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【结 构 式】

【分子编号】11229

【品名】1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate

【CA登记号】541-41-3

【 分 子 式 】C3H5ClO2

【 分 子 量 】108.5242

【元素组成】C 33.2% H 4.64% Cl 32.67% O 29.49%
与该中间体有关的原料药合成路线共 42 条
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合成路线1

该中间体在本合成路线中的序号：(XVII)

Key intermediate (XII) is prepared by chlorosulfonation of 2-chlorothiophene (XIV) with ClSO3H and PCl5 to give 5-chlorothien-2-ylsulfonyl chloride (XV), which by treatment with NH4OH in H2O/THF yields sulfonamide derivative (XVI). Finally, sulfonamide (XVI) is condensed with ethyl chloroformate (XVII) by means of Cs2CO3 in THF .

参考文献 中间体
合成目标
【1】 Scarborough, R.M., Pandey, A., Yiannikouros, G.P., Cruskie, M., White, D.C., Mehrotra, M. (Portola Pharmaceuticals, Inc.). Substituted-(quinazolinyl)phenyl thiophenyl-sulfonylureas, methods for making and intermediates thereof. US 2007208045, WO 2007056167.
【2】 Huang, W., Mehrotra, M., Zhang, X., Cannon, H., Grant, C.M. (Portola Pharmaceuticals, Inc.). [4-(6-Halo-7-substituted-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureas and forms and methods related thereto. EP 1951254, JP 2009515836, US 2007123547, WO 200705619.
【3】 Sharp, E., Quegan, L.J., Pandey, A., Wang, J., Nieder, M., Huang, W. (Portola Pharmaceuticals, Inc.). [4-(6-Fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea salts, in different crystalline forms, pharmaceutical compositions thereof. EP 2076510, JP 2010526105, WO 2008137809.
【4】 Sharp, E., Quegan, L.J., Pandey, A., Wang, J., Nieder, M., Huang, W. (Portola Pharmaceuticals, Inc.). [4-(6-Fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea salts, forms and methods related thereto. US 2009156620, WO 2010054020.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 69097 ethyl N-(5-chlorothien-2-ylsulfonyl)carbamate;[(5-Chlorothien-2-yl)sulfonyl]carbamic acid ethyl ester;Ethyl[(5-chlorothiophen-2-yl)sulfonyl]carbamate;N-[(5-chloro-2-thienyl)sulfonyl]- 849793-87-9 C7H8ClNO4S2 详情 详情
(XIV) 69098 2-chlorothiophene;2-Thienyl chloride 96-43-5 C4H3ClS 详情 详情
(XV) 61418 5-Chlorothiophene-2-sulfonyl chloride; 5-Chlorothiophene-2-sulfonyl chloride; 5-Chlorothiophene-2-sulphonyl chloride; 5-Chlorothiophene-2-sulphonyl chloride (Light & heat sensitive); 5-Chlorothiophene-2-sulphonylchloride; 5-Chlorothiophenesulphonyl chloride; 2,3-Dimethylthiophene 2766-74-7 C4H2Cl2O2S2 详情 详情
(XVI) 69099 5-chlorothiophene-2-sulfonamide 　 C4H4ClNO2S2 详情 详情
(XVII) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(B)

The condensation of (VIII) with 3-(p-fluorobenzoyl)propionic acid (A) by means of ethyl chloroformate (B) and triethylamine in CHCl3 gives the corresponding N,O-diacyl derivative (X), which is then reduced with LiAlH4 in refluxing THF yielding 5,9-dimethyl-2-[4''-(p-fluorophenyl)4''-hydroxy-1''-butyl]-2'-hydroxy-5,9-dimethyl-6,7-benzomorphane (XI). Finally, this compound is oxidized with Jones reagent (H2CrO4 in H2SO4).

参考文献 中间体
合成目标
【1】 Atsumi, T.; et al. (Sumitomo Chemical Co., Ltd.); Processes for producing 2-benzoylalkylbenzomorphan derivatives and their salts. DE 2114511; ES 389920; FR 2092005; GB 1311387 .
【2】 Castaner, J.; Paton, D.M.; ID-1229. Drugs Fut 1978, 3, 4, 298.
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) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(A) 39863 4-(4-fluorophenyl)-4-oxobutyric acid 366-77-8 C10H9FO3 详情 详情
(VIII) 36016 (1R,9R,13R)-1,13-dimethyl-10-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-trien-4-ol C14H19NO 详情 详情
(X) 39864 (1R,9R,13R)-10-[4-(4-fluorophenyl)-4-oxobutanoyl]-1,13-dimethyl-10-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-trien-4-yl 4-(4-fluorophenyl)-4-oxobutanoate C34H33F2NO5 详情 详情
(XI) 39865 (1R,9R,13R)-10-[4-(4-fluorophenyl)-4-hydroxybutyl]-1,13-dimethyl-10-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-trien-4-ol C24H30FNO2 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 reduction of triethyl phosphite (I) with ethyl chloroformate (II) gives phosphonoformic acid triethyl ester (III), which is hydrolyzed with refluxing aqueous NaOH. Other alkyl esters can be used instead.

参考文献 中间体
合成目标
【1】 McIntosh, C.L.; Carboxyphosphonates. US 4018854 .
【2】 McIntosh, C.L.; Carboxyphosphonate brush control agents. US 4042650 .
【3】 Castaner, J.; Blancafort, P.; Hopkins, S.J.; Serradell, M.N.; Foscarnet sodium. Drugs Fut 1980, 5, 7, 345.
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) 15487 triethyl phosphite 122-52-1 C6H15O3P 详情 详情
(II) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(III) 32722 Ethyl diethoxy(oxo)phosphoranecarboxylate; Phosphonoformic acid triethyl ester 1474-78-8 C7H15O5P 详情 详情

合成路线4

该中间体在本合成路线中的序号：(A)

The reaction of p-chlorobenzaldehyde (I) sodium cyanide and ethyl acetate gives ethyl 4-(p-chlorophenyl)-4-oxobutyrate (II), which is hydrolyzed with KOH to the corresponding free acid (III). The reduction of (III) with Zn and aqueous HCl affords 4-(p-chlorophenyl)butyric acid (IV), which is condensed with heptylamine (B) by means of oxalyl chloride (A) in refluxing benzene to yield N-heptyl-4-(p-chlorophenyl)butyramide (V), which is reduced with diborane in refluxing THF to afford N-heptyl-4-(p-chlorophenyl)butylamine (VI). The acetylation of (VI) with acetyl chloride (C) by means of Na2CO3 in acetone gives N-acetyl-N-heptyl-4-(p-chlorophenyl)butylamine (VII), which is reduced with diborane as before to yield N-ethyl-N-heptyl-4-(p-chlorophenyl)butylamine (VIII). The quaternization of (VIII) with refluxing ethyl bromide (D) gives N,N-diethyl-N-heptyl-4-(p-chlorophenyl)butylammonium bromide (IX), which by elution through a column with Dowex 1-X8, hydroxide form, resin is converted into N,N-diethyl-N-heptyl-4-(p-chlorophenyl)butyl ammonium hydroxide (X). Finally, this compound is salified with diluted aqueous phosphoric acid.

参考文献 中间体
合成目标
【1】 Fukuzawa, S.; et al.; JP 76131883 .
【2】 Muro, T.; et al.; US 4005084 .
【3】 Serradell, M.N.; Blancafort, P.; Castaner, J.; Y-8894. Drugs Fut 1981, 6, 7, 423.
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) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(B) 37495 Maleic acid; (Z)-2-Butenedioic acid 110-16-7 C4H4O4 详情 详情
(I) 37488 1-(benzylamino)-3-[2-(2-thienylmethyl)phenoxy]-2-propanol C21H23NO2S 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 37489 N-benzyl-2-chloro-N-[2-hydroxy-3-[2-(2-thienylmethyl)phenoxy]propyl]acetamide C23H24ClNO3S 详情 详情
(IV) 37490 4-benzyl-6-[[2-(2-thienylmethyl)phenoxy]methyl]-3-morpholinone C23H23NO3S 详情 详情
(V) 37491 4-benzyl-2-[[2-(2-thienylmethyl)phenoxy]methyl]morpholine; (4-benzyl-2-morpholinyl)methyl 2-(2-thienylmethyl)phenyl ether C23H25NO2S 详情 详情
(VI) 37492 ethyl 2-[[2-(2-thienylmethyl)phenoxy]methyl]-4-morpholinecarboxylate C19H23NO4S 详情 详情
(VII) 37493 2-[[2-(2-thienylmethyl)phenoxy]methyl]oxirane; 2-oxiranylmethyl 2-(2-thienylmethyl)phenyl ether C14H14O2S 详情 详情
(VIII) 37494 2-aminoethyl hydrogen sulfate 926-39-6 C2H7NO4S 详情 详情

合成路线5

该中间体在本合成路线中的序号：(V)

This compound has been obtained by two related ways: 1. The reaction of 1-benzyl-3-bromopiperidin-4-one (I) with sodium methoxide in methanol gives the intermediate epoxide, which in the reaction medium yields 1-benzyl-3-hydroxypiperidin-4-one dimethylacetal (III). The hydrogenation of (III) with H2 over Pd/C in methanol affords 3-hydroxypiperidin-4-one dimethylacetal (IV), which is condensed with ethyl chloroformate (V) by means of NaOH in THF to provide 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylic acid ethyl ester (VI), which is methylated with methyl iodide and NaH in DMF to give the 3,4,4-trimethoxy compound (VII). The hydrolysis of the acetal group of (VII) by means of H2SO4 in refluxing water yields the piperidinone (VIII), which by reductocondensation with benzylamine and H2 over Pd/C in methanol affords the cis- 4-(benzylamino)-3-methoxypiperidine-1-carboxylic acid ethyl ester (IX). The decarboxylation of (IX) by means of KOH in refluxing isopropanol provides the cis-4-(benzyloxy)-3-methoxypiperidine (X), which is alkylated with 3-(4-fluorophenoxy)propyl chloride (XI) by means of TEA in DMF, giving the N-substituted piperidine (XII). The deprotection of the amino group of (XII) by hydrogenation with H2 over Pd/C in methanol yields the 4-aminopiperidine (XIII), which is finally condensed with 4-amino-5-chloro-2-methoxybenzoic acid (XIV) by means of ethyl chloroformate and TEA in chloroform to obtain the target carboxamide. 2. The debenzylation of the cis- 4-(benzylamino)-3-methoxypiperidine-1-carboxylic acid ethyl ester (IX) with H2 over Pd/C in methanol gives the cis-4-amino-3-methoxypiperidine-1-carboxylic acid ethyl ester (XV), which is condensed with 4-amino-5-chloro-2-methoxybenzoic acid (XIV) by means of ethyl chloroformate and TEA in chloroform to yield the corresponding amide (XVI). The decarboxylation of (XVI) with KOH in refluxing isopropanol affords (XVII), with a free NH group that is alkylated with 3-(4-fluorophenoxy)propyl chloride (XI) by means of TEA in DMF to obtain the target carboxamide.

参考文献 中间体
合成目标
【1】 Van Daele, G.H.P.; et al.; Synthesis of cisapride, a gastrointestinal stimulant derived from cis-4-amino-3-methoxypiperidine. Drug Dev Res 1986, 8, 225.
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) 49566 1-benzyl-3-bromo-4-piperidinone C12H14BrNO 详情 详情
(II) 49567 3-benzyl-6-methoxy-7-oxa-3-azabicyclo[4.1.0]heptane; 3-benzyl-7-oxa-3-azabicyclo[4.1.0]hept-6-yl methyl ether C13H17NO2 详情 详情
(III) 49568 1-benzyl-4,4-dimethoxy-3-piperidinol C14H21NO3 详情 详情
(IV) 49557 4,4-dimethoxy-3-piperidinol C7H15NO3 详情 详情
(V) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(VI) 49556 ethyl 3-hydroxy-4,4-dimethoxy-1-piperidinecarboxylate C10H19NO5 详情 详情
(VII) 49569 ethyl 3,4,4-trimethoxy-1-piperidinecarboxylate C11H21NO5 详情 详情
(VIII) 49570 ethyl 3-methoxy-4-oxo-1-piperidinecarboxylate C9H15NO4 详情 详情
(IX) 49571 ethyl (3S,4R)-4-(benzylamino)-3-methoxy-1-piperidinecarboxylate C16H24N2O3 详情 详情
(X) 49572 (3S,4R)-N-benzyl-3-methoxy-4-piperidinamine; N-benzyl-N-[(3S,4R)-3-methoxypiperidinyl]amine C13H20N2O 详情 详情
(XI) 30524 3-chloropropyl 4-fluorophenyl ether; 1-(3-chloropropoxy)-4-fluorobenzene; 1-(4-Fluorophenoxy)-3-chloropropane 1716-42-3 C9H10ClFO 详情 详情
(XII) 49573 (3S,4R)-N-benzyl-1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinamine; N-benzyl-N-[(3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidinyl]amine C22H29FN2O2 详情 详情
(XIII) 49574 ethyl (3S,4R)-4-amino-3-methoxy-1-piperidinecarboxylate C9H18N2O3 详情 详情
(XIV) 12419 4-Amino-5-chloro-2-methoxybenzoic acid 7206-70-4 C8H8ClNO3 详情 详情
(XV) 49574 ethyl (3S,4R)-4-amino-3-methoxy-1-piperidinecarboxylate C9H18N2O3 详情 详情
(XVI) 49575 ethyl (3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinecarboxylate C17H24ClN3O5 详情 详情
(XVII) 49576 4-amino-5-chloro-2-methoxy-N-[(3S,4R)-3-methoxypiperidinyl]benzamide C14H20ClN3O3 详情 详情

合成路线6

该中间体在本合成路线中的序号：(E)

Dazopride can be prepared by the condensation of the 1,2-diethyl-4-aminopyrazolidine (VIII) with either 4-amino-5-chloro-2-methoxybenzoic acid in the presence of phosphorus trichloride-pyridine or the corresponding mixed anhydride (IX).

参考文献 中间体
合成目标
【1】 Munson, H.R. Jr.; Cale, A.D. Jr, Lo, Y.S.; Lunsford, C.D.; Synthetic and pharmacological properties of N-(1,2-dialkyl-4-pyrazolidinyl)benzamides - Selective gastric prokinetic agents. 187th ACS Natl Meet (April 8-13, St. Louis) 1984, 7, 9, 650.
【2】 Cale, A.D.Jr.; Lunsfod, C.D. (A.H. Robins Co. Inc.); N-(4-Pyrazolidinyl)benzamides and their amino precursors. US 4207327 .
【3】 Cale, A. Jr.; Dazopride succinate. Drugs Fut 1985, 10, 7, 553.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(E) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(D) 12419 4-Amino-5-chloro-2-methoxybenzoic acid 7206-70-4 C8H8ClNO3 详情 详情
(VIII) 27385 1,2-diethyl-4-pyrazolidinamine 70180-92-6 C7H17N3 详情 详情
(IX) 27388 4-Amino-5-chloro-2-methoxybenzoic acid ethoxycarbonyl anhydride C11H12ClNO5 详情 详情

合成路线7

该中间体在本合成路线中的序号：(IX)

Bromination of 2-hydroxy-5-methoxybenzaldehyde (I) in acetic acid / sodium acetate mixture gives bromoaldehyde (II). Condensation to the benzofuranylpyridine (IV) is achieved by heating a solution of (II) and 4-(chloromethyl)pyridine hydrochloride (III) in polyethylene glycol-400 in the presence of potassium carbonate. Quaternization of (IV) with dimethylsulfate in dichloromethane affords (V), which upon reduction with sodium borohydride gives intermediate (VI). Reduction of (VI) with platinum on charcoal in methanol/HBr solution yields the N-methylpiperidine (VII). Degradation of the N-methyl group with ethylchloroformate in toluene affords the carbamate (VIII). Final treatment of (VIII) with potassium hydroxide in n-butanol yields the free base of brofaremine, which is converted to its hydrochloride salt by treatment with hydrochloric acid in methanol.

参考文献 中间体
合成目标
【1】 Schenker, K.; Bernasconi, R. (Novartis AG); Tetrahydropyridine and piperidine derivatives and processes for the preparation thereof. DE 2653147; ES 453582; FR 2332754; GB 1565055; JP 52065277 .
【2】 Waldmeier, P.C.; Schilling, W.; Brofaremine Hydrochloride. Drugs Fut 1985, 10, 5, 371.
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) 29301 2-hydroxy-5-methoxybenzaldehyde 672-13-9 C8H8O3 详情 详情
(II) 29302 3-bromo-2-hydroxy-5-methoxybenzaldehyde C8H7BrO3 详情 详情
(III) 10844 4-(Chloromethyl)pyridine 10445-91-7 C6H6ClN 详情 详情
(IV) 29303 4-(7-bromo-5-methoxy-1-benzofuran-2-yl)pyridine C14H10BrNO2 详情 详情
(V) 29304 4-(7-bromo-5-methoxy-1-benzofuran-2-yl)-1-methylpyridinium (sulfonatooxy)methane C16H16BrNO6S 详情 详情
(VI) 29305 4-(7-bromo-5-methoxy-1-benzofuran-2-yl)-1-methyl-1,2,3,6-tetrahydropyridine C15H16BrNO2 详情 详情
(VII) 29306 4-(7-bromo-5-methoxy-1-benzofuran-2-yl)-1-methylpiperidine C15H18BrNO2 详情 详情
(VIII) 29307 ethyl 4-(7-bromo-5-methoxy-1-benzofuran-2-yl)-1-piperidinecarboxylate C17H20BrNO4 详情 详情
(IX) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(VII)

The condensation of ethyl cyanoacetate (I) with farnesylacetone (II) by means of acetic acid ammonium acetate in refluxing benzene gives ethyl 2-cyano-3,7,11,15-tetramethyl-6,10,14-hexadecatrienoate (III), which is decarbo-xylated with NaOH in propylene glycol at room temperature yielding 3,7,11,15-tetramethyl-6,10,14-hexadecatrienonitrile (IV). The hydrolysis of (IV) with KOH in propylene glycol water at 130 C affords 3,7,11,15-tetramethyl-6,10,14-hexa-decatrienoic acid (V), which is finally condensed with morpholine (VI) by means of ethyl chlorocarbonate (VII) and triethylamine in THF.

参考文献 中间体
合成目标
【1】 Yamatsu, I.; et al. (Eisai Co., Ltd.); Polyprenylcarboxylic acid amides useful for treating liver dysfunction. BE 0884754; DE 3030462; FR 2463122; FR 2497802; GB 2058782; JP 8126852; JP 8132442; US 4456603 .
【2】 Serradell, M.N.; Castaner, J.; E-0712. Drugs Fut 1985, 10, 5, 387.
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) 29329 (5E,9E)-6,10,14-trimethyl-5,9,13-pentadecatrien-2-one 762-29-8 C18H30O 详情 详情
(II) 11877 Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate 105-56-6 C5H7NO2 详情 详情
(III) 29330 ethyl (6E,10E)-2-cyano-3,7,11,15-tetramethyl-6,10,14-hexadecatrienoate C23H37NO2 详情 详情
(IV) 29331 (6E,10E)-3,7,11,15-tetramethyl-6,10,14-hexadecatrienenitrile C20H33N 详情 详情
(V) 29332 (6E,10E)-3,7,11,15-tetramethyl-6,10,14-hexadecatrienoic acid C20H34O2 详情 详情
(VI) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(VII) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情

合成路线9

该中间体在本合成路线中的序号：(A)

This compound can be prepared by two related ways: 1) The reaction of (3,5-dimethoxyphenyl)ethylamine (I) with ethyl chlorocarbonate (A) in CH2Cl2 gives ethyl N-[2-(3,5-dimethoxyphenyl)ethyl]carbamate (II), which is reduced with sodium dihydro-bis(2-methoxyethyl)aluminate in THF yielding N-methyl-(3,5-dimethoxyphenyl)ethylamine (III). Partial hydrogenation of (III) with Li in dry NH3 affords N-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine (IV), which is hydrolyzed with refluxing aqueous acetic acid giving 3-[2-(methylamino)ethyl]cyclohexane-1,5-dione (V). The cyclocondensation of (V) with 2-amino-3-pentanone (VI) [prepared by reduction with Zn of 2-isonitroso-3-pentanone (VII)] in refluxing acetic acid yields 6-[2-(N-methylamino)ethyl]-2-methyl-3-ethyl-6,7-dihydro-(5H)-4(1H,5H)indolone (VIII). Finally, this compound is cyclized again with formaldehyde in refluxing octanol. 2) The cyclization of (III) with formaldehyde as before gives 3,4-dihydro-1H-6,8-dimethoxy-2-methylisoquinoline (IX), which is reduced partially with Li in dry NH3 as before yielding 1,2,3,4,4a,7-hexahydro-6,8-dimethoxy-2-methylisoquinoline (X). The hydrolysis of (X) with refluxing acetic acid affords octahydro-2-methylisoquinolin-6,8-dione (XI), which is then cyclized with (VI) as before. The racemic base is resolved by treatment with d-(+)-tartaric acid in methanol and a fractional crystallization.

参考文献 中间体
合成目标
【1】 Cheung, H.-C.; Todaro, L.; Morgan, K.D.; Blount, J.F.; n, G.L.; Boff, E.; Berger, L.; Davidson, A.B.; A dopamine receprtor model and its application in the design of a new class of igid pyrrolo[2,3-g]isoquinoline anti-psychotics. J Med Chem 1981, 24, 9, 1026-34.
【2】 Berger, L.; Olson, G.L. (F. Hoffmann-La Roche AG); Isoquinoline derivs., process for their preparation, intermediates and pharmaceutical compsns. containing them. EP 0010661 .
【3】 Serradell, M.N.; Blancafort, P.; Owen, R.T.; Castaner, J.; RO-22-1319. Drugs Fut 1983, 8, 10, 869.
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) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(I) 36206 3,5-dimethoxyphenethylamine; 2-(3,5-dimethoxyphenyl)-1-ethanamine 3213-28-3 C10H15NO2 详情 详情
(II) 36197 ethyl 3,5-dimethoxyphenethylcarbamate C13H19NO4 详情 详情
(III) 36198 N-(3,5-dimethoxyphenethyl)-N-methylamine; 2-(3,5-dimethoxyphenyl)-N-methyl-1-ethanamine C11H17NO2 详情 详情
(IV) 36199 2-(3,5-dimethoxy-2,5-cyclohexadien-1-yl)-N-methyl-1-ethanamine; N-[2-(3,5-dimethoxy-2,5-cyclohexadien-1-yl)ethyl]-N-methylamine C11H19NO2 详情 详情
(V) 36200 5-[2-(methylamino)ethyl]-1,3-cyclohexanedione C9H15NO2 详情 详情
(VI) 36203 2-amino-3-pentanone C5H11NO 详情 详情
(VII) 36202 2,3-pentanedione 2-oxime C5H9NO2 详情 详情
(VIII) 36201 3-ethyl-2-methyl-6-[2-(methylamino)ethyl]-1,5,6,7-tetrahydro-4H-indol-4-one C14H22N2O 详情 详情
(IX) 36207 6,8-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline; 6-methoxy-2-methyl-1,2,3,4-tetrahydro-8-isoquinolinyl methyl ether C12H17NO2 详情 详情
(X) 36204 6,8-dimethoxy-2-methyl-1,2,3,4,4a,7-hexahydroisoquinoline; 6-methoxy-2-methyl-1,2,3,4,4a,7-hexahydro-8-isoquinolinyl methyl ether C12H19NO2 详情 详情
(XI) 36205 2-methylhexahydro-6,8(2H,7H)-isoquinolinedione C10H15NO2 详情 详情

合成路线10

该中间体在本合成路线中的序号：(IV)

This compound can be obtained in three different ways: 1) Condensation of pyridine-2-carboxylic acid (Ia, R = H), with 1-phenyl methylpiperazine (II) at 160 C. 2) Condensation of methyl pyridine-2-carboxylate (Ib, R = CH3) with 1-phenylmethylpiperazine (II) at 140 C. 3) Reaction of 1-phenylmethylpiperazine (II) with a mixed anhydride (III) formed from (Ia) and ethyl chloroformate (IV).

参考文献 中间体
合成目标
【1】 Budai, Z.; Zolyomi, G.; Synthesis of 14C and 3H specifically labelled 1-benzyl-4-picolinoylpiperazine. J Label Compd Radiopharm 1981, 18, 427-432.
【2】 Budai, Z.; Mezei, T.; Lay, A.; A novel synthesis of pyridinecarboxylic acid piperazides. Acta Chim Acad Sci Hung 1980, 105, 241-246.
【3】 Budai, Z.; Mezei, T.; Lay, A. (Egis Pharmaceuticals Ltd.); Preparation of pyridinecaboxylic acid piperazides. DE 2828888; GB 2001062; HU 175075 .
【4】 Korosi, J.; et al. (Egis Pharmaceuticals Ltd.); Pyridine derivatives. DE 2215545; GB 1378964; HU 162396; JP 7644957 .
【5】 Nogradi, M.; Piberaline. Drugs Fut 1984, 9, 1, 30.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(Ia) 29950 2-pyridinecarboxylic acid；picolinic acid;Pyridine-2-carboxylic acid 98-98-6 C6H5NO2 详情 详情
(Ib) 29951 methyl 2-pyridinecarboxylate 2459-07-6 C7H7NO2 详情 详情
(II) 28542 N-Benzylpiperazine; 1-Benzylpiperazine 2759-28-6 C11H16N2 详情 详情
(III) 29952 ethyl 2-oxo-2-(2-pyridinyl)acetate C9H9NO3 详情 详情
(IV) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情

合成路线11

该中间体在本合成路线中的序号：(II)

The acylation of 4-aminothiophenol (I) with ethyl chloroformate (II) is performed in a nitrogen atmosphere in the presence of NaHCO3 in CH2Cl2 / water medium giving ethyl (4-mercaptophenyl)carbamate (III). This compound is condensed with cis-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dixolan-4-yl]methyl methanesulfonate (IV) in the presence of K2CO3 in refluxing acetone under nitrogen, affording the title compound, which is converted to the monohydrochloride with i-PrOH / HCl in 4-methyl-2-pentanone.

参考文献 中间体
合成目标
【1】 Heeres, J.; Van der Veken, L.J.E.; Novel (2-aryl-4-phenylthioalkyl-1,3-dioxolan-2-yl-methyl)azole derivatives. DE 3166517D; EP 0052905 .
【2】 Van Ginckel, R.; Geuens, G.; Heeres, J.; Tubulozole Hydrochloride. Drugs Fut 1984, 9, 12, 911.
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) 16490 4-aminophenylhydrosulfide; 4-aminothiophenol; 4-aminobenzenethiol 1193-02-8 C6H7NS 详情 详情
(II) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(III) 13295 ethyl 4-sulfanylphenylcarbamate C9H11NO2S 详情 详情
(IV) 34328 1-[[(2S,4S)-2-(2,4-dichlorophenyl)-4-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazole C17H20Cl2N2O3S 详情 详情

合成路线12

该中间体在本合成路线中的序号：(II)

Coupling of (IV) in a nitrogen atmosphere with 4-acetamidothiophenol (V) in refluxing acetone in the presence of K2CO3 affords cis-N-[4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethylthio]phenyl]acetamide, which is deacylated with NaOH in refluxing i-PrOH to give cis-4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-ylmethylthio]benzenamine (VII). This compound is converted with ethylchloroformate (II) into the title compound which is isolated as the monohydrochloride on treatment with i-PrOH / HCl.

参考文献 中间体
合成目标
【1】 Heeres, J.; Van der Veken, L.J.E.; Novel (2-aryl-4-phenylthioalkyl-1,3-dioxolan-2-yl-methyl)azole derivatives. DE 3166517D; EP 0052905 .
【2】 Van Ginckel, R.; Geuens, G.; Heeres, J.; Tubulozole Hydrochloride. Drugs Fut 1984, 9, 12, 911.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(IV) 34328 1-[[(2S,4S)-2-(2,4-dichlorophenyl)-4-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazole C17H20Cl2N2O3S 详情 详情
(V) 34329 N-(4-sulfanylphenyl)acetamide 1126-81-4 C8H9NOS 详情 详情
(VI) 34330 N-[4-([[(2S,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl]sulfanyl)phenyl]acetamide C22H21Cl2N3O3S 详情 详情
(VII) 34331 4-([[(2S,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl]sulfanyl)aniline; 4-([[(2S,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl]sulfanyl)phenylamine C20H19Cl2N3O2S 详情 详情

合成路线13

该中间体在本合成路线中的序号：(A)

4) The reaction of gentamicin C1a (I) with formaldehyde in ethanol gives 6'-N-methylenegentamicin C1a (III), which is then reduced with NaBH4, or with hot formic acid. 5) The reaction of gentamicin C1a (I) with ethyl chloroformate (C) by means of NaOH in dioxane yields ethyl 6'-carbamategentamicin C1a (IV), which is then reduced with LiAlH4 in THF.

参考文献 中间体
合成目标
【1】 Matsushima, H.; et al.; JP 75149647 .
【2】 Matsushima, H.; et al.; JP 75149646 .
【3】 Castaner, J.; Sweetman, A.J.; Serradell, M.N.; Blancafort, P.; Sagamicin. Drugs Fut 1979, 4, 5, 360.
【4】 Matsushima, H.; et al.; JP 75131949 .
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) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(I) 39511 (2R,3R,4R,5R)-2-[((1S,2R,3R,4S,6R)-4,6-diamino-3-[[(2R,3R,6S)-3-amino-6-(aminomethyl)tetrahydro-2H-pyran-2-yl]oxy]-2-hydroxycyclohexyl)oxy]-5-methyl-4-(methylamino)tetrahydro-2H-pyran-3,5-diol C19H39N5O7 详情 详情
(III) 39513 (2R,3R,4R,5R)-2-[[(1S,2R,3R,4S,6R)-4,6-diamino-3-([(2R,3R,6S)-3-amino-6-[(methyleneamino)methyl]tetrahydro-2H-pyran-2-yl]oxy)-2-hydroxycyclohexyl]oxy]-5-methyl-4-(methylamino)tetrahydro-2H-pyran-3,5-diol C20H39N5O7 详情 详情
(IV) 39514 ethyl [(2S,5R,6R)-5-amino-6-[((1R,2R,3S,4R,6S)-4,6-diamino-3-[[(2R,3R,4R,5R)-3,5-dihydroxy-5-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl]oxy]-2-hydroxycyclohexyl)oxy]tetrahydro-2H-pyran-2-yl]methylcarbamate C22H43N5O9 详情 详情

合成路线14

该中间体在本合成路线中的序号：(A)

The reaction of O-(p-chlorophenoxy)aniline hydrochloride (I) with ethyl chlorocarbonate (A) in pyridine ether gives ethyl O-(p-chlorophenoxy)phenylcarbanilate (II), which is condensed with N-carbetoxypiperazine (B) by means of Na2O or NaOCH3 in refluxing benzene to afford ethyl 4-[(O-(p-chlorophenoxy)phenyl)carbamoyl]-1-piperazine carboxylate (III). This product is finally decarboxylated and cyclized with P2O5 in refluxing POCl3.

参考文献 中间体
合成目标
【1】 Howell, C.F.; et al.; Treatment of depression with 2-chloro-11-(pipeazinyl)dibenz[b,f][1,4]oxazepines and acid addition salts thereof. BE 0698690; FR 7845M; GB 1192812; GB 1192812; NL 6706970; US 3663696; US 3681357 .
【2】 Playle, A.C.; Castaner, J.; Amoxapine. Drugs Fut 1976, 1, 11, 511.
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) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(B) 24694 N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine 120-43-4 C7H14N2O2 详情 详情
(I) 34008 1-(2,6-dimethylphenoxy)acetone oxime C11H15NO2 详情 详情
(II) 34089 ethyl 4-[[2-(4-chlorophenoxy)anilino]carbonyl]-1-piperazinecarboxylate; Ethyl-4-[(o-(p-Chlorophenoxy)phenyl)carbamoyl]-1-piperazine carboxylate C20H22ClN3O4 详情 详情
(III) 34090 2-chlorodibenzo[b,f][1,4]oxazepin-11-amine; 2-chlorodibenzo[b,f][1,4]oxazepin-11-ylamine C13H9ClN2O 详情 详情

合成路线15

该中间体在本合成路线中的序号：(A)

The reaction of 3-aminodiphenylamine (I) with ethyl chloroformate (A) gives ethyl 3-anilinocarbanilate (II), which is cyclized by heating with S and I2 to yield ethyl phenothiazine-2-carbamate (III). The condensation of (III) with 3-chloropropionyl chloride (B) in refluxing toluene affords ethyl 10-(3-chloropropionyl)phenothiazine-2-carbamate (IV), which is finally condensed with refluxing morpholine (C).

参考文献 中间体
合成目标
【1】 Gritsenko, A.N.; et al.; Synthesis of ethmosine [hydrochloride of the ethyl ester of 10-(beta-morpholylpropionyl)phenothiazine-2-carbamic acid], a new antiarrhytmic preparation. Khim Farm Zh 1972, 6, 9, 17-19.
【2】 Gritsenko, A.N.; et al.; Antiarhythmic pharmaceutical preparation containing ethyl 10-(beta-morpholylpropionyl) phenthiazine-2-carbamate hydrochloride. DE 2014201; US 3864487 .
【3】 Gritsenko, A.N.; et al.; Ethyl 10-(beta-N-morpholinylpropionyl)phenthiazine-2-carbamate and the hydrochloride thereof and a method for preparing the same. GB 1269969 .
【4】 Gritsenko, A.N.; et al.; Ethyl 10-(beta-morpholinylpropionyl)phenthiazine-2-carbamate hydrochloride. US 3740395 .
【5】 Castaner, J.; Roberts, P.J.; Moracizine. Drugs Fut 1978, 3, 2, 122.
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) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(B) 18936 3-chloropropanoyl chloride 625-36-5 C3H4Cl2O 详情 详情
(I) 33468 N(1)-phenyl-1,3-benzenediamine; N-(3-aminophenyl)-N-phenylamine C12H12N2 详情 详情
(II) 33469 ethyl 3-anilinophenylcarbamate; Diphenylamino-3-carbaminoethyl ester 86517-37-6 C15H16N2O2 详情 详情
(III) 33470 ethyl 10H-phenothiazin-2-ylcarbamate; Phenothiazine-2-ethylcarbamate 37711-29-8 C15H14N2O2S 详情 详情
(IV) 11351 ethyl N-[10-(3-chloropropanoyl)-10H-phenothiazin-2-yl]carbamate C18H17ClN2O3S 详情 详情
(C) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线16

该中间体在本合成路线中的序号：(X)

The reaction of 4-(4-fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (I) with formaldehyde and H2SO4 gives racemic 4-(4-fluorophenyl)-3-(hydroxymethyl)-1-methyl-1,2,3,6-tetrahydropyridine (II), which is submitted to optical resolution with (-)-dibenzoyltartaric acid, yielding the 3(S)-enantiomer (III). The reduction of (III) with H2 over Pd/C in ethanol affords trans-(3S,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)-1-methylpiperidine (IV), which is treated with SOCl2 to provide the corresponding chloromethyl derivative (V). The condensation of (V) with 1,3-benzodioxol-5-ol (VI) by means of NaOMe in methanol furnishes trans-(3S,4R)-3-(1,3-benzodioxol-5-yloxymethyl)-4-(4-fluorophenyl)-1-methylpiperidine (VII) , which is condensed with phenyl chloroformate (VIII) in dichloromethane to afford the phenyl carbamate (IX). Finally, the phenoxycarbonyl group of (IX) is removed by treatment with KOH in refluxing methylcellosolve or in refluxing toluene. Alternatively, the reaction of methylpiperidine (VII) with ethyl chloroformate (X) in toluene gives the ethyl carbamate (XI), which is finally treated with KOH in refluxing ethanol/water in order to eliminate its ethoxycarbonyl group. Alternatively, the reaction of methylpiperidine (VII) with vinyl chloroformate (XII) in dichloromethane gives the vinyl carbamate (XIII), which is finally treated with dry HCl gas in refluxing dichloromethane/methanol in order to eliminate its vinyloxycarbonyl group.

参考文献 中间体
合成目标
【1】 Lynch, I.R.; Richardson, J.E.; Buxton, P.C.; Curzons, A.D.; Wood-Kaezmar, M.W.; Barnes, R.D. (Ferrosan A/S; SmithKline Beecham plc); Piperidine derivs., their preparation and their use as medicaments. EP 0223403; JP 1987129280; US 4721723 .
【2】 Sato, F.; Amano, T.; Kameo, K.; Tanami, T.; Muto, K.; Ono, N.; Goto, J. (Taisho Pharmaceutical Co., Ltd.); Prostaglandin derivs.. JP 1997286775 .
【3】 Lucas, E. (SmithKline Beecham plc); Process for the preparation of paroxetine and structurally related cpds.. WO 0078753 .
【4】 Christensen, J.A.; Squires, R.F. (Ferrosan A/S); 4-Phenylpiperidine compounds. DE 2404113; ES 422734; FR 2215233; GB 1422263; JP 58174363; US 3912743 .
【5】 Lemmens, J.M.; Peters, T.H.A.; Picha, F. (Synthon BV); Process to produce paroxetine. WO 0266466 .
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) 10989 4-(4-Fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine C12H14FN 详情 详情
(II) 10990 [4-(4-Fluorophenyl)-1-methyl-1,2,3,6-tetrahydro-3-pyridinyl]methanol C13H16FNO 详情 详情
(III) 43486 [(3S)-4-(4-fluorophenyl)-1-methyl-1,2,3,6-tetrahydro-3-pyridinyl]methanol C13H16FNO 详情 详情
(IV) 43487 [(3S,4R)-4-(4-fluorophenyl)-1-methylpiperidinyl]methanol; trans-(3S)-4-(4-fluorophenyl)-1-methyl-3-piperidine methanol 105812-81-5 C13H18FNO 详情 详情
(V) 43488 (3S,4R)-3-(chloromethyl)-4-(4-fluorophenyl)-1-methylpiperidine C13H17ClFN 详情 详情
(VI) 10985 1,3-Benzodioxol-5-ol; Sesamol 533-31-3 C7H6O3 详情 详情
(VII) 10987 (3S,4R)-3-[(1,3-Benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-methylhexahydropyridine; 1,3-Benzodioxol-5-yl [(3S,4R)-4-(4-fluorophenyl)-1-methylhexahydro-3-pyridinyl]methyl ether C20H22FNO3 详情 详情
(VIII) 13580 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate 1885-14-9 C7H5ClO2 详情 详情
(IX) 13489 ethyl 4-(bromomethyl)-4-[[(1S)-1-methyl-2-propynyl]oxy]-1-piperidinecarboxylate C13H20BrNO3 详情 详情
(X) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(XI) 43490 ethyl (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-piperidinecarboxylate C22H24FNO5 详情 详情
(XII) 28068 1-[(Chlorocarbonyl)oxy]ethylene; Vinyl chloroformate 5130-24-5 C3H3ClO2 详情 详情
(XIII) 43491 vinyl (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-piperidinecarboxylate C22H22FNO5 详情 详情

合成路线17

该中间体在本合成路线中的序号：(VII)

Protected aminopentanoic acid derivative (I) is converted into phenylpentanone (II) by first treatment with thionyl chloride in refluxing benzene, followed by condensation with benzene and aluminum chloride. Reduction of (II) with aluminum isopropoxide in refluxing isopropanol provides phenylpentanol derivative (III), which is then treated with hydrazine hydrate in refluxing EtOH to furnish 2-amino-4-methyl-1-phenylpentane-1-ol (IV). Coupling of (IV) with chloro derivative (V) at 110-120 C yields derivative (VI), which is finally converted into the desired oxazolidinone by reaction with ethyl chlorocarbonate (VII) in chloroform followed by heating in toluene and treatment with aluminum isopropoxide.

参考文献 中间体
合成目标
【1】 Moritoh, N.; Satoh, M.; Shinozaki, H.; Masaki, M.; Hashimoto, K.; Kamishiro, T. (Nippon Chemiphar Co., Ltd.); 1,3-Oxazolidin-2-one derivs.. CH 663207; DE 3519261; ES 8800571; ES 8802152; FR 2571052; GB 2165237; JP 1986083170; US 4644063 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
13364 Benzene 71-43-2 C6H6 详情 详情
(I) 50833 (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-methylpentanoic acid C14H15NO4 详情 详情
(II) 50834 2-[(1S)-1-benzoyl-3-methylbutyl]-1H-isoindole-1,3(2H)-dione C20H19NO3 详情 详情
(III) 50835 2-[(1S)-1-[(R)-hydroxy(phenyl)methyl]-3-methylbutyl]-1H-isoindole-1,3(2H)-dione C20H21NO3 详情 详情
(IV) 50836 (1R,2S)-2-amino-4-methyl-1-phenyl-1-pentanol C12H19NO 详情 详情
(V) 50837 1-(3-chloropropyl)azepane C9H18ClN 详情 详情
(VI) 50838 (1R,2S)-2-[[3-(1-azepanyl)propyl]amino]-4-methyl-1-phenyl-1-pentanol C21H36N2O 详情 详情
(VII) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情

合成路线18

该中间体在本合成路线中的序号：(II), (IX)

This compound can be obtained in three similar ways: 1) The reaction of N-acetyl-L-methionine (I) with ethyl chloroformate (II) and triethylamine in chloroform gives the corresponding mixed anhydride (III), which is then condensed with 3,4-di(ethoxycarbonyloxy)phenethylamine tosylate (IV) by means of triethylamine in chloroform. 2) The reaction of N-acetyl-L-methionine (I) with N-hydroxysuccinimide (V) by means of dicyclohexylcarbodiimide (DDC) in dioxane gives the corresponding active ester (VI), which is then condensed with the amine (IV) as before. The active ester method can also be carried out in this case using N-hydroxyphthalimide, 1-hydroxybenzothiazole or 4-nitrophenol instead of N-hydroxysuccinimide (V). 3) The reaction of the active ester (VI) with dopamine (VII) by means of triethylamine in DMF gives the corresponding amide (VIII), which is then acylated with ethyl chloroformate (IX) in pyridine.

参考文献 中间体
合成目标
【1】 Kiguchi, T.; Hatashi, K.; Yamaguchi, I. (Tanabe Seiyaku Co., Ltd.); Phenethylamine derivs., process for preparing same and pharmaceutical compositions containing said phenethylamine derivs. EP 0007441; JP 1980007242 .
【2】 Prous, J.; Castaner, J.; DOCARPAMINE. Drugs Fut 1990, 15, 2, 122.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
60593 p-xylene C8H10 详情 详情
(II), (IX) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(I) 11228 (2S)-2-(Acetamido)-4-(methylsulfanyl)butyric acid 65-82-7 C7H13NO3S 详情 详情
(III) 11230 N-Acetyl-L-methionine ethoxycarbonyl anhydride C10H17NO5S 详情 详情
(IV) 11231 4-(2-aminoethyl)-2-[(ethoxycarbonyl)oxy]phenyl ethyl carbonate C14H19NO6 详情 详情
(V) 10264 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione 6066-82-6 C4H5NO3 详情 详情
(VI) 11233 N-[(1S)-1-[[(2,5-Dioxo-1-pyrrolidinyl)oxy]carbonyl]-3-(methylsulfanyl)propyl]acetamide C11H16N2O5S 详情 详情
(VII) 11234 4-(2-Aminoethyl)-1,2-benzenediol 51-61-6 C8H11NO2 详情 详情
(VIII) 11235 (2S)-2-(Acetamido)-N-(3,4-dihydroxyphenethyl)-4-(methylsulfanyl)butanamide 122570-36-9 C15H22N2O4S 详情 详情

合成路线19

该中间体在本合成路线中的序号：(B)

By reaction of 4-(p-fluorobenzoyl)piperidine (I) with 3-(2-chloroethyl)-2,4-(1H,3H)-quinazolinedione (II) by means of Na2CO3 in refluxing 4-methyl-2-pentanone. The starting compounds are prepared as follows: 1) The Grignard reaction of N-benzyl-4-cyanopiperidine (III) with p-fluorophenylmagnesium bromide (IV) ethyl ether gives N-benzyl-4-p-fluorobenzoyl)piperidine (V), which by reaction with Na2CO3 and ethyl chloroformate (A) is converted into N-ethoxycarbonyl-4-(p-fluorobenzoyl)piperidine (VI). Finally, this compound is hydrolyzed with 48% HBr to give (I). 2) The reaction of ethyl anthranilate (VII) with ethyl chloroformate (A) in refluxing xylene gives ethyl 2-(ethoxycarbonylamino)benzoate (VIII), which is cyclized with 2-aminoethanol (B) at 170 C to afford 3-(2-hydroxyethyl)-2,4-(1H,3H)-quinazolinedione (IX). Finally, this compound is treated with SOCl2 in refluxing chloroform to afford (II).

参考文献 中间体
合成目标
【1】 Van Der, M.; Keninis, L.; Vandenberk, J.; Van Heertum, A. (Janssen Pharmaceutica NV); Piperidinylalkyl quinazoline compounds, composition and method of use. EP 0013612; JP 55105679; US 4335127 .
【2】 Blancafort, P.; Paton, D.M.; Serradell, M.N.; Castaner, J.; Ketanserin. Drugs Fut 1981, 6, 11, 684.
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) 10259 Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol 141-43-5 C2H7NO 详情 详情
(B) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(I) 21497 (4-Fluorophenyl)(4-piperidinyl)methanone; 4-(4-Fluorobenzoyl)piperidine; 4-(p-Fluorobenzoyl)piperidine 56346-57-7 C12H14FNO 详情 详情
(II) 32277 3-(2-chloroethyl)-2,4(1H,3H)-quinazolinedione 5081-87-8 C10H9ClN2O2 详情 详情
(III) 29013 1-benzyl-4-piperidinecarbonitrile C13H16N2 详情 详情
(IV) 13643 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide 352-13-6 C6H4BrFMg 详情 详情
(V) 29014 (1-benzyl-4-piperidinyl)(4-fluorophenyl)methanone C19H20FNO 详情 详情
(VI) 29015 ethyl 4-(4-fluorobenzoyl)-1-piperidinecarboxylate C15H18FNO3 详情 详情
(VII) 32278 ethyl 2-aminobenzoate 87-25-2 C9H11NO2 详情 详情
(VIII) 32279 ethyl 2-[(ethoxycarbonyl)amino]benzoate C12H15NO4 详情 详情
(IX) 32280 3-(2-hydroxyethyl)-2,4(1H,3H)-quinazolinedione C10H10N2O3 详情 详情

合成路线20

该中间体在本合成路线中的序号：(VII)

The condensation of piperidine-4-carboxylic acid (VI) with ethyl chloroformate (VII) by means of Na2CO3 in toluene/water gives 1-(ethoxycarbonyl)piperidine-4-carboxylic acid (VIII), which is treated with SOCl2 to yield the corresponding acyl chloride (IX). The Friedel-Crafts condensation of (IX) with refluxing 1,3-difluorobenzene (X) by means of AlCl3 gives 4-(2,4-difluorobenzoyl)piperidine-1-carboxylic acid ethyl ester (XI), which is treated with concentrated HCl at 100 C to yield 4-(2,4-difluorobenzoyl)piperidine (XII). The condensation of piperidine (XII) with the 2-chloroethyl intermediate (V) by means of KI and NaHCO3 in refluxing acetonitrile affords the adduct (XIII), which is treated with hydroxylamine hydrochloride and KOH in refluxing pyridine/ethanol to provide the corresponding oxime (XIV). Finally, this compound is cyclized by means of KOH in refluxing water or with NaH in refluxing THF to afford in both cases the target 1,2-benzisoxazole.

参考文献 中间体
合成目标
【1】 Dalmases Barjoan, P.; Bosch Rovira, A.; Marquillas Olondriz, F.; Caldero Ges, J.M. (Vita-Invest, SA); Process for the preparation of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one. ES 2050069 .
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) 23044 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one 63234-80-0 C11H15ClN2O 详情 详情
(VI) 17402 4-nipecotic acid;piperidine-4-carboxylic acid;p-nipecotic acid; Isonipecotic acid; Hexahydroisonicotinic acid; 4-Piperidinecarboxylic acid 498-94-2 C6H11NO2 详情 详情
(VII) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(VIII) 50868 1-(ethoxycarbonyl)-4-piperidinecarboxylic acid C9H15NO4 详情 详情
(IX) 50869 ethyl 4-(chlorocarbonyl)-1-piperidinecarboxylate C9H14ClNO3 详情 详情
(X) 13095 m-Difluorobenzene; 1,3-Difluorobenzene 372-18-9 C6H4F2 详情 详情
(XI) 50870 ethyl 4-(2,4-difluorobenzoyl)-1-piperidinecarboxylate C15H17F2NO3 详情 详情
(XII) 23041 (2,4-difluorophenyl)(4-piperidinyl)methanone C12H13F2NO 详情 详情
(XIII) 50871 3-[2-[4-(2,4-difluorobenzoyl)-1-piperidinyl]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one C23H27F2N3O2 详情 详情
(XIV) 50872 3-(2-[4-[(2,4-difluorophenyl)(hydroxyimino)methyl]-1-piperidinyl]ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one C23H28F2N4O2 详情 详情

合成路线21

该中间体在本合成路线中的序号：(II)

A new synthesis of loracarbef has been described: The reaction of L-(+)-phenylglycine (I) with ethyl chloroformate (II) and NaOH in dichloromethane gives L-N-(ethoxycarbonyl)phenylglycine (III), which is reduced with BH3 in THF to the alcohol (IV). The cyclization of (IV) by means of NaH in THF affords oxazolidinone (V), which by alkylation with ethyl bromoacetate and hydrolysis with NaOH is converted into the oxazolidinone-3-acetic acid (VI), and the corresponding acyl chloride (VII). The cyclization of (VII) with 2-[3-(benzylimino)-1-propenyl]furan (VIII) by means of triethylamine in dichloromethane yields the azetidinone (IX), which is purified from its enantiomer by crystallization. The reduction of (IX) with H2 over Pd/C in dichloromethane gives 1-benzyl-2-[2-(2-furyl)ethyl]-3-(2-oxo-4-phenyloxazolidin-3-yl)azetidin-4-one (X) with a 100% optical purity. The cleavage of (X) with Li/NH3 in tert-butanol - THF yields 3(S)-amino-2(R)-[2-(2-furyl)ethyl]azetidin-4-one (XI), which is acylated with phenoxyacetyl chloride (XII) and NaHCO3 to the amide (XIII). Ozonolysis of (XIII) with O3, H2O2 in dichloromethane-methanol affords 3-[4-oxo-3(S)-phenoxyacetamido)azetidin-2(R)-yl]propanoic acid (XIV), which is then condensed with the magnesium salt of the malonic derivative (XV) in THF to yield the ketoester (XVI).

参考文献 中间体
合成目标
【1】 Boyer, B.D.; Bodurow, C.C.; Brennan, J.; et al.; An enantioselective synthesis of loracarbef (LY163892/KT3777). Tetrahedron Lett 1989, 30, 18, 2321.
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) 10716 (2S)-2-Amino-2-phenylethanoic acid; L-(+)-alpha-Phenylglycine 2935-35-5 C8H9NO2 详情 详情
(II) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(III) 12171 (2S)-2-[(Ethoxycarbonyl)amino]-2-phenylethanoic acid C11H13NO4 详情 详情
(IV) 12172 ethyl N-[(1S)-2-hydroxy-1-phenylethyl]carbamate C11H15NO3 详情 详情
(V) 12173 (4S)-4-Phenyl-1,3-oxazolan-2-one; (4S)-4-Phenyl-2-oxazolidinone; (S)-(+)-4-Phenyl-2-oxazolidinone 99395-88-7 C9H9NO2 详情 详情
(VI) 12174 2-[(4S)-2-Oxo-4-phenyl-1,3-oxazolan-3-yl]acetic acid C11H11NO4 详情 详情
(VII) 12175 2-[(4S)-2-Oxo-4-phenyl-1,3-oxazolan-3-yl]acetyl chloride C11H10ClNO3 详情 详情
(VIII) 12176 N-Benzyl-N-[(E,2E)-3-(2-furyl)-2-propenylidene]amine; N-[(E,2E)-3-(2-Furyl)-2-propenylidene](phenyl)methanamine C14H13NO 详情 详情
(IX) 12177 (4S)-3-[(2R,3S)-1-Benzyl-2-[(E)-2-(2-furyl)ethenyl]-4-oxoazetanyl]-4-phenyl-1,3-oxazolan-2-one C25H22N2O4 详情 详情
(X) 12178 (4S)-3-[(2R,3S)-1-Benzyl-2-[2-(2-furyl)ethyl]-4-oxoazetanyl]-4-phenyl-1,3-oxazolan-2-one C25H24N2O4 详情 详情
(XI) 12179 (3S,4R)-3-Amino-4-[2-(2-furyl)ethyl]-2-azetanone C9H12N2O2 详情 详情
(XII) 12180 Phenoxyacetyl chloride; 2-Phenoxyacetyl chloride 701-99-5 C8H7ClO2 详情 详情
(XIII) 12181 N-[(2R,3S)-2-[2-(2-Furyl)ethyl]-4-oxoazetanyl]-2-phenoxyacetamide C17H18N2O4 详情 详情
(XIV) 12182 3-[(2R,3S)-4-Oxo-3-[(2-phenoxyacetyl)amino]azetanyl]propionic acid C14H16N2O5 详情 详情
(XV) 12183 magnesium di[3-[(4-nitrobenzyl)oxy]-3-oxopropanoate] 75321-09-4 C20H16MgN2O12 详情 详情
(XVI) 12184 4-nitrobenzyl 3-oxo-5-[(2R,3S)-4-oxo-3-[(2-phenoxyacetyl)amino]azetanyl]pentanoate C23H23N3O8 详情 详情

合成路线22

该中间体在本合成路线中的序号：(VII)

NCU-190Na is synthesized by condensation of naphthoquinone (I) and phenylenediamine (II), but several isomers (IV) of benzo[a]phenazine are produced at the same time. Using ethyl chlorocarbonate, (III) is selectively produced and aminolysis of esters is also selective to the 6-position; thus, (V) is produced and can be converted to (VI) (NCU190Na). Various derivatives of (VI) can be synthesized in a similar manner. Compound (III) can also be prepared from naphthoquinone (I) and ethyl chloroformate (VII) to give ethyl 3-(ethoxycarbonyloxy)-1,4-dioxo-1,4-dihydro-2-naphthoate (VIII), which is condensed with phenylenediamine (II).

参考文献 中间体
合成目标
【1】 Watanabe, Y.; Soda, K.; Nakagami, J.; Sakakibara, Z.; Migita, Y.; Kumazawa, Y.; Selective synthsesis of new benzo(a)-phenazine-6-c. 108th Annu Meet Pharm Soc Jpn (April 4-7, Hiroshima) 1988, Abst 5E16 2-1.
【2】 Kumazawa, Y.; Nakagami, J.; Soda, K.; Nakaike, S.; Sakakibara, Z.; Watanabe, Y.; Migita, Y.; Synthesis and antitumor activity of new benzo(a)-p. 108th Annu Meet Pharm Soc Jpn (April 4-7, Hiroshima) 1988, Abst 5E16 11-2.
【3】 Migita, Y.; Eguchi, T.; Kumazawa, Y.; Nakagami, J.; Amano, T.; Sota, K.; Sakakibara, J. (Taisho Pharmaceutical Co., Ltd.); Benzo[a]phenazine derivs.. EP 0196910; ES 8706651; JP 1987000072; US 4686292 .
【4】 Hoshi, A.; NCU-190Na. Drugs Fut 1988, 13, 8, 726.
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) 22896 ethyl 3-hydroxy-1,4-dioxo-1,4-dihydro-2-naphthalenecarboxylate C13H10O5 详情 详情
(II) 22897 ethyl 4,5-diamino-2-methoxybenzoate C10H14N2O3 详情 详情
(III) 22898 diethyl 5-hydroxy-10-methoxybenzo[a]phenazine-6,9-dicarboxylate C23H20N2O6 详情 详情
(IV) 22899 diethyl 5-hydroxy-9-methoxybenzo[a]phenazine-6,10-dicarboxylate C23H20N2O6 详情 详情
(V) 22900 ethyl 6-([[2-(dimethylamino)ethyl]amino]carbonyl)-5-hydroxy-10-methoxybenzo[a]phenazine-9-carboxylate C25H26N4O5 详情 详情
(VII) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(VIII) 22902 ethyl 3-[(ethoxycarbonyl)oxy]-1,4-dioxo-1,4-dihydro-2-naphthalenecarboxylate C16H14O7 详情 详情

合成路线23

该中间体在本合成路线中的序号：

Michael addition of acrylonitrile (II) to 2-methyl-3-aminopropionitrile (I) gave dinitrile (III), which was cyclized to piperidone (IV) under Thorpe-Ziegler conditions. After protection of (IV) as the carbamate (V), hydrolysis of the nitrile with 85% H2SO4 provided ketoamide (VI). This was converted to enamine (VII) by condensation with benzylamine in refluxing xylene. Subsequent treatment of (VII) with H2S in DMF, followed by bromine in AcOH furnished isothiazole (VIII). The ethoxycarbonyl group of (VIII) was then replaced for a tert-butoxycarbonyl group by hydrolysis with HBr in AcOH to (IX), and then reaction with Boc2O to give a N,O-di-Boc intermediate, which was further treated with K2CO3 in MeOH to afford (X). After alkylation of the hydroxyl group of (X) with propargyl bromide (XI), the tert-butyl carbamate was removed with ethereal HCl to yield the racemic isothiazolopyridine (XII). Finally, the (S)-(+)-enantiomer of (XII) was resolved by crystallization as the diastereomeric salt with D-(+)-dibenzoyltartaric acid and, after liberation of the base with NaOH, was isolated as the fumarate salt.

参考文献 中间体
合成目标
【1】 Pedersen, H.; et al.; Synthesis and muscarinic receptor pharmacology of a series of 4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridine bioisosteres of arecoline. Bioorg Med Chem 1999, 7, 5, 795.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(I) 25580 3-amino-2-methylpropanenitrile C4H8N2 详情 详情
(II) 10847 Acrylonitrile 107-13-1 C3H3N 详情 详情
(III) 25581 3-[(2-cyanoethyl)amino]-2-methylpropanenitrile C7H11N3 详情 详情
(IV) 25582 5-methyl-4-oxo-3-piperidinecarbonitrile C7H10N2O 详情 详情
(V) 25583 ethyl 3-cyano-5-methyl-4-oxo-1-piperidinecarboxylate C10H14N2O3 详情 详情
(VI) 25584 ethyl 3-(aminocarbonyl)-5-methyl-4-oxo-1-piperidinecarboxylate C10H16N2O4 详情 详情
(VII) 25585 ethyl 5-(aminocarbonyl)-4-(benzylamino)-3-methyl-3,6-dihydro-1(2H)-pyridinecarboxylate C17H23N3O3 详情 详情
(VIII) 25586 ethyl 3-hydroxy-7-methyl-6,7-dihydroisothiazolo[4,5-c]pyridine-5(4H)-carboxylate C10H14N2O3S 详情 详情
(IX) 25587 7-methyl-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-ol C7H10N2OS 详情 详情
(X) 25588 tert-butyl 3-hydroxy-7-methyl-6,7-dihydroisothiazolo[4,5-c]pyridine-5(4H)-carboxylate C12H18N2O3S 详情 详情
(XI) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(XII) 25589 7-methyl-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-yl 2-propynyl ether C10H12N2OS 详情 详情

合成路线24

该中间体在本合成路线中的序号：

Michael addition of acrylonitrile (II) to 2-methyl-3-aminopropionitrile (I) gave dinitrile (III), which was cyclized to piperidone (IV) under Thorpe-Ziegler conditions. After protection of (IV) as the carbamate (V), hydrolysis of the nitrile with 85% H2SO4 provided ketoamide (VI). This was converted to enamine (VII) by condensation with benzylamine in refluxing xylene. Subsequent treatment of (VII) with H2S in DMF, followed by bromine in AcOH furnished isothiazole (VIII). The ethoxycarbonyl group of (VIII) was then replaced for a tert-butoxycarbonyl group by hydrolysis with HBr in AcOH to (IX), and then reaction with Boc2O to give a N,O-di-Boc intermediate, which was further treated with K2CO3 in MeOH to afford (X). After alkylation of the hydroxyl group of (X) with propargyl bromide (XI), the tert-butyl carbamate was removed with ethereal HCl to yield the racemic isothiazolopyridine (XII). Finally, the (R)-(-)-enantiomer of (XII) was resolved by crystallization as the diastereomeric salt with L-(-)-dibenzoyltartaric acid and, after liberation of the base with NaOH, was isolated as the fumarate salt .

参考文献 中间体
合成目标
【1】 Pedersen, H.; et al.; Synthesis and muscarinic receptor pharmacology of a series of 4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridine bioisosteres of arecoline. Bioorg Med Chem 1999, 7, 5, 795.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(I) 25580 3-amino-2-methylpropanenitrile C4H8N2 详情 详情
(II) 10847 Acrylonitrile 107-13-1 C3H3N 详情 详情
(III) 25581 3-[(2-cyanoethyl)amino]-2-methylpropanenitrile C7H11N3 详情 详情
(IV) 25582 5-methyl-4-oxo-3-piperidinecarbonitrile C7H10N2O 详情 详情
(V) 25583 ethyl 3-cyano-5-methyl-4-oxo-1-piperidinecarboxylate C10H14N2O3 详情 详情
(VI) 25584 ethyl 3-(aminocarbonyl)-5-methyl-4-oxo-1-piperidinecarboxylate C10H16N2O4 详情 详情
(VII) 25585 ethyl 5-(aminocarbonyl)-4-(benzylamino)-3-methyl-3,6-dihydro-1(2H)-pyridinecarboxylate C17H23N3O3 详情 详情
(VIII) 25586 ethyl 3-hydroxy-7-methyl-6,7-dihydroisothiazolo[4,5-c]pyridine-5(4H)-carboxylate C10H14N2O3S 详情 详情
(IX) 25587 7-methyl-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-ol C7H10N2OS 详情 详情
(X) 25588 tert-butyl 3-hydroxy-7-methyl-6,7-dihydroisothiazolo[4,5-c]pyridine-5(4H)-carboxylate C12H18N2O3S 详情 详情
(XI) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(XII) 25589 7-methyl-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-yl 2-propynyl ether C10H12N2OS 详情 详情

合成路线25

该中间体在本合成路线中的序号：(IV)

This compound has been obtained by three related ways: 1) The condensation of (R)-tryptophan (I) with 2,2-dimethylpropanal (II) by means of NaOH in refluxing methanol yields the corresponding inmine (III), which is cyclized with ethyl chloroformate (IV) in dichloromethane to afford the oxazolidine (V). the regioselective methylation of (V) with methyl iodide and lithium diisopropylamide (LDA) in THF gives the new methylated oxazolidine (VI), which is finally hydrolyzed with refluxing 6N HCl. 2) Ring opening of oxazolidine (VI) with LiOH in methanol gives (R)-N-(ethoxycarbonyl)-alpha-methyltryptophan methyl ester (VII), which is hydrolyzed with 6N HCl as before. 3) Ring opening of oxazolidine (VI) with LiOH in methanol/water gives (R)-N-(ethoxycarbonyl)-alpha-methyltryptophan (VIII), which is hydrolyzed with 6N HCl as before.

参考文献 中间体
合成目标
【1】 Zhang, L.J.; Finn, J.M.; A facile method for the asymmetric synthesis of alpha-methyltryptophan. J Org Chem 1995, 60, 17, 5719.
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) 19796 D-2-Amino-3-(3-indolyl)propionic acid; D-tryptophan 153-94-6 C11H12N2O2 详情 详情
(II) 19797 Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal 630-19-3 C5H10O 详情 详情
(III) 19798 2(R)-(2,2-Dimethylpropylideneamino)-3-(1H-indol-3-yl)proionic acid sodium salt C16H19N2NaO2 详情 详情
(IV) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(V) 19800 ethyl (2R,4S)-2-(tert-butyl)-4-(1H-indol-3-ylmethyl)-5-oxo-1,3-oxazolidine-3-carboxylate C19H24N2O4 详情 详情
(VI) 19801 ethyl (2R,4R)-2-(tert-butyl)-4-(1H-indol-3-ylmethyl)-4-methyl-5-oxo-1,3-oxazolidine-3-carboxylate C20H26N2O4 详情 详情
(VII) 19802 methyl (2R)-2-[(ethoxycarbonyl)amino]-3-(1H-indol-3-yl)-2-methylpropanoate C16H20N2O4 详情 详情
(VIII) 19802 methyl (2R)-2-[(ethoxycarbonyl)amino]-3-(1H-indol-3-yl)-2-methylpropanoate C16H20N2O4 详情 详情

合成路线26

该中间体在本合成路线中的序号：(I)

A short and efficient synthesis of xemilofiban has been achieved as follows: The reaction of ethyl chloroformate (I) with trimethylsilylacetylene (II) by means of butyllithium gives ethyl 3-(trimethylsilyl)propyonate (III), which is condensed with the lithium salt of ethyl acetate (IV) yielding ethyl 5-(trimethylsilyl)-3-oxo-4-pentynoate (V). The selective reduction of (V) with lyophilized baker's yeast (Saccharomyces cerevisiae, Sigma type II) affords ethyl 3(R)-hydroxy-5-(trimethylsilyl)-4-pentynoate (VI), which by reaction with ammonia (VII), diethyl azodicarboxylate (VIII) and triphenylphosphine, followed by hydrolysis with water gives 3(S)-amino-5-(trimethylsilyl)-4-pentynoate (IX). Finally, this compound is condensed with N-(4-amidinophenyl)succinamic acid (XI) by means of isobutyl chloroformate and N-methylmorpholine (NMM). The intermediate succinamic acid (XI) has been obtained by condensation of 4-aminobenzamidine (XII) with succinic anhydride (XIII) in DMF.

参考文献 中间体
合成目标
【1】 Cossy, J.; Schmitt, A.; Cinquin, C.; Buisson, D.; Belotti, D.; A very short, efficient and inexpensive synthesis of the prodrug form of SC-54701A a platelet aggregation inhibitor. Bioorg Med Chem Lett 1997, 7, 13, 1699.
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) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(II) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(III) 23898 ethyl 3-(trimethylsilyl)-2-propynoate 29394-58-9 C8H14O2Si 详情 详情
(IV) 23899 lithium 1-ethoxy-1-ethylenolate C4H7LiO2 详情 详情
(V) 23900 ethyl 3-oxo-5-(trimethylsilyl)-4-pentynoate C10H16O3Si 详情 详情
(VI) 23901 ethyl (3R)-3-hydroxy-5-(trimethylsilyl)-4-pentynoate C10H18O3Si 详情 详情
(VIII) 20989 Diethylazadicarboxylate; Diethyl Azodiformate; Azodiformic Acid Diethyl Ester; Diethyl Azodicarboxylate; Azodicarboxylic Acid Diethyl Ester; Diethyl 1,2-diazenedicarboxylate 1972-28-7 C6H10N2O4 详情 详情
(IX) 23904 ethyl (3S)-3-amino-5-(trimethylsilyl)-4-pentynoate C10H19NO2Si 详情 详情
(X) 16297 ethyl (3S)-3-amino-4-pentynoate C7H11NO2 详情 详情
(XI) 16296 4-[4-[amino(imino)methyl]anilino]-4-oxobutyric acid C11H13N3O3 详情 详情
(XII) 16295 4-aminobenzenecarboximidamide hydrochloride; 4-aminobenzamidine 3858-83-1 C7H9N3 详情 详情
(XIII) 11291 Dihydro-2,5-furandione; Succinic anhydride 108-30-5 C4H4O3 详情 详情

合成路线27

该中间体在本合成路线中的序号：(III)

Reduction of 4,5-dimethoxybenzocyclobutane-1-carbonitrile (I) with BH3 in THF gives 4,5-dimethoxybenzocyclobutan-1-ylmethylamine (II), which is treated with ethyl chloroformate (III) and triethylamine in dichloromethane to yield carbamate (IV). Reduction of carbamate (IV) by means of LiAlH4 in THF provides racemic N-(4,5-dimethoxybenzocyclobutan-1-yl)-N-methylamine (V), which is submitted to optical resolution with camphorsulfonic acid (CSA) to afford the desired (S)-enantiomer (VI). Reaction of the known 3-(3-chloropropyl)-7,8-dimethoxy-2,3-dihydro-1H-3-benzazepin-2-one (VII) with NaI in acetone yields the corresponding 3-iodopropyl derivative (VIII), which is condensed with the chiral amine (VI) by means of K2CO3 in acetone to afford adduct (IX). Finally, this compound is hydrogenated with H2 over Pd(OH)2 in AcOH.

参考文献 中间体
合成目标
【2】 Peglion, J.-L.; Vian, J.; Vilaine, J.-P.; Villeneuve, N.; Janiak, P.; Bidouard, J.-P. (ADIR et Cie.); Benzocyclobutyl- or indanyl-alkyl-amino-alkyl substd. 3-benzazepin-2-ones useful in the treatment of cardiovascular diseases. EP 0534859; FR 2681862; JP 1993213890; US 5296482 .
【1】 Sorbera, L.A.; Castaner, J.; Ivabradine Hydrochloride. Drugs Fut 2003, 28, 7, 652.
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) 62954 3,4-bis(methyloxy)bicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile C11H11NO2 详情 详情
(II) 62955 [3,4-bis(methyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-yl]methanamine; [3,4-bis(methyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-yl]methylamine C11H15NO2 详情 详情
(III) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(IV) 62956 ethyl [3,4-bis(methyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-yl]methylcarbamate C14H19NO4 详情 详情
(V) 62957 N-{[3,4-bis(methyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-N-methylamine; [3,4-bis(methyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine C12H17NO2 详情 详情
(VI) 62958 N-{[3,4-bis(methyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-N-methylamine; [3,4-bis(methyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine C12H17NO2 详情 详情
(VII) 24899 3-(3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one C15H18ClNO3 详情 详情
(VIII) 62959 3-(3-iodopropyl)-7,8-bis(methyloxy)-1,3-dihydro-2H-3-benzazepin-2-one C15H18INO3 详情 详情
(IX) 62960 3-{3-[{[3,4-bis(methyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino]propyl}-7,8-bis(methyloxy)-1,3-dihydro-2H-3-benzazepin-2-one C27H34N2O5 详情 详情

合成路线28

该中间体在本合成路线中的序号：(X)

Synthesis of EN 212779: Deprotection and esterification of pyrrolidine (IX) by first treatment with HCl (gas) in EtOH followed by reaction with ethyl chloroformate (X) and Et3N in acetone/H2O yields carbamate (XI), which is then reduced with LiBH4 in THF to give carbinol (XII). Conversion of alcohol (XII) into cyano derivative (XIII) is then accomplished by first tosylation with p-toluenesulfonic anhydride (Ts2O) and Et3N in dichloromethane followed by reaction with NaCN in DMF. Acidic ethanolysis of nitrile (XIII) by means of HCl in EtOH furnishes ethyl ester (XIV), which is reduced with LiAlH4 in THF to provide ethanol derivative (XV). Treatment of alcohol (XV) with Ts2O and Et3N in dichloromethane affords tosylate (XVI), which is converted into derivative (XVII) by condensation with intermediate (VIII) by means of KOtBu in dimethylacetamide (DMA). Debenzylation of (XVII) by hydrogenation over Pd/C in EtOH yields alcohol (XVIII), which is finally reduced with LiAlH4 in THF and hydrolyzed with HCl in dioxane to give the desired compound. Alternatively, the final product can be obtained by condensation of bromo derivative (XIX) with intermediate (VIII) by means of KOtBu in dimethylacetamide (DMA), furnishing compound (XX), which is finally reduced with LiAlH4 in THF and hydrolyzed with HCl.

参考文献 中间体
合成目标
【3】 Fujimoto, K.; Tanaka, N.; Asai, F.; Ito, T.; Koike, H. (Sankyo Co., Ltd.); Phenoxyalkylamines, -pyrrolidines and -piperidines for the treatment and prevention of circulatory diseases and psychosis. EP 0600717; JP 1994234736; JP 1994306025; US 5556864 .
【1】 Ogawa, T.; Sugidachi, A.; Goto, R.; Asai, T.; Tanaka, S.; Ito, R.; Hayakawa, M.; Fujimoto, K.; 2-(omega-Phenylalkyl)phenoxy)alkylamines III: Synthesis and selective serotonin-2 receptor binding (2). Chem Pharm Bull 2000, 48, 11, 1729.
【2】 Tanaka, N.; et al.; Antiplatelets with 5-HT2 receptor antagonistic action - Synthesis and structure-activity relationships of [2-(omega-phenylalkyl)phenoxy]alkylamines. 18th Symp Med Chem (Nov 25 1998, Kyoto) 1998, Abst 2-P-01.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 13604 2-(3-Methoxyphenethyl)phenol C15H16O2 详情 详情
(IX) 19059 (2R,4S)-4-(benzyloxy)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid 54631-81-1 C17H23NO5 详情 详情
(X) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(XI) 47634 diethyl (2S,4R)-4-(benzyloxy)-1,2-pyrrolidinedicarboxylate C17H23NO5 详情 详情
(XII) 47635 ethyl (2S,4R)-4-(benzyloxy)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate C15H21NO4 详情 详情
(XIII) 47636 ethyl (2R,4R)-4-(benzyloxy)-2-(cyanomethyl)-1-pyrrolidinecarboxylate C16H20N2O3 详情 详情
(XIV) 47637 ethyl (2S,4R)-4-(benzyloxy)-2-(2-ethoxy-2-oxoethyl)-1-pyrrolidinecarboxylate C18H25NO5 详情 详情
(XV) 47638 ethyl (2R,4R)-4-(benzyloxy)-2-(2-hydroxyethyl)-1-pyrrolidinecarboxylate C16H23NO4 详情 详情
(XVI) 47639 ethyl (2R,4R)-4-(benzyloxy)-2-(2-[[(4-methylphenyl)sulfonyl]oxy]ethyl)-1-pyrrolidinecarboxylate C23H29NO6S 详情 详情
(XVII) 47640 ethyl (2S,4R)-4-(benzyloxy)-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylate C31H37NO5 详情 详情
(XVIII) 47641 (2S,4R)-4-hydroxy-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylic acid C22H27NO5 详情 详情
(XIX) 47643 octyl (2S,4R)-2-(2-bromoethyl)-4-[[(dimethylamino)carbonyl]oxy]-1-pyrrolidinecarboxylate C18H33BrN2O4 详情 详情
(XX) 47644 octyl (2R,4R)-4-[[(dimethylamino)carbonyl]oxy]-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylate C33H48N2O6 详情 详情

合成路线29

该中间体在本合成路线中的序号：(II)

Synthesis of intermediate (XI): Treatment of 2,4-difluorophenol (I) with triethylamine and ethyl chloroformate (II) in dichloromethane yields O-ethoxycarbonyl-2,4-difluorophenol (III), which is then nitrated by means of HNO3/H2SO4 and hydrolyzed with Na2CO3 or NaHCO3 in MeOH/H2O to provide (IV). The nitro group of (IV) is then hydrogenated over Pd/C in EtOAc to afford 5-amino-2,4-difluorophenol (V), which is N-protected by reaction with pivaloyl chloride (VI) in pyridine to furnish pivaloylamino derivative (VII). Treatment of (VII) with 3,4-dihydro-2H pyran (VIII) and camphorsulfonic acid (CSA) in dichloromethane gives O-protected derivative (IX), which is converted into ethyl benzoate (X) by first reaction in THF with hexamethylphosphoric triamide (HMPA) and n-BuLi in hexane, followed by treatment with ethyl chloroformate (II). Finally, methylation of (X) by means of iodomethane (MeI) and LDA in THF/hexane yields intermediate (XI). Alternatively, intermediate (XI) can be also obtained by following this pathway: lithiation of derivative (IX) with LDA followed by treatment with TMSCl in THF affords trimethylsilylated compound (XII), which is converted into ethyl benzoate (XIII) by reaction with BuLi and ethyl chloroformate (II). Finally, TMS removal of (XIII) is achieved by treatment with tetrabutyl ammonium fluoride (TBAF) in THF to furnish derivative (X), which is methylated as described above.

参考文献 中间体
合成目标
【1】 Akama, T.; et al.; Synthesis of an ethyl 6-amino-3,5-difluorosalicylate derivative by sequential regioselective direct ortho-metalation; a practical synthesis of 4',5-diamino-3',6,8-trifluoroflavone, a potent antitumor agent. Synthesis 1997, 1446.
【2】 Saito, H.; Ishida, H.; Akama, T.; Kimura, U.; Gomi, K.; Structure-activity relationships of the 7-substituents of 5,4'-diamino-6,8,3'-trifluoroflavone, a potent antitumor agent. J Med Chem 1998, 41, 12, 2056.
【3】 Akama, T.; Ikeda, S.; Ishida, H.; Kimura, U.; Gomi, K.; Saito, H. (Kyowa Hakko Kogyo Co., Ltd.); 5-Aminoflavone derivs., their preparation and their use as antibacterial, anti-estrogenic and/or antitumor agent. EP 0638566; JP 1995109268 .
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) 21486 2,4-difluorophenol 367-27-1 C6H4F2O 详情 详情
(II) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(III) 46822 2,4-difluorophenyl ethyl carbonate C9H8F2O3 详情 详情
(IV) 46823 2,4-difluoro-5-nitrophenol C6H3F2NO3 详情 详情
(V) 46824 5-amino-2,4-difluorophenol C6H5F2NO 详情 详情
(VI) 13597 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride 3282-30-2 C5H9ClO 详情 详情
(VII) 46825 N-(2,4-difluoro-5-hydroxyphenyl)-2,2-dimethylpropanamide C11H13F2NO2 详情 详情
(VIII) 13684 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran 110-87-2 C5H8O 详情 详情
(IX) 46826 N-[2,4-difluoro-5-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2,2-dimethylpropanamide C16H21F2NO3 详情 详情
(X) 46827 ethyl 2-[(2,2-dimethylpropanoyl)amino]-3,5-difluoro-6-(tetrahydro-2H-pyran-2-yloxy)benzoate C19H25F2NO5 详情 详情
(XI) 46828 ethyl 2-[(2,2-dimethylpropanoyl)amino]-3,5-difluoro-4-methyl-6-(tetrahydro-2H-pyran-2-yloxy)benzoate C20H27F2NO5 详情 详情
(XII) 46829 N-[2,4-difluoro-5-(tetrahydro-2H-pyran-2-yloxy)-3-(trimethylsilyl)phenyl]-2,2-dimethylpropanamide C19H29F2NO3Si 详情 详情
(XIII) 46830 ethyl 2-[(2,2-dimethylpropanoyl)amino]-3,5-difluoro-6-(tetrahydro-2H-pyran-2-yloxy)-4-(trimethylsilyl)benzoate C22H33F2NO5Si 详情 详情

合成路线30

该中间体在本合成路线中的序号：

The intermediate N-Boc-amino acid (VII) was synthesized as shown in Scheme 25409101a. Treatment of 3-(tert-butoxycarbonylamino)-3-methylbutanoic acid (I) with ethyl chloroformate and Et3N, followed by reduction of the resulting mixed anhydride (II) with LiBH4, provided alcohol (III). Then, oxidation of (III) under Swern conditions yielded aldehyde (IV). Subsequent Horner-Emmons condensation of (IV) with triethyl phosphonoacetate (V) in the presence of potassium tert-butoxide gave ester (VI), which was saponified with LiOH to provide the required carboxylic acid (VII).

参考文献 中间体
合成目标
【1】 Hansen, T.K.; Ankersen, M.; Hansen, B.S.; Raun, K.; Nielsen, K.K.; Lau, J.; Peschke, B.; Lundt, B.F.; Thogersen, H.; Johansen, N.L.; Madsen, K.; Andersen, P.H.; Novel orally active growth hormone secretagogues. J Med Chem 1998, 41, 19, 3705.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
29841 Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride 79-37-8 C2Cl2O2 详情 详情
(I) 22193 3-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(II) 27229 3-(Tert-butoxycarbonylamino)-3-methyl butyric acid ethoxycarbonyl anhydride C13H23NO6 详情 详情
(III) 22194 tert-butyl 3-hydroxy-1,1-dimethylpropylcarbamate C10H21NO3 详情 详情
(IV) 22195 tert-butyl 1,1-dimethyl-3-oxopropylcarbamate C10H19NO3 详情 详情
(V) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(VI) 27230 ethyl (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoate C14H25NO4 详情 详情
(VII) 22191 (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoic acid C12H21NO4 详情 详情

合成路线31

该中间体在本合成路线中的序号：

Condensation of cyclopentanecarboxylic acid (VIII) with ethyl chloroformate in the presence of LDA afforded 1,1-cyclopentanedicarboxylic acid monoethyl ester (IX), which was coupled with phenethylamine (X) by means of TBTU to produce amide (XI). Ester hydrolysis of (XI) with NaOH gave carboxylic acid (XII), which was activated as the mixed anhydride (XIII) with isobutyl chloroformate, and then coupled to the chiral aminoboronate (VII), yielding diamide (XIV). Displacement of the bromine of (XIV) with NaN3, followed by hydrogenation of the resulting azide (XV) gave rise to amine (XVI). The chiral auxiliary of (XVI) was finally removed by treatment with phenylboronic acid.

参考文献 中间体
合成目标
【1】 Verbeuren, T.; Rupin, A.; De Nanteuil, G.; Gloanec, P.; New dicarbonyl cycloalkyl based thrombin inhibitors with improved activity and selectivity compared to (D)-Phe-Pro-boroArg derivatives . 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 201.
【2】 Gloanec, P.; Portevin, B.; Lila, C.; Rupin, A.; de Nanteuil, G.; Simonet, S.; Verbeuren, T. (ADIR et Cie.); Cpds. derived from boronic acid. EP 0792883; FR 2745288; US 5814622 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(VII) 32538 (1R)-5-bromo-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]-1-pentanamine; (1R)-5-bromo-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]pentylamine C15H27BBrNO2 详情 详情
(VIII) 20734 cyclopentanecarboxylic acid 3400-45-1 C6H10O2 详情 详情
(IX) 32539 1-(ethoxycarbonyl)cyclopentanecarboxylic acid C9H14O4 详情 详情
(X) 18333 Phenethylamine; 2-Phenyl-1-ethanamine 64-04-0 C8H11N 详情 详情
(XI) 32540 ethyl 1-[(phenethylamino)carbonyl]cyclopentanecarboxylate C17H23NO3 详情 详情
(XII) 32541 1-[(phenethylamino)carbonyl]cyclopentanecarboxylic acid C15H19NO3 详情 详情
(XIII) 32542 1-[N-(2-Phenylethyl)carbamoyl]cyclopentylcarbonyl isobutoxycarbonyl anhydride C20H27NO5 详情 详情
(XIV) 32543 N(1)-[(1R)-5-bromo-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]pentyl]-N(1)-phenethyl-1,1-cyclopentanedicarboxamide C30H44BBrN2O4 详情 详情
(XV) 32544 N(1)-[(1R)-5-azido-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]pentyl]-N(1)-phenethyl-1,1-cyclopentanedicarboxamide C30H44BN5O4 详情 详情
(XVI) 32545 N(1)-[(1R)-5-amino-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]pentyl]-N(1)-phenethyl-1,1-cyclopentanedicarboxamide C30H46BN3O4 详情 详情

合成路线32

该中间体在本合成路线中的序号：(IV)

The methylation of pyridine-4-carboxylic acid (X) gives the pyridinium iodide (XI), which is reduced with NaBH4 to yield 1-methyl-1,2,3,6-tetrahydropyridine-4-carboxylic acid ethyl ester (XII). The desmethylation of (XII) with ethyl chloroformate (XIII) affords 1,23,6-tetrahydropyridine-1,4-dicarboxylic acid diethyl ester (XIV), which is finally hydrolyzed and monodecarboxylated with HCl and TEA.

参考文献 中间体
合成目标
【1】 Christensen, V.; Krogsgaard-Larsen, P.; Falch, E.; Chemistry and pharmacology of the GABA agonists THIP (Gabodaxol) and isoguvacine. Drugs Fut 1984, 9, 8, 597.
【2】 Johnston, G.A.R.; Krogsgaard-Larsen, P.; Structure-activity studies on the inhibition of GABA binding to rat brain membranes by muscinol and related compounds. J Neurochem 1978, 30, 1377-1382.
【3】 Krogsgaard-Larsen, P.; Christensen, T.R.; GABA agonists. Synthesis and structure-activity studies on analogues of isoguvacine and THIP. Eur J Med Chem 1979, 14, 157-164.
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) 43671 ethyl isonicotinate 1570-45-2 C8H9NO2 详情 详情
(II) 43672 4-(ethoxycarbonyl)-1-methylpyridinium iodide C9H12INO2 详情 详情
(III) 43673 ethyl 1-methyl-1,2,3,6-tetrahydro-4-pyridinecarboxylate C9H15NO2 详情 详情
(IV) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(V) 43674 diethyl 3,6-dihydro-1,4(2H)-pyridinedicarboxylate C11H17NO4 详情 详情

合成路线33

该中间体在本合成路线中的序号：(IV)

The reaction of pyridine-4-carboxylic acid ethyl ester (I) with methyl iodide gives the pyridinium iodide (II), which is reduced with tritiated NaB3H4, yielding the tritiated tetrahydropyridine (III). The desmethylation of (III) with ethyl chloroformate (IV), followed by a treatment with HBr, affords the tritiated target compound.

参考文献 中间体
合成目标
【1】 Christensen, V.; Krogsgaard-Larsen, P.; Falch, E.; Chemistry and pharmacology of the GABA agonists THIP (Gabodaxol) and isoguvacine. Drugs Fut 1984, 9, 8, 597.
【2】 Krogsgaard-Larsen, P.; Christensen, S.B.; Preparations of deuterium labeled guvacine and isoguvacine. J Label Compd Radiopharm 1980, 17, 191-202.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 43671 ethyl isonicotinate 1570-45-2 C8H9NO2 详情 详情
(II) 43672 4-(ethoxycarbonyl)-1-methylpyridinium iodide C9H12INO2 详情 详情
(III) 43673 ethyl 1-methyl-1,2,3,6-tetrahydro-4-pyridinecarboxylate C9H15NO2 详情 详情
(IV) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情

合成路线34

该中间体在本合成路线中的序号：(XV)

The condensation of hydroxylamine with two equivalents of ethyl chloroformate (XV) afforded (XVI). The potassium salt of (XVI) was then alkylated with bromopropyl phosphonate (V) to yield (XVII), which was subsequently hydrolyzed to the intermediate (VIII) using HCl in HOAc.

参考文献 中间体
合成目标
【1】 Takeno, H.; Hemmi, K.; Hashimoto, M.; Kamiya, T. (Fujisawa Pharmaceutical Co., Ltd.); Hydroxyaminohydrocarbonphosphonic acids. DE 2733658; US 4182758; US 4206156 .
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) 39080 diethyl 3-bromopropylphosphonate C7H16BrO3P 详情 详情
(VIII) 39088 3-(hydroxyamino)propylphosphonic acid C3H10NO4P 详情 详情
(XV) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(XVI) 39092 1-[([[(ethoxycarbonyl)amino]oxy]carbonyl)oxy]ethane C6H11NO5 详情 详情
(XVII) 39094 4-ethoxy-8-(ethoxycarbonyl)-4,10-dioxo-3,9,11-trioxa-8-aza-4lambda(5)-phosphatridecane C13H26NO8P 详情 详情

合成路线35

该中间体在本合成路线中的序号：

Cyclization of (Xa, Xb) employing ethyl chloroformate and triethylamine generated the thiazoloazepine (XI) as the major diastereoisomer. Further hydrolysis of the methyl ester of (XI) with NaOH provided the key intermediate (XII). Finally, conversion to the title compound was accomplished by deprotection of the carbobenzoxy group of (XII) yielding (XIII), followed by coupling with S,S-2-acetylthio-3-methylpentanoic acid (XIV).

参考文献 中间体
合成目标
【1】 Akasaka, K.; et al.; Synthesis of a new dual metalloprotease inhibitor.II. Stereoselective synthesis of peptidomimetic [5.7]-bycyclic compounds. Chem Pharm Bull 1999, 47, 11, 1532.
【2】 Naka, H.; Negi, S.; Shimomura, N.; Ikuta, H.; Naito, T.; Fukuda, Y.; Shimizu, H.; Tagami, K.; Akasaka, K.; Yoneda, N.; Kotake, M.; Akamatsu, K.; Matsui, M.; Matsushima, T.; Komatsu, Y.; Suda, S. (Eisai Co., Ltd.); Preparation method of (9R)-optically active isomers and intermediates therefor. JP 1998291992 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(Xa) 35117 (2S,5R)-2-[[(benzyloxy)carbonyl]amino]-5-[(2R,4R)-4-(methoxycarbonyl)-1,3-thiazolidin-2-yl]hexanoic acid C19H26N2O6S 详情 详情
(Xb) 35118 (2S,5R)-2-[[(benzyloxy)carbonyl]amino]-5-[(2S,4R)-4-(methoxycarbonyl)-1,3-thiazolidin-2-yl]hexanoic acid C19H26N2O6S 详情 详情
(XI) 35119 methyl (3R,6S,9R,9aR)-6-[[(benzyloxy)carbonyl]amino]-9-methyl-5-oxooctahydro[1,3]thiazolo[3,2-a]azepine-3-carboxylate C19H24N2O5S 详情 详情
(XII) 35120 (3R,6S,9R,9aR)-6-[[(benzyloxy)carbonyl]amino]-9-methyl-5-oxooctahydro[1,3]thiazolo[3,2-a]azepine-3-carboxylic acid C18H22N2O5S 详情 详情
(XIII) 35121 (3R,6S,9R,9aR)-6-amino-9-methyl-5-oxooctahydro[1,3]thiazolo[3,2-a]azepine-3-carboxylic acid C10H16N2O3S 详情 详情
(XIV) 35122 (2S,3S)-2-(acetylsulfanyl)-3-methylpentanoic acid C8H14O3S 详情 详情

合成路线36

该中间体在本合成路线中的序号：(II)

Treatment of protected derivative (I) with ethyl chloroformate (II) and DMAP in dichloromethane yields (III), which is then protected by Mitsunobu reaction with benzyl alcohol (IV) in the presence of PPh3 and DEAD to provide (V). Coumarin (V) undergoes Mitsunobu reaction with noviose (VI) to afford alpha-glycoside (VII), which is converted into (VIII) by protection in 3'-OH by means of TESCl, imidazole and DIEA in dichloromethane (chromatographic separation of 3'- and 2'-TES-protected regioisomers is needed), followed by protection of the 2'-OH by treatment with DHP and catalytic TsOH in dichloromethane. Hydrogenolysis of (VIII) over Pd/C followed by desilylation with TBAF in THF affords intermediate (IX), which is then converted into N'-alkoxycarbamate (XII) by reaction with (X) and DMAP in dichloromethane to yield the corresponding p-nitrophenylcarbonate activated form, followed by reaction with hydroxylamine (XI) in DMF and catalysis of DMAP. Exchange of the 3-ester group in (XII) by hydroxylamine (XIII) in pyridine gives coumarin-3-hydroxamate derivative (XIV), which is finally deprotected of its THP form in MeOH and catalysis of TsOH.

参考文献 中间体
合成目标
【1】 Haesslein, J.-L.; Dupuis-Hamelin, C.; Periers, A.-M.; Ferroud, D.; Laurin, P.; Bonnefoy, A.; Lassaigne, P.; Misicki, B.; Klich, M.; Mauvais, P.; Coumarin inhibitors of gyrase B with N-propargyloxy-carbamate as an effective pyrrole bioisostere. Bioorg Med Chem Lett 2000, 10, 2, 161.
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) 42325 4-hydroxy-8-methyl-7-(tetrahydro-2H-pyran-2-yloxy)-2H-chromen-2-one C15H16O5 详情 详情
(II) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(III) 42326 ethyl 4-hydroxy-8-methyl-2-oxo-7-(tetrahydro-2H-pyran-2-yloxy)-2H-chromene-3-carboxylate C18H20O7 详情 详情
(IV) 18710 Benzyl alcohol; Phenylmethanol 100-51-6 C7H8O 详情 详情
(V) 42327 ethyl 4-(benzyloxy)-7-hydroxy-8-methyl-2-oxo-2H-chromene-3-carboxylate C20H18O6 详情 详情
(VI) 40547 (3R,4S,5R)-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2,3,4-triol C8H16O5 详情 详情
(VII) 42328 ethyl 4-(benzyloxy)-7-[[(2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-2-oxo-2H-chromene-3-carboxylate C27H30O10 详情 详情
(VIII) 42329 ethyl 4-(benzyloxy)-7-([(2R,3R,4R,5R)-5-methoxy-6,6-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-4-[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]oxy)-2-oxo-2H-chromene-3-carboxylate C38H52O11Si 详情 详情
(IX) 42330 ethyl 4-hydroxy-7-[[(2R,3R,4R,5R)-4-hydroxy-5-methoxy-6,6-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-2-yl]oxy]-2-oxo-2H-chromene-3-carboxylate C25H32O11 详情 详情
(X) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(XI) 38197 O-(2-propynyl)hydroxylamine; 3-(aminooxy)-1-propyne C3H5NO 详情 详情
(XII) 42331 ethyl 4-hydroxy-7-[[(2R,3R,4R,5R)-5-methoxy-6,6-dimethyl-4-([[(2-propynyloxy)amino]carbonyl]oxy)-3-(tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-2-yl]oxy]-2-oxo-2H-chromene-3-carboxylate C29H35NO13 详情 详情
(XIII) 42332 1-(aminooxy)-3-methyl-2-butene; O-(3-methyl-2-butenyl)hydroxylamine C5H11NO 详情 详情
(XIV) 42333 (3R,4R,5R,6R)-6-[[4-hydroxy-3-([[(3-methyl-2-butenyl)oxy]amino]carbonyl)-2-oxo-2H-chromen-7-yl]oxy]-3-methoxy-2,2-dimethyl-5-(tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-4-yl 2-propynyloxycarbamate C32H40N2O13 详情 详情

合成路线37

该中间体在本合成路线中的序号：(X)

Treatment of salicyl alcohol (I) with benzyl bromide (II) in DMF in the presence of KOtBu affords benzyloxybenzyl alcohol (III), which is converted into its chloride form (IV) by means of SOCl2 in THF. Reaction of (IV) with PPh3 in refluxing toluene gives triphenyl phosphonium chloride derivative (V), which is then subjected to a Wittig reaction with aldehyde (VI) to yield olefine (VII). Catalytic hydrogenolysis of (VII) over Pd/C provides phenol derivative (VIII), which is then alkylated by reaction with tosylate (XVI) and KOtBu in dimethylacetamide to yield (XVII). Finally, ethoxycarbonyl derivative (XVII) is reduced by means of LiAlH4 in THF and converted into its hydrochloride form by treatment with HCl in dioxane. Intermediate (XVI) can be prepared as follows: Protection of 2(S)-pyrrolidinemethanol (IX) by reaction with ethyl chloroformate in the presence of Et3N in dichloromethane affords carbamate (XI), which is tosylated by means of Ts2O and Et3N in dichloromethane to yield (XII). One carbon elongation of (XII) by reaction with NaCN in DMF provides (XIII), which is then converted into ester (XIV) by means of H2SO4 in EtOH. Reduction of ester (XIV) with LiAlH4 in THF gives alcohol (XV), which is finally tosylated by reaction with Ts2O and Et3N in dichloromethane.

参考文献 中间体
合成目标
【1】 Fujimoto, K.; Tanaka, N.; Asai, F.; Ito, T.; Koike, H. (Sankyo Co., Ltd.); Phenoxyalkylamines, -pyrrolidines and -piperidines for the treatment and prevention of circulatory diseases and psychosis. EP 0600717; JP 1994234736; JP 1994306025; US 5556864 .
【2】 Goto, R.; Hayakawa, M.; Ito, R.; Ogawa, T.; Sugidachi, A.; Tanaka, N.; Asai, F.; Fujimoto, K.; [2-(omega-Phenylalkyl)phenoxy]alkylamines II: Synthesis and selective serotonin-2 receptor binding. Chem Pharm Bull 2000, 48, 2, 245.
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) 42341 2-(hydroxymethyl)phenol 90-01-7 C7H8O2 详情 详情
(II) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(III) 42342 [2-(benzyloxy)phenyl]methanol C14H14O2 详情 详情
(IV) 42343 benzyl 2-(chloromethyl)phenyl ether; 1-(benzyloxy)-2-(chloromethyl)benzene C14H13ClO 详情 详情
(V) 42344 [2-(benzyloxy)benzyl](triphenyl)phosphonium chloride C32H28ClOP 详情 详情
(VI) 20589 3-methoxybenzaldehyde; m-Anisaldehyde 591-31-1 C8H8O2 详情 详情
(VII) 42345 1-(benzyloxy)-2-[(E)-2-(3-methoxyphenyl)ethenyl]benzene; benzyl 2-[(E)-2-(3-methoxyphenyl)ethenyl]phenyl ether C22H20O2 详情 详情
(VIII) 13604 2-(3-Methoxyphenethyl)phenol C15H16O2 详情 详情
(IX) 21347 (2S)pyrrolidinylmethanol 23356-96-9 C5H11NO 详情 详情
(X) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(XI) 42346 ethyl (2S)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate C8H15NO3 详情 详情
(XII) 42347 ethyl (2S)-2-([[(4-methylphenyl)sulfonyl]oxy]methyl)-1-pyrrolidinecarboxylate C15H21NO5S 详情 详情
(XIII) 42348 ethyl (2S)-2-(cyanomethyl)-1-pyrrolidinecarboxylate C9H14N2O2 详情 详情
(XIV) 42349 ethyl (2S)-2-(2-ethoxy-2-oxoethyl)-1-pyrrolidinecarboxylate C11H19NO4 详情 详情
(XV) 42350 ethyl (2S)-2-(2-hydroxyethyl)-1-pyrrolidinecarboxylate C9H17NO3 详情 详情
(XVI) 42351 ethyl (2S)-2-(2-[[(4-methylphenyl)sulfonyl]oxy]ethyl)-1-pyrrolidinecarboxylate C16H23NO5S 详情 详情
(XVII) 42352 ethyl (2S)-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylate C24H31NO4 详情 详情

合成路线38

该中间体在本合成路线中的序号：(C)

The starting phenylethylamine (I) is prepared by condensation of N-formyl-5-bromo-3,4-methylenedioxyphenylethylamine (VIII) with N-carbobenzoxy-3-methoxy-4-hydroxyphenylethylamine (IX) through an Ullman condensation catalysed by CuO, followed by elimination of the formyl group with HCl in methanol. Compound (VIII) is prepared as follows: 3,4-dihydroxy-5-bromobenzaldehyde (X) is methylenated with methylene bromide (A) and CuO in DMF giving 3,4-methylenedioxy-5-bromobenzaldehyde (XI), which is condensed with nitromethane (B) in acetic acid containing ammonium acetate affording 3,4-methylenedioxy-5-bromo-beta-nitrostyrene (XII). The reduction of (XII) under Clemensen conditions yields 3,4-methylenedioxy-5-bromophenylethylamine (XIII), which is finally formylated with formic acid in decalin. Compound (IX) is prepared as follows: 3-methoxy-4-hydroxy-beta-nitrostyrene (XIV) is treated with ethyl chloroformate (C) in pyridine yielding the corresponding ethoxycarbonyl derivative (XV), which is reduced under Clemensen conditions to 3-methoxy-4-ethoxycarbonyloxyphenylethylamine (XVI). Finally, this compound is treated first with benzyloxycarbonyl chloride and then with aqueous NaHCO3.

参考文献 中间体
合成目标
【1】 Tomita, M.; et al.; Synthesis of di-cepharanthine. Tetrahedron Lett 1967, 1201-06.
【2】 Serradell, M.N.; Blancafort, P.; Mealy, N.; Castañer, J.; Cepharanthine. Drugs Fut 1979, 4, 7, 481.
【3】 Kondo, H.; et al.; US 2206407 .
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) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(B) 39563 nitromethane 75-52-5 CH3NO2 详情 详情
(I) 39554 benzyl 4-[[6-(2-aminoethyl)-1,3-benzodioxol-4-yl]oxy]-3-methoxyphenethylcarbamate C26H28N2O6 详情 详情
(VIII) 39566 2-(7-bromo-1,3-benzodioxol-5-yl)ethylformamide C10H10BrNO3 详情 详情
(IX) 39570 benzyl 3-hydroxy-4-methoxyphenethylcarbamate C17H19NO4 详情 详情
(X) 39561 3-bromo-4,5-dihydroxybenzaldehyde 16414-34-9 C7H5BrO3 详情 详情
(XI) 39562 7-bromo-1,3-benzodioxole-5-carbaldehyde C8H5BrO3 详情 详情
(XII) 39564 4-bromo-6-[(E)-2-nitroethenyl]-1,3-benzodioxole C9H6BrNO4 详情 详情
(XIII) 39565 2-(7-bromo-1,3-benzodioxol-5-yl)ethylamine; 2-(7-bromo-1,3-benzodioxol-5-yl)-1-ethanamine C9H10BrNO2 详情 详情
(XIV) 39567 2-methoxy-5-[(E)-2-nitroethenyl]phenol C9H9NO4 详情 详情
(XV) 39568 ethyl 2-methoxy-5-[(E)-2-nitroethenyl]phenyl carbonate C12H13NO6 详情 详情
(XVI) 39569 5-(2-aminoethyl)-2-methoxyphenyl ethyl carbonate C12H17NO4 详情 详情
(C) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情

合成路线39

该中间体在本合成路线中的序号：(X)

Synthesis of EN 296245: Deprotection and esterification of pyrrolidine (IX) by first treatment with HCl (gas) in EtOH followed by reaction with ethyl chloroformate (X) and Et3N in acetone/H2O, yields carbamate (XI), which is then reduced with LiBH4 in THF to give derivative (XII). Conversion of alcohol (XII) into cyano derivative (XIII) is then accomplished by first tosylation with p-toluenesulfonic anhydride (Ts2O) and Et3N in dichloromethane, followed by reaction with NaCN in DMF. Acidic ethanolysis of nitrile (XIII) by means of HCl in EtOH furnishes ethyl ester (XIV), which is reduced with LiAlH4 in THF to provide derivative (XV). Treatment of alcohol (XV) with Ts2O and Et3N in dichloromethane affords tosylate (XVI), which is converted into derivative (XVII) by condensation with intermediate (VIII) by means of KOtBu in dimethylacetamide (DMA). Debenzylation of (XVII) by hydrogenation over Pd/C in EtOH yields alcohol (XVIII), which is converted into alcohol (XIX) by treatment with LiAlH4 in THF, followed by hydrolysis with HCl in dioxane. Alternatively, derivative (XIX) can be obtained by condensation of bromo derivative (XX) with intermediate (VIII) by means of KOtBu in dimethylacetamide (DMA) to furnish compound (XXI), followed by reduction with LiAlH4 in THF and hydrolysis with HCl. Finally, esterification of (XIX) with lauric anhydride (XXII) by means of DMAP in pyridine yields the target product.

参考文献 中间体
合成目标
【1】 Ogawa, T.; Sugidachi, A.; Goto, R.; Asai, T.; Tanaka, S.; Ito, R.; Hayakawa, M.; Fujimoto, K.; 2-(omega-Phenylalkyl)phenoxy)alkylamines III: Synthesis and selective serotonin-2 receptor binding (2). Chem Pharm Bull 2000, 48, 11, 1729.
【2】 Tanaka, N.; et al.; Antiplatelets with 5-HT2 receptor antagonistic action - Synthesis and structure-activity relationships of [2-(omega-phenylalkyl)phenoxy]alkylamines. 18th Symp Med Chem (Nov 25 1998, Kyoto) 1998, Abst 2-P-01.
【4】 Asai, F.; Fujimoto, K. (Sankyo Co., Ltd.); Compsn. containing diarylalkane deriv. as the active ingredient for treating or preventing pancreatitis. JP 1998212232; WO 9823271 .
【3】 Fujimoto, K.; Tanaka, N.; Asai, F.; Ito, T.; Koike, H. (Sankyo Co., Ltd.); Phenoxyalkylamines, -pyrrolidines and -piperidines for the treatment and prevention of circulatory diseases and psychosis. EP 0600717; JP 1994234736; JP 1994306025; US 5556864 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 13604 2-(3-Methoxyphenethyl)phenol C15H16O2 详情 详情
(IX) 19059 (2R,4S)-4-(benzyloxy)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid 54631-81-1 C17H23NO5 详情 详情
(X) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(XI) 47634 diethyl (2S,4R)-4-(benzyloxy)-1,2-pyrrolidinedicarboxylate C17H23NO5 详情 详情
(XII) 47635 ethyl (2S,4R)-4-(benzyloxy)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate C15H21NO4 详情 详情
(XIII) 47636 ethyl (2R,4R)-4-(benzyloxy)-2-(cyanomethyl)-1-pyrrolidinecarboxylate C16H20N2O3 详情 详情
(XIV) 47637 ethyl (2S,4R)-4-(benzyloxy)-2-(2-ethoxy-2-oxoethyl)-1-pyrrolidinecarboxylate C18H25NO5 详情 详情
(XV) 47638 ethyl (2R,4R)-4-(benzyloxy)-2-(2-hydroxyethyl)-1-pyrrolidinecarboxylate C16H23NO4 详情 详情
(XVI) 47639 ethyl (2R,4R)-4-(benzyloxy)-2-(2-[[(4-methylphenyl)sulfonyl]oxy]ethyl)-1-pyrrolidinecarboxylate C23H29NO6S 详情 详情
(XVII) 47640 ethyl (2S,4R)-4-(benzyloxy)-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylate C31H37NO5 详情 详情
(XVIII) 47641 (2S,4R)-4-hydroxy-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylic acid C22H27NO5 详情 详情
(XIX) 47642 (3R,5S)-5-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-methyl-3-pyrrolidinol C22H29NO3 详情 详情
(XX) 47643 octyl (2S,4R)-2-(2-bromoethyl)-4-[[(dimethylamino)carbonyl]oxy]-1-pyrrolidinecarboxylate C18H33BrN2O4 详情 详情
(XXI) 47644 octyl (2R,4R)-4-[[(dimethylamino)carbonyl]oxy]-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylate C33H48N2O6 详情 详情
(XXII) 47645 dodecanoic anhydride C24H46O3 详情 详情

合成路线40

该中间体在本合成路线中的序号：(VIII)

In one strategy, Horner–Emmons condensation of tetracyclic aldehyde (I) with pyridylmethyl phosphonate (II) by means of BuLi in THF gives the olefin adduct (III), which, after desilylation to the corresponding hydroxypyridine with TBAF in THF, is treated with Tf2O in pyridine to afford the pyridyl triflate (IV). Suzuki coupling of triflate (IV) with 3-fluorophenylboronic acid (V) by means of Pd(PPh3)4 and K2CO3 in toluene/EtOH/H2O at 100 °C gives the phenylpyridine derivative (VI). After hydrolysis of the ethylene ketal group in compound (VI) by means of HCl in acetone at 50 °C, the resulting tricyclic ketone is reductively aminated with NH3 and NaBH3CN in the presence of Ti(O-i-Pr)4 and TiCl4 in EtOH/CH2Cl2 to yield a diastereomeric mixture of primary amines that are separated by preparative TLC, providing the 6(R)-amine (VII). Finally, amine (VII) is acylated with ethyl chloroformate (VIII) in the presence of Et3N in CH2Cl2 .
In another strategy, N-acylation of the tricyclic amino acid (IX) with ethyl chloroformate (VIII) yields the carbamate (X), which, after reduction of the carboxyl group to the corresponding aldehyde (XI), is subjected to Wittig reaction with phosphonate (XII) .

参考文献 中间体
合成目标
【1】 Chackalamannil, S., Wang, Y., Greenlee, W.J. et al. Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity. J Med Chem 2008, 51(11): 3061-4.
【2】 Chackalamannil, S., Greenlee, W.J., Xia, Y., Chelliah, M., Clasby, M.C., Wang, Y., Veltri, E.P. (Schering Corp.). Tricyclic thrombin receptor antagonists. EP 1495018, EP 1860106, EP 1982984, EP 2062890, EP 2065384, JP 2005528406, JP 2010132710, US 2003216437, US 7304078, WO 200308928.
【3】 Sudhakar, A., Kwok, D.-I., Wu, G.G., Green, M.D., Thiruvengadam, T.K., Lim, N.K., Wang, T., Huang, M. (Schering Corp.). An exo-selective synthesis of himbacine analogs. EP 1846385, JP 2008526974, US 2006217422, US 7772276, WO 2006076452.
【4】 Wu, G., Sudhakar, A.R., Wang, T. et al. (Schering Corp.). Exo- and diastereo- selective synthesis of himbacine analogs. CA 2594871, EP 1848705, EP 2196454, EP 2196468, EP 2206697, JP 2008526972, US 2006247450, WO 2006076415.
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) 68713 (1'R,3a'R,4a'R,8a'R,9a'S)-1'-methyl-3'- oxodecahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho [2,3-c]furan]-9'-carbaldehyde 　 C16H22O5 详情 详情
(II) 68703 diethyl ((5-((triisopropylsilyl)oxy)pyridin-2-yl)methyl)phosphonate 　 C19H36NO4PSi 详情 详情
(III) 68712 (1'R,3a'R,4a'R,8a'R,9'S,9a'S)-1'-methyl-9'-((E)-2-(5-((triisopropylsilyl)oxy)pyridin-2-yl)vinyl)octahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho[2,3-c]furan]-3'(7'H)-one 　 C31H47NO5Si 详情 详情
(IV) 68711 6-((E)-2-((1'R,3a'R,4a'R,8a'R,9'S,9a'S)-1'-methyl-3'-oxodecahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho[2,3-c]furan]-9'-yl)vinyl)pyridin-3-yl trifluoromethanesulfonate 　 C23H26F3NO7S 详情 详情
(V) 68704 3-fluorophenylboronic acid;3-Fluorobenzeneboronic acid 768-35-4 C6H6BFO2 详情 详情
(VI) 68710 (1'R,3a'R,4a'R,8a'R,9'S,9a'S)-9'-((E)-2-(5-(3-fluorophenyl)pyridin-2-yl)vinyl)-1'-methyloctahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho[2,3-c]furan]-3'(7'H)-one 　 C28H30FNO4 详情 详情
(VII) 68709 7-amino-4-((E)-2-(5-(3-fluorophenyl)pyridin-2-yl)vinyl)-3-methyldecahydronaphtho[2,3-c]furan-1(3H)-one 　 C26H29FN2O2 详情 详情
(VIII) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(IX) 68708 (3S,3aS,4R,4aS,7S,8aS,9aS)-7-amino-3-methyl-1-oxododecahydronaphtho[2,3-c]furan-4-carboxylic acid 　 C14H21NO4 详情 详情
(X) 68707 (3S,3aS,4R,4aS,7S,8aS,9aS)-7-((ethoxycarbonyl)amino)-3-methyl-1-oxododecahydronaphtho[2,3-c]furan-4-carboxylic acid 　 C17H25NO6 详情 详情
(XI) 68706 ethyl ((1S,3aS,4aS,6S,8aS,9R,9aR)-9-formyl-1-methyl-3-oxododecahydronaphtho[2,3-c]furan-6-yl)carbamate 　 C17H25NO5 详情 详情
(XII) 68705 diethyl ((5-(3-fluorophenyl)pyridin-2-yl)methyl)phosphonate 　 C16H19FNO3P 详情 详情

合成路线41

该中间体在本合成路线中的序号：(VIII)

Hydrolysis of (5,5-ethylenedioxy-1-cyclohexenyl)acrylic acid (XVI) with p-TsOH followed by reductive amination with NH4OAc and NaBH3CN and N-acylation of the obtained amine with ethyl chloroformate (VIII) gives carbamate (XLI) as a racemic mixture, which is resolved by means of chiral HPLC, providing the (R)-enantiomer (XLII). Esterification of acid (XLII) with allylic alcohol (XXXII) in the presence of EDC and DMAP in CH2Cl2 yields the corresponding ester (XLIII), which by intramolecular Diels–Alder cyclization in xylene at 147 °C followed by epimerization in the presence of DBU furnishes the tricyclic intermediate (XLIV). Catalytic hydrogenation of alkene (XLIV) over Pt/C affords the saturated compound (XLV) , which is finally hydrolyzed with NaOH . Alternatively, condensation of nitro acid (XXXVII) with the hydroxypentynamide (XXX) by means of pivaloyl chloride, NMP and DMAP yields ester (XLVI), which is submitted to partial hydrogenation over Lindlar catalyst poisoned with quinoline to afford triene (XLVII). Thermal Diels–Alder cyclization of compound (XLVII) followed by epimerization in the presence of DBU provides the tricyclic carbamide (XLVIII). Simultaneous nitro group and olefin reduction in compound (XLVIII) by means of H2 and Pt/C or by transfer hydrogenation with HCOOH and Pd/C leads to the tricyclic amine (XLIX), which is finally acylated with ethyl chloroformate (VIII) to afford the corresponding carbamate (XLV) .
Other synthetic approaches to intermediate (X) include alkaline cleavage of benzothiazolyl ketone (L) (4) and hydrogenation/debenzylation of the unsaturated precursor (LI) over Pt/C .

参考文献 中间体
合成目标
【1】 Sudhakar, A., Kwok, D.-I., Wu, G.G., Green, M.D., Thiruvengadam, T.K., Lim, N.K., Wang, T., Huang, M. (Schering Corp.). An exo-selective synthesis of himbacine analogs. EP 1846385, JP 2008526974, US 2006217422, US 7772276, WO 2006076452.
【2】 Wu, G., Sudhakar, A.R., Wang, T. et al. (Schering Corp.). Exo- and diastereo- selective synthesis of himbacine analogs. CA 2594871, EP 1848705, EP 2196454, EP 2196468, EP 2206697, JP 2008526972, US 2006247450, WO 2006076415.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(X) 68707 (3S,3aS,4R,4aS,7S,8aS,9aS)-7-((ethoxycarbonyl)amino)-3-methyl-1-oxododecahydronaphtho[2,3-c]furan-4-carboxylic acid 　 C17H25NO6 详情 详情
(XVI) 68716 (E)-3-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)acrylic acid 　 C11H14O4 详情 详情
(XXXII) 68728 (R,E)-4-hydroxy-N,N-diphenylpent-2-enamide;4(R)-hydroxy-N,Ndiphenyl-2-pentenamide 　 C17H17NO2 详情 详情
(XLI) 68737 (E)-3-(5-((ethoxycarbonyl)amino)cyclohex-1-en-1-yl)acrylic acid 　 C12H17NO4 详情 详情
(XLII) 68738 (R,E)-3-(5-((ethoxycarbonyl)amino)cyclohex-1-en-1-yl)acrylic acid 　 C12H17NO4 详情 详情
(XLIII) 68739 (E)-(R,Z)-5-(diphenylamino)-5-oxopent-3-en-2-yl 3-((R)-5-((ethoxycarbonyl)amino)cyclohex-1-en-1-yl)acrylate 　 C29H32N2O5 详情 详情
(XLIV) 68745 ethyl ((1R,3aR,6S,8aR,9S,9aS)-9-(diphenylcarbamoyl)-1-methyl-3-oxo-1,3,3a,5,6,7,8,8a,9,9a-decahydronaphtho[2,3-c]furan-6-yl)carbamate 　 C29H32N2O5 详情 详情
(XLV) 68744 ethyl ((1R,3aR,4aR,6S,8aS,9S,9aS)-9-(diphenylcarbamoyl)-1-methyl-3-oxododecahydronaphtho[2,3-c]furan-6-yl)carbamate 　 C29H34N2O5 详情 详情
(XLVI) 68740 (E)-(R)-5-(diphenylamino)-5-oxopent-3-yn-2-yl 3-(5-nitrocyclohex-1-en-1-yl)acrylate 　 C26H24N2O5 详情 详情
(XLVII) 68741 (E)-(R,Z)-5-(diphenylamino)-5-oxopent-3-en-2-yl 3-(5-nitrocyclohex-1-en-1-yl)acrylate 　 C26H26N2O5 详情 详情
(XLVIII) 68743 (3R,3aS,4R,4aR,7S,9aS)-3-methyl-7-nitro-1-oxo-N,N-diphenyl-1,3,3a,4,4a,5,6,7,8,9a-decahydronaphtho[2,3-c]furan-4-carboxamide 　 C26H26N2O5 详情 详情
(XLIX) 68742 (3R,3aS,4R,4aR,7S,8aS,9aS)-7-amino-3-methyl-1-oxo-N,N-diphenyldodecahydronaphtho[2,3-c]furan-4-carboxamide 　 C26H30N2O3 详情 详情
(L) 68746 ethyl ((1R,3aR,4aR,6R,8aR,9S,9aS)-9-(benzo[d]thiazole-2-carbonyl)-1-methyl-3-oxododecahydronaphtho[2,3-c]furan-6-yl)carbamate 　 C24H28N2O5S 详情 详情
(LI) 68747 (3S,3aS,4R,4aS,7S,9aS)-benzyl 7-((ethoxycarbonyl)amino)-3-methyl-1-oxo-1,3,3a,4,4a,5,6,7,8,9a-decahydronaphtho[2,3-c]furan-4-carboxylate 　 C24H29NO6 详情 详情

合成路线42

该中间体在本合成路线中的序号：(VIII)

Partial hydrogenation of propargylic ester (LII) over Lindlar catalyst deactivated with quinoline in toluene gives the triene compound (LIII), which by intramolecular Diels–Alder reaction in NMP at 145 °C followed by epimerization with DBU yields the tricyclic adduct (LIV). Reduction of the nitro group of intermediate (LIV) by means of H2 and Pd/C yields amine (LV), which is finally N-acylated with ethyl chloroformate (VIII) to afford intermediate (L) .
The condensation of acid (XLII) with benzyl hydroxypentynoate (XXIII) by means of pivaloyl chloride, Et3N and DMAP yields ester adduct (LVI), which is submitted to partial hydrogenation in the presence of Lindlar catalyst and quinoline to afford trienoate (LVII). Finally, Diels–Alder cyclization of (LVII) and subsequent epimerization with DBU provides the tricyclic lactone (LI) .

参考文献 中间体
合成目标
【1】 Sudhakar, A., Kwok, D.-I., Wu, G.G., Green, M.D., Thiruvengadam, T.K., Lim, N.K., Wang, T., Huang, M. (Schering Corp.). An exo-selective synthesis of himbacine analogs. EP 1846385, JP 2008526974, US 2006217422, US 7772276, WO 2006076452.
【2】 Wu, G., Sudhakar, A.R., Wang, T. et al. (Schering Corp.). Exo- and diastereo- selective synthesis of himbacine analogs. CA 2594871, EP 1848705, EP 2196454, EP 2196468, EP 2206697, JP 2008526972, US 2006247450, WO 2006076415.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(L) 68746 ethyl ((1R,3aR,4aR,6R,8aR,9S,9aS)-9-(benzo[d]thiazole-2-carbonyl)-1-methyl-3-oxododecahydronaphtho[2,3-c]furan-6-yl)carbamate 　 C24H28N2O5S 详情 详情
(VIII) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(XXIII) 68723 (R)-benzyl 4-hydroxypent-2-ynoate 　 C12H12O3 详情 详情
(XLII) 68738 (R,E)-3-(5-((ethoxycarbonyl)amino)cyclohex-1-en-1-yl)acrylic acid 　 C12H17NO4 详情 详情
(LI) 68747 (3S,3aS,4R,4aS,7S,9aS)-benzyl 7-((ethoxycarbonyl)amino)-3-methyl-1-oxo-1,3,3a,4,4a,5,6,7,8,9a-decahydronaphtho[2,3-c]furan-4-carboxylate 　 C24H29NO6 详情 详情
(LII) 68749 (E)-(R)-5-(benzo[d]thiazol-2-yl)-5-oxopent-3-yn-2-yl 3-(5-nitrocyclohex-1-en-1-yl)acrylate 　 C21H18N2O5S 详情 详情
(LIII) 68748 (E)-(R,Z)-5-(benzo[d]thiazol-2-yl)-5-oxopent-3-en-2-yl 3-(5-nitrocyclohex-1-en-1-yl)acrylate 　 C21H20N2O5S 详情 详情
(LIV) 68751 (3R,3aS,4R,4aS,7S,9aS)-4-(benzo[d]thiazole-2-carbonyl)-3-methyl-7-nitro-3,3a,4,4a,5,6,7,8-octahydronaphtho[2,3-c]furan-1(9aH)-one 　 C21H20N2O5S 详情 详情
(LV) 68750 (3R,3aS,4R,4aS,7S,8aR,9aS)-7-amino-4-(benzo[d]thiazole-2-carbonyl)-3-methyldecahydronaphtho[2,3-c]furan-1(3H)-one 　 C21H24N2O3S 详情 详情
(LVI) 68753 (R)-benzyl 4-(((E)-3-((R)-5-((ethoxycarbonyl)amino)cyclohex-1-en-1-yl)acryloyl)oxy)pent-2-ynoate 　 C24H27NO6 详情 详情
(LVII) 68752 (R,Z)-benzyl 4-(((E)-3-((S)-5-((ethoxycarbonyl)amino)cyclohex-1-en-1-yl)acryloyl)oxy)pent-2-enoate 　 C24H29NO6 详情 详情
Extended Information