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【结 构 式】

【分子编号】22671

【品名】4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride

【CA登记号】100-07-2

【 分 子 式 】C8H7ClO2

【 分 子 量 】170.59508

【元素组成】C 56.33% H 4.14% Cl 20.78% O 18.76%
与该中间体有关的原料药合成路线共 22 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20合成路线21合成路线22

合成路线1

该中间体在本合成路线中的序号：(IV)

The silylation of 4-acetoxy-2-pyrrolidone (I) with trimethylchlorosilane (II) by means of triethyl amine in THF gives the corresponding N-trimethylsilyl derivative (III), which is condensed with 4-methoxybenzoyl chloride (IV) by means of NaHCO3 in THF yielding 1-(4-methoxybenzoyl)pyrrolin-2-one (V). Finally, this compound is reduced with H2 over Pd/C in ethyl acetate.

参考文献 中间体
合成目标
【1】 Kyburz, E.; Aschwanden, W. (F. Hoffmann-La Roche AG); 1-(p-Methoxy-p-hydroxy, and p-benzyloxybenzoyl)-2-pyrrolidinones. DD 141828; EP 0005143; EP 0044088; ES 477587; ES 483756; JP 54117468 .
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) 29095 4-Acetoxy-2-pyrrolidone; 5-Oxo-3-pyrrolidinyl acetate C6H9NO3 详情 详情
(II) 29096 Chloro(trimethyl)silane; Trimethylsilyl chloride; Trimethylchlorosilane 75-77-4 C3H9ClSi 详情 详情
(III) 29097 5-oxo-1-(trimethylsilyl)-3-pyrrolidinyl acetate C9H17NO3Si 详情 详情
(IV) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(V) 29098 1-(4-methoxybenzoyl)-1,5-dihydro-2H-pyrrol-2-one C12H11NO3 详情 详情

合成路线2

该中间体在本合成路线中的序号：(IV)

The condensation of 4-aminobutyric acid (VI) with acid chloride (IV) by means of NaOH in water gives 4-(4-methoxybenzoylamino)butyric acid (VII), which is then cyclized by means of P2O5 in phosphoric acid.

参考文献 中间体
合成目标
【1】 Kyburz, E.; Aschwanden, W. (F. Hoffmann-La Roche AG); 1-(p-Methoxy-p-hydroxy, and p-benzyloxybenzoyl)-2-pyrrolidinones. DD 141828; EP 0005143; EP 0044088; ES 477587; ES 483756; JP 54117468 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(VI) 13620 4-Amino-n-butyric acid; 4-Aminobutyric acid;Piperidinic acid;Piperidic acid 56-12-2 C4H9NO2 详情 详情
(VII) 29099 4-[(4-methoxybenzoyl)amino]butyric acid C12H15NO4 详情 详情

合成路线3

该中间体在本合成路线中的序号：(II)

By reaction of 2-pyrrolidinone (I) with p-methoxybenzoyl chloride (II) by means of triethylamine in ether or sodium hydride in DMF.

参考文献 中间体
合成目标
【1】 Kyburz, E.; Aschwanden, W.; 1-(P-Methoxy, p-hydroxy and p-benzyloxybenzoyl)-2-pyrrolidinones. EP 0005143; JP 54117468; US 4369139 .
【2】 Blancafort, P.; Serradell, M.N.; Mealy, N.E.; Leeson, P.A.; Castaner, J.; Aniracetam. Drugs Fut 1981, 6, 3, 127.
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) 27397 2-Pyrrolidinone 616-45-5 C4H7NO 详情 详情
(II) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情

合成路线4

该中间体在本合成路线中的序号：(II)

A new method for the synthesis of encainide has been reported: The acylation of methyl anthranilate (I) with 4-anisoyl chloride (II) by means of NaOH in methylene chloride gives methyl N-(p-anisoyl)anthranilate (III), which is condensed with 2-picoline (IV) by means of n-butyllithium in THF yielding 2-(2-pyridylacetyl)-p-anisanilide (V). Finally, this compound is reduced with H2 over Pt/C then with Pd/C, treated with formaldehyde and reduced again with H2 over Pt/C.

参考文献 中间体
合成目标
【1】 Madding, G.D. (Bristol-Myers Squibb Co.); Process for production of encainide. JP 58105963; NL 8204775; US 4394507 .
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) 11161 methyl 2-aminobenzoate; Methyl anthranilate 134-20-3 C8H9NO2 详情 详情
(II) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(III) 29100 methyl 2-[(4-methoxybenzoyl)amino]benzoate C16H15NO4 详情 详情
(IV) 17590 2-methylpyridine; 2-picoline 109-06-8 C6H7N 详情 详情
(V) 29101 4-methoxy-N-[2-[2-(2-pyridinyl)acetyl]phenyl]benzamide C21H18N2O3 详情 详情

合成路线5

该中间体在本合成路线中的序号：(A)

The condensation of 2-methylpyridine (I) with 2-nitrobenzaldehyde (II) in acetic anhydride gives 2-(2-nitrostyryl)pyridine (III), which is quaternized with methyl iodide in refluxing acetone yielding 2-(2-nitrostyryl)-1-methylpyridinium iodide (IV) . The reduction of (IV) with H2 over PtO2 in ethanol affords 2-(2-aminophenethyl)-1-methylpiperidine (V), which is then acylated with 4-methoxybenzoyl chloride (A) in pyridine.

参考文献 中间体
合成目标
【1】 Dykstra, S.J.; Minielli, J.L.; Substituted piperidines and a process for the preparation thereof. BE 0779951; CA 961038; CH 578529; DE 2210154; FR 2128584; GB 1346261; NL 161443C; NL 7202614 .
【2】 Kendrick, W.D.; Ferguson, H.C.; acid and quimidine analogs. 2-(o-Acylaminophenethyl)piperidines. J Med Chem 1973, 16, 9, 1015.
【3】 Castaner, J.; MJ 9067. Drugs Fut 1977, 2, 3, 176.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(I) 17590 2-methylpyridine; 2-picoline 109-06-8 C6H7N 详情 详情
(II) 11370 2-Nitrobenzaldehyde 552-89-6 C7H5NO3 详情 详情
(III) 40197 2-[(E)-2-(2-nitrophenyl)ethenyl]pyridine C13H10N2O2 详情 详情
(IV) 40198 1-methyl-2-[(E)-2-(2-nitrophenyl)ethenyl]pyridinium iodide C14H13IN2O2 详情 详情
(V) 40199 2-[2-(1-methyl-2-piperidinyl)ethyl]phenylamine; 2-[2-(1-methyl-2-piperidinyl)ethyl]aniline C14H22N2 详情 详情

合成路线6

该中间体在本合成路线中的序号：(A)

Nevadensin can be synthesized starting from methyl 2,6-dimethoxyphenyl acetate (I). This compound is nitrated and then hydrogenated, giving methyl 3,5-diamino-2,6-dimethoxyphenyl acetate (III). Treatment of the latter compound with stannous chloride-hydrochloric acid gives dimethoxyphloroglucinol (IV). Introduction of an acetyl group followed by interaction with p-methoxybenzoyl chloride (A) gives 4-acetyl-2,6-dimethoxyphloroglucinyl tri(p-methoxy) benzoate (VI). The latter compound, after being rearranged, is cyclized into 5,7-di(p-methoxy)benzoylnevadensin (VIII). Nevadensin can readily be obtained by the hydrolysis of the compound (VIII).

参考文献 中间体
合成目标
【1】 Feng, S.; Xu, Y.; Fan, G.; Studies on the antituberculosis principles from Lysionotus pauciflora Maxim. I. Isolation and identification of nevadensin. Acta Pharm Sin 1979, 14, 7, 447-448.
【2】 Su, C.; Han, G.; Zhang, Y.; Determination of nevadensin in biological specimens and its pharmacokinetic study. Chin Pharm Bull 1981, 2, 3, 182-185.
【3】 Ru-yun, J.; Nevadensin. Drugs Fut 1984, 9, 4, 271.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(I) 34188 2,6-dimethoxyphenyl acetate C10H12O4 详情 详情
(II) 34189 2,6-dimethoxy-3,5-dinitrophenyl acetate C10H10N2O8 详情 详情
(III) 34190 3,5-diamino-2,6-dimethoxyphenyl acetate C10H14N2O4 详情 详情
(IV) 34191 2,4-dimethoxy-1,3,5-benzenetriol C8H10O5 详情 详情
(V) 34192 1-(2,4,6-trihydroxy-3,5-dimethoxyphenyl)-1-ethanone C10H12O6 详情 详情
(VI) 34193 2-acetyl-4,6-dimethoxy-3,5-bis[(4-methoxybenzoyl)oxy]phenyl 4-methoxybenzoate C34H30O12 详情 详情
(VII) 34194 3-hydroxy-2,6-dimethoxy-5-[(4-methoxybenzoyl)oxy]-4-[3-(4-methoxyphenyl)-3-oxopropanoyl]phenyl 4-methoxybenzoate C34H30O12 详情 详情
(VIII) 34195 6,8-dimethoxy-5-[(4-methoxybenzoyl)oxy]-2-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yl 4-methoxybenzoate C34H28O11 详情 详情

合成路线7

该中间体在本合成路线中的序号：(IX)

The esterification of bromoacetic acid (I) with benzyl alcohol (II) gives the corresponding ester (III), which by reaction with triphenylphosphine (IV) in hot toluene yields the phosphonium bromide (V). The reaction of (V) with NaOH in water-dichloromethane affords benzyl(triphenylphosphoranylidene) acetate (VI), which is submitted to a Wittig condensation with 5-(hydroxymethyl)-2-pyrrolidone (VII) in the presence of Dess-Martin periodinane (DMPI) giving benzyl 3-(5-oxo-2-pyrrolidinyl)-2(E) propenoate (VIII). The acylation of (VIII) with 4-methoxybenzoyl chloride (IX) by means of triethylamine in hot toluene yields the corresponding amide (X), which is finally hydrogenated and deprotected with H2 over Pd/C in THF.

参考文献 中间体
合成目标
【1】 Huang, C.C.; Synthesis of carbon-14 labeled 1-(4-methoxybenzoyl. J Label Compd Radiopharm 1987, 24, 6, 675.
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) 23660 2-Bromoacetic acid 79-08-3 C2H3BrO2 详情 详情
(II) 18710 Benzyl alcohol; Phenylmethanol 100-51-6 C7H8O 详情 详情
(III) 12869 benzyl 2-bromoacetate 5437-45-6 C9H9BrO2 详情 详情
(IV) 12437 Triphenylphosphine; Triphenyl phosphine 603-35-0 C18H15P 详情 详情
(V) 22667 [2-(benzyloxy)-2-oxoethyl](triphenyl)phosphonium bromide C27H24BrO2P 详情 详情
(VI) 22668 benzyl 2-(triphenylphosphoranylidene)acetate C27H23O2P 详情 详情
(VII) 10079 5-(Hydroxymethyl)-2-pyrrolidinone 62400-75-3 C5H9NO2 详情 详情
(VIII) 22670 benzyl (E)-3-(5-oxo-2-pyrrolidinyl)-2-propenoate C14H15NO3 详情 详情
(IX) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(X) 22672 benzyl (E)-3-[1-(4-methoxybenzoyl)-5-oxo-2-pyrrolidinyl]-2-propenoate C22H21NO5 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 partial hydrolysis of perhydropyrrolizine-3,5-dione (I) in the presence of benzyl alcohol (II) by means of aqueous concentrated HCl at 98 C gives benzyl 5-oxopyrrolidine-2-propenoate (III), which is condensed with 4-methoxybenzoyl chloride (IV) by means of triethylamine in hot THF to afford benzyl 1-(4-methoxybenzoyl)-5-oxopyrrolidine-3-propanoate (V). Finally, this compound ls debenzylated by hydrogenolysis with H2 over Pd/C in THF.

参考文献 中间体
合成目标
【1】 (Pfizer Inc.); 1-Aroyl-5-oxo-2-pyrrolidinepropanoic acid derivs.. EP 0110575; ES 8600238 .
【2】 Castaner, J.; Serradell, M.N.; CI-933. Drugs Fut 1985, 10, 12, 972.
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) 29829 dihydro-1H-pyrrolizine-3,5(2H,6H)-dione C7H9NO2 详情 详情
(II) 18710 Benzyl alcohol; Phenylmethanol 100-51-6 C7H8O 详情 详情
(III) 29830 benzyl 3-(5-oxo-2-pyrrolidinyl)propanoate C14H17NO3 详情 详情
(IV) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(V) 29831 benzyl 3-[1-(4-methoxybenzoyl)-5-oxo-2-pyrrolidinyl]propanoate C22H23NO5 详情 详情

合成路线9

该中间体在本合成路线中的序号：(IV)

This compound can be obtained by two related ways: 1) The condensation of 2-methylindole (I) with 2-morpholinoethyl chloride (II) by means of KOH in hot DMSO gives 1-(2-morpholinoethyl)-2-methylindole (III), which is then submitted to a Friedel-Craft's reaction with 4-methoxybenzoyl chloride (IV) by means of AlCl3 in dichloromethane or ethylene dichloride. 2) The condensation of indole (I) with acyl chloride (IV) by means of methylmagnesium bromide in anhydrous ethyl ether gives 2-methyl-3-(4-methoxy benzoyl)indole (V), which is then condensed with morpholine (II) by means of K2CO3 in DMF.

参考文献 中间体
合成目标
【1】 Bell, M.R. (Sanofi-Synthelabo); 3-Carbonyl-1-aminoalkyl-1H-indoles useful as analgesics and preparation thereof. AU 8545764; EP 0171037; ES 8609246; ES 8800149; ES 8800901; ES 8800902; ES 8801203; JP 1986047463 .
【2】 Castaner, R.M.; Castaner, J.; Serradell, M.N.; WIN-48098. Drugs Fut 1987, 12, 9, 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) 28747 2-methyl-1H-indole 95-20-5 C9H9N 详情 详情
(II) 27355 4-(2-chloroethyl)morpholine 3647-69-6 C6H12ClNO 详情 详情
(III) 28748 4-[2-(2-methyl-1H-inden-1-yl)ethyl]morpholine C16H21NO 详情 详情
(IV) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(V) 28749 (4-methoxyphenyl)(2-methyl-1H-indol-3-yl)methanone C17H15NO2 详情 详情

合成路线10

该中间体在本合成路线中的序号：(A)

Friedel-Crafts acylation of 2,3-dichlorophenetole with 4-methoxybenzoyl chloride gives the substituted benzophenone (I). Selective cleavage of the ethyl ether in (I) with AlCl3 produces phenol (II). Alkylation of (II) with ethyl bromoacetate is followed by heating with 48% HBr to give the phenoxyacetic acid derivative (III). Amidomethylation of (III) using the Tscherniac-Einhorn procedure gives (IV), which affords A-49816 after hydrolysis with HCl/EtOH.

参考文献 中间体
合成目标
【1】 Plattner, J.J.; Horrom, B.W.; Dodge, P.W.; Ours, C.W.; Lee, C.-M.; Pernet, A.G.; El Masry, S.E.; Smital, J.R.; Bunnell, P.R.; [(Aminomethyl)aryloxy]acetic acid esters. A new cl. J Med Chem 1984, 27, 1579.
【2】 Luther, R.R.; Plattner, J.J.; A-49816. Drugs Fut 1988, 13, 12, 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
(A) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(B) 23019 1,2-dichloro-3-ethoxybenzene; 2,3-dichlorophenyl ethyl ether C8H8Cl2O 详情 详情
(I) 23021 (2,3-dichloro-4-ethoxyphenyl)(4-methoxyphenyl)methanone C16H14Cl2O3 详情 详情
(II) 23022 (2,3-dichloro-4-hydroxyphenyl)(4-methoxyphenyl)methanone C14H10Cl2O3 详情 详情
(III) 23023 2-[2,3-dichloro-4-(4-hydroxybenzoyl)phenoxy]acetic acid C15H10Cl2O5 详情 详情
(IV) 23024 2-[2,3-dichloro-4-(3-[[(2-chloroacetyl)amino]methyl]-4-hydroxybenzoyl)phenoxy]acetic acid C18H14Cl3NO6 详情 详情
(C) 23020 2-chloro-N-(hydroxymethyl)acetamide 2832-19-1 C3H6ClNO2 详情 详情

合成路线11

该中间体在本合成路线中的序号：(V)

Treatment of 2-hydroxy-5-nitrobenzyl bromide (I) with triphenylphosphine in refluxing chloroform provides phosphonium bromide derivative (II), which is converted into 2-butyl-5-nitro benzofuran (IV) by first reaction with pentanoyl chloride (III) in refluxing chloroform in the presence of pyridine, followed by treatment with Et3N in refluxing toluene. Acylation of (IV) with anisoyl chloride (V) by means of tin tetrachloride in dichloroethane furnishes 2-butyl-3-(4-methoxy benzoyl)-5-nitro benzofuran (VI), whose methoxy group is then converted into an hydroxy group by treatment with aluminum chloride in refluxing dichloroethane, yielding hydroxy benzoyl derivative (VII). Condensation of (VII) with N,N-dibutyl-N-(3-chloropropyl)amine (VIII) by means of K2CO3 in refluxing butanone affords compound (IX), which is then hydrogenated over PtO2 in EtOH to give amino derivative (X). Finally, the target product is obtained by reaction of (X) with methanesulfonyl chloride and Et3N in dichloroethane and hydrochloride salt formation with HCl in AcOEt/ethyl ether.

参考文献 中间体
合成目标
【1】 Gubin, J.; Lucchetti, J.; Inion, H.; Chatelain, P.; Rosseels, G.; Kilenyi, S. (Sanofi-Synthélabo); Benzofuran derivs., benzothiophenes, indoles or indolizines, process for production and compsns. containing them. EP 0471609; FR 2665444; JP 1992316554; US 5223510 .
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) 50821 alpha-Bromo-4-nitro-o-cresol; Koshland's reagent; 2-Hydroxy-5-nitrobenzyl bromide 772-33-8 C7H6BrNO3 详情 详情
(II) 50822 (2-hydroxy-5-nitrobenzyl)(triphenyl)phosphonium bromide C25H21BrNO3P 详情 详情
(III) 15116 pentanoyl chloride; valeryl chloride 638-29-9 C5H9ClO 详情 详情
(IV) 50823 2-butyl-5-nitro-1-benzofuran C12H13NO3 详情 详情
(V) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(VI) 50824 (2-butyl-5-nitro-1-benzofuran-3-yl)(4-methoxyphenyl)methanone C20H19NO5 详情 详情
(VII) 50825 (2-butyl-5-nitro-1-benzofuran-3-yl)(4-hydroxyphenyl)methanone C19H17NO5 详情 详情
(VIII) 50826 N,N-dibutyl-N-(3-chloropropyl)amine; N-butyl-N-(3-chloropropyl)-1-butanamine 36421-15-5 C11H24ClN 详情 详情
(IX) 50827 (2-butyl-5-nitro-1-benzofuran-3-yl)[4-[3-(dibutylamino)propoxy]phenyl]methanone C30H40N2O5 详情 详情
(X) 50828 (5-amino-2-butyl-1-benzofuran-3-yl)[4-[3-(dibutylamino)propoxy]phenyl]methanone C30H42N2O3 详情 详情

合成路线12

该中间体在本合成路线中的序号：(III)

Removal of the N-(benzyloxycarbonyl) group from the protected dipeptide (I) by catalytic hydrogenolysis provided the dipeptide Val-Pro-O-t-Bu (II), which was N-acylated with anisoyl chloride (III) to afford anisoyl dipeptide (IV). The tert-butyl ester group of (IV) was then cleaved using trifluoroacetic acid to afford (VI). Alternatively, the intermediate (VI) could be obtained from unprotected Val-Pro-OH (V) by treatment with trimethylsilyl chloride and subsequent acylation of the silyl ester with acid chloride (III). The anisoyl dipeptide (VI) was further condensed with racemic threo-aminoalcohol (VII), either in the presence of EDC and HOBt or via conversion to the mixed anhydride with isobutyl chloroformate, to furnish the corresponding peptide amide (VIII) as a diastereomeric mixture. Subsequent oxidation of the alcohol group of (VIII) to the trifluoromethyl ketone (IX) was carried out using a modified Pfitzner-Moffat procedure in the presence of DMSO, EDC and dichloroacetic acid or with KMnO4 in basic medium. The desired S,S,S-isomer was isolated from the epimeric mixture after repeated crystallizations.

参考文献 中间体
合成目标
【1】 Bohnert, C.M.; Bernstein, P.R.; Veale, C.A.; et al.; Orally active trifluoromethyl ketone inhibitors of. J Med Chem 1997, 40, 20, 3173.
【2】 Pegg, S.J.; Sependa, G.J.; Davies, E.P.; Veale, C.A. (AstraZeneca plc); Diastereomeric pure trifluoromethyl ketone peptide. EP 0743953; JP 1997508902; US 5739157; US 6037363; WO 9521855 .
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) 22770 tert-butyl (2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylate C22H32N2O5 详情 详情
(II) 22771 tert-butyl (2S)-1-[(2S)-2-amino-3-methylbutanoyl]-2-pyrrolidinecarboxylate C14H26N2O3 详情 详情
(III) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(IV) 22773 tert-butyl (2S)-1-[(2S)-2-[(4-methoxybenzoyl)amino]-3-methylbutanoyl]-2-pyrrolidinecarboxylate C22H32N2O5 详情 详情
(V) 22774 (2S)-1-[(2S)-2-amino-3-methylbutanoyl]-2-pyrrolidinecarboxylic acid C10H18N2O3 详情 详情
(VI) 22775 (2S)-1-[(2S)-2-[(4-methoxybenzoyl)amino]-3-methylbutanoyl]-2-pyrrolidinecarboxylic acid C18H24N2O5 详情 详情
(VII) 22776 (2R,3S)-3-amino-1,1,1-trifluoro-4-methyl-2-pentanol C6H12F3NO 详情 详情
(VIII) 22777 (2S)-1-[(2S)-2-[(4-methoxybenzoyl)amino]-3-methylbutanoyl]-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)-2-pyrrolidinecarboxamide C24H34F3N3O5 详情 详情
(IX) 22778 (2S)-1-[(2S)-2-[(4-methoxybenzoyl)amino]-3-methylbutanoyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)-2-pyrrolidinecarboxamide C24H32F3N3O5 详情 详情

合成路线13

该中间体在本合成路线中的序号：(III)

An alternative synthesis has been reported employing pure (2R,3S)-aminoalcohol (XVII). Treatment of isobutyl iodide (X) with sodium nitrite in the presence of urea in DMF afforded 2-methyl-1-nitropropane (XI). Further condensation of fluoral hydrate (XII) with this nitrocompound using K2CO3 provided a diastereomeric mixture of nitroalcohols (XIII). Fractional crystallization from pentane yielded the racemic threo-nitroalcohol (XIV), which was converted to the alredy reported racemic threo-aminoalcohol (VII) by catalytic hydrogenation. This compound (VII) was treated with triphosgene and NaOH to produce oxazolidone (XV). After conversion of (XV) to the corresponding lithium salt with BuLi at -70 C, its condensation with (-)-menthyl chloroformate gave a diastereomeric mixture of carbamates, from which the desired isomer (XVI) was isolated by fractional crystallization from ether/hexane. The chiral auxiliary and the oxazolidone ring were then cleaved by hydrolysis with KOH yielding the (2R,3S)-aminoalcohol (XVII)(1). The coupling of (XVII) with the amino protected dipeptide (XVIII) (obtained by treatment of peptide (I) with trifluoroacetic acid) afforded dipeptide amide (XIX), The N-(benzyloxycarbonyl) protecting group of (XIX) was subsequently removed by catalytic hydrogenation, and the resulting amino compound was condensed with anisoyl chloride (III) to furnish the anisoyl dipeptide (XX). Finally, oxidation of the alcohol group of (XX) using the modified Pfitner-Moffat procedure produced some epimerization of the resulting ketone, the oxidation with KMnO4 in the presence of NaOH yielded the target S,S,S-peptide.

参考文献 中间体
合成目标
【1】 Bohnert, C.M.; Bernstein, P.R.; Veale, C.A.; et al.; Orally active trifluoromethyl ketone inhibitors of. J Med Chem 1997, 40, 20, 3173.
【2】 Pegg, S.J.; Sependa, G.J.; Davies, E.P.; Veale, C.A. (AstraZeneca plc); Diastereomeric pure trifluoromethyl ketone peptide. EP 0743953; JP 1997508902; US 5739157; US 6037363; WO 9521855 .
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) 22770 tert-butyl (2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylate C22H32N2O5 详情 详情
(III) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(VII) 22776 (2R,3S)-3-amino-1,1,1-trifluoro-4-methyl-2-pentanol C6H12F3NO 详情 详情
(X) 18168 1-iodo-2-methylpropane 513-38-2 C4H9I 详情 详情
(XI) 11782 2-Methyl-1-nitropropane C4H9NO2 详情 详情
(XII) 22781 2,2,2-trifluoro-1,1-ethanediol 421-53-4 C2H3F3O2 详情 详情
(XIII) 11783 1,1,1-Trifluoro-4-methyl-3-nitro-2-pentanol C6H10F3NO3 详情 详情
(XIV) 22783 (2R,3S)-1,1,1-trifluoro-4-methyl-3-nitro-2-pentanol C6H10F3NO3 详情 详情
(XV) 22784 (4S,5R)-4-isopropyl-5-(trifluoromethyl)-1,3-oxazolidin-2-one C7H10F3NO2 详情 详情
(XVI) 22785 (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (4S,5R)-4-isopropyl-2-oxo-5-(trifluoromethyl)-1,3-oxazolidine-3-carboxylate C18H28F3NO4 详情 详情
(XVII) 22776 (2R,3S)-3-amino-1,1,1-trifluoro-4-methyl-2-pentanol C6H12F3NO 详情 详情
(XVIII) 22787 (2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylic acid C18H24N2O5 详情 详情
(XIX) 22788 benzyl (1S)-2-methyl-1-[[(2S)-2-([[(1S,2R)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]amino]carbonyl)pyrrolidinyl]carbonyl]propylcarbamate C24H34F3N3O5 详情 详情
(XX) 22789 (2S)-1-[(2S)-2-[(4-methoxybenzoyl)amino]-3-methylbutanoyl]-N-[(1S,2R)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]-2-pyrrolidinecarboxamide C24H34F3N3O5 详情 详情

合成路线14

该中间体在本合成路线中的序号：(XVI)

Synthesis of intermediate monosaccharide (XVIII): The reaction of tetraacetyl-D-xylose (IX) with HBr in HOAc gives the bromoglycoside (X), which by reaction with ethylmercaptane and lutidine yields the thio orthoester (XI). Hydrolysis of (XI) with NaOMe in methanol affords the deacetylated compound (XII), which is protected with Pmb-Cl and NaH to provide the diether (XIII). The cleavage of the cyclic thio orthoester with ZnCl2 in dichloromethane gives the 2-O-acetyl-thioglycoside (XIV), which is hydrolyzed with NaOMe in methanol to yield the alcohol (XV). Esterification of (XV) with 4-methoxybenzoyl chloride (XVI), DMAP and TEA affords the benzoate ester (XVII), which is finally converted into the target acetimidate (XVIII) by reaction with NBS in dichloromethane/water, and then with trichloroacetonitrile and DBU in the same solvent.

参考文献 中间体
合成目标
【1】 Jin, Z.; Yu, W.; A new strategy for the stereoselective introduction of steroid side chain via alpha-alkoxy vinyl cuprates: Total synthesis of a highly potent antitumor natural product OSW-1. J Am Chem Soc 2001, 123, 14, 3369.
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) 48943 (3R,4S,5R)-2,3,5-tris(acetoxy)tetrahydro-2H-pyran-4-yl acetate C13H18O9 详情 详情
(X) 23761 (2R,3R,4S,5R)-3,5-bis(acetoxy)-2-bromotetrahydro-2H-pyran-4-yl acetate C11H15BrO7 详情 详情
(XI) 48944 (2S,3aR,6R,7S,7aR)-6-(acetoxy)-2-(ethylsulfanyl)-2-methyltetrahydro-3aH-[1,3]dioxolo[4,5-b]pyran-7-yl acetate C13H20O7S 详情 详情
(XII) 48945 (2S,3aR,6R,7S,7aR)-2-(ethylsulfanyl)-2-methyltetrahydro-3aH-[1,3]dioxolo[4,5-b]pyran-6,7-diol C9H16O5S 详情 详情
(XIII) 48946 (2S,3aR,6R,7S,7aR)-2-(ethylsulfanyl)-6-[(4-methoxybenzyl)oxy]-2-methyltetrahydro-3aH-[1,3]dioxolo[4,5-b]pyran-7-yl 4-methoxybenzyl ether; (2S,3aR,6R,7S,7aR)-2-(ethylsulfanyl)-6,7-bis[(4-methoxybenzyl)oxy]-2-methyltetrahydro-3aH-[1,3]dioxolo[4,5-b]pyran C25H32O7S 详情 详情
(XIV) 48947 (2R,3R,4S,5R)-2-(ethylsulfanyl)-4,5-bis[(4-methoxybenzyl)oxy]tetrahydro-2H-pyran-3-yl acetate C25H32O7S 详情 详情
(XV) 48948 (2S,3R,4R,5R)-2-(ethylsulfanyl)-4,5-bis[(4-methoxybenzyl)oxy]tetrahydro-2H-pyran-3-ol C23H30O6S 详情 详情
(XVI) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(XVII) 48949 (2S,3R,4S,5R)-2-(ethylsulfanyl)-4,5-bis[(4-methoxybenzyl)oxy]tetrahydro-2H-pyran-3-yl 4-methoxybenzoate C31H36O8S 详情 详情
(XVIII) 48950 (3R,4S,5R)-4,5-bis[(4-methoxybenzyl)oxy]-2-[(2,2,2-trichloroethanimidoyl)oxy]tetrahydro-2H-pyran-3-yl 4-methoxybenzoate C31H32Cl3NO9 详情 详情

合成路线15

该中间体在本合成路线中的序号：(IX)

Synthesis of intermediate monosaccharide (XIII): The reaction of D-xylose (VII) with benzyl alcohol and HCl (gas) gives the 1-O-benzyl-D-xylose (VIII), which is regioselectively acylated with 4-methoxybenzoyl chloride (IX) and pyridine to yield 1-O-benzyl-2-O-(4-methoxybenzoyl)-D-xylose (X). The silylation of (X) with Tes-Cl and imidazole in DMF affords the disilylated compound (XI), which is debenzylated by hydrogenation with H2 over Pd/C in ethyl acetate to provide 2-O-(4-methoxybenzoyl)-3,4-O-bis(triethylsilyl)-D-xylose (XII). Finally, this compound is converted into the target trichloroacetimidate (XIII) by reaction with trichloroacetonitrile and DBU in dichloromethane.

参考文献 中间体
合成目标
【1】 Deng, S.; et al.; First total synthesis of an exceptionally potent antitumor saponin, OSW-1. J Org Chem 1999, 64, 1, 202.
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) 48970 2,3,4,5-Tetrahydroxypentanal; D-xylopyranose; D-(+)-Xylose; D-xylose; D-(+)-Wood Sugar; Xylose; Wood Sugar 58-86-6 C5H10O5 详情 详情
(VIII) 48971 (3R,4S,5R)-2-(benzyloxy)tetrahydro-2H-pyran-3,4,5-triol C12H16O5 详情 详情
(IX) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(X) 48972 (3R,4S,5R)-2-(benzyloxy)-4,5-dihydroxytetrahydro-2H-pyran-3-yl 4-methoxybenzoate C20H22O7 详情 详情
(XI) 48973 (3R,4R,5R)-2-(benzyloxy)-4,5-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-3-yl 4-methoxybenzoate C32H50O7Si2 详情 详情
(XII) 48974 (3R,4R,5R)-2-hydroxy-4,5-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-3-yl 4-methoxybenzoate C25H44O7Si2 详情 详情
(XIII) 48975 (3R,4R,5R)-2-[(2,2,2-trichloroethanimidoyl)oxy]-4,5-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-3-yl 4-methoxybenzoate C27H44Cl3NO7Si2 详情 详情

合成路线16

该中间体在本合成路线中的序号：(IV)

The cyclization of 2-methylbenzonitrile (I) with pyridine-2-carbonitrile (II) by means of potassium amide in liquid NH3 gives 3-(2-pyridyl)isoquinoline-1-amine (III), which is finally acylated with 4-methoxybenzoyl chloride (IV) by means of butyllithium in THF.

参考文献 中间体
合成目标
【1】 de Zwart, M.A.H.; van der Goot, H.; de Zwart, H.; Timmerman, H.; Synthesis and copper-dependent antimycoplasmal activity of 1-amino-3-(2-pyridyl)isoquinoline derivatives. 1. Amides. J Med Chem 1988, 31, 4, 716.
【2】 van Muijlwijk-Koezen, J.E.; Timmerman, H.; Link, R.; van der Goot, H.; Ijzerman, A.P.; A novel class of adenosine A3 receptor ligands. 2. Structure affinity profile of a series of isoquinoline and quinazoline compounds. J Med Chem 1998, 41, 21, 3994.
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) 28606 2-methylbenzonitrile 529-19-1 C8H7N 详情 详情
(II) 28607 2-pyridinecarbonitrile 100-70-9 C6H4N2 详情 详情
(III) 28608 3-(2-pyridinyl)-1-isoquinolinamine C14H11N3 详情 详情
(IV) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情

合成路线17

该中间体在本合成路线中的序号：(VI)

Regioselective ring opening of 3-nitrophthalic anhydride (I) with ammonia yielded amide (II), which was subjected to a Hofmann degradation with Br2 and KOH to afford 3-nitroanthranilic acid (III). Esterification of (III) to ster (IV) using MeOH/HCl, followed by reduction of the nitro group by catalytic hydrogenation, gave methyl 2,3-diaminobenzoate (V). Alternatively, diamino ester (V) was prepared by reduction of nitro acid (III), followed by catalytic esterification. Methyl 2,3-diaminobenzoate (V) was then selectively acylated at the 3-amino group with 4-methoxybenzoyl chloride (VI) producing amide (VII), which was cyclized to the benzimidazole (VIII) upon refluxing in HOAc. The corresponding amide (IX) was obtained by reaction of ester (VIII) with liquid ammonia at 100 C in a pressure vessel. Finally, the methyl ether group of (IX) was cleaved to the title phenol by treatment with boron tribromide.

参考文献 中间体
合成目标
【1】 Wood, M.D.; Taylor, S.G.; Reavill, C.; et al.; Pharmacological actions of a novel, high-affinity, and selective human dopamine D3 receptor antagonist, SB-277011-A. J Pharmacol Exp Ther 2000, 294, 3, 1154.
【2】 Griffin, R.J.; Calvert, A.H.; Newell, D.R.; Curtain, J.N.; Golding, B.T. (University of Newcastle upon Tyne); Benzimidazole cpds.. US 6100283 .
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) 46407 4-nitro-2-benzofuran-1,3-dione；3-nitrophthalic anhydride 641-70-3 C8H3NO5 详情 详情
(II) 46408 2-(aminocarbonyl)-3-nitrobenzoic acid C8H6N2O5 详情 详情
(III) 46409 2-amino-3-nitrobenzoic acid C7H6N2O4 详情 详情
(IV) 46410 methyl 2-amino-3-nitrobenzoate C8H8N2O4 详情 详情
(V) 18889 methyl 2,3-diaminobenzoate C8H10N2O2 详情 详情
(VI) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(VII) 46411 methyl 2-amino-3-[(4-methoxybenzoyl)amino]benzoate C16H16N2O4 详情 详情
(VIII) 46412 methyl 2-(4-methoxyphenyl)-1H-benzimidazole-4-carboxylate C16H14N2O3 详情 详情
(IX) 46413 2-(4-methoxyphenyl)-1H-benzimidazole-4-carboxamide C15H13N3O2 详情 详情

合成路线18

该中间体在本合成路线中的序号：(II)

Friedel-Crafts acylation of 2-methylbenzofuran (I) with p-anisoyl chloride (II) in the presence of SnCl4 afforded the benzoyl benzofuran derivative (III). Ketone (III) reduction to the corresponding benzyl benzofuran (IV) was accomplished employing either LiAlH4 or NaBH4 and ZnI2. The methyl ether group of (IV) was then cleaved with melted pyridine hydrochloride to give phenol (V). Aromatic iodination of (V) with either I2/KI or with ICl in morpholine led to the diiodo phenol (VI). This was then alkylated with ethyl bromoacetate (VII) to furnish ester (VIII), which was finally hydrolyzed with NaOH to the target carboxylic acid.

参考文献 中间体
合成目标
【1】 Singh, B.N.; Malm, J.; Mellin, C.; Li, Y.-L.; Nilsson, S.; Temciuc, M.; Carlsson, B.; Synthesis and preliminary characterization of a novel antiarrhythmic compound (KB130015) with an improved toxicity profile compared with amiodarone. J Med Chem 2002, 45, 3, 623.
【2】 Norinder, U.; Bajorath, J.; Stearns, J.F. (Karo Bio AB); Receptor ligands. WO 9220331 .
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) 56239 2-Methylbenzofuran C9H8O 详情 详情
(II) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(III) 56240 (4-methoxyphenyl)(2-methyl-1-benzofuran-3-yl)methanone C17H14O3 详情 详情
(IV) 56241 3-(4-methoxybenzyl)-2-methyl-1-benzofuran; methyl 4-[(2-methyl-1-benzofuran-3-yl)methyl]phenyl ether C17H16O2 详情 详情
(V) 56242 4-[(2-methyl-1-benzofuran-3-yl)methyl]phenol C16H14O2 详情 详情
(VI) 56243 2,6-diiodo-4-[(2-methyl-1-benzofuran-3-yl)methyl]phenol C16H12I2O2 详情 详情
(VII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(VIII) 56244 ethyl 2-{2,6-diiodo-4-[(2-methyl-1-benzofuran-3-yl)methyl]phenoxy}acetate C20H18I2O4 详情 详情

合成路线19

该中间体在本合成路线中的序号：(V)

Condensation of salicylaldehyde (I) with 2-bromoacetophenone (II) produced benzofuranyl phenyl ketone (III), which was reduced to 2-benzyl benzofuran (IV) under Wolff-Kishner conditions. Subsequent Friedel-Crafts acylation of (IV) with anisoyl chloride (V) employing SnCl4 afforded ketone (VI). Methyl ether cleavage in (VI) with concomitant intramolecular cyclization, followed by dehydration by means of BBr3 gave rise to benzo naphthofuran (VII). This was brominated in AcOH to yield tribromo derivative (VIII). Mitsunobu coupling of (VIII) with (S)-methyl-2-hydroxy-3-phenylpropionate (IX) furnished ether (X). Finally, the methyl ester group of (X) was hydrolyzed with KOH.

参考文献 中间体
合成目标
【1】 Dietrich, A.; Katz, A.; Sullivan, D.; Wrobel, J.; Sawicki, D.R.; Tio, C.; Li, Z.; Seestaller, L.; Wu, L.; Zhang, Z.-Y.; Sredy, J.; Moxham, C.; PTP1B inhibition and antihyperglycemic activity in the ob/ob mouse model of novel 11-arylbenzo[b]naphto[2,3-d]furans and 11-arylbenzo[b]naphtho[2,3-d]thiophenes. J Med Chem 1999, 42, 17, 3199-3202.
【2】 Dietrich, A.J.; Wrobel, J.E.; Li, Z. (American Home Products Corp.); 11-Aryl-benzo[b]naphtho[2,3-d]furans and 11-aryl-benzo[b]naphtho[2,3-d]thiophenes useful in the treatment of insulin resistance and hyperglycemia. WO 9958521 .
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) 21351 2-Hydroxybenzaldehyde;Salicylic aldehyde；2-Formylphenol;salicylaldehyde 90-02-8 C7H6O2 详情 详情
(II) 10315 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone 70-11-1 C8H7BrO 详情 详情
(III) 33663 1-benzofuran-2-yl(phenyl)methanone C15H10O2 详情 详情
(IV) 33664 2-benzyl-1-benzofuran C15H12O 详情 详情
(V) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(VI) 33665 (2-benzyl-1-benzofuran-3-yl)(4-methoxyphenyl)methanone C23H18O3 详情 详情
(VII) 33666 4-naphtho[2,3-b][1]benzofuran-11-ylphenol C22H14O2 详情 详情
(VIII) 33667 2,6-dibromo-4-(6-bromonaphtho[2,3-b][1]benzofuran-11-yl)phenol C22H11Br3O2 详情 详情
(IX) 13878 methyl (2R)-2-hydroxy-3-phenylpropanoate C10H12O3 详情 详情
(X) 33668 methyl (2R)-2-[2,6-dibromo-4-(6-bromonaphtho[2,3-b][1]benzofuran-11-yl)phenoxy]-3-phenylpropanoate C32H21Br3O4 详情 详情

合成路线20

该中间体在本合成路线中的序号：(X)

Treatment of salicylaldehyde (I) with methyl chloroacetate (II) in DMF in the presence of potassium carbonate provides methyl o-formylphenoxyacetate (III), which is converted into methyl 2-benzofuranecarboxylate (IV) by reaction with DBU in toluene. Reduction of (IV) by means of LiAlH4 in ether yields hydroxy derivative (V), which then reacts with SOCl2 in ether/DMF to furnish chloro derivative (VI). Treatment of (VI) with NaCN in DMSO affords cyano derivative (VII), which is converted into 2-benzofuraneacetic acid (VIII) by treatment with NaOH in boiling water. Esterification of (VIII) by treatment with HCl in refluxing MeOH affords methyl acetate derivative (IX), which is condensed with p-anisoyl chloride (X) by means of SnCl4 in 1,2-dichloroethane to yield compound (XI). Treatment of (XI) with aluminum powder and iodine crystals (to generate AlI3) in refluxing benzene gives acetic acid derivative (XII), which is iodinated with iodine and K2CO3 in H2O to give derivative (XIII). Esterification of (XIII) by means of iPrOH and H2SO4 provides isopropyl acetate derivative (XIV), which is finally converted into the desired product by reaction with diethylaminoethyl chloride (XV) in NaOH and CH2Cl2 in the presence of benzyltriethylammonium chloride.

参考文献 中间体
合成目标
【1】 Druzgala, P. (ARYx Therapeutics, Inc.); Benzoylbenzofurane derivs. for treatment of cardiac arrhythmia. EP 0703910; JP 1996511546; US 5364880; WO 9429289 .
【2】 Druzgala, P. (ARYx Therapeutics, Inc.); Cpd. for treatment of cardiac arrhythmia, synthesis, and methods of use. US 5849788 .
【3】 Druzgala, P. (ARYx Therapeutics, Inc.); Cpd. for treatment of cardiac arrhythmia, synthesis, and methods of use. US 6130240 .
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) 21351 2-Hydroxybenzaldehyde;Salicylic aldehyde；2-Formylphenol;salicylaldehyde 90-02-8 C7H6O2 详情 详情
(II) 10257 methyl 2-chloroacetate; methyl chloroacetate 96-34-4 C3H5ClO2 详情 详情
(III) 49708 methyl 2-(2-formylphenoxy)acetate C10H10O4 详情 详情
(IV) 49709 methyl 1-benzofuran-2-carboxylate C10H8O3 详情 详情
(V) 38335 1-benzofuran-2-ylmethanol C9H8O2 详情 详情
(VI) 49710 2-(chloromethyl)-1-benzofuran C9H7ClO 详情 详情
(VII) 38336 2-(1-benzofuran-2-yl)acetonitrile C10H7NO 详情 详情
(VIII) 49711 2-(1-benzofuran-2-yl)acetic acid C10H8O3 详情 详情
(IX) 49712 methyl 2-(1-benzofuran-2-yl)acetate C11H10O3 详情 详情
(X) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(XI) 49713 methyl 2-[3-(4-methoxybenzoyl)-1-benzofuran-2-yl]acetate C19H16O5 详情 详情
(XII) 49714 2-[3-(4-hydroxybenzoyl)-1-benzofuran-2-yl]acetic acid C17H12O5 详情 详情
(XIII) 49715 2-[3-(4-hydroxy-3,5-diiodobenzoyl)-1-benzofuran-2-yl]acetic acid C17H10I2O5 详情 详情
(XIV) 49716 isopropyl 2-[3-(4-hydroxy-3,5-diiodobenzoyl)-1-benzofuran-2-yl]acetate C20H16I2O5 详情 详情
(XV) 16194 2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine 100-35-6 C6H14ClN 详情 详情

合成路线21

该中间体在本合成路线中的序号：(VI)

Oxidation of 2,3-dimethylfuran (I) under Vilsmeier conditions with POCl3 in DMF affords aldehyde (II), which is then condensed with benzothiophene (III) by means of n-BuLi in THF to provide secondary alcohol (IV). Reduction of (IV) under Nutaitis conditions with NaBH4 and TFA in THF yields methylene congener (V), which is then treated with p-anisoyl chloride (VI) under Friedel-Crafts conditions with SnCl4 in CS2 to give 1-oxa-9-thiacyclopenta[b]fluorene heterocycle (VII). Demethylation of methyl ether (VII) with BBr3 in CH2Cl2 affords phenol (VIII), which is then bis-iodinated with molecular iodine and NaOH in MeOH to yield di-iodo phenol (IX). Compound (IX) is then condensed with (S)-2-hydroxy-3-phenylpropionic acid (X) under Mitsunobu conditions with DEAD and PPh3 in benzene to furnish (R)-2-benzyl-acetic acid derivative (XI), which is finally hydrolyzed by treatment with KOH in H2O/dioxane to provide the desired product.

参考文献 中间体
合成目标
【1】 Sredy, j.; Seesteller, L.; Li, Z.; Sawicki, D.R.; Wrobel, J.; Sullivan, D.; Synthesis and PTP1B inhibition of novel 4-aryl-1-oxa-9-thiacyclopenta[b]fluorenes. Bioorg Med Chem Lett 2000, 10, 14, 1535.
【2】 Li, Z.; Wrobel, J.E. (American Home Products Corp.); 4-Aryl-1-oxa-9-thia-cyclopenta[b]fluorenes. US 6057316 .
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) 48451 2,3-Dimethylfuran 14920-89-9 C6H8O 详情 详情
(II) 48452 4,5-Dimethyl-2-furaldehyde; 4,5-Dimethylfurfural C7H8O2 详情 详情
(III) 25578 1-benzothiophene 95-15-8 C8H6S 详情 详情
(IV) 48453 1-benzothiophen-2-yl(4,5-dimethyl-2-furyl)methanol C15H14O2S 详情 详情
(V) 48454 5-(1-benzothiophen-2-ylmethyl)-2,3-dimethylfuran C15H14OS 详情 详情
(VI) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(VII) 48455 4-(2,3-dimethyl[1]benzothieno[3,2-f][1]benzofuran-4-yl)phenyl methyl ether; 4-(4-methoxyphenyl)-2,3-dimethyl[1]benzothieno[3,2-f][1]benzofuran C23H18O2S 详情 详情
(VIII) 48456 4-(2,3-dimethyl[1]benzothieno[3,2-f][1]benzofuran-4-yl)phenol C22H16O2S 详情 详情
(IX) 48457 4-(2,3-dimethyl[1]benzothieno[3,2-f][1]benzofuran-4-yl)-2,6-diiodophenol C22H14I2O2S 详情 详情
(X) 39252 methyl (2S)-2-hydroxy-3-phenylpropanoate C10H12O3 详情 详情
(XI) 48458 methyl (2R)-2-[4-(2,3-dimethyl[1]benzothieno[3,2-f][1]benzofuran-4-yl)-2,6-diiodophenoxy]-3-phenylpropanoate C32H24I2O4S 详情 详情

合成路线22

该中间体在本合成路线中的序号：(IV)

Ring opening of the chiral epoxide (I) with 2-aminoethanol gave the trans-aminoalcohol (II). Subsequent intramolecular cyclization of (II) under Mitsunobu conditions afforded the chromenooxazine tricyclic system (III). The NH group of (III) was then acylated with anisoyl chloride (IV), yielding amide (V). This compound underwent epimerization at the C-10b position upon treatment with NaH to produce the more stable cis-fused isomer (VI). The methyl ether group of (VI) was finally cleaved by treatment with boron tribromide to furnish the corresponding phenol.

参考文献 中间体
合成目标
【1】 Lin, Y.-C.; Tsai, M.-C.; Chiu, H.-I.; Yu, H.-C.; Cheng, C.-Y.; N-acyl-1,2,3,4a,5,10b-hexahydro-[1]benzopyrano-[3,4-b][1,4]oxazine-9-carbonitriles as bladder-selective potassium channel openers. Bioorg Med Chem 2001, 9, 2, 383.
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) 48196 (1aR,7bR)-2,2-dimethyl-1a,7b-dihydro-2H-oxireno[2,3-c]chromene-6-carbonitrile C12H11NO2 详情 详情
(II) 48192 (3R,4S)-3-hydroxy-4-[(2-hydroxyethyl)amino]-2,2-dimethyl-3,4-dihydro-2H-chromene-6-carbonitrile C14H18N2O3 详情 详情
(III) 48193 (4aR,10bS)-5,5-dimethyl-1,2,3,4a,5,10b-hexahydrochromeno[3,4-b][1,4]oxazine-9-carbonitrile C14H16N2O2 详情 详情
(IV) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(V) 48194 (4aR,10bS)-1-(4-methoxybenzoyl)-5,5-dimethyl-1,2,3,4a,5,10b-hexahydrochromeno[3,4-b][1,4]oxazine-9-carbonitrile C22H22N2O4 详情 详情
(VI) 48195 (4aR,10bR)-1-(4-methoxybenzoyl)-5,5-dimethyl-1,2,3,4a,5,10b-hexahydrochromeno[3,4-b][1,4]oxazine-9-carbonitrile C22H22N2O4 详情 详情
Extended Information