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【结 构 式】

【分子编号】15967

【品名】propanoyl chloride; propionyl chloride

【CA登记号】79-03-8

【 分 子 式 】C3H5ClO

【 分 子 量 】92.5248

【元素组成】C 38.94% H 5.45% Cl 38.32% O 17.29%
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：(III)

The reaction of 6-chloro-4-oxo-1,2,3,4-tetrahydroquinoline (I) with propionic anhydride (II) or propionyl chloride (III) in pyridine gives 6-chloro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (IV), which is then treated with hydroxylamine hydrochloride in refluxing pyridine.

参考文献 中间体
合成目标
【1】 Suzuki, Y.; Ohnishi, H.; Yamaguchi, K.; Mochida, E.; Kosuzume, H.; Hypotensive diuretic pharmaceutical compositions containing tetrahydroquinoline derivatives. DE 3129719; FR 2487196; GB 2081091 .
【2】 Susumi, J.; Shoichi, K.; Koichi, K.; 4-Oximino-1,2,3,4- tetrahydroquinoline Derivatives. DE 3129718; FR 2487346; GB 2092130 .
【3】 Suzuki, Y.; Yamaguchi, K.; Ohnishi, H.; Takada, K.; Toyonaka, Y.; Orita, Y.; Pharmacological properties of 6-chloro-1-ethylcarbonyl-4-oxyimino-1,2,3,4-tetrahydroquinoline. Drugs Exp Clin Res 1981, 7, 6, 823-832.
【4】 Hillier, K.; Castaner, J.; Serradell, M.N.; Blancafort, P.; M-12,285. Drugs Fut 1983, 8, 3, 204.
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) 35973 6-chloro-2,3-dihydro-4(1H)-quinolinone C9H8ClNO 详情 详情
(II) 20095 propionic anhydride 123-62-6 C6H10O3 详情 详情
(III) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(IV) 35974 6-chloro-1-propionyl-2,3-dihydro-4(1H)-quinolinone C12H12ClNO2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

The Friedel-Kraft's condensation of 4-tert-butylphenol (I) with propionyl chloride (II) by means of FeCl3 in methylene chloride gives 2-hydroxy-5-tert-butylpropiophenone (III), which is then condensed with chloroacetylaminomethanol (IV) by means of H2SO4 in acetic acid affording 3-(chloroacetylaminomethyl)-5-tert-butyl-2-hydroxypropiophenone (V). Finally, this compound is hydrolyzed with HCl in methanol.

参考文献 中间体
合成目标
【1】 Hashimoto, K.; ONO-3144. Drugs Fut 1985, 10, 10, 825.
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) 29734 4-(tert-butyl)phenol 98-54-4 C10H14O 详情 详情
(II) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(III) 29735 1-[5-(tert-butyl)-2-hydroxyphenyl]-1-propanone C13H18O2 详情 详情
(IV) 23020 2-chloro-N-(hydroxymethyl)acetamide 2832-19-1 C3H6ClNO2 详情 详情
(V) 29736 N-[5-(tert-butyl)-2-hydroxy-3-propionylbenzyl]-2-chloroacetamide C16H22ClNO3 详情 详情

合成路线3

该中间体在本合成路线中的序号：(III)

The reduction of 1-(1-piperdinyl)acetone oxime (I) with LiAlH4 in ethyl ether, THF or dioxan gives 1-methyl2-(1-piperidinyl)ethylaine (II), which is acylated with propionyl chloride (III) in ether to afford propionamide (IV). The condensation of (IV) with 2-bromopyridine (V) by heating with K2CO3 and Cu (dust) provides compound (VI). Alternatively, (VI) can be obtained by heating N-[1-methyl-2-(1-piperidinyl)ethyl]-N-(2-pyridyl)amine (VII) with propionic anhydride (VIII). Finally, heating derivative (VI) with fumaric acid in acetone/EtOH allows formation of the desired compound as the corresponding fumarate salt.

参考文献 中间体
合成目标
【1】 (Almirall Prodesfarma, SA); Process for the preparation of 2-aminopyridine derivs.. ES 434325 .
【2】 Hoffmeister, F.; Wirth, W.; Kroneberg, H.-G.; Hiltmann, R.; Wollweber, H. (Bayer AG); Pyridine derivs. and their preparation (-N-tertiaryl aminoalkyl-N-acyl)amino pyridines. DE 1232147; US 3163654 .
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) 47242 1-(1-piperidinyl)acetone oxime C8H16N2O 详情 详情
(II) 47243 1-methyl-2-(1-piperidinyl)ethylamine; 1-(1-piperidinyl)-2-propanamine C8H18N2 详情 详情
(III) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(IV) 47244 N-[1-methyl-2-(1-piperidinyl)ethyl]propanamide C11H22N2O 详情 详情
(V) 29052 2-Bromopyridine；α-bromopyridine;α-bromoazine 109-04-6 C5H4BrN 详情 详情
(VI) 47245 N-[1-methyl-2-(1-piperidinyl)ethyl]-N-(2-pyridinyl)propanamide C16H25N3O 详情 详情
(VII) 47246 N-[1-methyl-2-(1-piperidinyl)ethyl]-2-pyridinamine; N-[1-methyl-2-(1-piperidinyl)ethyl]-N-(2-pyridinyl)amine C13H21N3 详情 详情
(VIII) 20095 propionic anhydride 123-62-6 C6H10O3 详情 详情

合成路线4

该中间体在本合成路线中的序号：(XIII)

The reaction of 4-oxopiperidine-1-carboxylic acid ethyl ester (I) with CHCl3, benzyl triethylammonium chloride and NaOH in THF/water gives the spirooxirane (II), which is treated with aniline (III) and NaOH to yield the anilide (IV). The methylation of the amide nitrogen by means of NaH and CH3I in THF affords the methylated anilide (V). The reaction of (V) with KOH in refluxing isopropanol causes elimination of its ethoxycarbonyl group, providing compound (VI), which is reduced with lithium triethylborohydride in THF to give 4-(hydroxymethyl)-4-(phenylamino)piperidine (VII). The condensation of (VII) with tetrazolone derivative (VIII) by means of KI in refluxing acetonitrile (or propionitrile) yields the adduct (XI), which is methylated with NaH and CH3I in THF to afford the methoxy derivative (XII). Finally, this compound is acylated with propionyl chloride (XIII) in chloroform to provide the target compound. The intermediate tetrazolone derivative (VIII) has been obtained by reaction of 1-ethyl-4,5-dihydro-1H-tetrazol-5-one (IX) with 1,2-dibromoethane (X) by means of TEA in acetonitrile.

参考文献 中间体
合成目标
【1】 Killgore, J.K.; Jacob, M. (Mallinckrodt Medical Inc.); New methods for the syntheses of alfentanil, sufentanil and remifentanil. WO 0140184 .
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) 13486 Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone 29976-53-2 C8H13NO3 详情 详情
(II) 49678 ethyl 2,2-dichloro-1-oxa-6-azaspiro[2.5]octane-6-carboxylate C9H13Cl2NO3 详情 详情
(III) 12294 Aniline; Phenylamine 62-53-3 C6H7N 详情 详情
(IV) 49679 ethyl 4-anilino-4-(anilinocarbonyl)-1-piperidinecarboxylate C21H25N3O3 详情 详情
(V) 49680 ethyl 4-anilino-4-[(methylanilino)carbonyl]-1-piperidinecarboxylate C22H27N3O3 详情 详情
(VI) 49681 4-anilino-N-methyl-N-phenyl-4-piperidinecarboxamide C19H23N3O 详情 详情
(VII) 49682 (4-anilino-4-piperidinyl)methanol C12H18N2O 详情 详情
(VIII) 14721 1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one C5H9BrN4O 详情 详情
(IX) 32218 1-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one 69048-98-2 C3H6N4O 详情 详情
(X) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(XI) 49683 1-[2-[4-anilino-4-(hydroxymethyl)-1-piperidinyl]ethyl]-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one C17H26N6O2 详情 详情
(XII) 49684 1-[2-[4-anilino-4-(methoxymethyl)-1-piperidinyl]ethyl]-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one C18H28N6O2 详情 详情
(XIII) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情

合成路线5

该中间体在本合成路线中的序号：(XI)

The reaction of 4-oxopiperidine-1-carboxylic acid ethyl ester (I) with CHCl3, benzyl triethylammonium chloride and NaOH in THF/water gives the spirooxirane (II), which is treated with aniline (III) and NaOH to yield the anilide (IV). The methylation of the amide nitrogen by means of NaH and CH3I in THF affords the methylated anilide (V). The reaction of (V) with KOH in refluxing isopropanol causes elimination of its ethoxycarbonyl group, providing compound (VI), which is reduced with lithium triethylborohydride in THF to give 4-(hydroxymethyl)-4-(phenylamino)piperidine (VII). The condensation of (VII) with 2-(2-thienyl)ethyl mesylate (VIII) by means of K2CO3 in refluxing acetonitrile yields the adduct (XI), which is methylated with NaH and CH3I in THF to afford the methoxy derivative (X). Finally, this compound is acylated with propionyl chloride (XI) in chloroform to provide the target compound.

参考文献 中间体
合成目标
【1】 Killgore, J.K.; Jacob, M. (Mallinckrodt Medical Inc.); New methods for the syntheses of alfentanil, sufentanil and remifentanil. WO 0140184 .
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) 13486 Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone 29976-53-2 C8H13NO3 详情 详情
(II) 49678 ethyl 2,2-dichloro-1-oxa-6-azaspiro[2.5]octane-6-carboxylate C9H13Cl2NO3 详情 详情
(III) 12294 Aniline; Phenylamine 62-53-3 C6H7N 详情 详情
(IV) 49679 ethyl 4-anilino-4-(anilinocarbonyl)-1-piperidinecarboxylate C21H25N3O3 详情 详情
(V) 49680 ethyl 4-anilino-4-[(methylanilino)carbonyl]-1-piperidinecarboxylate C22H27N3O3 详情 详情
(VI) 49681 4-anilino-N-methyl-N-phenyl-4-piperidinecarboxamide C19H23N3O 详情 详情
(VII) 49682 (4-anilino-4-piperidinyl)methanol C12H18N2O 详情 详情
(VIII) 49685 2-(2-thienyl)ethyl methanesulfonate C7H10O3S2 详情 详情
(IX) 35257 [4-anilino-1-[2-(2-thienyl)ethyl]-4-piperidinyl]methanol C18H24N2OS 详情 详情
(X) 49686 1-[2-(5-ethyl-2-thienyl)ethyl]-4-(methoxymethyl)-N-phenyl-4-piperidinamine; N-[1-[2-(5-ethyl-2-thienyl)ethyl]-4-(methoxymethyl)-4-piperidinyl]-N-phenylamine C21H30N2OS 详情 详情
(XI) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情

合成路线6

该中间体在本合成路线中的序号：(B)

2) The reaction of 7-methoxy-1-tetralone (VII) with isopentyl nitrite and potassium tert-butoxide in ethanol - ether gives 7-methoxy-2-oxyimino-1-tetralone (VIII), which by reduction with H2 over Pd/C in THF and acylation with propanoyl chloride is converted to 7-methoxy-2-propionamido-1-tetralone (IX). The reduction of (IX) with NaBH4 in ethanol yields the alcohol (X), which by further reduction with LiAlH4 in THF affords trans-7-methoxy-2-(proylamino)-1,2,3,4-tetrahydronaphthalen-1-ol (XI). The cyclization of (XI) with chloroacetyl chloride by means of NaH in THF - acetonitrile gives trans-9-methoxy-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphth[1,2-b]-1,4-oxazin-3-one (XII), which is reduced with LiAlH4 in THF to compound (VI), already obtained.

参考文献 中间体
合成目标
【1】 Jones, J.H.; McClure, D.E.; Grenda, V.J. (Merck & Co., Inc.); Hexahydronaphth(1,2-b)-1,4-oxazines, process for their preparation and pharmaceutical formulation containing them. EP 0080115 .
【2】 Williams, M.; Jones, J.H.; Randall, W.C.; Clineschmidt, B.V.; Martin, G.E.; Lumma, P.K.; Hirshfield, J.M.; Anderson, P.S.; McClure, D.E.; Lundell, G.F.; Baldwin, J.J.; Smith, G.; Synthesis of 4-substituted 2H-naphth[1,2-b]-1,4-oxazines, a new class of dopamine agonists. J Med Chem 1984, 27, 12, 1607.
【3】 Prous, J.; Castaner, J.; NAXAGOLIDE HYDROCHLORIDE < Prop INNM; USAN >. Drugs Fut 1989, 14, 10, 951.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(A) 21382 1-nitropentane 1002-16-0 C5H11NO2 详情 详情
(VI) 21381 (4aR,10bR)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-yl methyl ether C16H23NO2 详情 详情
(VII) 21385 7-methoxy-3,4-dihydro-1(2H)-naphthalenone 6836-19-7 C11H12O2 详情 详情
(VIII) 21386 7-methoxy-3,4-dihydro-1,2-naphthalenedione 2-oxime C11H11NO3 详情 详情
(IX) 21387 N-(7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)propanamide C14H17NO3 详情 详情
(X) 21388 N-[(1R,2R)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]propanamide C14H19NO3 详情 详情
(XI) 21389 (1R,2R)-7-methoxy-2-(propylamino)-1,2,3,4-tetrahydro-1-naphthalenol C14H21NO2 详情 详情
(XII) 21390 (4aR,10bR)-9-methoxy-4-propyl-4a,5,6,10b-tetrahydro-2H-naphtho[1,2-b][1,4]oxazin-3(4H)-one C16H21NO3 详情 详情
(C) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情

合成路线7

该中间体在本合成路线中的序号：(III)

The oxidation of flumethasone (I) with Pd(OAc)2, PPh3 and IO4H in DMA gives the 17-beta-carboxylic acid (II), which is selectively monoacylated with propionyl chloride (III) and Et2NH in acetone, yielding the 17-alpha-propionyloxy derivative (IV). The reaction of (IV) with N,N-dimethylthiocarbamoyl chloride (V), TEA and NaI in 2-butanone affords the thioanhydride (VI), which is finally treated with chlorofluoromethane and SHNa in DMA to provide the desired fluoromethyl thioester.

参考文献 中间体
合成目标
【1】 Cooper, A.J.; Chamberlin, S.A.; Hufnagel, J.J.; Barkalow, J.; Hossain, A.; Langridge, D.C. (Abbott Laboratories Inc.); Method for the preparation of fluticasone and related 17betaETA-carbothioic esters using a novel carbothioic acid synthesis and novel purification methods. WO 0162722 .
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) 14475 (6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-17-glycoloyl-11,17-dihydroxy-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one 2557-49-5 C22H28F2O5 详情 详情
(II) 14476 (6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic acid C21H26F2O5 详情 详情
(III) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(IV) 14477 (6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic acid C24H30F2O6 详情 详情
(V) 54928 Dimethylthiocarbamoyl chloride; N,N-Dimethylthiocarbamoyl chloride 16420-13-6 C3H6ClNS 详情 详情
(VI) 54929 　 C27H35F2NO6S 详情 详情
(VII) 54930 Chlorofluoromethane; Monochloromonofluoromethane 593-70-4 CH2ClF 详情 详情

合成路线8

该中间体在本合成路线中的序号：(XXXII)

6) Mass labeled saprisartan has been obtained as follows: The Wittig condensation of cyclopropylcarbonyl chloride (XXVII) with ethoxycarbonylmethylene triphenylphosphorane (XXVIII) by means of bis(trimethylsilyl)acetamide in dichloromethane gives 3-cyclopropyl-3-oxo-2-(triphenylphosphoranylidene)propionic acid ethyl ester (XXIX), which is oxidized with potassium peroxymonosulfate to the dicarbonyl compound (XXX). The cyclization of (XXX) with [all-13C]-propionaldehyde (XXXI) (obtained by hydrogenation of the corresponding acyl chloride (XXXII) with H2 over Pd/C in THF containing 2,6-lutidine) and [15N]-ammonium acetate by means of triethylamine in THF yields 4-cyclopropyl-2-[1,2-13C]-ethyl-[1,3-15N,2-13C]imidazole-5-carboxylic acid ethyl ester (XXXIII). The condensation of (XXXIII) with the benzofuran (XXI) (already described in Scheme 2) by means of K2CO3 in dimethylacetamide affords 1-[3-bromo-2-(2-nitrophenyl)benzofuran-5-ylmethyl]-4-cyclopropyl-2-[1,2-13C]-ethyl-[1,3-15N,2-13C]imidazole-5-carboxylic acid ethyl ester (XXXIV), which is finally treated sequentially with Fe and acetic acid to reduce the nitro group, with trifluoromethanesulfonic anhydride to acylate the amino group, with NaOH to hydrolyze the ester group, and with carbonyldiimidazole and ammonia to generate the amide group, thus obtaining mass labeled saprisartan. This sequence has already been described in Scheme 19090802a for the unlabeled compound.

参考文献 中间体
合成目标
【1】 Carr, R.M.; Cable, K.M.; Newman, J.J.; Sutherland, D.R.; Synthesis of isotopically labelled angiotensin II antagonist GR138950X. J Label Compd Radiopharm 1996, 38, 5, 453.
【2】 Robinson, K.A.; Robinson, C.P.; Castaner, J.; Saprisartan. Drugs Fut 1996, 21, 11, 1129.
【3】 Ross, B.C.; Middlemiss, D.; Scopes, D.I.C.; Jack, T.I.M.; Cardwell, K.S.; Dowle, M.D.; Judd, D.B.; Watson, S.P. (Glaxo Wellcome plc); 1H-Imidazol-1-yl-methyl benzofuran derivs. with the imidazolyl moiety being substd. by a cycloalkyl group. EP 0514198; JP 1994211846; US 5498722; WO 9220674 .
【4】 Judd, D.B.; Dowle, M.D.; Middlemiss, D.; et al.; Bromobenzofuran-based non-peptide antagonists of angiotensin II: GR138950, a potent antihypertensive agent with high oral bioavailability. J Med Chem 1994, 37, 19, 3108-20.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXI) 15956 3-bromo-5-(bromomethyl)-2-(2-nitrophenyl)-1-benzofuran C15H9Br2NO3 详情 详情
(XXVII) 14061 Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride 4023-34-1 C4H5ClO 详情 详情
(XXVIII) 14182 ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane 1099-45-2 C22H21O2P 详情 详情
(XXIX) 15964 ethyl 3-cyclopropyl-3-oxo-2-(triphenyl-lambda(5)-phosphanylidene)propanoate C26H25O3P 详情 详情
(XXX) 15965 ethyl 3-cyclopropyl-2,3-dioxopropanoate C8H10O4 详情 详情
(XXXI) 15966 propionaldehyde 123-38-6 C3H6O 详情 详情
(XXXI) 45291 propionaldehyde C3H6O 详情 详情
(XXXII) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(XXXII) 45290 propanoyl chloride C3H5ClO 详情 详情
(XXXIII) 15944 ethyl 4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate C11H16N2O2 详情 详情
(XXXIII) 15968 ethyl 4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate C11H16N2O2 详情 详情
(XXXIV) 15957 ethyl 1-[[3-bromo-2-(2-nitrophenyl)-1-benzofuran-5-yl]methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate C26H24BrN3O5 详情 详情
(XXXIV) 15969 ethyl 1-[[3-bromo-2-(2-nitrophenyl)-1-benzofuran-5-yl]methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate C26H24BrN3O5 详情 详情

合成路线9

该中间体在本合成路线中的序号：(IV)

1) The cyclization of phloroglucinol (I) with butyrylacetic acid ethyl ester (II) by means of concentrated sulfuric acid gives 5,7-dihydroxy-4-propyl-2H-1-benzopyran-2-one (III), which is condensed with propionyl chloride by means of AlCl3 in nitrobenzene, yielding the 8-propionyl derivative (V). The cyclization of (V) with 3-hydroxy-3-methylbuytyraldehyde dimethylacetal (VI) in refluxing pyridine affords the benzodipyran (VII), which is cyclized again with paraldehyde or acetaldehyde dimethylacetal by means of p-toluenesulfonic acid and trifluoroacetic acid in pyridine at 140 C to give a mixture of the diastereomeric racemates (VIII) and (IX), which are separated by column chromatography. The reduction of racemate (VIII) with NaBH4 /CeCl3 in ethanol yields a new mixture of the racemic hydroxy epimers (X) (racemic calanolide A) and (XI), which are separated by semipreparative HPLC. Racemic calanolide A (X) is finally submitted to optical resolution by semipreparative chiral HPLC.

参考文献 中间体
合成目标
【1】 Flavin, M.T.; Sheinkman, A.K.; Boulanger, W.A.; Khilevich, A.; Shone, R.L.; Rizzo, J.D.; Xu, Z.-Q.; Kucherenko, A.; Novel approach for synthesis of (±)-calanolide A a. Tetrahedron Lett 1995, 36, 31, 5475.
【2】 Flavin, M.T.; Rizzo, J.D.; Khilevich, A.; et al.; Synthesis, chromatographic resolution, and anti-hu. J Med Chem 1996, 39, 6, 1303.
【3】 Castañer, J.; Leeson, P.; Sorbera, L.A.; Calanolide A. Drugs Fut 1999, 24, 3, 235.
【4】 Bokesch, H.R.; Cardellina, J.H. II; Boyd, M.R.; McKee, T.C.; Resolution and comparative anti-HIV evaluation of the enantiomers of calanolides A and B. Bioorg Med Chem Lett 1995, 5, 9, 1011.
【5】 Boyd, M.R.; Cardellina, J.H. II; Gustafson, K.R.; McMahon, J.B.; Fuller, R.W.; Cragg, G.M.; Kashman, Y. (US Department of Health & Human Services); Calanolide antiviral cpds., compsns. and uses ther. EP 0633887; JP 1996502948; JP 1996507311; US 5591770; WO 9320082; WO 9428000 .
【6】 Brankovic, D.; Flavin, M.T.; Vilaychack, V.; Liao, S.; Zembower, D.; Lin, L.; Dzekhster, S.; Rizzo, J.D.; Mar, A.; Xu, Z.-Q.; Khilevich, A.; Liu, J. (MediChem Research, Inc.); Method for the preparation of (+)-calanolide A and. WO 9838193 .
【7】 Cragg, G.M.; Buckheit, R.W. Jr.; Fuller, R.W.; Gustafson, K.R.; Boyd, M.R.; Currens, M.J.; Cardellina, J.H. II; McMahon, J.B.; Hughes, S.H.; Kashman, Y.; The calanolides, a novel HIV-inhibitory class of c. J Med Chem 1992, 35, 15, 2735.
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) 11799 1,3,5-Benzenetriol; Fluoroglucinol 108-73-6 C6H6O3 详情 详情
(II) 12516 ethyl 3-oxohexanoate; ethyl butyrylacetate 3249-68-1 C8H14O3 详情 详情
(III) 22405 5,7-dihydroxy-4-propyl-2H-chromen-2-one C12H12O4 详情 详情
(IV) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(V) 22407 5,7-dihydroxy-8-propionyl-4-propyl-2H-chromen-2-one C15H16O5 详情 详情
(VI) 22408 4,4-dimethoxy-2-methyl-2-butanol C7H16O3 详情 详情
(VII) 22409 5-hydroxy-2,2-dimethyl-6-propionyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one C20H22O5 详情 详情
(VIII) 22410 (10R,11R)-6,6,10,11-tetramethyl-4-propyl-10,11-dihydro-2H,6H,12H-dipyrano[2,3-f:2,3-h]chromene-2,12-dione C22H24O5 详情 详情
(IX) 22411 (10R,11S)-6,6,10,11-tetramethyl-4-propyl-10,11-dihydro-2H,6H,12H-dipyrano[2,3-f:2,3-h]chromene-2,12-dione C22H24O5 详情 详情
(X) 22412 (10R,11S,12S)-12-hydroxy-6,6,10,11-tetramethyl-4-propyl-11,12-dihydro-2H,6H,10H-dipyrano[2,3-f:2,3-h]chromen-2-one C22H26O5 详情 详情
(XI) 22413 (10R,11S,12R)-12-hydroxy-6,6,10,11-tetramethyl-4-propyl-11,12-dihydro-2H,6H,10H-dipyrano[2,3-f:2,3-h]chromen-2-one C22H26O5 详情 详情

合成路线10

该中间体在本合成路线中的序号：(XX)

The intermediate 3-cyclohexyl-2(R)-methylpropionyl chloride (XVIII) has been obtained as follows: The reaction of 4(S)-isopropyloxazolidin-2-one (XIX) with propionyl chloride (XX) by means of BuLi in THF gives 4(S)-isopropyl-3-propionyloxazolidin-2-one (XXI), which is condensed with benzyl bromide (XXII) by means of LHMDS in THF yielding 4(S)-isopropyl-3-(2(R)-methyl-3-phenylpropionyl)oxazolidin-2-one (XXIII). The oxidative cleavage of (XXIII) with H2O2 in THF/water affords 2(R)-methyl-3-phenylpropionic acid (XXIV), which is hydrogenated with H2 over alumina providing 3-cyclohexyl-2(R)-methylpropionic acid (XXV). Finally, this compound is treated with oxalyl chloride in DMF to afford the desired intermediate 3-cyclohexyl-2(R)-methylpropionyl chloride (XVIII).

参考文献 中间体
合成目标
【1】 Gauthier, J.-A.; Moss, N. (Bio-Mega, Inc.; Boehringer Ingelheim GmbH); Herpes ribonucleotide reductase inhibitors. EP 0837845; JP 1999508246; US 5672586; WO 9700855 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVIII) 27157 (2R)-3-cyclohexyl-2-methylpropanoyl chloride C10H17ClO 详情 详情
(XIX) 12867 (4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone 17016-83-0 C6H11NO2 详情 详情
(XX) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(XXI) 11535 (4S)-4-Isopropyl-3-propionyl-1,3-oxazolidin-2-one 77877-19-1 C9H15NO3 详情 详情
(XXII) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(XXIII) 27167 (4S)-4-isopropyl-3-[(2R)-2-methyl-3-phenylpropanoyl]-1,3-oxazolidin-2-one C16H21NO3 详情 详情
(XXIV) 27168 (2R)-2-methyl-3-phenylpropionic acid C10H12O2 详情 详情
(XXV) 27169 (2R)-3-cyclohexyl-2-methylpropionic acid C10H18O2 详情 详情

合成路线11

该中间体在本合成路线中的序号：(V)

Chiral oxazolidinone intermediate (VI): The oxidation of the terminal double bond of the chiral acyl oxazolidinone (I) with O2 catalyzed by CuCl and PdCl2 in DMF/water gives the ketone (II), which is ketalized with propane-1,3-dithiol (III) and Ts-OH in AcOH to yield the thioketal (IV). Finally, the stereocontrolled acylation of (IV) with propionyl chloride (V) by means of LDA in THF affords the target oxazolidinone intermediate (VI)

参考文献 中间体
合成目标
【1】 Duan, M.S.; Paquette, L.A.; Highly diastereocontrolled synthesis of the C1-C25 domain of sanglifehrin A. Tetrahedron Lett 2000, 41, 20, 3789.
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) 60101 (4S)-4-benzyl-3-(5-hexenoyl)-1,3-oxazolidin-2-one C16H19NO3 详情 详情
(II) 60102 1-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-1,5-hexanedione C16H19NO4 详情 详情
(III) 29729 1,3-propanedithiol; 3-sulfanylpropylhydrosulfide 109-80-8 C3H8S2 详情 详情
(IV) 60103 (4S)-4-benzyl-3-[4-(2-methyl-1,3-dithian-2-yl)butanoyl]-1,3-oxazolidin-2-one C19H25NO3S2 详情 详情
(V) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(VI) 60104 (2R)-1-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-[2-(2-methyl-1,3-dithian-2-yl)ethyl]-1,3-pentanedione C22H29NO4S2 详情 详情

合成路线12

该中间体在本合成路线中的序号：(XVI)

The reaction of 2,3-dihydrobenzofuran (I) with dichloromethyl methyl ether (II) by means of TiCl4 in dichloromethane gives 2,3-dihydrobenzofuran-5-carbaldehyde (III), which is condensed with the phosphonate (IV) by means of NaH in THF to yield the propenoic ester (V). The reduction of (V) with H2 over Pd/C in ethanol affords the saturated propionic ester (VI), which is brominated with Br2 in HOAc providing the 7-bromo derivative (VII). Further bromination of (VII) with Br2 and Fe in HOAc gives the 6,7-dibromo derivative (VIII), which is hydrolyzed with NaOH in THF/water to yield the propionic acid derivative (IX). The reaction of (IX) with hot SOCl2 affords the corresponding acyl chloride (X), which is cyclized by means of AlCl3 in dichloroethane to provide 4,5-dibromo-2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-one (XI). The debromination of (XI) by means of H2 over Pd/C in Ac-OH gives 2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-one (XII), which is condensed with the phosphorane (XIII) by means of NaH in THF to yield 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ylidene)acetonitrile (XIV). The selective reduction of the cyano group of (XIV) by means of H2 over Raney cobalt in ethanol/NH3 affords 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ylidene)ethylamine (XV), which is condensed with propionyl chloride (XVI) by means of TEA in THF to provide the propionamide (XVII). Finally this compound is enantioselectively reduced with H2 over a chiral Ru catalyst (Ru(OAc)2-(S)-BINAP) in methanol to give rise to the target (S)-enantiomer. Alternatively, the reduction of 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ylidene)acetonitrile (XIV) with H2 over RaNi in ethanol/NH3 gives 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-yl)ethylamine (XVIII), which is acylated with propionyl chloride (XVI) and TEA in DMF to yield the racemic propionamide (XIX). Finally this compound is submitted to optical resolution by means of chiral HPLC to afford the target (S)-enantiomer.

参考文献 中间体
合成目标
【1】 Chilman-Blair, K.; Castaner, J.; Silvestre, J.S.; Bayes, M.; TAK-375. Drugs Fut 2003, 28, 10, 950.
【2】 Ohkawa, S.; Uchikawa, O.; Fukatsu, K.; Miyamoto, M. (Takeda Chemical Industries, Ltd.); Tricyclic cpds., their production and use. EP 0885210; JP 1998287665; JP 1999152281; WO 9732871 .
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) 14499 2,3-Dihydrobenzofuran; 2,3-dihydro-1-benzofuran 496-16-2 C8H8O 详情 详情
(II) 40668 dichloro(methoxy)methane; dichloromethyl methyl ether 4885-02-3 C2H4Cl2O 详情 详情
(III) 52198 2,3-Dihydrobenzo[b]furan-5-carboxaldehyde C9H8O2 详情 详情
(IV) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(V) 57393 ethyl (E)-3-(2,3-dihydro-1-benzofuran-5-yl)-2-propenoate C13H14O3 详情 详情
(VI) 57394 ethyl 3-(2,3-dihydro-1-benzofuran-5-yl)propanoate C13H16O3 详情 详情
(VII) 57395 ethyl 3-(7-bromo-2,3-dihydro-1-benzofuran-5-yl)propanoate C13H15BrO3 详情 详情
(VIII) 57396 ethyl 3-(6,7-dibromo-2,3-dihydro-1-benzofuran-5-yl)propanoate C13H14Br2O3 详情 详情
(IX) 57397 3-(6,7-dibromo-2,3-dihydro-1-benzofuran-5-yl)propanoic acid C11H10Br2O3 详情 详情
(X) 57398 3-(6,7-dibromo-2,3-dihydro-1-benzofuran-5-yl)propanoyl chloride C11H9Br2ClO2 详情 详情
(XI) 57399 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one C11H8Br2O2 详情 详情
(XII) 57400 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one C11H10O2 详情 详情
(XIII) 10045 Diethyl cyanomethylphosphonate 2537-48-6 C6H12NO3P 详情 详情
(XIV) 57401 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetonitrile C13H11NO 详情 详情
(XV) 57402 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)-1-ethanamine; 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)ethylamine C13H15NO 详情 详情
(XVI) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(XVII) 57403 N-[2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)ethyl]propanamide C16H19NO2 详情 详情
(XVIII) 57404 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)-1-ethanamine; 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine C13H17NO 详情 详情
(XIX) 57405 N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propanamide C16H21NO2 详情 详情

合成路线13

该中间体在本合成路线中的序号：(XVI)

The reaction of 2,3-dihydrobenzofuran (I) with DMF (II) and POCl3 gives 2,3-dihydrobenzofuran-5-carbaldehyde (III), which is condensed with the phosphonate (IV) by means of t-BuONa in toluene to yield the acrylate (V). The reduction of (V) with H2 over Pd/C in AcOH affords the corresponding propionate (VI), which is brominated with Br2 in AcOH to provide the dibromo derivative (VII). The hydrolysis of the ester group of (VII) in acidic medium gives the expected propionic acid derivative (VIII), which is treated with SOCl2 in dichloromethane to yield the propionyl chloride (IX). The cyclization of (IX) by means of AlCl3 in dichloromethane affords the 4,5-dibromo-2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-one (X), which is submitted to an hydrogenolytic debromination with H2 over Pd/C in methanol to provide the 2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-one (XI). The Wittig condensation of (XI) with phosphonate (XII) by means of NaOMe in toluene gives 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ylidene)acetonitrile (XIII), which is reduced with H2 and Raney-Co in toluene/MeOH to yield 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ylidene)ethylamine (XIV). The asymmetric reduction of (XIV) with H2 and a chiral Ru catalyst in toluene/MeOH affords the 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8(S)-yl)ethylamine (XV), which is finally acylated with propionyl chloride (XVI) and NaOH in aq. THF to provide the target chiral propionamide.

参考文献 中间体
合成目标
【1】 Ohkawa, S.; Discovery of the novel melatonin agonist TAK-375. 22nd Symp Med Chem (Nov 27 2002, Shizuoka) 2002, Abst IL 11.
【2】 Chilman-Blair, K.; Castaner, J.; Silvestre, J.S.; Bayes, M.; TAK-375. Drugs Fut 2003, 28, 10, 950.
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) 14499 2,3-Dihydrobenzofuran; 2,3-dihydro-1-benzofuran 496-16-2 C8H8O 详情 详情
(II) 45439 dimethylformamide C3H7NO 详情 详情
(III) 52198 2,3-Dihydrobenzo[b]furan-5-carboxaldehyde C9H8O2 详情 详情
(IV) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(V) 57393 ethyl (E)-3-(2,3-dihydro-1-benzofuran-5-yl)-2-propenoate C13H14O3 详情 详情
(VI) 57394 ethyl 3-(2,3-dihydro-1-benzofuran-5-yl)propanoate C13H16O3 详情 详情
(VII) 57396 ethyl 3-(6,7-dibromo-2,3-dihydro-1-benzofuran-5-yl)propanoate C13H14Br2O3 详情 详情
(VIII) 57397 3-(6,7-dibromo-2,3-dihydro-1-benzofuran-5-yl)propanoic acid C11H10Br2O3 详情 详情
(IX) 57398 3-(6,7-dibromo-2,3-dihydro-1-benzofuran-5-yl)propanoyl chloride C11H9Br2ClO2 详情 详情
(X) 57399 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one C11H8Br2O2 详情 详情
(XI) 57400 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one C11H10O2 详情 详情
(XII) 10045 Diethyl cyanomethylphosphonate 2537-48-6 C6H12NO3P 详情 详情
(XIII) 57401 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetonitrile C13H11NO 详情 详情
(XIV) 57402 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)-1-ethanamine; 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)ethylamine C13H15NO 详情 详情
(XV) 62217 2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]-1-ethanamine; 2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethylamine C13H17NO 详情 详情
(XVI) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情

合成路线14

该中间体在本合成路线中的序号：(V)

The condensation of 6-methoxyindan-1-one (I) with phosphonate (II) by means of NaH in THF gives 2-(6-methoxyindan-1-ylidene)acetonitrile (III), which is hydrogenated with h2 over Raney Co in ethanol/NH3 to yield 2-(6-methoxyindan-1-ylidene)ethylamine (IV). The acylation of (IV) with propionyl chloride (V) and TEA in THF affords the corresponding amide (VI), which is submitted to an asymmetric reduction with H2 and a chiral Ru catalyst to provide N-[2-(6-methoxyindan-1(S)-yl)ethyl]propionamide (VII). The bromination of (VII) with Br2 and NaOAc in methanol gives the 5-bromo derivative (VIII), which is demethylated by means of BBr3 in dichloromethane to yield the hydroxy compound (IX). The reaction of (IX) with allyl bromide (X) by means of NaH in DMF affords the allyl ether (XI), which is submitted to a Claisen rearrangement in N,N-diethylaniline at 200 C to provide the 7-allyl derivative (XII).The reaction of (XII) with ozone in methanol gives the acetaldehyde derivative (XIII), which is reduced with NaBH4 in methanol to yield the ethanol derivative (XIV). The hydrogenolysis of the Br substituent of (XIV) by means of H2 over Pd/C in methanol/TEA affords the dihydroxy compound (XV), which is treated with MsCl and pyridine to provide the mesylate (XVI). Finally, this compound is cyclized by means of TEA in refluxing ethyl acetate to furnish the target indeno[5,4-b]furan derivative.

参考文献 中间体
合成目标
【1】 Chilman-Blair, K.; Castaner, J.; Silvestre, J.S.; Bayes, M.; TAK-375. Drugs Fut 2003, 28, 10, 950.
【2】 Uchikawa, O.; Fukatsu, K.; Tokunoh, R.; et al.; Synthesis of a novel series of tricyclic indan derivatives as melatonin receptor agonists. J Med Chem 2002, 45, 19, 4222.
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) 34515 6-methoxy-1-phenyl-1-indanol C16H16O2 详情 详情
(II) 10045 Diethyl cyanomethylphosphonate 2537-48-6 C6H12NO3P 详情 详情
(III) 62218 2-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)acetonitrile C12H11NO 详情 详情
(IV) 62219 2-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)ethylamine; 2-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)-1-ethanamine C12H15NO 详情 详情
(V) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(VI) 62220 N-[2-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)ethyl]propanamide C15H19NO2 详情 详情
(VII) 62221 N-{2-[(1S)-6-methoxy-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide C15H21NO2 详情 详情
(VIII) 62222 N-{2-[(1S)-5-bromo-6-methoxy-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide C15H20BrNO2 详情 详情
(IX) 62223 N-{2-[(1S)-5-bromo-6-hydroxy-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide C14H18BrNO2 详情 详情
(X) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XI) 62224 N-{2-[(1S)-6-(allyloxy)-5-bromo-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide C17H22BrNO2 详情 详情
(XII) 62225 N-{2-[(1S)-7-allyl-5-bromo-6-hydroxy-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide C17H22BrNO2 详情 详情
(XIII) 62226 N-{2-[(1S)-5-bromo-6-hydroxy-7-(2-oxoethyl)-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide C16H20BrNO3 详情 详情
(XIV) 62227 N-{2-[(1S)-5-bromo-6-hydroxy-7-(2-hydroxyethyl)-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide C16H22BrNO3 详情 详情
(XV) 62228 N-{2-[(1S)-6-hydroxy-7-(2-hydroxyethyl)-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide C16H23NO3 详情 详情
(XVI) 62229 2-{(3S)-5-hydroxy-3-[2-(propionylamino)ethyl]-2,3-dihydro-1H-inden-4-yl}ethyl methanesulfonate C17H25NO5S 详情 详情

合成路线15

该中间体在本合成路线中的序号：(II)

Acylation of Meldrum's acid (I) with propionyl chloride (II) in the presence of pyridine gave propionyl derivative (III). Subsequent ring opening of (III) with ethanethiol (IV), followed by decarboxylation provided S-ethyl 3-oxothiovalerate (V). Propyl 3-amino-3-phenyl-2-propenoate (VII) was prepared by reaction of benzoylacetate (VI) with ammonium acetate in refluxing ethanol. Then, Hantzsch condensation of ketothioester (V), beta-enaminoester (VII), and butyraldehyde (VIII) in EtOH at 80 C in a sealed tube furnished the dihydropyridine (IX). Finally, oxidation of (IX) using chloranil (X) in boiling THF gave the target pyridine.

参考文献 中间体
合成目标
【1】 Li, A.-H.; Moro, S.; Melman, N.; Ji, X.D.; Jacobson, K.A.; Structure-activity relationships and molecular mod. J Med Chem 1998, 41, 17, 3186.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 21391 D-aspartic acid; (2R)-2-aminobutanedioic acid 1783-96-6 C4H7NO4 详情 详情
(I) 14738 Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester 2033-24-1 C6H8O4 详情 详情
(II) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(III) 23689 2,2-dimethyl-5-propionyl-1,3-dioxane-4,6-dione C9H12O5 详情 详情
(IV) 23712 1-ethanethiol; ethylhydrosulfide 75-08-1 C2H6S 详情 详情
(V) 23696 S-ethyl 3-oxopentanethioate C7H12O2S 详情 详情
(VI) 23692 propyl 3-oxo-3-phenylpropanoate C12H14O3 详情 详情
(VII) 23693 propyl (E)-3-amino-3-phenyl-2-propenoate C12H15NO2 详情 详情
(VIII) 23694 butyraldehyde 123-72-8 C4H8O 详情 详情
(IX) 23695 propyl 6-ethyl-5-[(ethylsulfanyl)carbonyl]-2-phenyl-4-propyl-1,4-dihydro-3-pyridinecarboxylate C23H31NO3S 详情 详情

合成路线16

该中间体在本合成路线中的序号：(II)

Acylation of Meldrum's acid (I) with propionyl chloride (II) in the presence of pyridine gave propionyl derivative (III). Subsequent ring opening of (III) with ethanethiol (IV), followed by decarboxylation provided S-ethyl 3-oxothiovalerate (V). Ethyl 3-amino-3-phenyl-2-propenoate (VII) was prepared by reaction of benzoylacetate (VI) with ammonium acetate in refluxing ethanol. Then, Hantzsch condensation of ketothioester (V), beta-enaminoester (VII), and propionaldehyde (VIII) in EtOH at 80 C in a sealed tube furnished the dihydropyridine (IX). Finally, oxidation of (IX) using chloranil (X) in boiling THF gave the target pyridine.

参考文献 中间体
合成目标
【1】 Li, A.-H.; Moro, S.; Melman, N.; Ji, X.D.; Jacobson, K.A.; Structure-activity relationships and molecular mod. J Med Chem 1998, 41, 17, 3186.
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) 14738 Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester 2033-24-1 C6H8O4 详情 详情
(II) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(III) 23689 2,2-dimethyl-5-propionyl-1,3-dioxane-4,6-dione C9H12O5 详情 详情
(IV) 23712 1-ethanethiol; ethylhydrosulfide 75-08-1 C2H6S 详情 详情
(V) 23696 S-ethyl 3-oxopentanethioate C7H12O2S 详情 详情
(VI) 23692 propyl 3-oxo-3-phenylpropanoate C12H14O3 详情 详情
(VII) 23693 propyl (E)-3-amino-3-phenyl-2-propenoate C12H15NO2 详情 详情
(VIII) 15966 propionaldehyde 123-38-6 C3H6O 详情 详情
(IX) 23699 ethyl 4,6-diethyl-5-[(ethylsulfanyl)carbonyl]-2-phenyl-1,4-dihydro-3-pyridinecarboxylate C21H27NO3S 详情 详情
(X) 21891 2,3,5,6-Tetrachloro-1,4-benzoquinone; 2,3,5,6-Tetrachlorobenzo-1,4-quinone; p-Chloranil 118-75-2 C6Cl4O2 详情 详情

合成路线17

该中间体在本合成路线中的序号：(II)

Acylation of Meldrum's acid (I) with propionyl chloride (II) in the presence of pyridine gave propionyl derivative (III). Subsequent ring opening of (III) with propanethiol (IV), followed by decarboxylation provided S-propyl 3-oxothiovalerate (V). Propyl 3-amino-3-(m-chlorophenyl)-2-propenoate (VII) was prepared by reaction of (3-chlorobenzoyl)acetate (VI) with ammonium acetate in refluxing ethanol. Then, Hantzsch condensation of ketothioester (V), beta-enaminoester (VII), and propionaldehyde (VIII) in EtOH at 80 C in a sealed tube furnished the dihydropyridine (IX). Finally, oxidation of (IX) using chloranil (X) in boiling THF gave the target pyridine.

参考文献 中间体
合成目标
【1】 Li, A.-H.; Moro, S.; Melman, N.; Ji, X.D.; Jacobson, K.A.; Structure-activity relationships and molecular mod. J Med Chem 1998, 41, 17, 3186.
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) 14738 Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester 2033-24-1 C6H8O4 详情 详情
(II) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(III) 23689 2,2-dimethyl-5-propionyl-1,3-dioxane-4,6-dione C9H12O5 详情 详情
(IV) 23703 propylhydrosulfide; 1-propanethiol 107-03-9 C3H8S 详情 详情
(V) 23704 S-propyl 3-oxopentanethioate C8H14O2S 详情 详情
(VI) 23705 propyl 3-(3-chlorophenyl)-3-oxopropanoate C12H13ClO3 详情 详情
(VII) 23706 propyl (E)-3-amino-3-(3-chlorophenyl)-2-propenoate C12H14ClNO2 详情 详情
(VIII) 15966 propionaldehyde 123-38-6 C3H6O 详情 详情
(IX) 23708 propyl 2-(3-chlorophenyl)-4,6-diethyl-5-[(propylsulfanyl)carbonyl]-1,4-dihydro-3-pyridinecarboxylate C23H30ClNO3S 详情 详情
(X) 21891 2,3,5,6-Tetrachloro-1,4-benzoquinone; 2,3,5,6-Tetrachlorobenzo-1,4-quinone; p-Chloranil 118-75-2 C6Cl4O2 详情 详情

合成路线18

该中间体在本合成路线中的序号：(II)

The acylation of 5-methoxy-1,2,3,4-tetrahydronaphthalene-2-(R)-amine (I) with propionyl chloride (II) and NaOH in dichloromethane/water gives the corresponding amide (III), which is reduced with LiAlH4 in refluxing THF yielding the corresponding secondary amine (IV). The alkylation of (IV) with bromoacetonitrile (V) by means of K2CO3 in refluxing acetone affords the expected tertiary amine (VI), which is reduced with LiAlH4 in refluxing THF providing the ethylenediamine (VII). Finally, this compound is benzoylated with benzoyl chloride and NaOH in dichloromethane/water.

参考文献 中间体
合成目标
【1】 Homan, E.J.; Grol, C.J.; Unelius, L.; Wilkstrom, H.V.; Copinga, S.; Jackson, D.M.; Synthesis and pharmacology of the enantiomers of the potential atypical antipsychotic agents 5-OMe-BPAT and 5-OMe-(2,6-di-OMe)-BPAT. Bioorg Med Chem 1999, 7, 7, 1263.
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) 31886 (2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenamine; (2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenylamine C11H15NO 详情 详情
(II) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(III) 31882 N-[(2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]propanamide; N-[(2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]propanamide C14H19NO2 详情 详情
(IV) 14649 (2S)-5-methoxy-N-propyl-1,2,3,4-tetrahydro-2-naphthalenamine; N-[(2S)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-N-propylamine C14H21NO 详情 详情
(V) 31883 2-bromoacetonitrile 590-17-0 C2H2BrN 详情 详情
(VI) 31884 2-[[(2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl](propyl)amino]acetonitrile C16H22N2O 详情 详情
(VII) 31885 N(1)-[(2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-N(1)-propyl-1,2-ethanediamine; N-(2-aminoethyl)-N-[(2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-N-propylamine C16H26N2O 详情 详情
(VIII) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情

合成路线19

该中间体在本合成路线中的序号：(IV)

The cyclization of floroglucinol (I) with ethyl 2-oxohexanoate (II) in acidic medium gives 5,7-dihydroxy-4-propyl-2H-1-benzopyran-2-one (III), which is submitted to a Friedel Crafts condensation with propionyl chloride (IV) / AlCl3 to yield the 8-propionyl derivative (V). Finally, the cyclization of (V) with 3-hydroxy-3-methylbutyraldehyde dimethyl acetal (VI) in refluxing pyridine affords the target compound.

参考文献 中间体
合成目标
【1】 Sudbeck, E.A.; Uckun, F.M. (Parker Hughes Institute); Calanolides for inhibiting BTK. WO 0056737 .
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) 11799 1,3,5-Benzenetriol; Fluoroglucinol 108-73-6 C6H6O3 详情 详情
(II) 12516 ethyl 3-oxohexanoate; ethyl butyrylacetate 3249-68-1 C8H14O3 详情 详情
(III) 22405 5,7-dihydroxy-4-propyl-2H-chromen-2-one C12H12O4 详情 详情
(IV) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(V) 22407 5,7-dihydroxy-8-propionyl-4-propyl-2H-chromen-2-one C15H16O5 详情 详情
(VI) 22408 4,4-dimethoxy-2-methyl-2-butanol C7H16O3 详情 详情

合成路线20

该中间体在本合成路线中的序号：

Alkylation of (7-methoxy-1-naphthyl)acetonitrile (I) with iodomethane in the presence of NaH gave the corresponding naphthylpropionitrile (II), which was reduced to amine (III) by catalytic hydrogenation over Raney-Ni. Finally, condensation of (III) with butyryl chloride in the presence of triethylamine provided the title butyramide.

参考文献 中间体
合成目标
【1】 Andrieux, J.; Jellimann, C.; Langlois, M.; Mathé-Allainmat, M.; le Gall, M.; Synthesis of beta-substituted naphth-1-yl ethylamido derivatives as new melatoninergic agonists. Bioorg Med Chem 1999, 7, 12, 2945.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(I) 36604 2-(7-methoxy-1-naphthyl)acetonitrile C13H11NO 详情 详情
(II) 36605 2-(7-methoxy-1-naphthyl)propanenitrile C14H13NO 详情 详情
(III) 36606 2-(7-methoxy-1-naphthyl)-1-propanamine; 2-(7-methoxy-1-naphthyl)propylamine C14H17NO 详情 详情

合成路线21

该中间体在本合成路线中的序号：(II)

The Friedel-Crafts' condensation of propionyl chloride (I) with 2,3-dihydrobenzo[b]thiophene (II) in dichloroethylene gives 5-propionyl-2,3-dihydrobenzo[b]thiophene (III), which is brominated with Br2 in THF yielding 5-(2-bromopropionyl)-2,3-dihydrobenzo[b]thiophene (IV). Finally this compound is condensed with 4-phenylbutylamine (V) in refluxing methanol and reduced with NaBH4 in the solvent

参考文献 中间体
合成目标
【1】 Serradell, M.N.; Castaner, J.; Thorpe, P.J.; Tibalosin. Drugs Fut 1984, 9, 12, 909.
【2】 Lambellin, G.; Roba, J.; Gillet, C.; Roncocci, R. (Continental Pharma); BE 848496; FR 2370470; FR 2370472; GB 1565080; JP 7797952 .
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) 61080 2,3-dihydro-1-benzothiophene C8H8S 详情 详情
(II) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(III) 61081 1-(2,3-dihydro-1-benzothiophen-6-yl)-1-propanone C11H12OS 详情 详情
(IV) 61082 2-bromo-1-(2,3-dihydro-1-benzothiophen-6-yl)-1-propanone C11H11BrOS 详情 详情
(V) 37811 4-phenyl-1-butanamine; 4-phenylbutylamine 13214-66-9 C10H15N 详情 详情

合成路线22

该中间体在本合成路线中的序号：(II)

Preparation of the 15-methylerythromycin A precursor (XI) is accomplished by a chemobiosynthetic approach, utilizing the diketide surrogate (IX). Synthesis of (IX) is carried out as follows. Acylation of (S)-4-benzyl-2-oxazolidinone (I) with propionyl chloride (II) affords the N-propionyl oxazolidinone (III). Diastereoselective aldol condensation of (III) with butyraldehyde (IV) employing dibutylboron triflate leads to adduct (V). Deacetylation of cysteamine hydrochloride (VI) with Ac2O provides (VII). Then, selective hydrolysis of the thioester function of (VII) under alkaline conditions provides thiol (VIII). Condensation of the acyl oxazolidinone (V) with thiol (VIII) in the presence of AlMe3 gives rise to the thioester substrate (IX) (1). Incubation of a recombinant Streptomyces coelicolor strain with the diketide surrogate (IX) leads to the production of 6-deoxy-15-methylerythronolide B (X). Subsequent bioconversion of the aglycone (X) in a Saccharopolyspora erythraea strain affords the desired 15-methylerythromycin A (XI).

参考文献 中间体
合成目标
【1】 Macielag, M.; Abbanat, D.; Ashley, G.; Foleno, B.; Fu, H.; Li, Y.; Wira, E.; Bush, K.; Structure-activity studies of 15-methyl ketolides: Optimization of the heterocyclic substituent. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1662.
【2】 Hlasta, D.; Khosla, C.; Chu, D.T.W.; Ashley, G.; Henninger, T.C.; Grant, E.B. (Ortho-McNeil Pharmaceutical, Inc.); Ketolide antibacterials. WO 0232918 .
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) 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
(II) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(III) 25713 (4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one C13H15NO3 详情 详情
(IV) 23694 butyraldehyde 123-72-8 C4H8O 详情 详情
(V) 62287 (4S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2-methylhexanoyl]-1,3-oxazolidin-2-one C17H23NO4 详情 详情
(VI) 13186 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine 60-23-1 C2H7NS 详情 详情
(VII) 62288 Ethanethioic acid, S-[2-(acetylamino)ethyl] ester; N,S-DIACETYLCYSTEAMINE; (TM)S-(2-(ACETYLAMINO)ETHYL) ETHANETHIOATE}; N,S-DIACETYL-BETA-MERCAPTOETHYLAMINE; N,s-Diacetylcysteamine; N-2-Mercaptoethylacetamide-acetate; {S-[2-(ACETYLAMINO)ETHYL] ETHANETHIOATE}; N,S-DIACETYLCYSTEAMINE*; N,S-Diacetyl-.beta.-mercaptoethylamine 1420-88-8 C6H11NO2S 详情 详情
(VIII) 20034 N-(2-sulfanylethyl)acetamide 1190-73-4 C4H9NOS 详情 详情
(IX) 62289 S-[2-(acetylamino)ethyl] (2S,3R)-3-hydroxy-2-methylhexanethioate C11H21NO3S 详情 详情
(X) 62290 (3R,4S,5R,6S,7S,9R,11R,12S,13R,14R)-4,6,12-trihydroxy-3,5,7,9,11,13-hexamethyl-14-propyl-2,10-oxacyclotetradecanedione C22H40O6 详情 详情
(XI) 62291 (3R,4S,5R,6R,7S,9R,11R,12R,13S,14R)-6-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-7,12,13-trihydroxy-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-14-pr C38H69NO13 详情 详情
Extended Information