was then prepared by reaction of (VIII) with benzyl bromide and DBU. Hydroboration of the olefinic double bond of (IX) by means of 9-borabicyclononane, followed by oxidative treatment with H2O2 gave rise to the primary alcohol (X). This was converted to carbonate (XI) upon reaction with p-nitrophenyl chloroformate and N-methylmorpholine (NMM). Coupling of (XI) with lysine derivative (XII) then yielded carbamate (XIII).

参考文献 中间体
合成目标
【1】 Xue, C.-B.; Cherney, R.J.; DeCicco, C.P.; Degrado, W.F.; He, X.; Hodge, C.N.; Jacobson, I.C.; Magolda, R.L.; Arner, E.C.; Duan, J.; Nelson, D.J. (DuPont Pharmaceuticals Co.); Novel macrocyclic cpds. as metalloprotease inhibitors. EP 0863885; JP 2000502050; WO 9718207 .
【2】 Nelson, D.; Magolda, R.L.; Jacobson, I.C.; He, X.; Arner, E.; Cherney, R.J.; Duan, J.; Xue, C.-B.; Decicco, C.P.; Degrado, W.F. (DuPont Pharmaceuticals Co.); Novel macrocyclic cpds. as metalloprotease inhibitors. EP 0981521; WO 9851665 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(I) 25390 4-methylpentanoyl chloride 38136-29-7 C6H11ClO 详情 详情
(II) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(III) 25391 (4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one C16H21NO3 详情 详情
(IV) 25392 tert-butyl (3R)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-5-methylhexanoate C22H31NO5 详情 详情
(V) 25393 (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-4-methylpentanoic acid C12H22O4 详情 详情
(VI) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(VII) 35082 (2R,3R)-3-(tert-butoxycarbonyl)-2-isobutyl-5-hexenoic acid C15H26O4 详情 详情
(VIII) 35083 (2R,3S)-3-(tert-butoxycarbonyl)-2-isobutyl-5-hexenoic acid C15H26O4 详情 详情
(IX) 35084 4-benzyl 1-(tert-butyl) (2S,3R)-2-allyl-3-isobutylbutanedioate C22H32O4 详情 详情
(X) 35085 4-benzyl 1-(tert-butyl) (2S,3R)-2-(3-hydroxypropyl)-3-isobutylbutanedioate C22H34O5 详情 详情
(XI) 35086 1-benzyl 4-(tert-butyl) (2R,3S)-2-isobutyl-3-(3-[[(4-nitrophenoxy)carbonyl]oxy]propyl)butanedioate C29H37NO9 详情 详情
(XII) 35087 methyl (2S)-6-amino-2-[[(benzyloxy)carbonyl]amino]hexanoate C15H22N2O4 详情 详情
(XIII) 35088 17-benzyl 16-(tert-butyl) 5-methyl (5S,16S,17R)-19-methyl-3,11-dioxo-1-phenyl-2,12-dioxa-4,10-diazaicosane-5,16,17-tricarboxylate C38H54N2O10 详情 详情

合成路线35

该中间体在本合成路线中的序号：

6-Methoxy-alpha-tetralone (I) was converted to the corresponding oxime (II) by treatment with hydroxylamine in the presence of sodium acetate. Subsequent Beckmann rearrangement of (II) employing polyphosphoric acid produced a mixture of two regioisomeric lactams from which the required 1-benzazepine (III) was isolated by flash chromatography. Iodination of (III) to give (IV) was carried out following a previously described metodolgy. Displacement of the iodolactam (IV) with ammonia in aqueous ethanol furnished the racemic primary amine, which was resolved by means of L-pyroglutamic acid. The desired (S)-amine (V) was protected as the benzyl carbamate (VII) by treatment with N-(benzyloxycarbonyloxy)succinimide (VI). Then, selective alkylation of the lactam ring nitrogen of (VII) with tert-butyl bromoacetate in the presence of lithium hexamethyldisilazide provided ester (VIII). After hydrogenolysis of the carbobenzoy moiety of (VIII), the resulting amino lactam (IX) was condensed with benzylsulfonyl chloride (X) to give sulfonamide (XI). Deprotection of the tert-butyl ester of (XI) with trifluoroacetic acid afforded carboxylic acid (XII), which was coupled with nitroargininal ethyl aminal (XIII), yielding amide (XIV).

参考文献 中间体
合成目标
【1】 Tamura, S.Y.; Goldman, E.A.; Semple, J.E.; Bergum, P.W.; Novel benzo-fused lactam scaffolds as factor Xa inhibitors. Bioorg Med Chem Lett 1999, 9, 17, 2573.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(I) 17594 6-methoxy-3,4-dihydro-1(2H)-naphthalenone; 6-Methoxytetralone; 6-Methoxy-1-tetralone; 3,4-dihydro-6-methoxy-1(2H)-naphthalenone 1078-19-9 C11H12O2 详情 详情
(II) 38125 6-methoxy-3,4-dihydro-1(2H)-naphthalenone oxime C11H13NO2 详情 详情
(III) 38126 7-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one C11H13NO2 详情 详情
(IV) 38127 3-iodo-7-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one C11H12INO2 详情 详情
(V) 38128 (3S)-3-amino-7-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one C11H14N2O2 详情 详情
(VI) 30663 N-benzyloxycarbonyloxysuccinimide; 1-[[(Benzyloxy)carbonyl]oxy]-2,5-pyrrolidinedione 13139-17-8 C12H11NO5 详情 详情
(VII) 38129 benzyl (3S)-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-ylcarbamate C19H20N2O4 详情 详情
(VIII) 38130 tert-butyl 2-((3S)-3-[[(benzyloxy)carbonyl]amino]-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate C25H30N2O6 详情 详情
(IX) 38131 tert-butyl 2-[(3S)-3-amino-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate C17H24N2O4 详情 详情
(X) 25151 phenylmethanesulfonyl chloride 1939-99-7 C7H7ClO2S 详情 详情
(XI) 38132 tert-butyl 2-[(3S)-3-[(benzylsulfonyl)amino]-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate C24H30N2O6S 详情 详情
(XII) 38133 2-[(3S)-3-[(benzylsulfonyl)amino]-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetic acid C20H22N2O6S 详情 详情
(XIII) 38136 　 C8H17N5O3 详情 详情
(XIV) 38134 　 C28H37N7O8S 详情 详情

合成路线36

该中间体在本合成路线中的序号：

2-Pyrrolidinone (I) was protected as the N-Boc derivative (II) and then alkylated with 3-bromo-2-methylpropene (III) in the presence of LDA to yield (IV). Further alkylation of (IV) with tert-butyl bromoacetate gave the dialkylated pyrrolidinone (V). Catalytic hydrogenation of the 2-methylpropenyl substituent of (V) produced the racemic isobutyl analogue (VI), which was resolved by means of chiral HPLC. The desired (S)-enantiomer (VII) was deprotected by treatment with magnesium ethoxide, affording pyrrolidinone (VIII). N-Alkylation of the pyrrolidinone (VIII) with triflate (IX) furnished adduct (X), which was hydrolyzed to carboxylic acid (XI) with methanolic NaOH. After activation of (XI) with carbonyl diimidazole, coupling with methylamine gave rise to amide (XII). Cleavage of the tert-butyl ester group of (XII) employing trifluoroacetic acid produced carboxylic acid (XIII). This was finally coupled with hydroxylamine using EDC and HOBt.

参考文献 中间体
合成目标
【1】 Jacobsen, E.J. (Pharmacia & Upjohn AB); Hydroxamic acid derivs. for use with the treatment of diseases related to connective tissue degradation. EP 0898562; JP 2000506163; US 5712300; WO 9732846 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11021 Methanamine; Methylamine 74-89-5 CH5N 详情 详情
17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(I) 27397 2-Pyrrolidinone 616-45-5 C4H7NO 详情 详情
(II) 40014 tert-butyl 2-oxo-1-pyrrolidinecarboxylate C9H15NO3 详情 详情
(III) 40015 3-bromo-2-methyl-1-propene 1458-98-6 C4H7Br 详情 详情
(IV) 40016 tert-butyl 3-(2-methyl-2-propenyl)-2-oxo-1-pyrrolidinecarboxylate C13H21NO3 详情 详情
(V) 40017 tert-butyl 3-[2-(tert-butoxy)-2-oxoethyl]-3-(2-methyl-2-propenyl)-2-oxo-1-pyrrolidinecarboxylate C19H31NO5 详情 详情
(VI) 40018 tert-butyl 3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxo-1-pyrrolidinecarboxylate C19H33NO5 详情 详情
(VII) 40019 tert-butyl (3S)-3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxo-1-pyrrolidinecarboxylate C19H33NO5 详情 详情
(VIII) 40020 tert-butyl 2-[(3S)-3-isobutyl-2-oxopyrrolidinyl]acetate C14H25NO3 详情 详情
(IX) 40025 methyl (2R)-2-cyclohexyl-2-[[(trifluoromethyl)sulfonyl]oxy]ethanoate C10H15F3O5S 详情 详情
(X) 40021 methyl (2S)-2-[(3S)-3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]-2-cyclohexylethanoate C23H39NO5 详情 详情
(XI) 40022 (2S)-2-[(3S)-3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]-2-cyclohexylethanoic acid C22H37NO5 详情 详情
(XII) 40023 tert-butyl 2-[(3S)-1-[(1S)-1-cyclohexyl-2-(methylamino)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]acetate C23H40N2O4 详情 详情
(XIII) 40024 2-[(3S)-1-[(1S)-1-cyclohexyl-2-(methylamino)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]acetic acid C19H32N2O4 详情 详情

合成路线37

该中间体在本合成路线中的序号：

2-Pyrrolidinone (I) was protected as the N-Boc derivative (II) and then alkylated with 3-bromo-2-methylpropene (III) in the presence of LDA to yield (IV). Further alkylation of (IV) with tert-butyl bromoacetate gave the dialkylated pyrrolidinone (V). Catalytic hydrogenation of the 2-methylpropenyl substituent of (V) produced the racemic isobutyl analogue (VI), which was resolved by means of chiral HPLC. The desired (S)-enantiomer (VII) was deprotected by treatment with magnesium ethoxide, affording pyrrolidinone (VIII). Triflate (XI) was obtained from D-phenyllactic acid (IX) by formation of the methyl ester (X) upon treatment with iodomethane, followed by reaction with trifluoromethanesulfonic anhydride and pyridine. N-Alkylation of the pyrrolidinone (VIII) with triflate (XI) furnished adduct (XII), which was hydrolyzed to carboxylic acid (XIII) with methanolic NaOH. After activation of (XIII) with carbonyl diimidazole, coupling with methylamine gave rise to amide (XIV). Cleavage of the tert-butyl ester group of (XIV) employing trifluoroacetic acid produced carboxylic acid (XV). This was finally coupled with hydroxylamine using EDC and HOBt.

参考文献 中间体
合成目标
【1】 Jacobsen, E.J. (Pharmacia & Upjohn AB); Hydroxamic acid derivs. for use with the treatment of diseases related to connective tissue degradation. EP 0898562; JP 2000506163; US 5712300; WO 9732846 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11021 Methanamine; Methylamine 74-89-5 CH5N 详情 详情
17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(I) 27397 2-Pyrrolidinone 616-45-5 C4H7NO 详情 详情
(II) 40014 tert-butyl 2-oxo-1-pyrrolidinecarboxylate C9H15NO3 详情 详情
(III) 40015 3-bromo-2-methyl-1-propene 1458-98-6 C4H7Br 详情 详情
(IV) 40016 tert-butyl 3-(2-methyl-2-propenyl)-2-oxo-1-pyrrolidinecarboxylate C13H21NO3 详情 详情
(V) 40017 tert-butyl 3-[2-(tert-butoxy)-2-oxoethyl]-3-(2-methyl-2-propenyl)-2-oxo-1-pyrrolidinecarboxylate C19H31NO5 详情 详情
(VI) 40018 tert-butyl 3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxo-1-pyrrolidinecarboxylate C19H33NO5 详情 详情
(VII) 40019 tert-butyl (3S)-3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxo-1-pyrrolidinecarboxylate C19H33NO5 详情 详情
(VIII) 40020 tert-butyl 2-[(3S)-3-isobutyl-2-oxopyrrolidinyl]acetate C14H25NO3 详情 详情
(IX) 40026 (2R)-2-hydroxy-3-phenylpropionic acid 7326-19-4 C9H10O3 详情 详情
(X) 13878 methyl (2R)-2-hydroxy-3-phenylpropanoate C10H12O3 详情 详情
(XI) 40027 methyl (2R)-3-phenyl-2-[[(trifluoromethyl)sulfonyl]oxy]propanoate C11H11F3O5S 详情 详情
(XII) 40028 methyl (2S)-2-[(3S)-3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]-3-phenylpropanoate C24H35NO5 详情 详情
(XIII) 40029 (2S)-2-[(3S)-3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]-3-phenylpropionic acid C23H33NO5 详情 详情
(XIV) 40030 tert-butyl 2-[(3S)-1-[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]acetate C24H36N2O4 详情 详情
(XV) 40031 2-[(3S)-1-[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]acetic acid C20H28N2O4 详情 详情

合成路线38

该中间体在本合成路线中的序号：

Condensation of 3-nitro-1,2-phenylenediamine (I) with trifluoroacetic acid provided benzimidazole (II). Reduction of the nitro group of (II) by means of hydrazine in the presence of FeCl3 and activated carbon gave amine (III), which was coupled with 2,6-dichlorobenzoyl chloride (IV) yielding amide (V). Alkylation of (V) with tert-butyl bromoacetate afforded benzimidazoleacetic acid tert-butyl ester (VI). After trifluoroacetic acid-promoted cleavage of the tert-butyl ester of (VI) the resulting carboxylic acid (VII) was coupled with morpholine (VIII) using EDC to furnish the title morpholide.

参考文献 中间体
合成目标
【1】 Oku, T.; Kawai, Y.; Yatabe, T.; Sato, S.; Yamazaki, H.; Kayakiri, N.; Yoshihara, K. (Fujisawa Pharmaceutical Co., Ltd.); Benzimidazole derivs. and their use in the prevention and/or the treatment of bone diseases. EP 0863881; JP 1999513364; WO 9710219 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(I) 38446 2-amino-3-nitrophenylamine; 3-nitro-1,2-benzenediamine 3694-52-8 C6H7N3O2 详情 详情
(II) 38447 4-nitro-2-(trifluoromethyl)-1H-benzimidazole C8H4F3N3O2 详情 详情
(III) 38448 2-(trifluoromethyl)-1H-benzimidazol-4-ylamine; 2-(trifluoromethyl)-1H-benzimidazol-4-amine C8H6F3N3 详情 详情
(IV) 25087 2,6-dichlorobenzoyl chloride 4659-45-4 C7H3Cl3O 详情 详情
(V) 38449 2,6-dichloro-N-[2-(trifluoromethyl)-1H-benzimidazol-4-yl]benzamide C15H8Cl2F3N3O 详情 详情
(VI) 38450 tert-butyl 2-[4-[(2,6-dichlorobenzoyl)amino]-2-(trifluoromethyl)-1H-benzimidazol-1-yl]acetate C21H18Cl2F3N3O3 详情 详情
(VII) 38451 2-[4-[(2,6-dichlorobenzoyl)amino]-2-(trifluoromethyl)-1H-benzimidazol-1-yl]acetic acid C17H10Cl2F3N3O3 详情 详情
(VIII) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线39

该中间体在本合成路线中的序号：(III)

Synthesis of the dipeptide intermediate (IX): The esterification of D-cyclohexylalanine (I) by means of SOCl2 and methanol gives the methyl ester (II), which is condensed with tert-butyl bromoacetate (III) by means of DIEA in acetonitrile to yield the N-substituted cyclohexylalanine (IV). The reaction of (IV) with Boc2O and DIEA in DMF affords the N-protected compound (V), which is hydrolyzed with NaOH in dioxane/water to provide the free N-substituted cyclohexylalanine (VI). The condensation of (VI) with L-proline benzyl ester (VII) by means of HOBT and DCC in DMF gives the dipeptide (VIII), which is finally debenzylated by means of H2 over Pd/C in methanol to yield the target dipeptide intermediate (IX).

参考文献 中间体
合成目标
【1】 Adang, A.E.P.; De Man, A.P.A.; Vogel, G.M.T.; Grootenhuis, P.D.J.; Smit, M.J.; Peters, C.A.M.; Visser, A.; Rewinkel, J.B.M.; van Dinther, T; Lucas, H.; Kelder, J.; van Aelst, S.; Meuleman, D.G.; van Boeckel, C.A.A.; Unique overlap in the prerequisites for thrombin inhibition and oral bioavailability resulting in potent oral antithrombotics. J Med Chem 2002, 45, 20, 4419.
【2】 Adang, A.E.P.; Peters, J.A.M.; Van Boeckel, C.A.A.; Rewinkel, J.B.M. (Akzo Nobel N.V.); Thrombin inhibitors. WO 9807308 .
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) 39357 (2S)-2-amino-3-cyclohexylpropionic acid; L-Cyclohexylalanine 27527-05-5 C9H17NO2 详情 详情
(II) 60226 methyl 2-amino-3-cyclohexylpropanoate C10H19NO2 详情 详情
(III) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(IV) 60227 methyl 3-cyclohexyl-2-({2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}amino)propanoate C16H29NO4 详情 详情
(V) 60228 methyl 3-cyclohexyl-2-({[(1,1-dimethylethyl)oxy]carbonyl}{2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}amino)propanoate C21H37NO6 详情 详情
(VI) 60229 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-N-{2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}alanine C20H35NO6 详情 详情
(VII) 20930 benzyl (2S)-2-pyrrolidinecarboxylate 16652-71-4 C12H15NO2 详情 详情
(VIII) 60230 phenylmethyl 1-[3-cyclohexyl-2-({[(1,1-dimethylethyl)oxy]carbonyl}{2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}amino)propanoyl]-2-pyrrolidinecarboxylate C32H48N2O7 详情 详情
(IX) 23165 (2S)-1-((2R)-2-[(tert-butoxycarbonyl)[2-(tert-butoxy)-2-oxoethyl]amino]-3-cyclohexylpropanoyl)-2-pyrrolidinecarboxylic acid C25H42N2O7 详情 详情

合成路线40

该中间体在本合成路线中的序号：(XII)

Synthesis of intermediate (VI): Treatment of pyridone (X) with diphenyl phosphoryl azide (DPPA) followed by reaction with benzyl alcohol affords the protected derivative (XI), which then reacts with tert-butyl bromoacetate (XII) by means of Cs2CO3 to provide the acetate derivative (XIII). Hydrogenation of (XIII) over Pd/C allows Cbz removal, giving amine (XIV), which is then condensed with iodo derivative (XV) to furnish sulfonamide compound (XVI). Finally, hydrolysis of (XVI) is achieved by treatment with TFA to afford the target intermediate (VI).

参考文献 中间体
合成目标
【1】 Soll, R.M.; Lu, T.; Tomczuk, B.E.; Spurlino, J.; Pan, W.; Bone, R.; Green, D.W.; Heteroaryl keto thrombin inhibitors: Design and synthesis. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 285.
【2】 Tumczuk, B.E.; Pan, W.; Soll, R.M.; Lu, T. (3-Dimensional Pharmaceuticals, Inc.); Heteroaryl protease inhibitors and diagnostic imaging agents. WO 0104117 .
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) 44786 2-[3-[[(2-iodobenzyl)sulfonyl]amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetic acid C15H15IN2O5S 详情 详情
(X) 44789 6-methyl-2-oxo-1,2-dihydro-3-pyridinecarboxylic acid C7H7NO3 详情 详情
(XI) 26603 benzyl 6-methyl-2-oxo-1,2-dihydro-3-pyridinylcarbamate C14H14N2O3 详情 详情
(XII) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(XIII) 26604 tert-butyl 2-[3-[[(benzyloxy)carbonyl]amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetate C20H24N2O5 详情 详情
(XIV) 26605 tert-butyl 2-[3-amino-6-methyl-2-oxo-1(2H)-pyridinyl]acetate C12H18N2O3 详情 详情
(XV) 44791 (2-iodophenyl)methanesulfonyl chloride C7H6ClIO2S 详情 详情
(XVI) 44790 tert-butyl 2-[3-[[(2-iodobenzyl)sulfonyl]amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetate C19H23IN2O5S 详情 详情

合成路线41

该中间体在本合成路线中的序号：(XIII)

The reaction of N-(benzyloxycarbonyl)-L-valine (I) with paraformaldehyde and Ts-OH gives the oxazolidinone (II), which is treated with trimethyl trifluoromethylsilane and CsF in THF to yield the trifluoromethyloxazolidine (III). The cleavage of the oxazolidine ring of (III) by means of ZnCl2 and NaBH4 in t-butyl methyl ether affords the protected aminoalcohol (IV), which is deprotected by means of H2 over Pd(OH)2 in ethyl acetate to provide the free aminoalcohol (V). The condensation of (V) with N-(benzyloxycarbonyl)-L-valyl-L-proline (VI) by means of EDC in dichloromethane gives the protected tripeptide analogue (VII), which is deprotected with H2 over Pd(OH)2 in ethanol to yield the tripeptide analogue (VIII). The condensation of (VIII) with the imidazolidinoneacetic acid derivative (IX) by means of EDC, as before, affords the acylated tripeptide (X), which is oxidized with DMP in dichloromethane to provide the acylated-L-valyl-L-prolyl-L-valyl-trifluoromethane (XI). Finally, this compound is deprotected with TFA in dichloromethane to give the target peptide analogue. The imidazolidinoneacetic acid derivative (IX) intermediate is obtained as follows: the reaction of 2-imidazolidinone (XII) with tert-butyl 2-bromoacetate (XIII) by means of lithium tert-butoxide in DMF gives the bis tert-butyl acetate (XIV), which is selectively monohydrolyzed by means of KOH in hot ethanol/water to afford the target imidazolidinoneacetic acid derivative (IX).

参考文献 中间体
合成目标
【1】 Sato, F.; Inoue, Y.; Honda, S.; Komiya, M.; Takemura, T.; Omodani, T.; Shiratake, R. (Dainippon Pharmaceutical Co., Ltd.); Heterocyclic cpds., intermediates thereof and elastase inhibitors. EP 1157998; JP 2000256396; WO 0052032 .
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) 18092 (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid C13H17NO4 详情 详情
(II) 55779 benzyl (4S)-4-isopropyl-5-oxo-1,3-oxazolidine-3-carboxylate C14H17NO4 详情 详情
(III) 55780 benzyl (4S,5R)-5-hydroxy-4-isopropyl-5-(trifluoromethyl)-1,3-oxazolidine-3-carboxylate C15H18F3NO4 详情 详情
(IV) 55781 benzyl (1S,2S)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropylcarbamate C14H18F3NO3 详情 详情
(V) 55782 (2S,3S)-3-amino-1,1,1-trifluoro-4-methyl-2-pentanol C6H12F3NO 详情 详情
(VI) 22787 (2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylic acid C18H24N2O5 详情 详情
(VII) 55783 benzyl (1S)-2-methyl-1-{[(2S)-2-({[(1S,2S)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]amino}carbonyl)pyrrolidinyl]carbonyl}propylcarbamate C24H34F3N3O5 详情 详情
(VIII) 55784 (2S)-1-[(2S)-2-amino-3-methylbutanoyl]-N-[(1S,2S)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]-2-pyrrolidinecarboxamide C16H28F3N3O3 详情 详情
(IX) 55785 2-{3-[2-(tert-butoxy)-2-oxoethyl]-2-oxo-1-imidazolidinyl}acetic acid C11H18N2O5 详情 详情
(X) 55786 tert-butyl 2-(3-{2-[((1S)-2-methyl-1-{[(2S)-2-({[(1S,2S)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]amino}carbonyl)pyrrolidinyl]carbonyl}propyl)amino]-2-oxoethyl}-2-oxo-1-imidazolidinyl)acetate C27H44F3N5O7 详情 详情
(XI) 55787 tert-butyl 2-(3-{2-[((1S)-2-methyl-1-{[(2S)-2-({[(1S)-3,3,3-trifluoro-1-isopropyl-2-oxopropyl]amino}carbonyl)pyrrolidinyl]carbonyl}propyl)amino]-2-oxoethyl}-2-oxo-1-imidazolidinyl)acetate C27H42F3N5O7 详情 详情
(XII) 36228 2-imidazolidinone 120-93-4 C3H6N2O 详情 详情
(XIII) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(XIV) 55788 tert-butyl 2-{3-[2-(tert-butoxy)-2-oxoethyl]-2-oxo-1-imidazolidinyl}acetate C15H26N2O5 详情 详情

合成路线42

该中间体在本合成路线中的序号：(V)

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).

参考文献 中间体
合成目标
【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

合成路线43

该中间体在本合成路线中的序号：(IV)

The reaction of pyrimidine-2,4(1H,3H)-dione (I) with benzyl 2-bromoacetate (II) by means of K2CO3 in DMF gives the pyrimidine-1-acetic acid benzyl ester (III), which is condensed with tert-butyl 2-bromoacetate (IV) by means of NaH in DMF to yield the pyrimidine bis acetate (V). Selective deprotection of the benzyl ester of (V) by means of H2 over Pd(OH)2 in ethyl acetate affords the mono acetic acid derivative (VI), which is condensed with the free amino group of the tripeptide analogue (VII) by means of EDC in pyridine to provide the acylated tripeptide analogue (VIII). The oxidation of the secondary OH group of (VIII) by means of DMP in dichloromethane furnishes the acylated 2-(L-valyl-L-prolyl-L-valyl)benzoxazole derivative (IX), which is finally deprotected with TFA in dichloromethane to give the target tripeptide analogue.

参考文献 中间体
合成目标
【1】 Sato, F.; Inoue, Y.; Honda, S.; Komiya, M.; Takemura, T.; Omodani, T.; Shiratake, R. (Dainippon Pharmaceutical Co., Ltd.); Heterocyclic cpds., intermediates thereof and elastase inhibitors. EP 1157998; JP 2000256396; WO 0052032 .
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) 30912 (2R,3S)-N,6-dimethoxy-2-(4-methoxyphenyl)-N-methyl-2,3-dihydro-1-benzothiophene-3-carboxamide C19H21NO4S 详情 详情
(II) 12869 benzyl 2-bromoacetate 5437-45-6 C9H9BrO2 详情 详情
(III) 55789 benzyl 2-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]acetate C13H12N2O4 详情 详情
(IV) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(V) 55790 tert-butyl 2-[3-[2-(benzyloxy)-2-oxoethyl]-2,6-dioxo-1(2H,6H)-pyrimidinyl]acetate C19H22N2O6 详情 详情
(VI) 55791 2-[3-[2-(tert-butoxy)-2-oxoethyl]-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]acetic acid C12H16N2O6 详情 详情
(VII) 55792 (2S)-1-[(2S)-2-amino-3-methylbutanoyl]-N-{(1S)-1-[(S)-1,3-benzoxazol-2-yl(hydroxy)methyl]-2-methylpropyl}-2-pyrrolidinecarboxamide C22H32N4O4 详情 详情
(VIII) 55793 tert-butyl 2-[3-(2-{[(1S)-1-({(2S)-2-[({(1S)-1-[(S)-1,3-benzoxazol-2-yl(hydroxy)methyl]-2-methylpropyl}amino)carbonyl]pyrrolidinyl}carbonyl)-2-methylpropyl]amino}-2-oxoethyl)-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]acetate C34H46N6O9 详情 详情
(IX) 55794 tert-butyl 2-[3-{2-[((1S)-1-{[(2S)-2-({[(1S)-1-(1,3-benzoxazol-2-ylcarbonyl)-2-methylpropyl]amino}carbonyl)pyrrolidinyl]carbonyl}-2-methylpropyl)amino]-2-oxoethyl}-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]acetate C34H44N6O9 详情 详情

合成路线44

该中间体在本合成路线中的序号：(X)

Alkylation of the allylic alcohol (IX) with tert-butyl bromoacetate (X) under phase-transfer conditions afforded ester (XI), which was then subjected to titanium isopropoxide-mediated transesterification to the corresponding isopropyl ester (XII). Conversion of secondary alcohol (XII) into chloride (XIV) was performed via the mesylate (XIII), which was then treated with tetrabutylammonium chloride in hot toluene. Finally, acidic cleavage of the tetrahydropyranyl ether groups of (XIV) led to the title compound.

参考文献 中间体
合成目标
【1】 Hellberg, M.R.; et al.; 3-Oxa-15-cyclohexyl prostaglandin DP receptor agonists as topical antiglaucoma agents. Bioorg Med Chem 2002, 10, 6, 2031.
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) 56287 (1S,2R,3R,4R)-3-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-2-[(Z)-4-hydroxy-2-butenyl]-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentanol C28H48O6 详情 详情
(X) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(XI) 56288 tert-butyl 2-({(Z)-4-[(1R,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-2-butenyl}oxy)acetate C34H58O8 详情 详情
(XII) 56291 isopropyl 2-({(Z)-4-[(1R,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-2-butenyl}oxy)acetate C33H56O8 详情 详情
(XIII) 56292 isopropyl 2-({(Z)-4-[(1R,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-5-[(methylsulfonyl)oxy]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-2-butenyl}oxy)acetate C34H58O10S 详情 详情
(XIV) 56293 isopropyl 2-({(Z)-4-[(1R,2R,3R,5R)-5-chloro-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-2-butenyl}oxy)acetate C33H55ClO7 详情 详情

合成路线45

该中间体在本合成路线中的序号：(X)

In a different route, hydrogenation of (R)-3-chloro-1-phenyl-1-propanol (XV) over Rh/Al2O3 gave the cyclohexyl carbinol (XVI), which was protected as the ethoxyethyl ether (XVII) by treatment with ethyl vinyl ether in the presence of pyridinium tosylate. Lithiation of chloride (XVII), followed by exchange with lithium (2-thienyl)cyanocuprate, generated the organocuprate reagent (XVIII), which produced a conjugate addition to enone (XIX) to afford the methylene ketone (XX). Protecting group exchange in (XX) was effected by acidic cleavage of the ethoxyethyl group, followed by silylation with t-butyldimethylsilyl triflate, yielding the bis-silylated compound (XXI). The Z-vinylstannane reagent (XXII) was subjected to a stereospecific transmetalation with Me2Cu(CN)Li2 and the resulting cuprate underwent conjugate addition to enone (XXI) yielding adduct (XXIII). Reduction of ketone (XXIII) with L-Selectride®, followed by acidic cleavage of the ethoxyethyl group, provided diol (XXIV). Alkylation of (XXIV) with tert-butyl bromoacetate (X), followed by transterification as above, furnished the isopropyl ester (XXV). The remaining hydroxyl group of (XXV) was subsequently exchanged by a chloride (XXVI) via the corresponding mesylate. Finally, desilylation of (XXVI) with HF in THF gave rise to the title compound.

参考文献 中间体
合成目标
【1】 Hellberg, M.R.; et al.; 3-Oxa-15-cyclohexyl prostaglandin DP receptor agonists as topical antiglaucoma agents. Bioorg Med Chem 2002, 10, 6, 2031.
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) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(XV) 37782 (1R)-3-chloro-1-phenyl-1-propanol C9H11ClO 详情 详情
(XVI) 56294 (1R)-3-chloro-1-cyclohexyl-1-propanol C9H17ClO 详情 详情
(XVII) 56295 (1R)-3-chloro-1-cyclohexylpropyl 2-ethoxyethyl ether; 1-[(1R)-3-chloro-1-(2-ethoxyethoxy)propyl]cyclohexane C13H25ClO2 详情 详情
(XVIII) 56296 {[(3R)-3-cyclohexyl-3-(2-ethoxyethoxy)propyl]cuprio}lithium C13H25CuLiO2 详情 详情
(XIX) 56297 (4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[(diethylamino)methyl]-2-cyclopenten-1-one C16H31NO2Si 详情 详情
(XX) 56298 (3R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-[(3R)-3-cyclohexyl-3-(2-ethoxyethoxy)propyl]-2-methylenecyclopentanone C25H46O4Si 详情 详情
(XXI) 56299 (3R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-((3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclohexylpropyl)-2-methylenecyclopentanone C27H52O3Si2 详情 详情
(XXII) 56300 2-ethoxyethyl (Z)-3-(tributylstannyl)-2-propenyl ether; tributyl[(Z)-3-(2-ethoxyethoxy)-1-propenyl]stannane C19H40O2Sn 详情 详情
(XXIII) 56301 (2R,3R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-((3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclohexylpropyl)-2-[(Z)-4-(2-ethoxyethoxy)-2-butenyl]cyclopentanone C34H66O5Si2 详情 详情
(XXIV) 56302 (1S,2R,3R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-((3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclohexylpropyl)-2-[(Z)-4-hydroxy-2-butenyl]cyclopentanol C30H60O4Si2 详情 详情
(XXV) 56303 isopropyl 2-({(Z)-4-[(1R,2R,3R,5S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-((3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclohexylpropyl)-5-hydroxycyclopentyl]-2-butenyl}oxy)acetate C35H68O6Si2 详情 详情
(XXVI) 56304 isopropyl 2-({(Z)-4-[(1R,2R,3R,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-((3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclohexylpropyl)-5-chlorocyclopentyl]-2-butenyl}oxy)acetate C35H67ClO5Si2 详情 详情

合成路线46

该中间体在本合成路线中的序号：(VI)

Esterification of 3-(4-hydroxyphenyl)propionic acid (I), followed by alkylation of the phenolic hydroxyl, provided methyl 3-(4-benzyloxyphenyl)propionate (II), which was hydrolyzed to the corresponding carboxylic acid (III) by means of LiOH. Coupling of carboxylic acid (III) with the chiral auxiliary (S)-4-benzyl-2-oxazolidinone (IV) gave the oxazolide (V), which was subjected to diastereoselective alkylation with tert-butyl bromoacetate (VI), yielding (VII). Subsequent removal of the chiral auxiliary group of (VII) using lithium hydroperoxide afforded the (R)-acid (VIII). Alkylation of the dianion of acid (VIII) with allyl bromide (IX) and further epimerization in the presence of LDA and Et2AlCl furnished the anti-dialkylated succinate (X). The carboxyl group of (X) was then alkylated using benzyl bromide and DBU to produce the corresponding benzyl ester (XI). Olefin (XI) hydroboration followed by oxidative work-up gave rise to the primary alcohol (XII). This was acylated with 4-nitrophenyl chloroformate (XIII) to provide the activated carbonate (XIV).

参考文献 中间体
合成目标
【1】 Xue, C.-B.; et al.; Discovery of macrocyclic hydroxamic acids containing biphenylmethyl derivatives at P1', a series of selective TNF-alpha converting enzyme inhibitors with potent cellular activity in the inhibition of TNF-alpha release. J Med Chem 2001, 44, 21, 3351.
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) 25691 3-(4-hydroxyphenyl)propionic acid 501-97-3 C9H10O3 详情 详情
(II) 53167 methyl 3-[4-(benzyloxy)phenyl]propanoate n/a C17H18O3 详情 详情
(III) 53168 3-[4-(benzyloxy)phenyl]propanoic acid 50463-48-4 C16H16O3 详情 详情
(IV) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(V) 53169 (4S)-4-benzyl-3-{3-[4-(benzyloxy)phenyl]propanoyl}-1,3-oxazolidin-2-one n/a C26H25NO4 详情 详情
(VI) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(VII) 53170 tert-butyl (3R)-4-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-[4-(benzyloxy)benzyl]-4-oxobutanoate n/a C32H35NO6 详情 详情
(VIII) 53171 (2R)-2-[4-(benzyloxy)benzyl]-4-(tert-butoxy)-4-oxobutanoic acid n/a C22H26O5 详情 详情
(IX) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(X) 53172 (2R,3S)-2-[4-(benzyloxy)benzyl]-3-(tert-butoxycarbonyl)-5-hexenoic acid n/a C25H30O5 详情 详情
(XI) 53173 4-benzyl 1-(tert-butyl) (2S,3R)-2-allyl-3-[4-(benzyloxy)benzyl]butanedioate n/a C32H36O5 详情 详情
(XII) 53174 1-benzyl 4-(tert-butyl) (2R,3S)-2-[4-(benzyloxy)benzyl]-3-(3-hydroxypropyl)butanedioate n/a C32H38O6 详情 详情
(XIII) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(XIV) 53175 1-benzyl 4-(tert-butyl) (2R,3S)-2-[4-(benzyloxy)benzyl]-3-(3-{[(4-nitrophenoxy)carbonyl]oxy}propyl)butanedioate n/a C39H41NO10 详情 详情

合成路线47

该中间体在本合成路线中的序号：(IV)

Acylation of Evans oxazolidinone (II) with heptanoyl chloride (I) provides the chiral adduct (III). The lithium enolate of (III) is then diastereoselectively alkylated with tert-butyl bromoacetate (IV) to afford the succinate derivative (V). Removal of the chiral auxiliary group of (V) with lithium peroxide furnishes the carboxylic acid (VI), which is further activated as the succinimidyl ester (VII) upon treatment with N-hydroxysuccinimide and DCC. The activated ester (VII) is then condensed with L-valine (VIII), producing amide (IX). Subsequent coupling of (IX) with N-aminoproline methyl ester (X) leads to hydrazide (XI). After acidic tert-butyl ester cleavage in (XI), the resultant carboxylic acid (XII) is condensed with hydroxylamine to yield the desired hydroxamic acid.

参考文献 中间体
合成目标
【1】 Borella, C.; et al.; Asymmetric solid phase and solution parallel synthesis and antitumor properties of actinonin analogs. Proc Am Assoc Cancer Res 2002, 43.
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) 57557 Enanthic chloride; Enanthyl chloride; Heptanoic acid chloride; Heptanoyl chloride; Heptanoyl chloride; n-Heptanoyl chloride; Oenanthic chloride 2528-61-2 C7H13ClO 详情 详情
(II) 12867 (4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone 17016-83-0 C6H11NO2 详情 详情
(III) 57558 (4S)-3-heptanoyl-4-isopropyl-1,3-oxazolidin-2-one C13H23NO3 详情 详情
(IV) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(V) 57559 tert-butyl (3R)-3-{[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}octanoate C19H33NO5 详情 详情
(VI) 57560 (2R)-2-[2-(tert-butoxy)-2-oxoethyl]heptanoic acid C13H24O4 详情 详情
(VII) 57561 tert-butyl (3R)-3-{[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl}octanoate C17H27NO6 详情 详情
(VIII) 37828 L-2-Amino-3-methylbutyric acid; L-2-Aminoisovaleric acid; 2-Aminoisovaleric acid; L-2-Amino-3-methylbutyric acid; L-alpha-Aminoisovaleric acid; L-valine; (S)-(+)-Valine; (S)-alpha-Aminoisovaleric acid 72-18-4 C5H11NO2 详情 详情
(IX) 57562 (2S)-2-({(2R)-2-[2-(tert-butoxy)-2-oxoethyl]heptanoyl}amino)-3-methylbutanoic acid C18H33NO5 详情 详情
(X) 57563 methyl (2S)-1-amino-2-pyrrolidinecarboxylate C6H12N2O2 详情 详情
(XI) 57564 methyl (2S)-1-{[(2S)-2-({(2R)-2-[2-(tert-butoxy)-2-oxoethyl]heptanoyl}amino)-3-methylbutanoyl]amino}-2-pyrrolidinecarboxylate C24H43N3O6 详情 详情
(XII) 57565 (3R)-3-({[(1S)-1-({[(2S)-2-(methoxycarbonyl)pyrrolidinyl]amino}carbonyl)-2-methylpropyl]amino}carbonyl)octanoic acid C20H35N3O6 详情 详情

合成路线48

该中间体在本合成路线中的序号：(X)

Alkylation of the allylic alcohol (IX) with tert-butyl bromoacetate (X) under phase-transfer conditions afforded ester (XI), which was then converted into chloro derivative (XII) by treatment with a mixture of CH3CN/CCl4/pyridine and then PPh3. Acidic cleavage of the tetrahydropyranyl ether groups of (XII) led to the dihydroxy derivative (XIII), which was finally subjected to saponification with LiOH in MeOH to yield the desired product.

参考文献 中间体
合成目标
【1】 Hellberg, M.R.; et al.; 3-Oxa-15-cyclohexyl prostaglandin DP receptor agonists as topical antiglaucoma agents. Bioorg Med Chem 2002, 10, 6, 2031.
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) 56287 (1S,2R,3R,4R)-3-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-2-[(Z)-4-hydroxy-2-butenyl]-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentanol C28H48O6 详情 详情
(X) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(XI) 56288 tert-butyl 2-({(Z)-4-[(1R,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-2-butenyl}oxy)acetate C34H58O8 详情 详情
(XII) 56289 tert-butyl 2-({(Z)-4-[(1R,2R,3R,5R)-5-chloro-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-2-butenyl}oxy)acetate C34H57ClO7 详情 详情
(XIII) 56290 tert-butyl 2-[((Z)-4-{(1R,2R,3R,5R)-5-chloro-2-[(3R)-3-cyclohexyl-3-hydroxypropyl]-3-hydroxycyclopentyl}-2-butenyl)oxy]acetate C24H41ClO5 详情 详情

合成路线49

该中间体在本合成路线中的序号：(II)

Alkylation of 3-hydroxybenzaldehyde (I) with t-butyl bromoacetate (II) affords t butyl (3-formylphenoxy)acetate (III). Aldehyde (III) is then converted to oxime (IV) upon treatment with hydroxylamine in MeOH. Reduction of oxime (IV) to the benzylic amine (V) is carried out by catalytic hydrogenation in the presence of Raney nickel. Subsequent reductive alkylation of amine (V) with 4-t-butylbenzaldehyde (VI) furnishes the secondary amine (VII). This is then acylated by pyridine-3-sulfonyl chloride (VIII) producing sulfonamide (IX). The t-butyl ester group of (IX) is finally cleaved with trifluoroacetic acid to give the corresponding carboxylic acid.

参考文献 中间体
合成目标
【1】 Rosati, R.L.; Lefker, B.A.; Cameron, K.O. (Pfizer Inc.); Prostaglandin agonists and their use to treat bone disorders. EP 1021410; JP 2001519414; US 6498172; WO 9919300 .
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) 28537 3-hydroxybenzaldehyde 100-83-4 C7H6O2 详情 详情
(II) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(III) 64442 tert-butyl 2-(3-formylphenoxy)acetate C13H16O4 详情 详情
(IV) 64443 tert-butyl 2-{3-[(hydroxyimino)methyl]phenoxy}acetate C13H17NO4 详情 详情
(V) 64444 tert-butyl 2-[3-(aminomethyl)phenoxy]acetate C13H19NO3 详情 详情
(VI) 16638 4-(tert-butyl)benzaldehyde; 4-tert-Butyl-benzaldehyde 939-97-9 C11H14O 详情 详情
(VII) 64445 tert-butyl 2-[3-({[4-(tert-butyl)benzyl]amino}methyl)phenoxy]acetate C24H33NO3 详情 详情
(VIII) 64446 3-pyridinesulfonyl chloride C5H4ClNO2S 详情 详情
(IX) 64447 tert-butyl 2-(3-{[[4-(tert-butyl)benzyl](3-pyridinylsulfonyl)amino]methyl}phenoxy)acetate C29H36N2O5S 详情 详情

合成路线50

该中间体在本合成路线中的序号：(II)

4-Hydroxydiphenylmethane (I) is condensed with tert-butyl bromoacetate (II) in the presence of NaH and Bu-4NI to form the aryloxyacetate adduct (III). Ester group reduction in (III) employing LiAlH4 provides alcohol (IV), which is further treated with p-toluenesulfonyl chloride in pyridine, yielding tosylate (V) (1,2). Finally, condensation of tosylate (V) with ethyl isonipecotate (VI) furnishes the title compound (1-3).

参考文献 中间体
合成目标
【1】 Pyrrolidine and piperidine analogues of SC-57461A as potent, orally active inhibitors of leukotriene A(4) hydrolase. Bioorg Med Chem Lett 2002, 12, 23, 3383.
【2】 Chandrakumar, N.S.; Chen, B.B.; Clare, M.; Desai, B.N.; Djuric, S.W.; Docter, S.H.; Gasiecki, A.F.; Haack, R.A.; Liang, C.-D.; Miyashiro, J.M.; Penning, T.D.; Russell, M.A.; Yu, S.S. (Pfizer Inc.); LTA4 hydrolase inhibitor pharmaceutical compsns. and methods of use. JP 1998512542; WO 9610999 .
【3】 Chandrakumar, N.S.; Chen, B.B.; Clare, M.; Desai, B.N.; Djuric, S.W.; Docter, S.H.; Gasiecki, A.; Haack, R.A.; Liang, C.-D.; Miyashiro, J.M.; Penning, T.D.; Russell, M.A.; Yu, S.S. (Pfizer Inc.); LTA4 hydrolase inhibitors. EP 0804427; EP 1221441; JP 1998512848; WO 9611192 .
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) 50817 4-Hydroxydiphenylmethane; 4-Benzylphenol; alpha-Phenyl-p-cresol; p-Benzylphenol 101-53-1 C13H12O 详情 详情
(II) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(III) 64434 tert-butyl 2-(4-benzylphenoxy)acetate C19H22O3 详情 详情
(IV) 64435 2-(4-benzylphenoxy)-1-ethanol C15H16O2 详情 详情
(V) 64436 2-(4-benzylphenoxy)ethyl 4-methylbenzenesulfonate C22H22O4S 详情 详情
(VI) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情

合成路线51

该中间体在本合成路线中的序号：(II)

Alkylation of 4-hydroxydiphenylmethane (I) with tert-butyl bromoacetate (II) in the presence of NaH and Bu4NI in DMF affords ether (III). The ester function of (III) is then reduced by LiAlH4 to furnish the primary alcohol (IV), which is subsequently activated as the corresponding tosylate (V) (1,2). Condensation of tosylate (V) with 5-azabenzimidazole (VI) gives rise to a mixture of the three possible regioisomers (VII), (VIII) and (IX), which can be separated by means of flash chromatography. The desired isomer (IX) is then converted to the N-oxide (X) employing m-chloroperbenzoic acid in CHCl3 (1-3). Finally, reaction of N-oxide (X) with cyanotrimethylsilane produces the target nitrile (3).

参考文献 中间体
合成目标
【1】 Synthesis of imidazopyridines and purines as potent inhibitors of leukotriene A4 hydrolase. Bioorg Med Chem Lett 2003, 13, 6, 1137.
【2】 Chandrakumar, N.S.; Chen, B.B.; Clare, M.; Desai, B.N.; Djuric, S.W.; Docter, S.H.; Gasiecki, A.; Haack, R.A.; Liang, C.-D.; Miyashiro, J.M.; Penning, T.D.; Russell, M.A.; Yu, S.S. (Pfizer Inc.); LTA4 hydrolase inhibitors. EP 0804427; EP 1221441; JP 1998512848; WO 9611192 .
【3】 Chandrakumar, N.S.; Chen, B.B.; Clare, M.; Desai, B.N.; Djuric, S.W.; Docter, S.H.; Gasiecki, A.F.; Haack, R.A.; Liang, C.-D.; Miyashiro, J.M.; Penning, T.D.; Russell, M.A.; Yu, S.S. (Pfizer Inc.); LTA4 hydrolase inhibitor pharmaceutical compsns. and methods of use. JP 1998512542; WO 9610999 .
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) 50817 4-Hydroxydiphenylmethane; 4-Benzylphenol; alpha-Phenyl-p-cresol; p-Benzylphenol 101-53-1 C13H12O 详情 详情
(II) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(III) 64434 tert-butyl 2-(4-benzylphenoxy)acetate C19H22O3 详情 详情
(IV) 64435 2-(4-benzylphenoxy)-1-ethanol C15H16O2 详情 详情
(V) 64436 2-(4-benzylphenoxy)ethyl 4-methylbenzenesulfonate C22H22O4S 详情 详情
(VI) 64437 1H-imidazo[4,5-c]pyridine C6H5N3 详情 详情
(VII) 64438 4-benzylphenyl 2-(5H-imidazo[4,5-c]pyridin-5-yl)ethyl ether; 5-[2-(4-benzylphenoxy)ethyl]-5H-imidazo[4,5-c]pyridine C21H19N3O 详情 详情
(VIII) 64439 4-benzylphenyl 2-(3H-imidazo[4,5-c]pyridin-3-yl)ethyl ether; 3-[2-(4-benzylphenoxy)ethyl]-3H-imidazo[4,5-c]pyridine C21H19N3O 详情 详情
(IX) 64440 1-[2-(4-benzylphenoxy)ethyl]-1H-imidazo[4,5-c]pyridine; 4-benzylphenyl 2-(1H-imidazo[4,5-c]pyridin-1-yl)ethyl ether C21H19N3O 详情 详情
(X) 64441 1-[2-(4-benzylphenoxy)ethyl]-1H-imidazo[4,5-c]pyridin-5-ium-5-olate C21H19N3O2 详情 详情

合成路线52

该中间体在本合成路线中的序号：(II)

　

参考文献 中间体
合成目标
【1】 Krishnan L, Sum PE, Daigneault S, et aL. 2006. Process for the prepantion of tigecycline and methods of preparing 9-aminominocycline. W0 2006130500
【2】 Krishnan L, Sum PE, Daigneault S, et al. 2006. Preparation of tigecycline and 9-nitrominocycline. W0 2006130501
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) 66846 (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 hydrochloride 　 C23H28N4O7.HCl 详情 详情
(I) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情
(II) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(III) 66841 tert-butyl 2-(tert-butylamino)acetate 　 C10H21NO2 详情 详情
(IV) 66842 2-(tert-butylamino)acetic acid hydrochloride 　 C6H13NO2.HCl 详情 详情
(V) 66843 2-(tert-butylamino)acetyl chloride hydrochloride 　 C6H12ClNO.HCl 详情 详情
(VI) 65813 Minocycline hydrochloride; [4S-(4alpha,4aalpha,5aalpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxonaphthacene-2-carboxamide monohydrochloride 13614-98-7 C23H27N3O7.HCl 详情 详情
(VII) 66844 (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 monosulfate 　 C23H26N4O9.2H2SO4 详情 详情
(VIII) 66845 (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 monosulfate 　 C23H28N4O7.2H2SO4 详情 详情

合成路线53

该中间体在本合成路线中的序号：(IX)

Chlorination of 6-bromo-2-naphthoic acid (I) with SOCl2 , optionally in the presence of DMF in THF , affords the corresponding acid chloride (II), which by reaction with (i-Pr)2NH , optionally in the presence of Et3N in THF , provides amide (III). Metalation of 6-bromo-N,N-diisopropyl-2-naphthamide (III) with BuLi in THF followed by condensation with 1-tritylimidazole-4-carbaldehyde (IV) gives the diarylcarbinol (V), which by oxidation with MnO2 in CH2Cl2 yields the corresponding ketone (VI) . Compound (VI) can also be obtained directly by condensation of lithiated naphthamide (III) (by means of BuLi in THF) with N-methoxy-N-methyl-1-tritylimidazole-4-carboxamide (VII) . Asymmetric Reformatsky reaction of ketone (VI) with either bromo (2-ethoxy-2-oxoethyl)zinc (VIIIa) or bromo (2-tert-butoxy-2-oxoethyl)zinc (VIIIb) [prepared in situ by reaction of tert-butyl bromoacetate (IX) with Zn and TMSCl ] by means of cinchonine, and optionally pyridine, in THF provides the 3(S)-hydroxy-3-(4-imidazolyl)-3-(2-naphthyl)propionic acid ethyl and tert-butyl esters (Xa) and (Xb) , respectively. Reduction of esters (Xa) or (Xb) by means of Red-Al in toluene yields the propane-1,3-diol derivative (XI), which by activation with MsCl in the presence of DIEA in THF followed by cyclization with MeOH in the presence of DIEA in acetonitrile affords the 7(S)-(2-naphthyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ol derivative (XII). Finally, the N,N-diisopropylnaphthamide derivative (XII) is treated with CH3NH2 in the presence of BuLi in THF .

参考文献 中间体
合成目标
【1】 Kaku, T., Hitaka, T., Ojida, A. et al. Discovery of TAK-700, a naphthylmethylimidazole derivative, as a highly selective, orally active 17, 20 lyase inhibitor for prostate cancer. 240th ACS Natl Meet (Aug 22-26, Boston) 2010, Abst MEDI 96.
【2】 Hitaka, T., Kusaka, M., Aoki, I., Ojida, A., Matsunaga, N., Adachi, M., Tasaka, A. (Takeda Pharmaceutical Co., Ltd.). Novel imidazole derivatives, production method thereof and use thereof. EP 1334106, EP 1681290, JP 2003201282, JP 2006045239, US 7141598, WO 2002040484.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIIIa) 68259 bromo (2-ethoxy-2-oxoethyl)zinc;(2-ethoxy-2-oxoethyl)zinc bromide 　 C4H7BrO2Zn 详情 详情
(VIIIb) 68260 bromo (2-tert-butoxy-2-oxoethyl)zinc;(2-(tert-butoxy)-2-oxoethyl)zinc bromide 　 C6H11BrO2Zn 详情 详情
(Xa) 68262 3(S)-hydroxy-3-(4-imidazolyl)-3-(2-naphthyl)propionic acid ethyl 　 C44H45N3O4 详情 详情
(Xb) 68263 (S)-tert-butyl 3-(6-(diisopropylcarbamoyl)naphthalen-2-yl)-3-hydroxy-3-(1-trityl-1H-imidazol-4-yl)propanoate 　 C46H49N3O4 详情 详情
(I) 42564 6-Bromo-2-naphthoic acid；(6-Bromonaphthalen-2-yl)acetic acid;6-Bromo-2-naphthalenecarboxylic acid 5773-80-8 C11H7BrO2 详情 详情
(II) 68255 6-bromo-2-naphthoyl chloride 　 C11H6BrClO 详情 详情
(III) 68256 6-bromo-N,N-diisopropyl-2-naphthamide 　 C17H20BrNO 详情 详情
(IV) 27712 1-trityl-1H-imidazole-4-carbaldehyde；1-Tritylimidazole-4-carboxaldehyde 33016-47-6 C23H18N2O 详情 详情
(V) 68257 6-(hydroxy(1-trityl-1H-imidazol-4-yl)methyl)-N,N-diisopropyl-2-naphthamide 　 C40H39N3O2 详情 详情
(VI) 68258 N,N-diisopropyl-6-(1-trityl-1H-imidazole-4-carbonyl)-2-naphthamide 　 C40H37N3O2 详情 详情
(VII) 68261 N-methoxy-N-methyl-1-trityl-1H-imidazole-4-carboxamide 　 C25H23N3O2 详情 详情
(IX) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(XI) 68264 (S)-6-(1,3-dihydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl)-N,N-diisopropyl-2-naphthamide 　 C42H43N3O3 详情 详情
(XII) 68265 7(S)-(2-naphthyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ol;(S)-6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N,N-diisopropyl-2-naphthamide 　 C23H27N3O2 详情 详情
Extended Information