Yaozh News Star Club Edu BBS TOP100 Customer Service APP
Iphone Download Android Download
  • English
  • 简体中文
Login Register
Search
Current Location： Home > Feedback Help Print

【结 构 式】

【分子编号】10388

【品名】Morpholine

【CA登记号】110-91-8

【 分 子 式 】C4H9NO

【 分 子 量 】87.1216

【元素组成】C 55.15% H 10.41% N 16.08% O 18.36%
与该中间体有关的原料药合成路线共 77 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20合成路线21合成路线22合成路线23合成路线24合成路线25合成路线26合成路线27合成路线28合成路线29合成路线30合成路线31合成路线32合成路线33合成路线34合成路线35合成路线36合成路线37合成路线38合成路线39合成路线40合成路线41合成路线42合成路线43合成路线44合成路线45合成路线46合成路线47合成路线48合成路线49合成路线50合成路线51合成路线52合成路线53合成路线54合成路线55合成路线56合成路线57合成路线58合成路线59合成路线60合成路线61合成路线62合成路线63合成路线64合成路线65合成路线66合成路线67合成路线68合成路线69合成路线70合成路线71合成路线72合成路线73合成路线74合成路线75合成路线76合成路线77

合成路线1

该中间体在本合成路线中的序号：(II)

The reaction of 3-trifluoromethylbenzaldehyde (I) with morpholine (II) and potassium cyanide by means of p-toluenesulfonic acid in refluxing THF gives alpha-(3-trifluoromethylphenyl)-4-morpholineacetonitrile (III), which is condensed with ethyl acrylate (IV) by means of KOH in THF yielding gamma-cyano-gamma-(3-trifluoromethylphenyl)-4-morpholinebutyric acid ethyl ester (V). The cyclization of (V) with hydrazine in refluxing ethanol affords 4,5-dihydro-6-(3-trifluoromethylphenyl)-3(2H)-pyridazinone (VI), which is dehydrogenated by treatment with Br2 in hot acetic acid to give 6-(3-trifluoromethylphenyl)-3(2H)-pyridazinone (VII). The reaction of (VII) with POCl3 at 100 C affords 3-chloro-6-(3-trifluoromethylphenyl)pyridazine (VIII), which is finally cyclized with acetylhydrazine (IX) in refluxing n-butanol.

参考文献 中间体
合成目标
【1】 Allen, G.R. Jr.; Hanifin, J.W. Jr.; Moran, D.B.; Albright, J.D.; 6-Phenyl-1,2,4-triazolo{8 4,3-b{9 pyridazine hypotensive agents. US 4112095 .
【2】 Albright, J.D.; et al.; Synthesis and anxiolytic activity of 6-(substituted-phenyl)-1,2,4-triazolo[4,3-b]pyridazines. J Med Chem 1981, 24, 5, 592-600.
【3】 Owen, R.T.; Serradell, M.N.; Blancafort, P.; Castaner, J.; CL-218,872. Drugs Fut 1983, 8, 3, 191.
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) 35964 3-(trifluoromethyl)benzaldehyde 454-89-7 C8H5F3O 详情 详情
(II) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(III) 35965 2-(4-morpholinyl)-2-[3-(trifluoromethyl)phenyl]acetonitrile C13H13F3N2O 详情 详情
(IV) 10164 ethyl acrylate 140-88-5 C5H8O2 详情 详情
(V) 35966 ethyl 4-cyano-4-(4-morpholinyl)-4-[3-(trifluoromethyl)phenyl]butanoate C18H21F3N2O3 详情 详情
(VI) 35937 3-amino-6-chloro-4-phenyl-3,4-dihydro-4-quinazolinol C14H12ClN3O 详情 详情
(VII) 35968 6-[3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone C11H7F3N2O 详情 详情
(VIII) 35969 3-chloro-6-[3-(trifluoromethyl)phenyl]pyridazine C11H6ClF3N2 详情 详情
(IX) 29262 acetohydrazide 1068-57-1 C2H6N2O 详情 详情

合成路线2

该中间体在本合成路线中的序号：(A)

The reaction of 6-isopropyl-4-oxo-4H-1-benzopyran-3-carbonitrile (I) with morpholine (A) and DMF in hot water gives 2-amino-6-isopropyl-4-oxo-4H-1-benzopyran-3-carboxaldehyde (II), which is cyclized with ethyl cyanoacetate (III) by means of piperidine (B) in refluxing ethanol yielding ethyl 2-amino-7-isopropyl-1-azaxanthone-3-carboxylate (IV). Finally, this compound is saponified by a treatment with sulfuric acid in refluxing acetic acid water.

参考文献 中间体
合成目标
【1】 Nohara, A.; Sugihara, H.; Ukawa, K. (Takeda Chemical Industries, Ltd.); 1-Azaxanthone-3-carboxylic acid. BE 0864647; DE 2809720; FR 2383185; GB 1597024; GB 1597025; JP 78111096; JP 78111097; JP 7988298; US 4143042; US 4255576; US 4299963 .
【2】 Serradell, M.N.; Castaner, J.; AA-673. Drugs Fut 1984, 9, 5, 311.
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) 10158 Piperidine 110-89-4 C5H11N 详情 详情
(A) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(I) 30568 6-isopropyl-4-oxo-4H-chromene-3-carbonitrile C13H11NO2 详情 详情
(II) 30569 2-amino-6-isopropyl-4-oxo-4H-chromene-3-carbaldehyde C13H13NO3 详情 详情
(III) 11877 Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate 105-56-6 C5H7NO2 详情 详情
(IV) 30570 ethyl 2-amino-7-isopropyl-5-oxo-5H-chromeno[2,3-b]pyridine-3-carboxylate C18H18N2O4 详情 详情

合成路线3

该中间体在本合成路线中的序号：(V)

The reaction of phenyl isothiocyanate (I) with 2-imino-1-methyl pyrrolidine (II) in benzene gives N-(1-methyl-2-pyrrolidinylidene)-N'-phenylthiourea (III), which is treated with iodomethane in refluxing acetone to afford methyl N-1-methyl-2-pyrrolidinylidene)-N'-phenylcarbamidothioate (IV). Finally, this compound is treated with morpholine in refluxing isopropanol.

参考文献 中间体
合成目标
【1】 Rasmussen, C.R. (Ortho-McNeil Pharmaceutical, Inc.); Nitrogen heterocyclic carboximidamide compounds. US 4211867 .
【2】 Castaner, J.; Serradell, M.N.; Linogliride. Drugs Fut 1986, 11, 4, 265.
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) 22146 1-isothiocyanatobenzene; phenyl isothiocyanate 103-72-0 C7H5NS 详情 详情
(II) 27770 1-methyl-2-pyrrolidinimine C5H10N2 详情 详情
(III) 27771 N-(1-methyl-2-pyrrolidinylidene)-N'-phenylthiourea C12H15N3S 详情 详情
(IV) 27772 1-methyl-2-[[(methylsulfanyl)(phenylimino)methyl]imino]pyrrolidine C13H17N3S 详情 详情
(V) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线4

该中间体在本合成路线中的序号：(C)

An alternative method of producing the 1,2-diethyl-4aminopyrazolidine (VIII) is by reduction of the corresponding nitro compound (VII), which is derived from 1,3-dimorpholino-2-nitropropane (VI) and 1,2-diethylhydrazine (II).

参考文献 中间体
合成目标
【1】 Lo, Y.S.; Munson, H.R.Jr. (A.H. Robins Co. Inc.); Synthesis of 4-nitro-1,2-hydrocarbyl pyrazolidines and process for preparation thereof. DE 3130833; FR 2490639; FR 2491065; GB 2081713; JP 3204859; JP 57059868; US 4309552; US 4358599 .
【2】 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
(II) 27381 1,2-diethylhydrazine C4H12N2 详情 详情
(VI) 27386 4-[3-(4-morpholinyl)-2-nitropropyl]morpholine C11H21N3O4 详情 详情
(VII) 27387 1,2-diethyl-4-nitropyrazolidine C7H15N3O2 详情 详情
(VIII) 27385 1,2-diethyl-4-pyrazolidinamine 70180-92-6 C7H17N3 详情 详情
(C) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线5

该中间体在本合成路线中的序号：(VI)

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6

该中间体在本合成路线中的序号：(VIII)

This compound can be prepared in several different ways: 1) By reaction of p-chlorobenzoyl chloride (I) with N-(2-aminoethyl)morpholine (II) in pyridine. 2) By reaction of p-chlorobenzoyl anhydride (III) with N-(2-aminoethyl)morpholine (II) in pyridine. 3) By reaction of methyl p-chlorobenzoate (IV) with N-(2-aminoethyl)morpholine (II) at 120 C. 4) By reaction of N-(p-chlorobenzoyl)succinimide (V) with N-(2-aminoethyl)morpholine (II) in dioxane. 5) By reaction of p-nitrophenyl p-chlorobenzoate (VI) with N-(2-aminoethyl)morpholine (II) in THF. 6) By reaction of p-chloro-N-(2-chloroethyl)benzamide (VII) with morpholine (VIII) at 100 C. 7) By reaction of p-chlorobenzoylaziridine (IX) with morpholine (VIII) in refluxing toluene. 8) By reaction of p-chlorobenzaldehyde (X) with N-(2-aminoethyl)morpholine (II) in refluxing benzene to give 4-[2-[(p-chlorobenzylidene)amino]ethyl]morpholine (XI), followed by an oxidation with H2O2 in methanol. 9) By reaction of p-chloro-N-(2-morpholinoethyl)thiobenzamide (XII) with lead tetraacetate in refluxing water. 11) By reaction of p-chlorobenzoic acid (XIV) with N-(2-aminoethyl)morpholine (II) by means of dicyclohexylcarbodiimide in pyridine, or by means of chloroformic acid ethyl ester and triethylamine in acetone. 10) By isomerization of (alpha-(p-chlorophenyl)-N-(2-morpholinoethyl)nitrone (XIII) in hot acetic acid - acetic anhydride, followed by a treatment with NaOH.

参考文献 中间体
合成目标
【1】 Bukard, W.; Wyss, P.C. (F. Hoffmann-La Roche AG); Benzamides. BE 0851422; CA 1076112; DE 2706179; FR 2340940; GB 1512194; JP 52100476; NL 7701144; US 4210754; ZA 7700488 .
【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Grau, M.; Moclobemide. Drugs Fut 1983, 8, 2, 124.
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) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情
(II) 12880 4-(2-Aminoethyl)morpholine; 2-(4-Morpholinyl)ethylamine; 2-(4-Morpholinyl)-1-ethanamine; N-(2-Aminoethyl)morpholine; N-Morpholine ethanamide 2038-03-1 C6H14N2O 详情 详情
(III) 30702 4-chloro-1-benzenecarboxylic anhydride C14H8Cl2O3 详情 详情
(IV) 30703 methyl 4-chlorobenzoate 1126-46-1 C8H7ClO2 详情 详情
(V) 30704 1-(4-chlorobenzoyl)-2,5-pyrrolidinedione C11H8ClNO3 详情 详情
(VI) 30705 4-nitrophenyl 4-chlorobenzoate C13H8ClNO4 详情 详情
(VII) 30706 4-chloro-N-(2-chloroethyl)benzamide C9H9Cl2NO 详情 详情
(VIII) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(IX) 30707 1-aziridinyl(4-chlorophenyl)methanone C9H8ClNO 详情 详情
(X) 29029 4-chlorobenzaldehyde 104-88-1 C7H5ClO 详情 详情
(XI) 30708 N-[(E)-(4-chlorophenyl)methylidene]-2-(4-morpholinyl)-1-ethanamine; N-[(E)-(4-chlorophenyl)methylidene]-N-[2-(4-morpholinyl)ethyl]amine C13H17ClN2O 详情 详情
(XII) 30709 4-chloro-N-[2-(4-morpholinyl)ethyl]benzenecarbothioamide C13H17ClN2OS 详情 详情
(XIII) 30710 [(Z)-(4-chlorophenyl)methylidene][2-(4-morpholinyl)ethyl]ammoniumolate C13H17ClN2O2 详情 详情
(XIV) 18359 p-chlorobenzoic acid; 4-chlorobenzoic acid 74-11-3 C7H5ClO2 详情 详情

合成路线7

该中间体在本合成路线中的序号：(A)

Heating of 3,6-dichloropyridazine (I) with hydrazine hydrate at 100 C gives 6-chloro-3-pyridazinylhydrazine (II). The hydrazino group is protected by transforming it with camphor (III) to the camphorhydrazone (IV), which is aminated by heating with morpholine to give the morpholinylhydrazone (V). After liberating the hydrazine function by acidic hydrolysis in a biphasic system, the resulting 6-morpholino-3-pyridazinylhydrazine (VI) is reacted either with tert-butylacetoacetate (VII) or with tert-butylpropiolate (VIII) to yield RGH-5526.

参考文献 中间体
合成目标
【1】 Inoue, H.; Yoshida, M.; Aizawa, H.; et al.; Eur J Med Chem 1984, 19, 6, 111-117.
【2】 Szilagyi, G.; et al. (Gedeon Richter Ltd.); Morpholino pyridazinylhydrazones. DE 2825861; FR 2394535; GB 2000125; HU 176972; JP 54016486; US 4259328; US 4308386 .
【3】 Nogradi, M.; RGH-5526. Drugs Fut 1985, 10, 1, 32.
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) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(I) 11292 3,6-Dichloropyridazine 141-30-0 C4H2Cl2N2 详情 详情
(II) 28922 3-chloro-6-hydrazinopyridazine 17284-97-8 C4H5ClN4 详情 详情
(III) 28926 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one 464-48-2 C10H16O 详情 详情
(IV) 28923 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one N-(6-chloro-3-pyridazinyl)hydrazone C14H19ClN4 详情 详情
(V) 28924 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one N-[6-(4-morpholinyl)-3-pyridazinyl]hydrazone C18H27N5O 详情 详情
(VI) 24847 4-(6-hydrazino-3-pyridazinyl)morpholine C8H13N5O 详情 详情
(VII) 27907 Acetoacetic acid tert-butyl ester;3-Oxo-butanoic acid 1,1-dimethylethyl estertert-butyl 3-oxobutanoate 1694-31-1 C8H14O3 详情 详情
(VIII) 28925 tert-butyl propiolate 13831-03-3 C7H10O2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(A)

The reaction of maleopimaric acid (I) with aqueous ammonia and heating at 170 C gives maleopimarimide (II), which by reaction with oxalyl chloride in benzene is converted into the corresponding acyl chloride (III). The reaction of (III) with morpholine (A) in benzene yields maleopimarimidyl morpholide (IV), which is finally condensed with ethanolamine (B) in refluxing methanol.

参考文献 中间体
合成目标
【1】 Danswan, G.W.; Ramm, P.J.; Matharu, S.; Taylor, J.B.; hepatoprotective agents. II. Maleopimaridyl morpholides. Arzneim-Forsch Drug Res 1976, 26, 12, 2190-92.
【2】 Thorpe, P.; Castaner, J.; RU 18492. Drugs Fut 1977, 2, 9, 623.
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) 10259 Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol 141-43-5 C2H7NO 详情 详情
(A) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(I) 40150 (1S,4R,5R,9R,10R,12R,13R,17R)-19-isopropyl-5,9-dimethyl-14,16-dioxo-15-oxapentacyclo[10.5.2.0(1,10).0(4,9).0(13,17)]nonadec-18-ene-5-carboxylic acid C24H32O5 详情 详情
(II) 40151 (1S,4R,5R,9R,10R,12R,13R,17R)-19-isopropyl-5,9-dimethyl-14,16-dioxo-15-azapentacyclo[10.5.2.0(1,10).0(4,9).0(13,17)]nonadec-18-ene-5-carboxylic acid C24H33NO4 详情 详情
(III) 40152 (1S,4R,5R,9R,10R,12R,13R,17R)-19-isopropyl-5,9-dimethyl-14,16-dioxo-15-azapentacyclo[10.5.2.0(1,10).0(4,9).0(13,17)]nonadec-18-ene-5-carbonyl chloride C24H32ClNO3 详情 详情
(IV) 40153 (1S,4R,5R,9R,10R,12R,13R,17R)-19-isopropyl-5,9-dimethyl-5-(4-morpholinylcarbonyl)-15-azapentacyclo[10.5.2.0(1,10).0(4,9).0(13,17)]nonadec-18-ene-14,16-dione C28H40N2O4 详情 详情

合成路线9

该中间体在本合成路线中的序号：(A)

The reaction of maleopimaric acid (I) with SOCl2 in benzene produces the corresponding acyl chloride (V), which is then condensed with morpholine (A) by means of Et3N in benzene yielding maleopimaryl morpholide (VI). Finally, (VI) is condensed with ethanolamine (B) in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Taylor, J.B.; et al. (Aventis Pharma SA); Novel derivatives of maleopimaric acid. DE 2351343; FR 2202691; GB 1417996; JP 49093356; US 3998823 .
【2】 Thorpe, P.; Castaner, J.; RU 18492. Drugs Fut 1977, 2, 9, 623.
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) 10259 Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol 141-43-5 C2H7NO 详情 详情
(A) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(I) 40150 (1S,4R,5R,9R,10R,12R,13R,17R)-19-isopropyl-5,9-dimethyl-14,16-dioxo-15-oxapentacyclo[10.5.2.0(1,10).0(4,9).0(13,17)]nonadec-18-ene-5-carboxylic acid C24H32O5 详情 详情
(V) 40155 (1S,4R,5R,9R,10R,12R,13R,17R)-19-isopropyl-5,9-dimethyl-14,16-dioxo-15-oxapentacyclo[10.5.2.0(1,10).0(4,9).0(13,17)]nonadec-18-ene-5-carbonyl chloride C24H31ClO4 详情 详情
(VI) 40154 (1S,4R,5R,9R,10R,12R,13R,17R)-19-isopropyl-5,9-dimethyl-5-(4-morpholinylcarbonyl)-15-oxapentacyclo[10.5.2.0(1,10).0(4,9).0(13,17)]nonadec-18-ene-14,16-dione C28H39NO5 详情 详情

合成路线10

该中间体在本合成路线中的序号：(A)

Compound can be prepared in two different ways: 1) The condensation of 4,5-dichloro-2-methyl-3-(2H)pyridazinone (I) with morpholine (A) in refluxing ethanol gives 2-methyl-4-chloro-5-morpholino-3(2H)-pyridazinone (II), which is then treated with sodium ethoxide in refluxing ethanol. 2) The reaction of 2-methyl-4,6-dichloro-5-morpholino-3(2H)pyridazinone (III) with sodium ethoxide in refluxing ethanol gives 2-methyl-4-ethoxy-5-morpholino-6-chloro-3(2H)-pyridazinone (IV), which is then reduced with H2 over Pd/C in THF.

参考文献 中间体
合成目标
【1】 Satoda, I.; et al.; JP 7224030 .
【2】 Satoda, I.; et al.; 2-Alkyl-4-alkoxy-5-morpholino-3-2H-pyridazinones and their method of preparation. GB 1351569 .
【3】 Satoda, I.; et al.; Verfahren zur Herstellung von 2-Alkyl-4-alkoxy-5-morpholino-3(2H)-pyridazinon. DE 2225218 .
【4】 Kishikawa, T.; Matsuo, T.; JP 7659882 .
【5】 Castaner, J.; Blancafort, P.; M-73101. Drugs Fut 1978, 3, 10, 756.
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) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(I) 33532 4,5-dichloro-2-methyl-3(2H)-pyridazinone 933-76-6 C5H4Cl2N2O 详情 详情
(II) 33533 4-chloro-2-methyl-5-(4-morpholinyl)-3(2H)-pyridazinone C9H12ClN3O2 详情 详情
(III) 33534 4,6-dichloro-2-methyl-5-(4-morpholinyl)-3(2H)-pyridazinone C9H11Cl2N3O2 详情 详情
(IV) 33535 6-chloro-4-ethoxy-2-methyl-5-(4-morpholinyl)-3(2H)-pyridazinone C11H16ClN3O3 详情 详情

合成路线11

该中间体在本合成路线中的序号：(C)

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12

该中间体在本合成路线中的序号：(X)

Delmopinol can be obtained by three different ways: 1) The reaction of 2-(benzylamino)-6-propylnonan-1-ol (I) with ethylene oxide (II) in ethanol at 100 C yields the corresponding N-(2-hydroxyethyl)derivative (III), which is cyclized with H2SO4 at 140-150 C to 4-benzyl-3-(4-propylheptyl)morpholine (IV). The debenzylation of (IV) by hydrogenolysis with H2 over Pd/C affords the free morpholine (V), which is finally condensed with 2-chloroethanol (VI) by means of KI and KOH in refluxing ethanol. 2) The Grignard condensation of 4-heptanone (VII) with allyl bromide (VIII) in ethyl ether gives 4-propyl-1-hepten-4-ol (IX), which is cyclocondensed with morpholine (X) by means of H2O2 and Na2WO4 in methanol to yield 4-(perhydroisoxazol[3,2-c][1,4]oxazin-2-ylmethyl)-4-heptanol (XI). Reductive ring opening of (XI) by hydrogenation with H2 over Pd/C and p-toluenesulfonic acid in isopropanol affords a mixture of the morpholine (V) and the hydroxymorpholine (XII). This mixture, without separation, is treated first with SOCl2 in chloroform to perform Cl-OH interchange, then with NaOH to obtain the corresponding double bond, and finally, the mixture is hydrogenated with H2 over Ra-nickel and triethylamine in dioxane in order to obtain pure (V), already obtained. 3) The acylation of the alkylmorpholine (V) with oxalic acid monomethyl ester (XIII) by means of triethylamine in refluxing benzene gives the corresponding condensation compound (XIV), which is then reduced with LiAlH4 in refluxing ethyl ester.

参考文献 中间体
合成目标
【1】 Mealy, N.; Ngo, J.; Castaner, J.; Delmopinol Hydrochloride. Drugs Fut 1996, 21, 8, 787.
【2】 (Ferrosan AB); New morpholino cpds. their process of preparation and medicines containing them. BE 0888052; BE 0901496 .
【3】 Hernestam, S.; Thelin, B.; Seifert, E.; Nilsson, A. (Pharmacia & Upjohn AB); Substd. isoxazolidines and isoxazolines. WO 9014342 .
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) 10380 2-(Benzylamino)-6-propyl-1-nonanol C19H33NO 详情 详情
(II) 10393 Oxirane; Ethylene oxide 75-21-8 C2H4O 详情 详情
(III) 10381 2-[Benzyl(2-hydroxyethyl)amino]-6-propyl-1-nonanol C21H37NO2 详情 详情
(IV) 10382 4-Benzyl-3-(4-propylheptyl)morpholine C21H35NO 详情 详情
(V) 10383 3-(4-Propylheptyl)morpholine C14H29NO 详情 详情
(VI) 10384 2-Chloro-1-ethanol; Ethylene chlorohydrin 107-07-3 C2H5ClO 详情 详情
(VII) 10385 4-Heptanone; Dipropyl ketone 123-19-3 C7H14O 详情 详情
(VIII) 10386 Allyl(bromo)magnesium 1730-25-2 C3H5BrMg 详情 详情
(IX) 10387 4-Propyl-1-hepten-4-ol C10H20O 详情 详情
(X) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(XI) 10389 4-(Hexahydroisoxazolo[3,2-c][1,4]oxazin-2-ylmethyl)-4-heptanol C14H27NO3 详情 详情
(XII) 10390 1-(1,4-Oxazinan-3-yl)-4-propyl-2-heptanol C14H29NO2 详情 详情
(XIII) 10391 2-Methoxy-2-oxoacetic acid C3H4O4 详情 详情
(XIV) 10392 2-Oxo-2-[3-(4-propylheptyl)morpholino]acetic acid C16H29NO4 详情 详情

合成路线13

该中间体在本合成路线中的序号：(A)

The reaction of bicyclo[3.2.0]hept-2-en-6-one (I) with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) in acetic acid gives 3-endo-acetoxy-2-exo-bromo-bicyclo[3.2.0]heptan-6-one (II), which is treated with morpholine in dichloromethane to yield 5-endo-acetoxy-7-anti morpholinobicyclo[2.2.l]heptan-2-one (III). Hydrolysis of (III) with NaOH gives the norbornanone (IV), which is alkylated with biphenyl methylbromide under phase transfer catalysis to give 5-endo[(1,1'-biphenyl)-4 yl]methoxy-7-anti-morpholinobicyclo[2.2.1]heptan 2-one (V). Baeyer-Villiger oxidation followed by partial reduction with diisobutylaluminum hydride (Dibal) gives the aldehyde (VI), which is then homologated to the aldehyde (VII) using methoxymethylenetriphenyl phosphorane and subsequent treatment with 2N HCl. Condensation of (VII) with 3 carboxypropyl triphenylphosphorane in tetrahydrofuran affords the acid (VIII). Finally, this compound is oxidized with Jones' reagent.

参考文献 中间体
合成目标
【1】 Lumley, P.; AH-23848. Drugs Fut 1986, 11, 2, 85.
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) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(A) 24427 6-(2-[1,1'-biphenyl]-4-ylethoxy)-8-(4-morpholinyl)-2-oxabicyclo[3.2.1]octan-3-one C25H29NO4 详情 详情
(I) 24421 (1S,5R)bicyclo[3.2.0]hept-2-en-6-one C7H8O 详情 详情
(II) 24422 3-Acetoxy-2-bromobicyclo[3,2,0]hept-2-en-6-one C8H9BrO 详情 详情
(III) 24424 5(endo)-Acetoxy-7(R)-(4-morpholinyl)bicyclo[2,2,1]heptan-2-one C12H19NO2 详情 详情
(IV) 24425 5-hydroxy-7-(4-morpholinyl)bicyclo[2.2.1]heptan-2-one C11H17NO3 详情 详情
(V) 24426 5-(2-[1,1'-biphenyl]-4-ylethoxy)-7-(4-morpholinyl)bicyclo[2.2.1]heptan-2-one C25H29NO3 详情 详情
(VI) 24428 2-[(1R,2R,3R,5S)-5-(2-[1,1'-biphenyl]-4-ylethoxy)-3-hydroxy-2-(4-morpholinyl)cyclopentyl]acetaldehyde C25H31NO4 详情 详情
(VII) 24429 3-[(1R,2R,3R,5S)-5-(2-[1,1'-biphenyl]-4-ylethoxy)-3-hydroxy-2-(4-morpholinyl)cyclopentyl]propanal C26H33NO4 详情 详情
(VIII) 24431 (E)-6-[(1R,2R,3R,5S)-5-(2-[1,1'-biphenyl]-4-ylethoxy)-3-hydroxy-2-(4-morpholinyl)cyclopentyl]-3-hexenoic acid C29H37NO5 详情 详情
(C) 24430 3-Carboxypropyltriphenylphosphonium bromide C22H23BrO2P 详情 详情

合成路线14

该中间体在本合成路线中的序号：(A)

Condensation of (rac)-propylene-1,2-diaminetetraacetic acid (I) with formamide gives (rac)-1,2-bis(3,5-dioxopiperazin-1-yl)propane (II). The latter compound is heated with morpholine, and then treated with aqueous formaldehyde. Probimane separates on cooling of the reaction mixture.

参考文献 中间体
合成目标
【1】 Ren, Y.-F. (Zenyaku Kogyo Co., Ltd.); Bis-dioxopiperazine derivs., process for their preparation, antitumor agents comprising them and compsns. containing them. EP 0125475; JP 1984190976; JP 1985025975; JP 1985069070; US 4737497 .
【2】 Ruyun, J.; Probimane. Drugs Fut 1988, 13, 5, 418.
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) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(I) 22133 2-[[2-[bis(carboxymethyl)amino]-1-methylethyl](carboxymethyl)amino]acetic acid C11H18N2O8 详情 详情
(II) 22134 4-[2-(3,5-dioxo-1-piperazinyl)propyl]-2,6-piperazinedione C11H16N4O4 详情 详情

合成路线15

该中间体在本合成路线中的序号：(II)

The reaction of 4-(1H-imidazol-1-yl)benzaldehyde (I) with morpholine (A) and KCN in dioxane water by means of p-toluenesulfonic acid gives [4-(1H-imidazol-1-yl)phenyl](4morpholinyl)acetonitrile (II), which is condensed with crotononitrile (III) by means of KOH in methanol yielding 4-[4-(1H-imidazol-1-yl)phenyl]-3-methyl-4-oxobutyronitrile (IV). The hydrolysis of (IV) with hot aqueous HCl affords 4-[4-(1H-imidazol-1-yl)phenyl]-3-methyl-4-oxobutanoic acid (V), which is finally cyclized with hydrazine in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Guengerich, F.P.; Cardiotonic agents. 1. 4,5-Dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)pyridazinones: Novel positive inotropic agents for the treatment of congestive heart failure. J Med Chem 1984, 27, 9, 1099.
【2】 Sircar, I.; Bristol, J.A. (Pfizer Inc.); Substituted 4,5-dihydro-6-(substituted)phenyl-3(2H)-pyridazinones and 6-(substituted)phenyl-3(2H)-pyridazinones. CA 1190548; DD 208615; EP 0075436 .
【3】 Castaner, J.; Serradell, M.N.; CI-930. Drugs Fut 1985, 10, 6, 449.
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) 29649 4-(1H-imidazol-1-yl)benzaldehyde 10040-98-9 C10H8N2O 详情 详情
(II) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(III) 29650 2-[4-(1H-imidazol-1-yl)phenyl]-2-(4-morpholinyl)acetonitrile C15H16N4O 详情 详情
(IV) 24144 (E)-2-butenenitrile 4786-20-3 C4H5N 详情 详情
(V) 29651 4-[4-(1H-imidazol-1-yl)phenyl]-3-methyl-4-oxobutanenitrile C14H13N3O 详情 详情
(VI) 29652 4-[4-(1H-imidazol-1-yl)phenyl]-3-methyl-4-oxobutyric acid C14H14N2O3 详情 详情

合成路线16

该中间体在本合成路线中的序号：

4-[2-(2-Phenylethyl)benzyl]morpholine hydrochloride (ICF-650) has been obtained as follows: Methyl 2-(2-phenylethyl)benzoate (I) is reduced (LiAlH4) to the corresponding alcohol, converted (SOCl2) to (II) and then condensed with morpholine to give ICF-650.

参考文献 中间体
合成目标
【1】 Carrara, M.; Rampa, A.; ICF-650. Drugs Fut 1987, 12, 1, 22.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10388 Morpholine 110-91-8 C4H9NO 详情 详情
(I) 22938 methyl 2-phenethylbenzoate C16H16O2 详情 详情
(II) 22939 1-(chloromethyl)-2-phenethylbenzene C15H15Cl 详情 详情

合成路线17

该中间体在本合成路线中的序号：(C)

The starting 3-fluorothiophenol (I) is obtained either from 3-fluoro-1-bromobenzene (II) by reaction with Mg and a following treatment with S, or from 3-fluoroaniline (III) by the Leuckart method via 3-fluorobenzenediazonium xanthate and 3-fluorophenyl xanthate. Two different ways were described for obtaining the acid (VI): 1) Reaction of (I) with 5-chloro-2-iodobenzoic acid (A) in a boiling aqueous KOH solution in the presence of Cu, which leads to the acid (IV). This is transformed in three steps (reduction with sodium dihydrodibis(2-methoxyethoxy)aluminate, followed by reaction with SOCl2 in pyridine, and final reaction with NaCN in boiling aqueous ethanol) to the nitrile (V), which is hydrolyzed with a boiling solution of KOH in aqueous ethanol. 2) Reaction of (I) with 2,5-dichloro acetophenone (B) in dimethylformamide at 150 C in the presence of Cu. The resulting ketone (VII) is proceased by the Kindler's modification of the Willgerodt reaction: treatment with S in boiling morpholine (C) gives the thiomorpholide (VIII), which is hydrolyzed either with a boiling ethanolic KOH solution or with a refluxing mixture of dilute H2SO4 and acetic acid. The acid (VI), obtained by both routes, is cyclized with polyphosphoric acid at 150 C to the ketone (IX), which is reduced with sodium borohydride in aqueous ethanol to the alcohol (X). Treatment with HCl in benzene in the presence of CaCl2 affords the reactive chloride (XI), which can be converted to the final product (XIV) by two methods: (b) substitution reaction of (XI) with 1-(ethoxycarbonyl)piperazine (D), followed by alkaline hydrolysis of the carbamate (XII) and addition of the secondary amine (XIII) to acrylamide in tert-butyl alcohol in the presence of benzyltriethylammonium hydroxide. (a) substitution reaction with 3-(1-piperazinyl)propionamide (E) in boiling chloroform gives directly (XIV);

参考文献 中间体
合成目标
【1】 Rand, K.H.; Houck, H.; Coll Czech Chem Commun 1975, 40, 2887.
【2】 Nagaoka, M.R.; et al.; Coll Czech Chem Commun 1968, 33, 1852.
【3】 Coll Czech Chem Commun 1978, 43, 1276.
【4】 Parola, M.; Robino, G.; Pastacaldi, S.; Gentilini, P.; Pinzani, M.; Marra, F.; Coll Czech Chem Commun 1986, 51, 2598.
【5】 Yu, D.; Mortin, L.I.; Zhang, X.; Alder, J.; Li, T.; Coll Czech Chem Commun 1967, 32, 2021.
【6】 Ghiro, L.; et al.; Z Physik Chem (Leipzig) 1931, 156 A, 3, 397.
【7】 Pomykácek, J.; Diabac, A.; Protiva, M.; Valchár, M.; Jilek, J.; Cervena, I. (SPOFA - United Pharmaceutical Works); N-Substd.-2-chloro-7-fluoro-10-piperazino-10, 11-dihydrobenzo[b,f]thiepins and acid addition salts thereof. EP 0189310; JP 1986204181; US 4678788 .
【8】 Protiva, M.; VUFB-15496. Drugs Fut 1987, 12, 7, 636.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(F) 10851 Acrylamide 79-06-1 C3H5NO 详情 详情
(D) 24694 N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine 120-43-4 C7H14N2O2 详情 详情
(A) 28004 5-chloro-2-iodobenzoic acid 13421-00-6 C7H4ClIO2 详情 详情
(B) 28005 1-(2,5-dichlorophenyl)-1-ethanone 2476-37-1 C8H6Cl2O 详情 详情
(E) 28016 3-(1-piperazinyl)propanamide C7H15N3O 详情 详情
(I) 28003 3-fluorobenzenethiol 2557-77-9 C6H5FS 详情 详情
(II) 28002 1-bromo-3-fluorobenzene; 3-Bromofluorobenzene 1073-06-9 C6H4BrF 详情 详情
(III) 20697 3-fluoroaniline; 3-fluorophenylamine 372-19-0 C6H6FN 详情 详情
(IV) 28006 5-chloro-2-[(3-fluorophenyl)sulfanyl]benzoic acid C13H8ClFO2S 详情 详情
(V) 28007 2-[5-chloro-2-[(3-fluorophenyl)sulfanyl]phenyl]acetonitrile C14H9ClFNS 详情 详情
(VI) 28008 2-[5-chloro-2-[(3-fluorophenyl)sulfanyl]phenyl]acetic acid C14H10ClFO2S 详情 详情
(VII) 28009 1-[5-chloro-2-[(3-fluorophenyl)sulfanyl]phenyl]-1-ethanone C14H10ClFOS 详情 详情
(VIII) 28010 2-[5-chloro-2-[(3-fluorophenyl)sulfanyl]phenyl]-1-(4-morpholinyl)-1-ethanethione C18H17ClFNOS2 详情 详情
(IX) 28011 2-chloro-7-fluorodibenzo[b,f]thiepin-10(11H)-one C14H8ClFOS 详情 详情
(X) 28012 2-chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepin-10-ol C14H10ClFOS 详情 详情
(XI) 28013 2,10-dichloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepine C14H9Cl2FS 详情 详情
(XII) 28014 ethyl 4-(2-chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepin-10-yl)-1-piperazinecarboxylate C21H22ClFN2O2S 详情 详情
(XIII) 28015 1-(2-chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepin-10-yl)piperazine C18H18ClFN2S 详情 详情
(C) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线18

该中间体在本合成路线中的序号：

Starting from 4-dicarbethoxybutan-1-one (I) and o-chlorocyanoacetophenone (II), in the presence of sufur the aminobenzoylthiophene (III) was obtained. Saponification, decarboxylation and esterification yielded the mono ester (IV), which was acetylated to (V). Amination and ring closure gave the corresponding diazepinone (VII). Sulfuration of (VII), treatment with hydrazine and then with orthoacetate yielded the triazolo compound (X). Saponification of (X) and amidation with morpholine in the presence of carbodiimidazole gave WEB 2086.

参考文献 中间体
合成目标
【1】 Weber, K.-H.; Bechtel, W.D.; Brotizolam radioimmunoassay: Development, evaluati. J Pharm Sci 1985, 74, 1265.
【2】 Weber, K.-H.; Walther, G.; Harreus, A.; Casals Stenzel, J.; Muacevic, G.; Tröger, W. (Boehringer Ingelheim GmbH); Thieno-triazolo-1,4-diazepino-2-carboxamides, proc. AU 8652728; DE 3502392; EP 0194416; ES 8802426; ES 8802523; JP 1986176591; JP 1990191281; US 4968794; US 5082839; US 5155103 .
【3】 Weber, K.H.; WEB 2086. Drugs Fut 1988, 13, 3, 242.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10388 Morpholine 110-91-8 C4H9NO 详情 详情
(I) 12923 3-(2-Chlorophenyl)-3-oxopropanenitrile 40018-25-5 C9H6ClNO 详情 详情
(II) 22030 diethyl 2-(3-oxopropyl)malonate C10H16O5 详情 详情
(III) 22032 diethyl 2-[[5-amino-4-(2-chlorobenzoyl)-2-thienyl]methyl]malonate C19H20ClNO5S 详情 详情
(IV) 22033 methyl 3-[5-amino-4-(2-chlorobenzoyl)-2-thienyl]propanoate C15H14ClNO3S 详情 详情
(V) 22034 methyl 3-[5-[(2-bromoacetyl)amino]-4-(2-chlorobenzoyl)-2-thienyl]propanoate C17H15BrClNO4S 详情 详情
(VI) 22035 methyl 3-[5-[(2-aminoacetyl)amino]-4-(2-chlorobenzoyl)-2-thienyl]propanoate C17H17ClN2O4S 详情 详情
(VII) 22036 methyl 3-[5-(2-chlorophenyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepin-7-yl]propanoate C17H15ClN2O3S 详情 详情
(VIII) 22037 methyl 3-[5-(2-chlorophenyl)-2-thioxo-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepin-7-yl]propanoate C17H15ClN2O2S2 详情 详情
(IX) 22038 methyl 3-[5-(2-chlorophenyl)-2-[(Z)hydrazono]-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-7-yl]propanoate C17H17ClN4O2S 详情 详情
(X) 22039 methyl 3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]propanoate C19H17ClN4O2S 详情 详情
(XI) 22040 3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]propionic acid C18H15ClN4O2S 详情 详情

合成路线19

该中间体在本合成路线中的序号：(VI)

Nitroacetaldehyde oxime (I) is formed from nitromethane in the presence of NaOH and is converted in acidic media with 2-aminobenzoic acid (II) to 2-(2-nitroethylideneamino)benzoic acid (III). Cyclization of (III) in acetic anhydride by means of potassium acetate yields 4-hydroxy-3-nitroquinoline (IV), which is converted to 4-chloro-3-nitroquinoline (V) in boiling POCl3. Reaction of (V) with morpholinecarboximidamide (VIII) (formed from morpholine (VI) and S-methylisothiourea hemisulfate (VII) in ethanol) affords troquidazole.

参考文献 中间体
合成目标
【1】 Berényi, E.; Varga, L.; Pallos, L.; Petöcz, L.; Ladányi, L.; Tömpe, P.; Hartai, E.; Kovács, A. (Egis Pharmaceuticals Ltd.); N-(3-Nitroquinolin-4-yl)guanidine derivatives as radiosensitizers. (EGIS Pharm., Ltd.). BE 0904864; CH 668069; ES 8707231; GB 2176185; JP 1987048668; US 4652562 .
【2】 Nógrádi, M.; Berényi, E.; Blaskó, G.; Troquidazole. Drugs Fut 1992, 17, 5, 384.
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) 11660 2-Nitroacetaldehyde oximesodium salt C2H3N2NaO3 详情 详情
(II) 11661 2-Aminobenzoic acid;Anthranilic acid; o-Aminobenzoic acid 118-92-3 C7H7NO2 详情 详情
(III) 11662 2-[[(E)-2-Nitroethylidene]amino]benzoic acid C9H8N2O4 详情 详情
(IV) 11663 3-Nitro-4-quinolinol; 3-Nitro-quinolin-4-ol C9H6N2O3 详情 详情
(V) 11664 4-Chloro-3-nitroquinoline C9H5ClN2O2 详情 详情
(VI) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(VII) 10272 [[Amino(imino)methyl]sulfanyl]methane 2986-19-8 C2H6N2S 详情 详情
(VIII) 11667 4-Morpholinecarboximidamide C5H11N3O 详情 详情

合成路线20

该中间体在本合成路线中的序号：(B)

By reaction of ethyl 2-fluoro-4-biphenylylacetate (I) first with diethyl carbonate and sodium ethoxide, and then with dimethyl sulfate in ethanol to give diethyl 2-fluoro-4-biphenylyl-alpha-methylmalonate (II), which was hydrolyzed with NaOH in ethanol and finally decarboxylated at 180-200 C. The starting product (I) was obtained as follows: the Ullman condensation of 4-bromo-3-nitroacetophenone (III) gives 2-nitro-4-acetylbiphenyl (IV), which was reduced to the corresponding amino compound (V). This, by the Schieman reaction was converted into 2-fluoro-4-acetylbiphenyl (VI), which by heating with sulfur and morpholine (B) gave 2-fluoro-4-biphenylylacetic acid (VII), and finally (VII) was esterified by refluxing with ethanol and H2SO4.

参考文献 中间体
合成目标
【1】 Adams, S.S.; et al.; 2-(Mono- and difluoro-4-biphenyl)propionic acids. US 3755427 .
【2】 Thorpe, P.; Castaner, J.; Flurbiprofen. Drugs Fut 1976, 1, 7, 323.
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) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(A) 13364 Benzene 71-43-2 C6H6 详情 详情
(I) 34107 ethyl 2-(2-fluoro[1,1'-biphenyl]-4-yl)acetate C16H15FO2 详情 详情
(II) 34108 diethyl 2-(2-fluoro[1,1'-biphenyl]-4-yl)-2-methylmalonate C20H21FO4 详情 详情
(III) 34109 1-(4-bromo-3-nitrophenyl)-1-ethanone 18640-58-9 C8H6BrNO3 详情 详情
(IV) 34110 1-(2-nitro[1,1'-biphenyl]-4-yl)-1-ethanone C14H11NO3 详情 详情
(V) 34111 1-(2-amino[1,1'-biphenyl]-4-yl)-1-ethanone C14H13NO 详情 详情
(VI) 34112 1-(2-fluoro[1,1'-biphenyl]-4-yl)-1-ethanone C14H11FO 详情 详情
(VII) 34113 2-(2-fluoro[1,1'-biphenyl]-4-yl)acetic acid C14H11FO2 详情 详情

合成路线21

该中间体在本合成路线中的序号：(VIII)

1) Synthesis of N(tau)-tert-butoxycarbonyl-N(alpha)-[2(R)-(morpholinocarbonylmethyl)-3-(1-naphthyl)propionyl]histidine: The condensation of diethyl succinate (III) with 1-naphthaldehyde (IV) by means of sodium ethoxide in refluxing methanol gives 2-(1-naphthylmethylene)succinic acid diethyl ester (V), which is hydrolyzed to the corresponding acid (VI) with NaOH. The cyclization of (VI) with refluxing SOCl2 affords the anhydride (VII), which is treated with morpholine (VIII) in ethyl acetate, yielding 2-(morpholinocarbonylmethyl)-3-(1-naphthyl)acrylic acid (IX). Hydrogenation of (IX) with H2 over Pd/C in methanol affords the corresponding propionic acid (X), which is then condensed with histidine methyl ester (XI) by means of DCC and HONB as before, giving a racemic mixture that is submitted to optical resolution by repeated crystallization of its salycylic acid salt, thus yielding N-[2(R)-(morpholinocarbonylmethyl)-3-(1-naphthyl)propionyl]histidine methyl ester (XII). Finally, this compound is hydrolyzed with NaOH and protected with tert-butoxycarbonyl anhydride to give (I).

参考文献 中间体
合成目标
【1】 Harada, H.; Iyobe, A.; Tsubaki, A.; Yamaguchi, T.; Kamijo, T.; Kiso, Y.; Iizuka, K.; Hirata, K.; A practical synthesis of an orally potent renin inhibitor, isopropyl (2R,3S)-4-cyclohexyl-2-hydroxy-3-[N-[(2R)-2-morpholinocarbonylmethyl-3-(1-naaphthyl)propionyl]-L-histidyl]aminobutyrate. J Chem Soc - Perkins Trans I 1990, 9, 2497-500.
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) 12312 (2S)-3-[1-(tert-Butoxycarbonyl)-1H-imidazol-5-yl]-2-[[(2R)-4-(4-morpholinyl)-2-(1-naphthylmethyl)-4-oxobutanoyl]amino]propionic acid C30H36N4O7 详情 详情
(III) 12313 diethyl succinate 123-25-1 C8H14O4 详情 详情
(IV) 12314 1-Naphthaldehyde 66-77-3 C11H8O 详情 详情
(V) 12315 diethyl 2-[(Z)-1-naphthylmethylidene]succinate C19H20O4 详情 详情
(VI) 12316 2-[(Z)-1-Naphthylmethylidene]succinic acid C15H12O4 详情 详情
(VII) 12317 3-[(Z)-1-Naphthylmethylidene]-2,5(4H)-furandione C15H10O3 详情 详情
(VIII) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(IX) 12319 (Z)-2-(2-Morpholino-2-oxoethyl)-3-(1-naphthyl)-2-propenoic acid C19H19NO4 详情 详情
(X) 12320 4-Morpholino-2-(1-naphthylmethyl)-4-oxobutyric acid C19H21NO4 详情 详情
(XI) 12321 methyl (2S)-2-amino-3-(1H-imidazol-5-yl)propanoate; Methyl-L-histidine 1499-46-3 C7H11N3O2 详情 详情
(XII) 12322 methyl (2S)-3-(1H-imidazol-5-yl)-2-[[(2R)-4-morpholino-2-(1-naphthylmethyl)-4-oxobutanoyl]amino]propanoate C26H30N4O5 详情 详情

合成路线22

该中间体在本合成路线中的序号：(II)

The condensation of the cyclopeptide analogue (I) with morpholine (II) and formaldehyde by means of MsOH in hot methanol gives the 4-morpholinylmethyl derivative (III), which by a treatment with NaOAc in hot acetic acid yields the methylene derivative (IV). Finally this compound is condensed with quinuclidine-3(S)-thiol in hot acetone.

参考文献 中间体
合成目标
【1】 Bastart, J.P.; Paris, J.M.; Radisson, X. (Aventis SA); Pristinaymcin IA or viginiamycin derivs. and their preparation. EP 0432029 .
【2】 Barriere, J.C.; Paris, J.M.; RP 59500 and related semisynthetic streptogramins. Drugs Fut 1993, 18, 9, 833.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IIIa) 41286 　 C50H63N9O11 详情 详情
(IIIb) 41287 　 C50H63N9O11 详情 详情
(I) 41285 N-[(6R,9S,10R,13S,15aS,22S,24aS)-22-[4-(dimethylamino)benzyl]-6-ethyl-10,23-dimethyl-5,8,12,15,17,21,24-heptaoxo-13-phenyldocosahydro-12H-pyrido[2,1-f]pyrrolo[2,1-l][1,4,7,10,13,16]oxapentaazacyclononadecin-9-yl]-3-hydroxy-2-pyridinecarboxamide C45H54N8O10 详情 详情
(II) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(IV) 41288 　 C46H54N8O10 详情 详情
(V) 41289 (3S)-1-azabicyclo[2.2.2]octane-3-thiol; (3S)-1-azabicyclo[2.2.2]oct-3-ylhydrosulfide 4595-82-8 C7H13NS 详情 详情

合成路线23

该中间体在本合成路线中的序号：(IX)

The starting product (I) is obtained as follows: The acylation of 4(S)-isopropyloxazolidin-2-one (IV) with 3-(1-naphthyl)propionyl chloride (III) by means of butyllithium in THF-hexane yields 4(S)-isopropyl-3-[3-(1-naphthyl)propionyl]oxazolidin-2-one (V), which is condensed with benzyl bromoacetate (VI) by means of lithium diisopropylamide in THF to afford 3-[3-(benzyloxycarbonyl)-2(R)-(1-naphthylmethyl)propionyl]-4(S)-isoprop yloxazolidin-2-one (VII). The hydrogenolysis of (VII) with H2 over Pd/C in ethanol gives the carboxylic acid (VIII), which is condensed with morpholine (IX) by means of triethylamine and diethylphosphoryl cyanide in THF yielding 4(S)-isopropyl-3-[3-(morpholinocarbonyl)-2(R)-(1-naphthylmethyl)propion yl]oxazolidin-2-one (X). Finally, this compound is hydrolyzed with LiOH in THF - water to afford the acid (I).

参考文献 中间体
合成目标
【1】 Nishi, T.; Nagahori, H.; Saito, F.; et al.; Syntheses and biological activities of renin inhibitors containing statine analogues. Chem Pharm Bull 1990, 38, 1, 103-9.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 12866 3-(1-Naphthyl)propanoyl chloride C13H11ClO 详情 详情
(IV) 12867 (4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone 17016-83-0 C6H11NO2 详情 详情
(V) 12868 (4S)-4-Isopropyl-3-[3-(1-naphthyl)propanoyl]-1,3-oxazolidin-2-one C19H21NO3 详情 详情
(VI) 12869 benzyl 2-bromoacetate 5437-45-6 C9H9BrO2 详情 详情
(VII) 12870 benzyl (3R)-4-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-3-(1-naphthylmethyl)-4-oxobutanoate C28H29NO5 详情 详情
(VIII) 12871 (3R)-4-[(4S)-4-Isopropyl-2-oxo-1,3-oxazolidin-3-yl]-3-(1-naphthylmethyl)-4-oxobutyric acid C21H23NO5 详情 详情
(IX) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(X) 12873 Boc-L-phenylalanine;N-[(1,1-Dimethylethoxy)carbonyl]-L-phenylalanine;N-(tert-Butoxycarbonyl)-L-phenylalanine;(R)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid;N-Boc-Lhomophenylalanine；(2R)-1-[(4S)-4-Isopropyl-2-oxo-1,3-oxazolidin-3-yl]-4-(4-morpholinyl)-2-(1-naphthylmethyl)-1,4-butanedione C25H30N2O5 详情 详情

合成路线24

该中间体在本合成路线中的序号：(III)

The acylation of 2,3-dihydrobenzofuran (I) with acetyl chloride and AlCl3 in dichloromethane gives 5-acetyl-2,3-dihydrobenzofuran (II), which by reaction with sulfur, morpholine (III) and p-toluenesulfonic acid at high temperature yields 2-(2,3-dihydrobenzofuran-5-yl)thioacetic acid morpholide (IV). The hydrolysis of (IV) with H2SO4 in refluxing water-acetic acid affords 2-(2,3-dihydrobenzofuran-5-yl) acetic acid (V), which is esterified to (VI) with ethanol and H2SO4 in refluxing toluene. The condensation of the ester (VI) with 4-(methylthio)benzoyl chloride (VII) by means of SnCl4 in refluxing dichloromethane gives ethyl 2-[7-[4-(methylthio)benzoyl]benzofuran-5-yl]acetate (VIII), which by hydrolysis with NaOH in refluxing methanol-water yields the corresponding acid (IX). Finally, this compound is dehydrogenated with N-bromosuccinimide (NBS) and dibenzoyl peroxide in refluxing CCl4.

参考文献 中间体
合成目标
【1】 Dunn, J.P. [Syntex (Syntex (USA) LLC); Aroyl benzofuran and benzothiophene acetic and propionic acids, processes for their production and pharmaceutical compositions containing them. AU 8430593; EP 0132130; ES 8604554; ES 8607960; JP 85038376 .
【2】 Prous, J.; Castaner, J.; TIFURAC SODIUM < Rec INNM; USAN >. Drugs Fut 1989, 14, 8, 775.
【3】 Tomolonis, A.J.; Dunn, J.P.; Ackerman, N.A.; Analgetic and antiinflammatory 7-aroylbenzofuran-5-yl acetic acids and 7-aroylbenzothiophene-5-ylacetic acids. J Med Chem 1986, 29, 11, 2326.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 14499 2,3-Dihydrobenzofuran; 2,3-dihydro-1-benzofuran 496-16-2 C8H8O 详情 详情
(II) 21233 1-(2,3-dihydro-1-benzofuran-5-yl)-1-ethanone 90843-31-5 C10H10O2 详情 详情
(III) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(IV) 21235 2-(2,3-dihydro-1-benzofuran-5-yl)-1-(4-morpholinyl)-1-ethanethione C14H17NO2S 详情 详情
(V) 14500 2-(2,3-dihydro-1-benzofuran-5-yl)acetic acid 69999-16-2 C10H10O3 详情 详情
(VI) 21237 ethyl 2-(2,3-dihydro-1-benzofuran-5-yl)acetate C12H14O3 详情 详情
(VII) 21238 4-(methylsulfanyl)benzoyl chloride C8H7ClOS 详情 详情
(VIII) 21239 ethyl 2-[7-[4-(methylsulfanyl)benzoyl]-2,3-dihydro-1-benzofuran-5-yl]acetate C20H20O4S 详情 详情
(IX) 21240 2-[7-[4-(methylsulfanyl)benzoyl]-2,3-dihydro-1-benzofuran-5-yl]acetic acid C18H16O4S 详情 详情

合成路线25

该中间体在本合成路线中的序号：(IV)

The condensation of (2alpha,3alpha,5alpha,16alpha,17alpha)-2,3:16,17-diepoxyandrostan-17-ol acetate (I) with pyrrolidine (II) by means of NaOH in methanol, followed by reduction with NaBH4 in the same solvent gives (2alpha,3alpha,5alpha,16beta,17beta)-2,3-epoxy-16-(1-pyrrolidinyl) androstan-17-ol (III), which is further condensed with morpholine (IV) in refluxing water yielding (2beta,3alpha,5alpha,16beta,17beta)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (V). Partial acetylation of (V) with acetyl chloride in dichloromethane at room temperature affords the corresponding 17-acetoxy derivative (VI), which is finally quaternized with allyl bromide (VII) in dichloromethane.

参考文献 中间体
合成目标
【1】 Savage, D.S.; Sleig, T.; Carlyle, I.G. (Akzo Nobel N.V.); Novel 2beta-morpholino-androstane derivs. and process for their preparation. AU 8814570; EP 0287150; JP 1988277693; US 4894369 .
【2】 Pento, J.T.; Castaner, J.; Rocuronium Bromide. Drugs Fut 1994, 19, 9, 841.
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) 13647 (1aR,2aS,2bS,4aS,5aR,6aS,6bR,8aS,9aS)-2a,4a-dimethylhexadecahydro-4bH-oxireno[2'',3'':4',5']cyclopenta[1',2':7,8]phenanthro[2,3-b]oxiren-4-yl acetate C21H30O4 详情 详情
(II) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情
(III) 13649 (1R,2S,3aS,3bR,5aS,6aS,7aR,8aS,8bS,10aS)-8a,10a-Dimethyl-2-(1-pyrrolidinyl)hexadecahydro-1H-cyclopenta[7,8]phenanthro[2,3-b]oxiren-1-ol C23H37NO2 详情 详情
(IV) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(V) 13651 (2S,3S,5S,8R,9S,10S,13S,14S,16S,17R)-10,13-Dimethyl-2-(4-morpholinyl)-16-(1-pyrrolidinyl)hexadecahydro-1H-cyclopenta[a]phenanthrene-3,17-diol C27H46N2O3 详情 详情
(VI) 13652 (2S,3S,5S,8R,9S,10S,13S,14S,16S,17R)-3-hydroxy-10,13-dimethyl-2-(4-morpholinyl)-16-(1-pyrrolidinyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate C29H48N2O4 详情 详情
(VII) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情

合成路线26

该中间体在本合成路线中的序号：(VI)

Morpholine (VI) was treated with carbonyl diimidazole (VII), and the resulting imidazolide (VIII) was further condensed with ethylenediamine (IX) to give urea (X). Reaction of epoxide (V) with amine (X) furnished the title compound.

参考文献 中间体
合成目标
【1】 Iguchi, S.; Kawamura, M.; Miyamoto, T. (Ono Pharmaceutical Co., Ltd.); Novel esters of phenylalkanoic acid. EP 0397031; JP 1991072475; JP 1994073044; US 5013734 .
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) 48334 [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 3-[4-[(2S)oxiranylmethoxy]phenyl]propanoate C18H24O6 详情 详情
(VI) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(VII) 11353 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) 530-62-1 C7H6N4O 详情 详情
(VIII) 48336 1H-imidazol-1-yl(4-morpholinyl)methanone C8H11N3O2 详情 详情
(IX) 14754 ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine 107-15-3 C2H8N2 详情 详情
(X) 32153 N-(2-aminoethyl)-4-morpholinecarboxamide; 4-[N-(2-Aminoethyl)carbamoyl]morpholine C7H15N3O2 详情 详情

合成路线27

该中间体在本合成路线中的序号：(XV)

Alternatively, intermediate (XIII) can be obtained as follows: Heating of ethyl (S)-lactate (XIV) with morpholine affords amide (XVI), which then reacts with 3,4-dihydro-2H-pyran (A) in the presence of p-TsOH to give protected derivative (XVII). Grignard reaction between (XVII), bromo derivative (XVIII) and Mg turnings in THF yields protected ketone (XIX), which is treated with pyridinium p-toluenesulfonate (PPTS) (THP group removal) and reprotected by means of Tf2O and DIEA to give triflate derivative (XX). Conversion of (XX) into intermediate (XIII) is achieved by reaction with triazolone (VII) and NaH in THF.

参考文献 中间体
合成目标
【1】 Tasaka, A.; Tamura, N.; Matsushita, Y.; Teranishi, K.; Hayashi, R.; Okonogi, K.; Itoh, K.; Optically active antifungal azoles. I. Synthesis and antifungal activity of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol and stereoisomers. Chem Pharm Bull 1993, 41, 6, 1035-42.
【2】 Kitazaki, T.; et al.; Optically active antifungal azoles. IX. An alternative synthetic route for 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone and its analogs. Chem Pharm Bull 1999, 47, 3, 360.
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) 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
(VII) 43502 4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one C11H9F4N3O2 详情 详情
(XIII) 43507 2-[(1R)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one C20H15F6N3O3 详情 详情
(XIV) 43508 propyl (2S)-2-hydroxypropanoate 616-09-1 C6H12O3 详情 详情
(XV) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(XVI) 41498 (2S)-2-hydroxy-1-(4-morpholinyl)-1-propanone C7H13NO3 详情 详情
(XVII) 43509 (2S)-1-(4-morpholinyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone C12H21NO4 详情 详情
(XVIII) 15488 1-bromo-2,4-difluorobenzene 348-57-2 C6H3BrF2 详情 详情
(XIX) 43511 (2S)-1-(2,4-difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone C14H16F2O3 详情 详情
(XX) 43510 (1S)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl trifluoromethanesulfonate C10H7F5O4S 详情 详情

合成路线28

该中间体在本合成路线中的序号：(XI)

Acylation of 1-acetyl-1,2,3,4-tetrahydroquinoline (I) with 2-chloropropionyl chloride (II) by means of AlCl3 provides the quinoline derivative (III), which is deacetylated by treatment with HCl to give 1,2,3,4-tetrahydro-6-(2-chloropropionyl)quinoline (IV). Condensation of compound (IV) with O-ethyl hydrazinethioformate (V) in refluxing acetonitrile yields the thiadiazinone (VI), which is then N-acylated at the quinoline ring with 3,4-dimethoxybenzoyl chloride (VII) by means of Et3N in methylene chloride to give the racemate EMD-53998 [rac-(VIII)]. Optical resolution of EMD-53998 can be performed by two different ways: a) enantioseparation via chromatography with Chiralpak AD in 100% EtOH as eluent and b) acylation of EMD-53998 with (S)-camphanoyl chloride (IX) by means of Et3N in methylene chloride followed by treatment with morpholine in the same solvent to afford a mixture of (­)-EMD-53998 (EMD-57439) and the camphanoyl amide (X), which are separated by chromatography. Finally, the (+)-enantiomer, EMD-57033, is isolated by further treatment of amide (X) with morpholine in methylene chloride.

参考文献 中间体
合成目标
【1】 Strube, J.; Jupke, A.; Schmidt-Traub, H.; Schulte, M.; Epping, A.; Devant, R.; Design, optimization, and operation of SMB chromatography in the production of enantiomerically pure pharmaceuticals. Chirality 1999, 11, 440.
【2】 Castaner, J.; Doggrell, S.A.; Brown, L.; EMD-57033. Drugs Fut 2002, 27, 1, 14.
【3】 Jonas, R.; Piulats, J.; Lues, I.; Klockow, M. (Merck Patent GmbH); Thiadiazinones. AU 8816646; DE 3719031; DE 3744149; EP 0294647; JP 1988310886; US 4916128 .
【4】 Klockow, M.; Lues, I.; Jonas, R.; Preparation of the enantiomers of the novel Ca-sensitizer EMD 53 998. Bioorg Med Chem Lett 1992, 2, 6, 589.
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) 51475 1-[3,4-dihydro-1(2H)-quinolinyl]-1-ethanone C11H13NO 详情 详情
(II) 12926 2-Chloropropanoyl chloride; 2-Chloropropionyl chloride 7623-09-8 C3H4Cl2O 详情 详情
(III) 51476 1-(1-acetyl-1,2,3,4-tetrahydro-6-quinolinyl)-2-chloro-1-propanone C14H16ClNO2 详情 详情
(IV) 51477 2-chloro-1-(1,2,3,4-tetrahydro-6-quinolinyl)-1-propanone C12H14ClNO 详情 详情
(V) 51478 O-ethyl 1-hydrazinecarbothioate C3H8N2OS 详情 详情
(VI) 51479 6-methyl-5-(1,2,3,4-tetrahydro-6-quinolinyl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one C13H15N3OS 详情 详情
(VII) 13488 (2S)-3-Butyn-2-ol; (S)-(-)-3-Butyn-2-ol 2914-69-4 C4H6O 详情 详情
(VIII) 51480 5-[1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-6-quinolinyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one C22H23N3O4S 详情 详情
(IX) 16583 (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride; (-)-Camphanic chloride 39637-74-6 C10H13ClO3 详情 详情
(X) 51481 5-[1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-6-quinolinyl]-6-methyl-3-[[(4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]hept-1-yl]carbonyl]-3,6-dihydro-2H-1,3,4-thiadiazin-2-one C32H35N3O7S 详情 详情
(XI) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线29

该中间体在本合成路线中的序号：(I)

The condensation of morpholine (I) with 3,4-difluoronitrobenzene (II) by means of diisopropylethylamine in refluxing acetonitrile gives 3-fluoro-4-(4-morpholinyl)nitrobenzene (III), which is reduced with ammonium formate over Pd/C in THF/methanol to the corresponding aniline (IV). The reaction of (IV) with benzyloxycarbonyl chloride and NaHCO3 in acetone/water yields the carbamate ester (V), which is cyclized with 2(R),3-epoxypropyl butyrate (VI) by means of butyllithium in THF affording 5(R)-(hydroxymethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]oxazolidin-2-one (VII). The reaction of (VII) with methanesulfonyl chloride and triethylamine in dichloromethane gives the mesylate (VIII), which by reaction with NaN3 in hot DMF is converted into the azide (IX). The reduction of (IX) with H2 over Pd/C in ethyl acetate affords the corresponding amine (X), which is finally acetylated with acetic anhydride and pyridine.

参考文献 中间体
合成目标
【1】 Brickner, S.J.; Hutchinson, D.K.; Barbachyn, M.R.; et al.; Synthesis and antibacterial activity of U-100592 and U-100766, two oxazolidinone antibacterial agents for the potential treatment of multidrug-resistant Gram-positive bacterial infections. J Med Chem 1996, 39, 3, 673.
【2】 Lizondo, J.; Rabasseda, X.; Castañer, J.; Linezolid. Drugs Fut 1996, 21, 11, 1116.
【3】 Barbachyn, M.R.; Brickner, S.J.; Hutchinson, D.K. (Pharmacia Corp.); Substd. oxazine and thiazine oxazolidinone antimicrobials. EP 0717738; JP 1997502436; WO 9507271 .
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) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(II) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(III) 17014 4-(2-fluoro-4-nitrophenyl)morpholine C10H11FN2O3 详情 详情
(IV) 17015 3-fluoro-4-morpholinophenylamine; 3-fluoro-4-morpholinoaniline; 3-fluoro-4-(4-morpholinyl)phenylamine; 3-Fluoro-4-(4-morpholinyl)benzeneamine 93246-53-8 C10H13FN2O 详情 详情
(V) 17016 benzyl N-(3-fluoro-4-morpholinophenyl)carbamate C18H19FN2O3 详情 详情
(VI) 17017 (2S)oxiranylmethyl butyrate C7H12O3 详情 详情
(VII) 17018 (5R)-3-(3-fluoro-4-morpholinophenyl)-5-(hydroxymethyl)-1,3-oxazolan-2-one 168828-82-8 C14H17FN2O4 详情 详情
(VIII) 17019 [(5R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-1,3-oxazolan-5-yl]methyl methanesulfonate 174649-09-3 C15H19FN2O6S 详情 详情
(IX) 17020 (5R)-5-(azidomethyl)-3-(3-fluoro-4-morpholinophenyl)-1,3-oxazolan-2-one C14H16FN5O3 详情 详情
(X) 17021 (5S)-5-(aminomethyl)-3-(3-fluoro-4-morpholinophenyl)-1,3-oxazolan-2-one C14H18FN3O3 详情 详情

合成路线30

该中间体在本合成路线中的序号：(X)

Treatment of cyanuric chloride (I) with methylmagnesium chloride afforded 2,4-dichloro-6-methyltriazine (II), which was condensed with aniline (III) to produce the anilinotriazine (IV). Subsequent displacement of the remaining chlorine atom of (IV) with morpholine (V) provided (VI). The target compound was then obtained by N-alkylation with iodoethane in the presence of NaH, followed by conversion to the methanesulfonate salt).

参考文献 中间体
合成目标
【1】 Arvanitis, A.G.; Chorvat, R.J.; Gilligan, P.J.; et al.; Non-peptide corticotropin-releasing hormone antago. J Med Chem 1999, 42, 5, 805.
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) 23813 2,4,6-Trichloro-s-triazine; Cyanuric chloride; Trichlorocyanidine; Tricyanogen chloride; 2,4,6-Trichloro-1,3,5-triazine 108-77-0 C3Cl3N3 详情 详情
(II) 23814 2,4-dichloro-6-methyl-1,3,5-triazine C4H3Cl2N3 详情 详情
(III) 23815 2-bromo-4,6-dimethoxyphenylamine; 2-bromo-4,6-dimethoxyaniline C8H10BrNO2 详情 详情
(IV) 23816 N-(2-bromo-4,6-dimethoxyphenyl)-N-(4-chloro-6-methyl-1,3,5-triazin-2-yl)amine; N-(2-bromo-4,6-dimethoxyphenyl)-4-chloro-6-methyl-1,3,5-triazin-2-amine C12H12BrClN4O2 详情 详情
(VI) 23818 N-(2-bromo-4,6-dimethoxyphenyl)-N-[4-methyl-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amine; N-(2-bromo-4,6-dimethoxyphenyl)-4-methyl-6-(4-morpholinyl)-1,3,5-triazin-2-amine C16H20BrN5O3 详情 详情
(X) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线31

该中间体在本合成路线中的序号：(XI)

4-Amino-1-benzylpiperidine (II) was acylated with 5-methyl-2-nitrobenzoyl chloride (I) to afford the ortho-nitrobenzamide (III), which was reduced to the amino derivative (IV) by catalytic hydrogenation in the presence of Pd/C. Treatment of (IV) with ethyl chloroformate produced the bis-carbamate (V) with concomitant cleavage of the N-benzyl group. This was cyclized to the dioxoquinazoline (VI) upon treatment with KOH in refluxing EtOH. After N-methylation employing iodomethane and NaH in DMF, hydrolysis of the carbamate group with concentrated HBr yielded the piperidinylquinazoline (VIII). This was then condensed with 2,4-dichloro-6,7-diethoxyquinazoline (IX) to furnish adduct (X). Finally, displacement of the remaining chlorine of (X) with morpholine (XI) in hot NMP gave rise to the title compound.

参考文献 中间体
合成目标
【1】 Kase, H.; Fujiwara, S.; Okamura, Y.; Karasawa, A.; Nonaka, H.; Yao, K.; Takai, H.; Synthesis and evaluation of adenosine transporter inhibitors. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PC-19.
【2】 Fujiwara, S.; Okamura, Y.; Takai, H.; Nonaka, H.; Moriyama, T. (Kyowa Hakko Kogyo Co., Ltd.); Quinazoline deriv.. EP 0726267; JP 1997165385; US 5948784; WO 9606841 .
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) 44744 5-methyl-2-nitrobenzoyl chloride C8H6ClNO3 详情 详情
(II) 34808 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine 50541-93-0 C12H18N2 详情 详情
(III) 44746 N-(1-benzyl-4-piperidinyl)-5-methyl-2-nitrobenzamide C20H23N3O3 详情 详情
(IV) 44747 2-amino-N-(1-benzyl-4-piperidinyl)-5-methylbenzamide C20H25N3O 详情 详情
(V) 44748 ethyl 4-([2-[(ethoxycarbonyl)amino]-5-methylbenzoyl]amino)-1-piperidinecarboxylate C19H27N3O5 详情 详情
(VI) 44749 ethyl 4-[6-methyl-2,4-dioxo-1,4-dihydro-3(2H)-quinazolinyl]-1-piperidinecarboxylate C17H21N3O4 详情 详情
(VII) 44750 ethyl 4-[1,6-dimethyl-2,4-dioxo-1,4-dihydro-3(2H)-quinazolinyl]-1-piperidinecarboxylate C18H23N3O4 详情 详情
(VIII) 44751 1,6-dimethyl-3-(4-piperidinyl)-2,4(1H,3H)-quinazolinedione C15H19N3O2 详情 详情
(IX) 44752 2,4-dichloro-6,7-diethoxyquinazoline; 2,4-dichloro-6-ethoxy-7-quinazolinyl ethyl ether C12H12Cl2N2O2 详情 详情
(X) 44753 3-[1-(2-chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,6-dimethyl-2,4(1H,3H)-quinazolinedione C27H30ClN5O4 详情 详情
(XI) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线32

该中间体在本合成路线中的序号：(XI)

Nitration of chromanone (I) with fuming HNO3 at -35 C afforded 6-nitro-4-chromanone (II). Subsequent aldol condensation of (II) with glyoxylic acid (III) in the presence of H2SO4 produced the alpha-beta-unsaturated acid (IV). Further hydrogenation of the nitro, keto, and olefin groups of (IV) with concomitant esterification produced the benzopyranylacetate (V). After protection of (V) as the N-Boc derivative (VI), optical resolution was achieved by preparative HPLC on a Chiralcel-OD column. The desired (S)-enantiomer (VI) was deprotected using ethanolic HCl to afford amine (VII), which was condensed with 4-cyanobenzoyl chloride (VIII) to give amide (IX). Treatment of (IX) with HCl-EtOH produced imidate (X), and subsequent treatment with morpholine (XI) furnished the target amidine, which was isolated as the hydrochloride salt.

参考文献 中间体
合成目标
【1】 Okumura, K.; Shimazaki, T.; Aoki, Y.; Yamashita, H.; Tanaka, E.; Banba, S.; Yazawa, K.; Kibayashi, K.; Banno, H.; New platelet fibrinogen receptor glycoprotein IIb-. J Med Chem 1998, 41, 21, 4036.
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) 14461 2,3-Dihydro-4H-chromen-4-one; 4-Chromanone 491-37-2 C9H8O2 详情 详情
(II) 23176 6-nitro-2,3-dihydro-4H-chromen-4-one C9H7NO4 详情 详情
(III) 15618 2-Oxoacetic acid; Glyoxylic Acid 298-12-4 C2H2O3 详情 详情
(IV) 23178 2-[6-nitro-4-oxo-2H-chromen-3(4H)-ylidene]acetic acid C11H7NO6 详情 详情
(V) 23179 methyl 2-(6-amino-3,4-dihydro-2H-chromen-3-yl)acetate C12H15NO3 详情 详情
(VI) 23180 methyl 2-[(3S)-6-[(tert-butoxycarbonyl)amino]-3,4-dihydro-2H-chromen-3-yl]acetate C17H23NO5 详情 详情
(VII) 23181 ethyl 2-[(3S)-6-amino-3,4-dihydro-2H-chromen-3-yl]acetate C13H17NO3 详情 详情
(VIII) 19280 4-cyanobenzoyl chloride 6068-72-0 C8H4ClNO 详情 详情
(IX) 23183 ethyl 2-[(3S)-6-[(4-cyanobenzoyl)amino]-3,4-dihydro-2H-chromen-3-yl]acetate C21H20N2O4 详情 详情
(X) 23184 ethyl 2-[(3S)-6-([4-[ethoxy(imino)methyl]benzoyl]amino)-3,4-dihydro-2H-chromen-3-yl]acetate C23H26N2O5 详情 详情
(XI) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线33

该中间体在本合成路线中的序号：(II)

The condensation of (R)-lactic acid (I) with morpholine (II) gives the corresponding morpholide (III), which is protected at the hydroxyl position with dihydropyran (IV) to yield the tetrahydropyranyl ether (V). The Grignard reaction of (V) with 2,4-difluorophenylmagnesium bromide (VI) affords the chiral 1-propanone (VII), which by a Corey's diastereoselective epoxidation with trimethylsulfoxonium iodide is converted into the oxirane (VIII). The opening of the oxirane ring of (VIII) by means of 1,2,4-triazole (IX) and NaH provides the tertiary alcohol (X), which is treated with pyridine p-toluenesulfonate to give the deprotected diol (XI) as a (2R,3R) and (2R,3S) 4:1 diastereomeric mixture, from which the desired (2R,3R)-isomer (XII) was isolated by crystallization. The reaction of (XII) with Ms-Cl and TEA, followed by cyclization with NaOMe, yields the oxirane (XIII), which is finally condensed with 7-chloroquinazolin-4(3H)-one (XIV) by means of K2CO3 in hot NMP.

参考文献 中间体
合成目标
【1】 Tasaka, A.; Tamura, N.; Matsushita, Y.; Teranishi, K.; Hayashi, R.; Okonogi, K.; Itoh, K.; Optically active antifungal azoles. I. Synthesis and antifungal activity of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol and stereoisomers. Chem Pharm Bull 1993, 41, 6, 1035-42.
【2】 Bartroli Orpi, J.; Anguita Lopez, M. (J. Uriach & Cia., SA); Method for preparing pyrimidone derivs. with antifungal activity. ES 2159488; WO 0166519 .
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) 11591 methyl (2R)-2-hydroxypropanoate 17392-83-5 C4H8O3 详情 详情
(II) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(III) 56718 (2R)-2-hydroxy-1-(4-morpholinyl)-1-propanone C7H13NO3 详情 详情
(IV) 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
(V) 45574 (2R)-1-(4-morpholinyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone C12H21NO4 详情 详情
(VI) 20262 bromo(2,4-difluorophenyl)magnesium C6H3BrF2Mg 详情 详情
(VII) 56717 (2S)-1-(2,4-difluorophenyl)-2-methyl-3-tetrahydro-2H-pyran-2-yl-1-propanone C15H18F2O2 详情 详情
(VIII) 56719 2-({(1R)-1-[2-(2,4-difluorophenyl)-2-oxiranyl]ethyl}oxy)tetrahydro-2H-pyran; (1R)-1-[2-(2,4-difluorophenyl)-2-oxiranyl]ethyl tetrahydro-2H-pyran-2-yl ether C15H18F2O3 详情 详情
(IX) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(X) 56720 (3R)-2-(2,4-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanol C17H21F2N3O3 详情 详情
(XI) 56721 (3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol C12H13F2N3O2 详情 详情
(XII) 13106 (2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol C12H13F2N3O2 详情 详情
(XIII) 31738 1-[[(2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole C12H11F2N3O 详情 详情
(XIV) 50077 7-chloro-4(3H)-quinazolinone C8H5ClN2O 详情 详情

合成路线34

该中间体在本合成路线中的序号：(XI)

Nitration of chromanone (I) with fuming HNO3 at -35 C afforded 6-nitro-4-chromanone (II). Subsequent aldol condensation of (II) with glyoxylic acid (III) in the presence of H2SO4 produced the alpha-beta-unsaturated acid (IV). Further hydrogenation of the nitro, keto, and olefin groups of (IV) with concomitant esterification produced the benzopyranylacetate (V). After protection of (V) as the N-Boc derivative (VI), optical resolution was achieved by preparative HPLC on a Chiralcel-OD column. The desired (S)-enantiomer (VI) was deprotected using ethanolic HCl to afford amine (VII), which was condensed with 4-cyanobenzoyl chloride (VIII) to give amide (IX). Treatment of (IX) with HCl-EtOH produced imidate (X), and subsequent treatment with morpholine (XI) furnished amidine (XII). Finally, basic hydrolysis of the ester function provided the target amidinoacid, which was isolated as the hydrochloride salt.

参考文献 中间体
合成目标
【1】 Okumura, K.; Shimazaki, T.; Aoki, Y.; Yamashita, H.; Tanaka, E.; Banba, S.; Yazawa, K.; Kibayashi, K.; Banno, H.; New platelet fibrinogen receptor glycoprotein IIb-. J Med Chem 1998, 41, 21, 4036.
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) 14461 2,3-Dihydro-4H-chromen-4-one; 4-Chromanone 491-37-2 C9H8O2 详情 详情
(II) 23176 6-nitro-2,3-dihydro-4H-chromen-4-one C9H7NO4 详情 详情
(III) 15618 2-Oxoacetic acid; Glyoxylic Acid 298-12-4 C2H2O3 详情 详情
(IV) 23178 2-[6-nitro-4-oxo-2H-chromen-3(4H)-ylidene]acetic acid C11H7NO6 详情 详情
(V) 23179 methyl 2-(6-amino-3,4-dihydro-2H-chromen-3-yl)acetate C12H15NO3 详情 详情
(VI) 23180 methyl 2-[(3S)-6-[(tert-butoxycarbonyl)amino]-3,4-dihydro-2H-chromen-3-yl]acetate C17H23NO5 详情 详情
(VII) 23181 ethyl 2-[(3S)-6-amino-3,4-dihydro-2H-chromen-3-yl]acetate C13H17NO3 详情 详情
(VIII) 19280 4-cyanobenzoyl chloride 6068-72-0 C8H4ClNO 详情 详情
(IX) 23183 ethyl 2-[(3S)-6-[(4-cyanobenzoyl)amino]-3,4-dihydro-2H-chromen-3-yl]acetate C21H20N2O4 详情 详情
(X) 23184 ethyl 2-[(3S)-6-([4-[ethoxy(imino)methyl]benzoyl]amino)-3,4-dihydro-2H-chromen-3-yl]acetate C23H26N2O5 详情 详情
(XI) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(XII) 23186 ethyl 2-[(3S)-6-([4-[imino(4-morpholinyl)methyl]benzoyl]amino)-3,4-dihydro-2H-chromen-3-yl]acetate C25H29N3O5 详情 详情

合成路线35

该中间体在本合成路线中的序号：(XIII)

The reduction of diethyl 3-(methoxymethoxy)glutarate (I) with LiAlH4 in THF gives 3-(methoxymethoxy)pentane-1,5-diol (II), which is treated with Ts-OH and TEA in THF to yield the disulfonate (III). The condensation of (III) with 5-ethoxyindolin-2-one (IV) by means of tBu-OK in THF affords the spiro compound (V), which is deprotected with HCl in methanol to afford the spiranic alcohol (VI). The oxidation of (VI) with pyridinium chlorochromate (PCC) over Al2O3 provides the spiranic cyclohexanone (VII), which is treated with 2-chloroethanol (VIII) and Ms-OH in toluene to give the ketal (IX). The reaction of (IX) with zinc borohydride and trimethylsilyl chloride in ethyl ether/dichloromethane yields the 2-chloroethoxy derivative (X), which is condensed with 4-(N-tert-butylcarbamoyl)-2-methoxybenzenesulfonyl chloride (XI) by means of tBu-OK in THF to afford the adduct (XII). Finally, the target compound is obtained by condensation of (XII) with morpholine (XIII) by means of NaI in DMF, followed by treatment with fumaric acid.

参考文献 中间体
合成目标
【1】 Di Malta, A.; Foulon, L.; Garcia, G.; Nisato, D.; Roux, R.; Serradeil-Legal, C.; Valette, G.; Wagnon, J. (Sanofi-Synthélabo); Derivs. of 1-benzenesulfonyl-1,3-dihydro-indol-2-one, their preparation and pharmaceutical compsns. containing them. CA 2129215; EP 0636608; FR 2708605; JP 1995247269 .
【2】 Foulon, L.; Garcia, G.; Serradeil-Le Gal, C.; Valette, G. (Sanofi-Synthelabo); 3-Spiro-indolin-2-one derivs. as vasopressin and/or oxytocin receptor ligands. EP 0873309; FR 2740136; JP 1999509232; JP 2001302631; US 5994350; WO 9715556 .
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) 50294 diethyl 3-(methoxymethoxy)pentanedioate C11H20O6 详情 详情
(II) 50295 3-(methoxymethoxy)-1,5-pentanediol C7H16O4 详情 详情
(III) 50296 3-(methoxymethoxy)-5-[[(4-methylphenyl)sulfonyl]oxy]pentyl 4-methylbenzenesulfonate C21H28O8S2 详情 详情
(IV) 50297 5-ethoxy-1,3-dihydro-2H-indol-2-one C10H11NO2 详情 详情
(V) 50298 　 C17H23NO4 详情 详情
(VI) 50299 　 C15H19NO3 详情 详情
(VII) 50300 　 C15H17NO3 详情 详情
(VIII) 10384 2-Chloro-1-ethanol; Ethylene chlorohydrin 107-07-3 C2H5ClO 详情 详情
(IX) 50301 　 C19H25Cl2NO4 详情 详情
(X) 50302 　 C17H22ClNO3 详情 详情
(XI) 50284 4-[(tert-butylamino)carbonyl]-2-methoxybenzenesulfonyl chloride C12H16ClNO4S 详情 详情
(XII) 50303 　 C29H37ClN2O7S 详情 详情
(XIII) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线36

该中间体在本合成路线中的序号：(IV)

The reaction of 2,4-dichloro-5-(trifluoromethyl)nitrobenzene (I) with aminomethanephosphonic acid (II) by means of NaOH in ethanol/water gives the anilinomethanephosphonic acid (III), which is condensed first with morpholine (IV) by heating at 120 C and esterified with triethyl orthoformate at 150 C yielding 5-(4-morpholinyl)-2-nitro-4-(trifluoromethyl)phenylaminomethyl phosphonic acid diethyl ester (V). The reduction of the nitro group of (V) with H2 over Pd/C in ethanol affords the corresponding amino-derivative (VI), which is cyclized with oxalic acid monoethyl ester monochloride (VII) by means of triethylamine in THF providing the quinoxaline (VIII). Finally, this compound is hydrolyzed to the free phosphonic acid with trimethylbromo silane in acetonitrile.

参考文献 中间体
合成目标
【1】 Huth, A.; Turski, L. (Schering AG); Quinoxalindione derivs., their preparation and their use in drugs. DE 4314591; DE 4344486; EP 0696288; EP 1002796; JP 1996508037; US 5750525; WO 9425469 .
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) 28301 1,5-dichloro-2-nitro-4-(trifluoromethyl)benzene 400-70-4 C7H2Cl2F3NO2 详情 详情
(II) 28302 aminomethylphosphonic acid 1066-51-9 CH6NO3P 详情 详情
(III) 28303 [5-chloro-2-nitro-4-(trifluoromethyl)anilino]methylphosphonic acid C8H7ClF3N2O5P 详情 详情
(IV) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(V) 28304 diethyl [5-(4-morpholinyl)-2-nitro-4-(trifluoromethyl)anilino]methylphosphonate C16H23F3N3O6P 详情 详情
(VI) 28305 diethyl [2-amino-5-(4-morpholinyl)-4-(trifluoromethyl)anilino]methylphosphonate C16H25F3N3O4P 详情 详情
(VII) 11043 Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride 4755-77-5 C4H5ClO3 详情 详情
(VIII) 28306 diethyl [7-(4-morpholinyl)-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydro-1(2H)-quinoxalinyl]methylphosphonate C18H23F3N3O6P 详情 详情

合成路线37

该中间体在本合成路线中的序号：(XXVII)

Reaction of mesylate (XVII) with triazole sodium salt (XVIII) gave (XIX). Ozonization of olefinic double bond, followed by treatment with Me2S and K2CO3 provided ketone (XX). Then, haloform reaction with NaOBr gave acid (XXI), and reduction with LiAlH4 in cold Et2O afforded primary alcohol (XXII). Alcohol (XXII) was converted to mesylate (XXIII), and this was condensed with 4-(trifluoromethoxy)phenol (XXIV) to give ether (XXV). Deprotection of the trityl group with formic acid in EtOAc and subsequent reaction with methanesulfonyl chloride provided mesylate (XXVI), which was finally condensed with morpholine (XXVII) to furnish the target compound.

参考文献 中间体
合成目标
【1】 Tsukuda, T.; Watanabe, M.; Ontsuka, H.; Hattori, K.; Shirai, M.; Shimma, N.; Synthesis of novel antifungal agents (2). Bioorg Med Chem Lett 1998, 8, 14, 1825.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVII) 18762 1-Ethoxyethylene; Ethyl vinyl ether；Ethoxyethene 109-92-2 C4H8O 详情 详情
(XVIII) 16341 1H-1,2,4-triazol-1-ylsodium C2H2N3Na 详情 详情
(XIX) 18775 2-[(1S,2R,3R,4R)-4-isopropenyl-2-methoxy-1-methyl-3-(1H-1,2,4-triazol-1-ylmethyl)cyclohexyl]ethyl trityl ether; 1-([(1R,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexyl]methyl)-1H-1,2,4-triazole C35H41N3O2 详情 详情
(XX) 18776 1-[(1R,2R,3R,4S)-3-methoxy-4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-4-[2-(trityloxy)ethyl]cyclohexyl]-1-ethanone C34H39N3O3 详情 详情
(XXI) 18777 (1R,2R,3R,4S)-3-methoxy-4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-4-[2-(trityloxy)ethyl]cyclohexanecarboxylic acid C33H37N3O4 详情 详情
(XXII) 18778 [(1R,2R,3R,4S)-3-methoxy-4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-4-[2-(trityloxy)ethyl]cyclohexyl]methanol C33H39N3O3 详情 详情
(XXIII) 18779 [(1R,2R,3R,4S)-3-methoxy-4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-4-[2-(trityloxy)ethyl]cyclohexyl]methyl methanesulfonate C34H41N3O5S 详情 详情
(XXIV) 18780 4-(trifluoromethoxy)phenol 828-27-3 C7H5F3O2 详情 详情
(XXV) 18781 1-([(1R,2R,3S,6R)-2-methoxy-3-methyl-6-[[4-(trifluoromethoxy)phenoxy]methyl]-3-[2-(trityloxy)ethyl]cyclohexyl]methyl)-1H-1,2,4-triazole; 2-((1S,2R,3R,4R)-2-methoxy-1-methyl-3-(1H-1,2,4-triazol-1-ylmethyl)-4-[[4-(trifluoromethoxy)phenoxy]methyl]cyclohexyl)ethyl trityl ether C40H42F3N3O4 详情 详情
(XXVI) 18782 2-((1S,2R,3R,4R)-2-methoxy-1-methyl-3-(1H-1,2,4-triazol-1-ylmethyl)-4-[[4-(trifluoromethoxy)phenoxy]methyl]cyclohexyl)ethyl methanesulfonate C22H30F3N3O6S 详情 详情
(XXVII) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线38

该中间体在本合成路线中的序号：(III)

The condensation of 3-(4-morpholinylmethyl)-2H-1-benzopyran-8-ol (VI) with 2(R)-(p-toluenesulfonyloxymethyl)-4-(triphenylmethyl)morpholine (XVI) by means of K2CO3 in DMF gives the protected target compound (XVII), which is finally deprotected with acetic acid and salified with methanesulfonic acid. The intermediates benzopyran (VI) and morpholine (XVI) have been obtained as follows: Benzopyran (VI): The reaction of 8-methoxy-4H-1-benzopyran-3-carboxylic acid (I) with SOCl2 in refluxing toluene gives the acyl chloride (II), which is condensed with morpholine (III) in dioxane yielding the methanone (IV). The reaction of (IV) with BBr3 in dichloromethane affords the 1-(8-hydroxy-2H-1-benzopyran-3-yl)-1-(4-morpholinyl)methanone (V), which is reduced with LiAlH4 in THF giving the desired intermediate benzopyran (VI). Morpholine (XVI): The reaction of benzyl (S)-glycicyl ether (VII) with benzylamine (VIII) gives 1-(benzylamino)-3-(benzyloxy)-2(R)-propanol (IX), which is cyclized with chloroacetyl chloride (X) and triethylamine in dichloromethane yielding the morpholinone (XI). The reduction of (XI) with LiAlH4 in ethyl ether affords the fully protected morpholine (XII), which is debenzylated with H2 over Pd/C in ethanol giving 2(R)-(hydroxyethyl)morpholine (XIII). The reaction of (XIII) with trityl chloride (XIV) and TEA in dichloromethane yields the N-tritylmorpholine (XV), which is finally tosylated with tosyl chloridde and pyridine affording the desired intermediate morpholine (XVI).

参考文献 中间体
合成目标
【1】 Berg, S.; et al.; (R)-(+)-2[[[3-(Morpholinomethyl)-2H-chromen-8-yl]oxy]methyl]morpholine methanesulfonate: A new selective rat 5-hydroxytryptamine1B receptor antagonist. J Med Chem 1998, 41, 11, 1934.
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) 28621 8-methoxy-2H-chromene-3-carboxylic acid 57543-59-6 C11H10O4 详情 详情
(II) 28622 8-methoxy-2H-chromene-3-carbonyl chloride C11H9ClO3 详情 详情
(III) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(IV) 28623 (8-methoxy-2H-chromen-3-yl)(4-morpholinyl)methanone C15H17NO4 详情 详情
(V) 28624 (8-hydroxy-2H-chromen-3-yl)(4-morpholinyl)methanone C14H15NO4 详情 详情
(VI) 28625 3-(4-morpholinylmethyl)-2H-chromen-8-ol C14H17NO3 详情 详情
(VII) 22645 (1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl (2S)-2-methylbutanoate; Lovastatin 75330-75-5 C24H36O5 详情 详情
(VIII) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(IX) 28626 (2S)-1-(benzylamino)-3-(benzyloxy)-2-propanol C17H21NO2 详情 详情
(X) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(XI) 28627 (6R)-4-benzyl-6-[(benzyloxy)methyl]-3-morpholinone C19H21NO3 详情 详情
(XII) 28628 benzyl [(2R)-4-benzylmorpholinyl]methyl ether C19H23NO2 详情 详情
(XIII) 12353 (2R)-1,4-Oxazinan-2-ylmethanol C5H11NO2 详情 详情
(XIV) 28630 Triphenylchloromethane; 1-[Chloro(diphenyl)methyl]benzene; Trityl chloride 76-83-5 C19H15Cl 详情 详情
(XV) 28629 [(2R)-4-tritylmorpholinyl]methanol C24H25NO2 详情 详情
(XVI) 28631 [(2R)-4-tritylmorpholinyl]methyl 4-methylbenzenesulfonate C31H31NO4S 详情 详情
(XVII) 28632 (2R)-2-([[3-(4-morpholinylmethyl)-2H-chromen-8-yl]oxy]methyl)-4-tritylmorpholine C38H40N2O4 详情 详情

合成路线39

该中间体在本合成路线中的序号：(III)

The condensation of 6-chloro-4-(trifluoromethyl)quinazolin-2(1H)-one (V) with lithium cyclopropylacetylene (VI) (LiHMDS is used as strong base) catalyzed by the chiral moderator (IV) in toluene/THF gives the target compound. The chiral moderator (IV) has been obtained as follows: The epoxidation of (+)-3-carene (I) with MCPBA in dichloromethane gives the corresponding epoxide (II), which is then condensed with morpholine (III) by means of MgBr2 as catalyst.

参考文献 中间体
合成目标
【1】 Kauffman, G.S.; Dorow, R.L.; Davulcu, A.H.; Radesca, L.A.; Harris, G.D.; Fortunak, J.M.; Parsons, R.L.; Nugent, W.A. (DuPont Pharmaceuticals Co.); Asymmetric synthesis of quinazolin-2-ones useful as HIV reverse transcriptase inhibitors. WO 0170707 .
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) 47239 (1S,6R)-3,7,7-trimethylbicyclo[4.1.0]hept-3-ene 13466-78-9 C10H16 详情 详情
(II) 47240 (1S,3S,5R,7R)-3,8,8-trimethyl-4-oxatricyclo[5.1.0.0(3,5)]octane C10H16O 详情 详情
(III) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(IV) 47241 (1S,3S,4S,6R)-3,7,7-trimethyl-4-(4-morpholinyl)bicyclo[4.1.0]heptan-3-ol C14H25NO2 详情 详情
(V) 36610 6-chloro-4-(trifluoromethyl)-2(1H)-quinazolinone C9H4ClF3N2O 详情 详情
(VI) 36611 (2-cyclopropylethynyl)lithium C5H5Li 详情 详情

合成路线40

该中间体在本合成路线中的序号：(III)

The condensation of 5,6-difluoro-4-(trifluoromethyl)quinazolin-2(1H)-one (V) with lithium cyclopropylacetylene (VI) (LiHMDS is used as strong base) catalyzed by the chiral moderator (IV) in toluene/THF gives the target compound with an enantiomeric excess of 94%, which increases up to 99.6% after working up (crystallization in heptane). The chiral moderator (IV) has been obtained as follows: The epoxidation of (+)-3-carene (I) with MCPBA in dichloromethane gives the corresponding epoxide (II), which is then condensed with morpholine (III) using MgBr as a catalyst.

参考文献 中间体
合成目标
【1】 Kauffman, G.S.; et al.; An efficient chiral moderator prepared for inexpensive (+)-3-carene: Synthesis of the HIV-1 non-nucleoside reverse transcriptase inhibitor DPC 963. Org Lett 2000, 2, 20, 3119.
【2】 Kauffman, G.S.; Dorow, R.L.; Davulcu, A.H.; Radesca, L.A.; Harris, G.D.; Fortunak, J.M.; Parsons, R.L.; Nugent, W.A. (DuPont Pharmaceuticals Co.); Asymmetric synthesis of quinazolin-2-ones useful as HIV reverse transcriptase inhibitors. WO 0170707 .
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) 47239 (1S,6R)-3,7,7-trimethylbicyclo[4.1.0]hept-3-ene 13466-78-9 C10H16 详情 详情
(II) 47240 (1S,3S,5R,7R)-3,8,8-trimethyl-4-oxatricyclo[5.1.0.0(3,5)]octane C10H16O 详情 详情
(III) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(IV) 47241 (1S,3S,4S,6R)-3,7,7-trimethyl-4-(4-morpholinyl)bicyclo[4.1.0]heptan-3-ol C14H25NO2 详情 详情
(V) 36616 5,6-difluoro-4-(trifluoromethyl)-2(1H)-quinazolinone C9H3F5N2O 详情 详情
(VI) 36611 (2-cyclopropylethynyl)lithium C5H5Li 详情 详情

合成路线41

该中间体在本合成路线中的序号：(IX)

The known diarylimidazole (I) was protected as the N-[2-(trimethylsilyl)ethoxy]methyl derivative (II) by treatment with 2-(trimethylsilyl)ethoxymethyl chloride and NaH. Lithiation of (II) with BuLi at -78 C, followed by quenching with N-formylmorpholine (III) provided aldehyde (IV). This was converted to the dimethyl acetal (V) upon treatment with trimethyl orthoformate and p-toluenesulfonic acid. Further condensation of (V) with methyl 2,2-bis(hydroxymethyl)propionate (VI) produced the dioxane derivative (VII) as a mixture of cis and trans isomers. Basic hydrolysis of the methyl ester group of (VII) afforded the corresponding carboxylic acid. The desired trans isomer (VIII) was then isolated by selective precipitation of the acidified methanolic solution. Finally, coupling of (VIII) with morpholine (IX) using EDC and HOBt furnished the title amide.

参考文献 中间体
合成目标
【1】 McLay, I.M.; Halley, F.; Souness, J.E.; et al.; The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-anthritic efficacy. Bioorg Med Chem 2001, 9, 2, 537.
【2】 Halley, F.; Porter, B.; Bamborough, P.L.; Lewis, R.A.; Ratcliffe, A.J.; Wallace, P.A.; McLay, I.M.; McKenna, J.M.; Lythgoe, D.J.; Collis, A.J. (Rhone-Poulenc Rorer Ltd.); Imidazolyl-cyclic acetals. EP 0988301; WO 9856788 .
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) 33798 4-[4-(4-fluorophenyl)-1H-imidazol-5-yl]pyridine C14H10FN3 详情 详情
(II) 33799 [4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-1-yl]methyl 2-(trimethylsilyl)ethyl ether; 4-(4-(4-fluorophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazol-5-yl)pyridine C20H24FN3OSi 详情 详情
(III) 33800 4-morpholinecarbaldehyde 4394-85-8 C5H9NO2 详情 详情
(IV) 33801 4-(4-fluorophenyl)-5-(4-pyridinyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazole-2-carbaldehyde C21H24FN3O2Si 详情 详情
(V) 33802 [2-(dimethoxymethyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-1-yl]methyl 2-(trimethylsilyl)ethyl ether; 4-(2-(dimethoxymethyl)-4-(4-fluorophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazol-5-yl)pyridine C23H30FN3O3Si 详情 详情
(VI) 33803 methyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate C6H12O4 详情 详情
(VII) 33804 methyl 2-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-5-methyl-1,3-dioxane-5-carboxylate C21H20FN3O4 详情 详情
(VIII) 33805 2-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-5-methyl-1,3-dioxane-5-carboxylic acid C20H18FN3O4 详情 详情
(IX) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线42

该中间体在本合成路线中的序号：(IX)

DPC-961 (I) can be obtained by several different related ways: 1) Condensation of 2'-amino-5'-chloro-2,2,2-trifluoroacetophenone (II) with trimethylsilyl isocyanate in the presence of dimethylaminopyridine in THF, followed by desilylation with tetrabutylammonium fluoride in THF, provides the quinazoline derivative (III), which is dehydrated employing molecular sieves in refluxing toluene to yield the imine (IV). Treatment of compound (IV) with lithium cyclopropylacetylide (V) in THF in the presence of BF3.Et2O gives the racemic adduct (VI). Finally, the desired (S)-enantiomer (I) is isolated by means of chiral HPLC . 2) Condensation of 6-chloro-4-(trifluoromethyl)quinazolin-2(1H)-one (IV) with lithium cyclopropylacetylide (V) catalyzed by the chiral auxiliary (X) in toluene/THF gives directly DPC-961. The chiral auxiliary (X) can be synthesized as follows: Epoxidation of (+)-3-carene (VII) with MCPBA in dichloromethane gives the corresponding epoxide (VIII), which is then condensed with morpholine (IX) by means of MgBr2 as catalyst.

参考文献 中间体
合成目标
【1】 Sorbera, L.A.; Rabasseda, X.; Silvestre, J.S.; Leeson, P.A.; DPC-083. Drugs Fut 2002, 27, 4, 331.
【2】 Rodgers, J.D.; Koo, S.S.; Corbett, J.W.; et al.; Expanded-spectrum nonnucleoside reverse transcriptase inhibitors inhibit clinically relevant mutant variants of human immunodeficiency virus type 1. Antimicrob Agents Chemother 1999, 43, 12, 2893.
【3】 Corbett, J.W.; Ko, S.S.; Rodgers, J.D.; et al.; Inhibition of clinically relevant mutant variant of HIV-1 by quinazolinone non-nucleoside reverse transcriptase inhibitors. J Med Chem 2000, 43, 10, 2019.
【4】 Corbett, J.W.; Ko, S.S. (DuPont Pharmaceuticals Co.); 4,4-Disubstd.-3,4-dihydro-2(1H)-quinazolinones useful as HIV reverse transcriptase inhibitors. US 6124302; WO 9845276 .
【5】 Kauffman, G.S.; Dorow, R.L.; Davulcu, A.H.; Radesca, L.A.; Harris, G.D.; Fortunak, J.M.; Parsons, R.L.; Nugent, W.A. (DuPont Pharmaceuticals Co.); Asymmetric synthesis of quinazolin-2-ones useful as HIV reverse transcriptase inhibitors. WO 0170707 .
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) 36613 (4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone C14H10ClF3N2O 详情 详情
(II) 16572 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoro-1-ethanone C8H5ClF3NO 详情 详情
(III) 36609 6-chloro-4-hydroxy-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone C9H6ClF3N2O2 详情 详情
(IV) 36610 6-chloro-4-(trifluoromethyl)-2(1H)-quinazolinone C9H4ClF3N2O 详情 详情
(V) 36611 (2-cyclopropylethynyl)lithium C5H5Li 详情 详情
(VI) 47241 (1S,3S,4S,6R)-3,7,7-trimethyl-4-(4-morpholinyl)bicyclo[4.1.0]heptan-3-ol C14H25NO2 详情 详情
(VII) 47239 (1S,6R)-3,7,7-trimethylbicyclo[4.1.0]hept-3-ene 13466-78-9 C10H16 详情 详情
(VIII) 47240 (1S,3S,5R,7R)-3,8,8-trimethyl-4-oxatricyclo[5.1.0.0(3,5)]octane C10H16O 详情 详情
(IX) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线43

该中间体在本合成路线中的序号：

The reaction of 2,4-dichlorophenol (I) with 2-chloroacetophenone (II) by means of a copper catalyst and sodium hydroxide gives 2-(2,4-dichlorophenoxy)acetophenone (III), which is treated with sulfur in refluxing morpholine yielding 2-(2,4-dichlorophenoxy)phenylthioacetomorpholide (IV). Finally, this compound is hydrolyzed with KOH in refluxing methanol.

参考文献 中间体
合成目标
【1】 Arrigoni-Martelli, E.; Castañer, J.; Fenclofenac. Drugs Fut 1977, 2, 10, 665.
【2】 Godfrey, K.E. (Reckitt & Colman Pharmaceuticals); Substituted 2-phenoxyphenylacetic acids. DE 2117826; FR 2092044; GB 1308327; US 3766263 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10388 Morpholine 110-91-8 C4H9NO 详情 详情
(I) 40047 2,4-dichlorophenol 120-83-2 C6H4Cl2O 详情 详情
(II) 34006 1-(2-chlorophenyl)-1-ethanone 2142-68-9 C8H7ClO 详情 详情
(III) 40172 1-[2-(2,4-dichlorophenoxy)phenyl]-1-ethanone C14H10Cl2O2 详情 详情
(IV) 40173 2-[2-(2,4-dichlorophenoxy)phenyl]-1-(4-morpholinyl)-1-ethanethione C18H17Cl2NO2S 详情 详情

合成路线44

该中间体在本合成路线中的序号：(B)

Ethylenediaminetetraacetic acid (EDTA) (I) on heating with formamide (A), afforded IGRF-154 (II). The latter compound was suspended in dimethylformamide (C), heated with morpholine (B) in ethanol and then refluxed with formalin. The final product crystallized on cooling.

参考文献 中间体
合成目标
【1】 Ren, Y.F.; et al.; An investigation of a new antineoplastic agent bimolane (AT-1727). Kexue Tongbao 1980, 23, 4, 189-190.
【2】 Ji Ru-Yun; Bimolane. Drugs Fut 1981, 6, 11, 667.
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) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(A) 16598 Formamide 75-12-7 CH3NO 详情 详情
(I) 39018 2-[[2-[bis(carboxymethyl)amino]ethyl](carboxymethyl)amino]acetic acid C10H16N2O8 详情 详情
(II) 28033 4-[2-(3,5-dioxo-1-piperazinyl)ethyl]-2,6-piperazinedione C10H14N4O4 详情 详情
(C) 33491 Dimethylformamide 68-12-2 C3H7NO 详情 详情

合成路线45

该中间体在本合成路线中的序号：(VIII)

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

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

合成路线46

该中间体在本合成路线中的序号：(VIII)

N-protection of 4,4'-diamnostilbene-2,2'-disulfonic acid (I) with 9-fluorenylmethyl chloroformate (Fmoc-Cl) by means of Na2CO3 in dioxane yields Fmoc-protected derivative (II), which reacts with triisopropylorthoformate in refluxing dioxane to provide bis(isopropyl) ester (III). Removal of the Fmoc-protecting groups of (III) by means of piperidine in DMF affords diamino compound (IV), which is then condensed with acid chloride (V) by means of K2CO3 in THF to provide compound (VI) [acid chloride (V) can be obtained by first treatment of p-(methylsulfanyl)benzoic acid (VII) with morpholine (VIII) in chlorosulfonic acid to give (IX), followed by reaction with oxalyl chloride in THF/DMF]. Finally, the target compound is obtained by treatment of bis(isopropyl) ester (VI) with sodium iodide (NaI) in acetone.

参考文献 中间体
合成目标
【1】 Wrobel, J.; Rogers, J.F.; Synthesis of stilbene (bis)sulfonic acid, (bis)benzamides as FSH antagonists. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 314.
【2】 Rogers, J.F.; Jetter, J.W.; Wrobel, J.E.; Green, D.M.; Kao, W. (American Home Products Corp.); Aryl sulfonic acids and derivs. as FSH antagonists. WO 0058277 .
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) 46706 5-amino-2-[(E)-2-(4-amino-2-sulfophenyl)ethenyl]benzenesulfonic acid 81-11-8 C14H14N2O6S2 详情 详情
(II) 46707 5-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2-[(E)-2-(4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2-sulfophenyl)ethenyl]benzenesulfonic acid C44H34N2O10S2 详情 详情
(III) 46708 isopropyl 5-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2-[(E)-2-[4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2-(isopropoxysulfonyl)phenyl]ethenyl]benzenesulfonate C50H46N2O10S2 详情 详情
(IV) 46709 isopropyl 5-amino-2-[(E)-2-[4-amino-2-(isopropoxysulfonyl)phenyl]ethenyl]benzenesulfonate C20H26N2O6S2 详情 详情
(V) 46712 4-(methylsulfanyl)-3-(4-morpholinylsulfonyl)benzoyl chloride C12H14ClNO4S2 详情 详情
(VI) 46711 isopropyl 2-[(E)-2-(2-(isopropoxysulfonyl)-4-[[4-(methylsulfanyl)-3-(4-morpholinylsulfonyl)benzoyl]amino]phenyl)ethenyl]-5-[[4-(methylsulfanyl)-3-(4-morpholinylsulfonyl)benzoyl]amino]benzenesulfonate C44H52N4O14S6 详情 详情
(VII) 30683 4-(methylsulfanyl)benzoic acid 13205-48-6 C8H8O2S 详情 详情
(VIII) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(IX) 46710 4-(methylsulfanyl)-3-(4-morpholinylsulfonyl)benzoic acid C12H15NO5S2 详情 详情

合成路线47

该中间体在本合成路线中的序号：(VIII)

Tosylation of the primary hydroxyl group of (I) affords tosylate (II), which is then subjected to reaction with MeSNa and tetrabutylammonium iodide (n-Bu4NI) in THF followed by oxidation with NaIO4 in MeOH/H2O to provide sulfoxide (III). Derivative (III) is then heated with K2CO3 in 1,2-dichlorobenzene to yield olefin (IV), which is subjected to reaction with triethylsilyl chloride (TESCl) and imidazole in DMF to give the disilylated compound (V). Derivative (V) is then subjected to a Johnson-Remeiux reaction by first treatment with OsO4 and NMO in MeOH/THF/H2O followed by oxidation with NaIO4 in MeOH/THF/H2O to afford aldehyde (VI), which is then reduced by means of NaBH4 in MeOH to furnish alcohol (VII). Reaction between (VII) and morpholine (VIII) in refluxing MeOH affords baccatin III derivative (IX) (1), which is treated with TsOH in MeOH and then with acetic anhydride and DMSO to yield compound (X). Desulfurylation of (X) by refluxing with Raney-Ni in EtOH followed by removal of the TES protecting group by reaction with HF-pyridine affords intermediate (XI), which is finally converted into the desired compound by introduction of the phenylisoserine side-chain using protected beta-lactam (XII) and NaHMDS in THF followed by TBS removal by treatment with HF-pyridine.

参考文献 中间体
合成目标
【1】 Iimura, S.; et al.; Synthesis and antitumor activity of non-prodrug water-soluble taxoid: 10-C-Aminoalkylated docetaxel analogs. Heterocycles 2000, 53, 12, 2719.
【2】 Chiba, J.; Ohsuki, S.; Jimbo, T.; Iwahana, M.; Terasawa, H.; Yoshino, T.; Uoto, K.; Soga, T.; Iimura, S.; Orally active docetaxel analogue: Synthesis of 10-deoxy-10-C-morpholinoethyl docetaxel analogues. Bioorg Med Chem Lett 2001, 11, 3, 407.
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) 50147 (1S,2S,3R,4S,9S,10S,12R,15S)-4-(acetoxy)-1,15-dihydroxy-12-(3-hydroxypropyl)-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C38H56O10Si 详情 详情
(II) 50148 (1S,2S,3R,4S,9S,10S,12R,15S)-4-(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-12-(3-[[(4-methylphenyl)sulfonyl]oxy]propyl)-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C45H62O12SSi 详情 详情
(III) 50149 (1S,2S,3R,4S,9S,10S,12R,15S)-4-(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-12-[3-(methylsulfinyl)propyl]-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C39H58O10SSi 详情 详情
(IV) 50150 (1S,2S,3R,4S,9S,10S,12R,15S)-4-(acetoxy)-12-allyl-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C38H54O9Si 详情 详情
(V) 50151 (1S,2S,3R,4S,9S,10S,12R,15S)-4-(acetoxy)-12-allyl-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9,15-bis[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C44H68O9Si2 详情 详情
(VI) 50152 (1S,2S,3R,4S,9S,10S,12R,15S)-4-(acetoxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-12-(2-oxoethyl)-9,15-bis[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C43H66O10Si2 详情 详情
(VII) 50153 (1S,2S,3R,4S,9S,10S,12R,15S)-4-(acetoxy)-1-hydroxy-12-(2-hydroxyethyl)-10,14,17,17-tetramethyl-11-oxo-9,15-bis[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C43H68O10Si2 详情 详情
(VIII) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(IX) 50154 (1S,2S,3R,4S,9S,10S,12R,15S)-4-(acetoxy)-1-hydroxy-10,14,17,17-tetramethyl-12-[2-(4-morpholinyl)ethyl]-11-oxo-9,15-bis[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C47H75NO10Si2 详情 详情
(X) 50155 (1S,2S,3R,4S,9S,10S,12R,15S)-4-(acetoxy)-1-hydroxy-10,14,17,17-tetramethyl-9-[(methylsulfanyl)methoxy]-12-[2-(4-morpholinyl)ethyl]-11-oxo-15-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C43H65NO10SSi 详情 详情
(XI) 50156 (1S,2S,3R,4S,9S,10S,12R,15S)-4-(acetoxy)-1,15-dihydroxy-9-methoxy-10,14,17,17-tetramethyl-12-[2-(4-morpholinyl)ethyl]-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C36H49NO10 详情 详情
(XII) 50157 tert-butyl (3R,4S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-oxo-4-phenyl-1-azetidinecarboxylate C20H31NO4Si 详情 详情

合成路线48

该中间体在本合成路线中的序号：(V)

In an alternative synthesis, the chloropropoxy derivative (III) was similarly condensed with 2,4-dichloroaniline (II) to give (IV), which was then treated with morpholine (V), yielding the title compound.

参考文献 中间体
合成目标
【1】 Boschelli, D.H.; Wang, Y.D.; Ye, F.; et al.; Synthesis and Src kinase inhibitory activity of a series of 4-phenylamino-3-quinolinecarbonitriles. J Med Chem 2001, 44, 5, 822.
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) 48518 2,4-dichlorobenzeneamine; 2,4-Dichloroaniline 554-00-7 C6H5Cl2N 详情 详情
(III) 48519 4-chloro-7-(3-chloropropoxy)-6-methoxy-3-quinolinecarbonitrile C14H12Cl2N2O2 详情 详情
(IV) 48520 7-(3-chloropropoxy)-4-(2,4-dichloroanilino)-6-methoxy-3-quinolinecarbonitrile C20H16Cl3N3O2 详情 详情
(V) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线49

该中间体在本合成路线中的序号：(V)

Reduction of the keto group of 5-delta-methylene pristinamycin IA (I) by means of NaBH4 in the presence of CeCl3 provided the allyl alcohol (II). Subsequent chlorination of (II) with SOCl2, furnished a mixture of compounds containing the 5-delta-(chloromethyl) (III) and the 5-gamma-chloro-5-delta-methylene (IV) derivatives. Treatment of the crude mixture with morpholine (V) in refluxing acetonitrile yielded the title 5-delta-morpholinomethyl analogue.

参考文献 中间体
合成目标
【1】 Barriere, J.C.; Bacque, E.; Puchault, G.; Dutruc-Rooset, G.; Doerflinger, G.; Berthaud, N.; Design and synthesis of RPR202868, the pristinamycin I component of RPR202868/RPR132552, a new oral streptogramin. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-359.
【2】 Barriere, J.-C.; Pantel, G.; Bacqué, E.; Doerflinger, G.; Dutruc-Rosset, G. (Aventis Pharma SA); Streptogramin derivs., production thereof and compsns. containing the same. EP 1204675; FR 2796949; US 6541451; WO 0110895 .
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) 41288 　 C46H54N8O10 详情 详情
(II) 59348 N-{(6R,9S,10R,13S,15aS,22S,24aS)-22-[4-(dimethylamino)benzyl]-6-ethyl-17-hydroxy-10,23-dimethyl-18-methylene-5,8,12,15,21,24-hexaoxo-13-phenyldocosahydro-12H-pyrido[2,1-f]pyrrolo[2,1-l][1,4,7,10,13,16]oxapentaazacyclononadecin-9-yl}-3-hydroxy-2-pyridinecarboxamide C46H56N8O10 详情 详情
(III) 59349 N-{(6R,9S,10R,13S,15aS,22S,24aS)-18-(chloromethyl)-22-[4-(dimethylamino)benzyl]-6-ethyl-10,23-dimethyl-5,8,12,15,21,24-hexaoxo-13-phenyl-1,2,3,5,6,7,8,9,10,13,14,15,15a,16,19,21,22,23,24,24a-icosahydro-12H-pyrido[2,1-f]pyrrolo[2,1-l][1,4,7,10,13,16]oxapentaazacyclononadecin-9-yl}-3-hydroxy-2-pyridinecarboxamide C46H55ClN8O9 详情 详情
(IV) 59350 N-{(6R,9S,10R,13S,15aS,22S,24aS)-17-chloro-22-[4-(dimethylamino)benzyl]-6-ethyl-10,23-dimethyl-18-methylene-5,8,12,15,21,24-hexaoxo-13-phenyldocosahydro-12H-pyrido[2,1-f]pyrrolo[2,1-l][1,4,7,10,13,16]oxapentaazacyclononadecin-9-yl}-3-hydroxy-2-pyridinecarboxamide C46H55ClN8O9 详情 详情
(V) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线50

该中间体在本合成路线中的序号：(V)

In an alternative method, Michael addition of morpholine (V) to the unsaturated ketone (I) gave adduct (VI). Subsequent ketone reduction in (VI) with NaBH4 provided the corresponding alcohol (VII) as a diastereomeric mixture. Dehydration of alcohol (VII), upon treatment with diethylaminosulfur trifluoride, then yielded the title compound.

参考文献 中间体
合成目标
【1】 Barriere, J.-C.; Pantel, G.; Bacqué, E.; Doerflinger, G.; Dutruc-Rosset, G. (Aventis Pharma SA); Streptogramin derivs., production thereof and compsns. containing the same. EP 1204675; FR 2796949; US 6541451; WO 0110895 .
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) 41288 　 C46H54N8O10 详情 详情
(V) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(VI) 59352 N-[(6R,9S,10R,13S,15aS,22S,24aS)-22-[4-(dimethylamino)benzyl]-6-ethyl-10,23-dimethyl-18-(4-morpholinylmethyl)-5,8,12,15,17,21,24-heptaoxo-13-phenyldocosahydro-12H-pyrido[2,1-f]pyrrolo[2,1-l][1,4,7,10,13,16]oxapentaazacyclononadecin-9-yl]-3-hydroxy-2-pyridinecarboxamide C50H63N9O11 详情 详情
(VII) 59351 N-[(6R,9S,10R,13S,15aS,22S,24aS)-22-[4-(dimethylamino)benzyl]-6-ethyl-17-hydroxy-10,23-dimethyl-18-(4-morpholinylmethyl)-5,8,12,15,21,24-hexaoxo-13-phenyldocosahydro-12H-pyrido[2,1-f]pyrrolo[2,1-l][1,4,7,10,13,16]oxapentaazacyclononadecin-9-yl]-3-hydroxy-2-pyridinecarboxamide C50H65N9O11 详情 详情

合成路线51

该中间体在本合成路线中的序号：(IX)

Condensation of 2,2-bis(hydroxymethyl)propionic acid (VIII) with morpholine (IX) in the presence of DCC and HOBt gave amide (X). The cyclic ketal (XI) was then obtained by acid-catalyzed condensation of imidazole aldehyde (VII) with diol (X) using azeotropic removal of water. Oxidation of the sulfide group of (XI) with meta-chloroperbenzoic acid furnished sulfone (XII). The methylsulfonyl group of (XII) was finally displaced with cyclopropylamine (XIII) to provide the title compound

参考文献 中间体
合成目标
【1】 Collis, A.J.; Wilsher, N.E.; Foster, M.L.; Redford, E.J.; McLay, I.M.; Page, K.M.; Maslen, C.; Halley, F.; Souness, J.E.; RPR203494 a pyrimidine analogue of the p38 inhibitor RPR200765A with an improved in vitro potency. Bioorg Med Chem Lett 2001, 11, 5, 693.
【2】 Halley, F.; Porter, B.; Bamborough, P.L.; Lewis, R.A.; Ratcliffe, A.J.; Wallace, P.A.; McLay, I.M.; McKenna, J.M.; Lythgoe, D.J.; Collis, A.J. (Rhone-Poulenc Rorer Ltd.); Imidazolyl-cyclic acetals. EP 0988301; WO 9856788 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 49201 4-(4-fluorophenyl)-5-[2-(methylsulfanyl)-4-pyrimidinyl]-1H-imidazole-2-carbaldehyde C15H11FN4OS 详情 详情
(VIII) 49202 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid C5H10O4 详情 详情
(IX) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(X) 49203 3-hydroxy-2-(hydroxymethyl)-2-methyl-1-(4-morpholinyl)-1-propanone C9H17NO4 详情 详情
(XI) 49204 (2-[4-(4-fluorophenyl)-5-[2-(methylsulfanyl)-4-pyrimidinyl]-1H-imidazol-2-yl]-5-methyl-1,3-dioxan-5-yl)(4-morpholinyl)methanone C24H26FN5O4S 详情 详情
(XII) 49205 (2-[4-(4-fluorophenyl)-5-[2-(methylsulfonyl)-4-pyrimidinyl]-1H-imidazol-2-yl]-5-methyl-1,3-dioxan-5-yl)(4-morpholinyl)methanone C24H26FN5O6S 详情 详情
(XIII) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情

合成路线52

该中间体在本合成路线中的序号：(II)

By heating a mixture of 3,4,5-trimethoxybenzaldehyde (I), tetrahydro-1,4-oxazine (II) and precipitated sulfur, at 140 C

参考文献 中间体
合成目标
【1】 Banfi, S.; et al.; Research on 3,4,5-trimethoxy-benzamides. Note III. Synthesis and CNS depressant activity of new alkoxythiobenzamides. Chim Ther 1973, 4, 3, 462.
【2】 Castaner, J.; de Angelis, L.; Trithiozine. Drugs Fut 1976, 1, 8, 397.
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) 11136 3,4,5-Trimethoxybenzaldehyde 86-81-7 C10H12O4 详情 详情
(II) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线53

该中间体在本合成路线中的序号：(A)

The Friedel-Kraft's reaction of 2-isopropylindan (I) with acetic anhydride in methylene chloride gives 2-isopropyl-5-acetylindan (VII), which by with sulfur and morpholine (A) at 140 C gives 2-(2-isopropyl-5-indanyl)acetylmorpholinothioamide (XI), which is hydrolyzed to 2-(2-isopropyl-5-indanyl)acetic acid (XII). The esterification of (XII) with ethanol - H2SO4 yields the corresponding ethyl ester (XIII), which is condensed with diethyl carbonate (XIV) by means of sodium ethoxide in refluxing ethanol affording diethyl (2-isopropyl-5-indanyl)malonate (XV), which is methylated with methyl iodide and sodium ethoxide in refluxing ethanol to give diethyl methyl-(2-isopropyl-5-indanyl)malonate (XVI). Finally this compound is hydrolyzed and decarboxylated by treatment with NaOH in refluxing hydrazine hydrate Compound (XII) can also be obtained by a Wolf-Kistner reduction of ketoacid (IV) in refluxing hydrazine hydrate

参考文献 中间体
合成目标
【1】 Teulon, J,M,; et al. (Hexachimie SA); BE 824522; CA 1063618; CH 603533; CH 605567; DD 117209; DD 118271; DD 123319; DE 2504689; FR 2260334; GB 1492175; JP 76125367; JP 76125368; NL 7501518; NL 7501519; US 4069326; US 4088787; US 4182896; ZA 7500707 .
【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Arrigoni, Martelli, E.; Isoprofen. Drugs Fut 1981, 6, 8, 471.
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) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(I) 60960 2-isopropylindane C12H16 详情 详情
(IV) 60962 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)-2-oxoacetic acid C14H16O3 详情 详情
(VII) 60965 1-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)-1-ethanone C14H18O 详情 详情
(XI) 60966 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)-1-(4-morpholinyl)-1-ethanethione C18H25NOS 详情 详情
(XII) 60967 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)acetic acid C14H18O2 详情 详情
(XIII) 60968 ethyl 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)acetate C16H22O2 详情 详情
(XIV) 17470 diethyl carbonate; diethylcarbonate 105-58-8 C5H10O3 详情 详情
(XV) 60969 diethyl 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)malonate C19H26O4 详情 详情
(XVI) 60970 ethyl 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)propanoate C17H24O2 详情 详情

合成路线54

该中间体在本合成路线中的序号：(II)

The title compound was obtained by Mannich reaction between 2,6-diisopropylphenol (I), morpholine (II) and formaldehyde, followed by conversion to the corresponding hydrochloride salt.

参考文献 中间体
合成目标
【1】 Cooke, A.; et al.; Water-soluble propofol analogues with intravenous anaesthetic activity. Bioorg Med Chem Lett 2001, 11, 7, 927.
【2】 Buchanan, K.; et al.; Novel water-soluble propofol analogs with intravenous anaesthetic activities. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 226.
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) 20249 2,6-Diisopropylphenol 2078-54-8 C12H18O 详情 详情
(II) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线55

该中间体在本合成路线中的序号：(II)

The condensation of 4-chloro-2,6-pyridinedicarboxylic acid (I) with morpholine (II) afforded the morpholinopyridinedicarboxylic acid (III), which was further esterified with MeOH and HCl to produce diester (IV). Reduction of (IV) with NaBH4 and CaCl2 gave hydroxy ester (V). After protection of the hydroxyl group of (V) as the trimethylsilylethoxymethyl derivative (VII), the ester group was hydrolyzed under basic conditions yielding acid (VIII). This was then subjected to a Curtius rearrangement with DPPA in the presence of tert-butanol to generate the tert-butyl carbamate (IX). Alkylation of carbamate (IX) with 3-methoxy-5-nitrobenzyl bromide (X) and NaH furnished the N-benzyl carbamate derivative (XI). The nitro group of (XI) was then reduced to amine (XII) by catalytic hydrogenation over Pd/C.

参考文献 中间体
合成目标
【1】 Fukami, T.; Mase, T.; Tsuchiya, Y.; Kanatani, A.; Fukuroda, T. (Banyu Pharmaceutical Co., Ltd.); Aminopyridine derivs.. EP 0889034; US 6011039; WO 9734873 .
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) 58799 4-chloro-2,6-pyridinedicarboxylic acid C7H4ClNO4 详情 详情
(II) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(III) 58800 4-(4-morpholinyl)-2,6-pyridinedicarboxylic acid C11H12N2O5 详情 详情
(IV) 58801 dimethyl 4-(4-morpholinyl)-2,6-pyridinedicarboxylate C13H16N2O5 详情 详情
(V) 58802 ethyl 6-(hydroxymethyl)-4-(4-morpholinyl)-2-pyridinecarboxylate C13H18N2O4 详情 详情
(VI) 27243 [2-(chloromethoxy)ethyl](trimethyl)silane 76513-69-4 C6H15ClOSi 详情 详情
(VII) 58803 ethyl 4-(4-morpholinyl)-6-({[2-(trimethylsilyl)ethoxy]methoxy}methyl)-2-pyridinecarboxylate C19H32N2O5Si 详情 详情
(VIII) 58804 4-(4-morpholinyl)-6-({[2-(trimethylsilyl)ethoxy]methoxy}methyl)-2-pyridinecarboxylic acid C17H28N2O5Si 详情 详情
(IX) 58805 tert-butyl 4-(4-morpholinyl)-6-({[2-(trimethylsilyl)ethoxy]methoxy}methyl)-2-pyridinylcarbamate C21H37N3O5Si 详情 详情
(X) 58806 3-(bromomethyl)-5-nitrophenyl methyl ether; 1-(bromomethyl)-3-methoxy-5-nitrobenzene C8H8BrNO3 详情 详情
(XI) 58807 tert-butyl 3-methoxy-5-nitrobenzyl[4-(4-morpholinyl)-6-({[2-(trimethylsilyl)ethoxy]methoxy}methyl)-2-pyridinyl]carbamate C29H44N4O8Si 详情 详情
(XII) 58808 tert-butyl 3-amino-5-methoxybenzyl[4-(4-morpholinyl)-6-({[2-(trimethylsilyl)ethoxy]methoxy}methyl)-2-pyridinyl]carbamate C29H46N4O6Si 详情 详情

合成路线56

该中间体在本合成路线中的序号：(II)

A similar method, but using a different protection strategy, has been reported. 4-Hydroxy-2,6-pyridinedicarboxylic acid (XVIII) was condensed with morpholine (II) to provide, after Fischer esterification, the morpholinopyridine diester (IV). Reduction of (IV) with calcium borohydride furnished hydroxy ester (V). Protection of (V) as the corresponding tetrahydropyranyl ether, followed by ester group saponification, afforded (XIX). Curtius rearrangement of acid (XIX) in the same conditions as above gave carbamate (XX), which was alkylated with benzyl chloride (XXI) yielding (XXII). After reduction of the nitroderivative (XXII) with iron and ammonium chloride, the resultant amine (XXIII) was acylated by allyl chloroformate to produce carbamate (XXIV). Then, acidic treatment removed the tetrahydropyranyl-protecting group to afford alcohol (XIV), which was finally processed as in the above method.

参考文献 中间体
合成目标
【1】 Haga, Y.; Tsuchiya, Y.; Mase, T.; et al.; Potent and selective aminopyridine NPY Y1 receptor antagonists. 21st Symp Med Chem (Nov 28 2001, Kyoto) 2001, Abst 2P-38.
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) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(IV) 58801 dimethyl 4-(4-morpholinyl)-2,6-pyridinedicarboxylate C13H16N2O5 详情 详情
(V) 58802 ethyl 6-(hydroxymethyl)-4-(4-morpholinyl)-2-pyridinecarboxylate C13H18N2O4 详情 详情
(XIV) 58810 allyl 3-({(tert-butoxycarbonyl)[6-(hydroxymethyl)-4-(4-morpholinyl)-2-pyridinyl]amino}methyl)-5-methoxyphenylcarbamate C27H36N4O7 详情 详情
(XVIII) 58814 4-hydroxy-2,6-pyridinedicarboxylic acid C7H5NO5 详情 详情
(XIX) 58815 4-(4-morpholinyl)-6-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-pyridinecarboxylic acid C16H22N2O5 详情 详情
(XX) 58816 tert-butyl 4-(4-morpholinyl)-6-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-pyridinylcarbamate C20H31N3O5 详情 详情
(XXI) 58817 3-(chloromethyl)-5-nitrophenyl methyl ether; 1-(chloromethyl)-3-methoxy-5-nitrobenzene C8H8ClNO3 详情 详情
(XXII) 58818 tert-butyl 3-methoxy-5-nitrobenzyl{4-(4-morpholinyl)-6-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-pyridinyl}carbamate C28H38N4O8 详情 详情
(XXIII) 58819 tert-butyl 3-amino-5-methoxybenzyl{4-(4-morpholinyl)-6-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-pyridinyl}carbamate C28H40N4O6 详情 详情
(XXIV) 58820 allyl 3-[((tert-butoxycarbonyl){4-(4-morpholinyl)-6-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-pyridinyl}amino)methyl]-5-methoxyphenylcarbamate C32H44N4O8 详情 详情

合成路线57

该中间体在本合成路线中的序号：(II)

The reductocondensation of 3-bromo-4-fluorobenzaldehyde (I) with morpholine (II) by means of NaBH(OAc)3 in dichloroethane gives 4-(3-bromo-4-fluorobenzyl)morpholine (III), which is condensed with N-methoxy-N-methylacetamide (IV) by means of BuLi in THF to yield 1-[2-fluoro-5-(4-morpholinylmethyl)phenyl]ethanone (V). The reaction of (V) with an excess diethyl carbonate (VI) by means of NaH affords the 3-oxopropanoate derivative (VII), which is treated with triethyl orthoformate (VIII) and Ac2O at 150 C to provide the ethoxymethylene compound (IX). The reaction of (IX) with morpholine-4-amine (X) in ethanol gives the aminomethylene derivative (XI), which is cyclized by means of NaH in hot THF to yield the quinolone-3-carboxylate (XII). Finally, this compound is condensed with 4-chlorobenzylamine (XIII) by heating at 190 C to afford the target quinolone-3-carboxamide.

参考文献 中间体
合成目标
【1】 Pargas, R.E.M.; Tucker, J.A.; Schnute, M.E.; et al.; 1-Amino-4-oxo-1,4-dihydroquinolines with broad-spectrum antiherpetic activity. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1669.
【2】 Thaisrivongs, S.; Strohbach, J.W.; Turner, S.R.; Vaillancourt, V.A.; Tucker, J.A.; Schnute, M.E. (Pharmacia Corp.); Quinolinecarboxamides as antiviral agents. EP 1140850; US 6248739; WO 0040561 .
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) 51550 3-Bromo-4-fluorobenzaldehyde 77771-02-9 C7H4BrFO 详情 详情
(II) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(III) 53185 4-(3-bromo-4-fluorobenzyl)morpholine n/a C11H13BrFNO 详情 详情
(IV) 17426 N-methoxy-N-methylacetamide 78191-00-1 C4H9NO2 详情 详情
(V) 53186 1-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-1-ethanone n/a C13H16FNO2 详情 详情
(VI) 17470 diethyl carbonate; diethylcarbonate 105-58-8 C5H10O3 详情 详情
(VII) 53187 ethyl 3-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-3-oxopropanoate n/a C16H20FNO4 详情 详情
(VIII) 21304 Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether 122-51-0 C7H16O3 详情 详情
(IX) 53188 ethyl (Z)-3-ethoxy-2-[2-fluoro-5-(4-morpholinylmethyl)benzoyl]-2-propenoate n/a C19H24FNO5 详情 详情
(X) 35977 4-morpholinylamine; 4-morpholinamine 4319-49-7 C4H10N2O 详情 详情
(XI) 53191 ethyl (Z)-2-[2-fluoro-5-(4-morpholinylmethyl)benzoyl]-3-(4-morpholinylamino)-2-propenoate n/a C21H28FN3O5 详情 详情
(XII) 53192 ethyl 1-(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate n/a C21H27N3O5 详情 详情
(XIII) 23378 (4-chlorophenyl)methanamine; 4-chlorobenzylamine 104-86-9 C7H8ClN 详情 详情

合成路线58

该中间体在本合成路线中的序号：(II)

The reductocondensation of 3-bromo-4-fluorobenzaldehyde (I) with morpholine (II) by means of NaBH(OAc)3 in dichloroethane gives 4-(3-bromo-4-fluorobenzyl)morpholine (III), which is condensed with N-methoxy-N-methylacetamide (IV) by means of BuLi in THF to yield 1-[2-fluoro-5-(4-morpholinylmethyl)phenyl]ethanone (V). The reaction of (V) with an excess diethyl carbonate (VI) by means of NaH affords the 3-oxopropanoate derivative (VII), which is treated with triethyl orthoformate (VIII) and Ac2O at 150 C to provide the ethoxymethylene compound (IX). The reaction of (IX) with piperazine-1-amine (X) in ethanol gives the aminomethylene derivative (XI), which is cyclized by means of NaH in hot THF to yield the quinolone-3-carboxylate (XII). Finally, this compound is condensed with 4-chlorobenzylamine (XIII) by heating at 190 C to afford the target quinolone-3-carboxamide.

参考文献 中间体
合成目标
【1】 Pargas, R.E.M.; Tucker, J.A.; Schnute, M.E.; et al.; 1-Amino-4-oxo-1,4-dihydroquinolines with broad-spectrum antiherpetic activity. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1669.
【2】 Thaisrivongs, S.; Strohbach, J.W.; Turner, S.R.; Vaillancourt, V.A.; Tucker, J.A.; Schnute, M.E. (Pharmacia Corp.); Quinolinecarboxamides as antiviral agents. EP 1140850; US 6248739; WO 0040561 .
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) 51550 3-Bromo-4-fluorobenzaldehyde 77771-02-9 C7H4BrFO 详情 详情
(II) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(III) 53185 4-(3-bromo-4-fluorobenzyl)morpholine n/a C11H13BrFNO 详情 详情
(IV) 17426 N-methoxy-N-methylacetamide 78191-00-1 C4H9NO2 详情 详情
(V) 53186 1-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-1-ethanone n/a C13H16FNO2 详情 详情
(VI) 17470 diethyl carbonate; diethylcarbonate 105-58-8 C5H10O3 详情 详情
(VII) 53187 ethyl 3-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-3-oxopropanoate n/a C16H20FNO4 详情 详情
(VIII) 21304 Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether 122-51-0 C7H16O3 详情 详情
(IX) 53188 ethyl (Z)-3-ethoxy-2-[2-fluoro-5-(4-morpholinylmethyl)benzoyl]-2-propenoate n/a C19H24FNO5 详情 详情
(X) 40655 4-Methyl-1-piperazinamine; 1-Amino-4-methylpiperazine; 4-Methyl-1-piperazinylamine 6928-85-4 C5H13N3 详情 详情
(XI) 53189 ethyl (Z)-2-[2-fluoro-5-(4-morpholinylmethyl)benzoyl]-3-[(4-methyl-1-piperazinyl)amino]-2-propenoate n/a C22H31FN4O4 详情 详情
(XII) 53190 ethyl 1-(4-methyl-1-piperazinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate n/a C22H30N4O4 详情 详情
(XIII) 23378 (4-chlorophenyl)methanamine; 4-chlorobenzylamine 104-86-9 C7H8ClN 详情 详情

合成路线59

该中间体在本合成路线中的序号：(XII)

The esterification of vanillic acid (I) with benzyl bromide and K2CO3 in DMF gives the protected benzyl ester (II), which is nitrated with conc. HNO3 in acetic acid to yield 4-benzyloxy-5-methoxy-2-nitrobenzoic acid benzyl ester (III). The reduction of (III) with SnCl2 in ethyl acetate affords the corresponding 2-amino compound (IV), which is cyclized with ammonium formate in DMF at 150 C to provide the quinazolinone (V). The reaction of (V) with refluxing SOCl2 gives the chloro derivative (VI), which is condensed with 1-(tert-butoxycarbonyl)piperazine (VII) by means of DIEA in hot THF to give the 4-piperazinyl quinazoline (VIII). The reductive cleavage of the benzyl protecting group of (VIII) by means of H2 over P/C in ethanol yields the hydroxy compound (IX), which is condensed with 3-(tosyloxy)propyl chloride (X) by means of Cs2CO3 in DMF to afford the corresponding ether (XI). The reaction of the tosyloxy group of (XI) with morpholine (XII) in DMF provides the morpholinyl derivative (XIII), which is Boc deprotected by treatment with HCl in dioxane to give the piperazinyl precursor (XIV). Finally, this compound is condensed with 4-isopropoxyphenyl isocyanate (XV) in DMF to yield the target piperazine carboxamide.

参考文献 中间体
合成目标
【1】 Nomoto, Y.; Scarborough, R.M.; Ichimura, M.; Fujiwara, S.; Ide, S.; Oda, S.; Pandey, A.; Tsukuda, E.; Matsuno, K.; Irie, J. (Kyowa Hakko Kogyo Co., Ltd.; Millennium Pharmaceuticals, Inc.); Quinazoline derivs. as kinase inhibitors. WO 0216351 .
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) 17786 4-hydroxy-3-methoxybenzoic acid; Vanillic acid 121-34-6 C8H8O4 详情 详情
(II) 55576 phenylmethyl 3-(methyloxy)-4-[(phenylmethyl)oxy]benzoate C22H20O4 详情 详情
(III) 55577 phenylmethyl 5-(methyloxy)-2-nitro-4-[(phenylmethyl)oxy]benzoate C22H19NO6 详情 详情
(IV) 55578 phenylmethyl 2-amino-5-(methyloxy)-4-[(phenylmethyl)oxy]benzoate C22H21NO4 详情 详情
(V) 31530 7-(benzyloxy)-6-methoxy-4(3H)-quinazolinone C16H14N2O3 详情 详情
(VI) 51531 1-(4-chloro-3-nitrobenzyl)-2-methyl-1H-benzimidazole C15H12ClN3O2 详情 详情
(VII) 13225 N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate 143238-38-4 C9H18N2O2 详情 详情
(VIII) 55579 1,1-dimethylethyl 4-{6-(methyloxy)-7-[(phenylmethyl)oxy]-4-quinazolinyl}-1-piperazinecarboxylate C25H30N4O4 详情 详情
(IX) 55580 1,1-dimethylethyl 4-[7-hydroxy-6-(methyloxy)-4-quinazolinyl]-1-piperazinecarboxylate C18H24N4O4 详情 详情
(X) 55581 3-Chloropropyl-p-toluenesulfonate C10H13ClO3S 详情 详情
(XI) 55582 1,1-dimethylethyl 4-{6-(methyloxy)-7-[(3-{[(4-methylphenyl)sulfonyl]oxy}propyl)oxy]-4-quinazolinyl}-1-piperazinecarboxylate C28H36N4O7S 详情 详情
(XII) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(XIII) 55586 1,1-dimethylethyl 4-(6-(methyloxy)-7-{[3-(4-morpholinyl)propyl]oxy}-4-quinazolinyl)-1-piperazinecarboxylate C25H37N5O5 详情 详情
(XIV) 55587 methyl 7-{[3-(4-morpholinyl)propyl]oxy}-4-(1-piperazinyl)-6-quinazolinyl ether; 6-(methyloxy)-7-{[3-(4-morpholinyl)propyl]oxy}-4-(1-piperazinyl)quinazoline C20H29N5O3 详情 详情
(XV) 55585 1-isocyanato-4-[(1-methylethyl)oxy]benzene; 4-[(1-methylethyl)oxy]phenyl isocyanate C10H11NO2 详情 详情

合成路线60

该中间体在本合成路线中的序号：(XI)

2-Bromoaniline (VIII) is acylated by bromoacetyl chloride (IX) in pyridine to produce the corresponding bromoacetanilide (X). Subsequent displacement of the aliphatic bromide of (X) with morpholine (XI) furnishes the morpholinoacetanilide (XII). Alkylation at the amide N of (XII) with iodomethane and NaH leads to the N-methyl amide (XIII). Stille coupling of aryl bromide (XIII) with tributyl (1-ethoxyvinyl)tin (XIV) yields the enol ether (XV). Bromination of enol ether (XV) with N-bromosuccinimide in moist THF produces the bromo acetophenone (XVI), which is further reacted with NaN3 to give the azido ketone (XVII). The target amino oxazole compound is finally obtained by condensation of azido ketone (XVII) with isothiocyanate (VII) in the presence of PPh3 in hot dioxane.

参考文献 中间体
合成目标
【1】 Liu, C.; Leftheris, K.; Pitts, W.J.; Iwanowicz, E.J.; Dhar, T.G.M.; Gu, H.H. (Bristol-Myers Squibb Co.); Cpds. derived from an amine nucleus that are inhibitors of IMPDH enzyme. EP 1126843; US 6399773; WO 0025780 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 61697 3-methoxy-4-(1,3-oxazol-5-yl)phenyl isothiocyanate; 5-(4-isothiocyanato-2-methoxyphenyl)-1,3-oxazole C11H8N2O2S 详情 详情
(VIII) 27739 2-bromoaniline 615-36-1 C6H6BrN 详情 详情
(IX) 27903 2-Bromoacetyl chloride 22118-09-8 C2H2BrClO 详情 详情
(X) 61698 2-bromo-N-(2-bromophenyl)acetamide C8H7Br2NO 详情 详情
(XI) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(XII) 61699 N-(2-bromophenyl)-2-(4-morpholinyl)acetamide C12H15BrN2O2 详情 详情
(XIII) 61700 N-(2-bromophenyl)-N-methyl-2-(4-morpholinyl)acetamide C13H17BrN2O2 详情 详情
(XIV) 19760 ethyl 1-(tributylstannyl)vinyl ether; tributyl(1-ethoxyvinyl)stannane 97674-02-7 C16H34OSn 详情 详情
(XV) 61850 N-[2-(1-ethoxyvinyl)phenyl]-N-methyl-2-(4-morpholinyl)acetamide C17H24N2O3 详情 详情
(XVI) 61851 N-[2-(2-bromoacetyl)phenyl]-N-methyl-2-(4-morpholinyl)acetamide C15H19BrN2O3 详情 详情
(XVII) 61852 N-[2-(2-azidoacetyl)phenyl]-N-methyl-2-(4-morpholinyl)acetamide C15H19N5O3 详情 详情

合成路线61

该中间体在本合成路线中的序号：(XIII)

In a related synthetic strategy, acylation of 2-bromoaniline (I) with acetoxyacetyl chloride (II) affords the acetoxy acetanilide (III). Alkylation of amide (III) with iodomethane and NaH leads to the N-methyl amide (IV). Then, Stille coupling of aryl bromide (IV) with tributyl (1-ethoxyvinyl)tin (V) gives rise to the enol ether (VI). Bromination of (VI) with N-bromosuccinimide in moist THF, followed by displacement of the resultant bromo ketone (VII) with NaN3 provides azido ketone (VIII). The key oxazole (X) is then obtained by condensation of azido ketone (VIII) with isothiocyanate (IX) in the presence of PPh3. Alkaline hydrolysis of the acetate ester (X) yields alcohol (XI), which is converted to mesylate (XII) by means of methanesulfonyl chloride and triethylamine. The mesylate group is finally displaced with morpholine (XIII) to furnish the title compound.

参考文献 中间体
合成目标
【1】 Dhar, T.G.M.; Guo, J.; Shen, Z.; et al.; A modified approach to 2-(N-aryl)-1,3-oxazoles: application to the synthesis of the IMPDH inhibitor BMS-337197 and analogues. Org Lett 2002, 4, 12, 2091.
【2】 Dhar, T.G.M.; et al.; Discovery of N-[2-[2-[[3-methoxy-4-(5-oxazolyl)phenyl]-amino]-5-oxazolyl]phenyl]-N-methyl-4-morpholineacetamide as a novel and potent inhibitor of inosine monophosphate dehydrogenase with excellent in vivo activity. J Med Chem 2002, 45, 11, 2127.
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) 27739 2-bromoaniline 615-36-1 C6H6BrN 详情 详情
(II) 10456 Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate 13831-31-7 C4H5ClO3 详情 详情
(III) 61853 2-(2-bromoanilino)-2-oxoethyl acetate C10H10BrNO3 详情 详情
(IV) 61854 2-[2-bromo(methyl)anilino]-2-oxoethyl acetate C11H12BrNO3 详情 详情
(V) 19760 ethyl 1-(tributylstannyl)vinyl ether; tributyl(1-ethoxyvinyl)stannane 97674-02-7 C16H34OSn 详情 详情
(VI) 61855 2-[2-(1-ethoxyvinyl)(methyl)anilino]-2-oxoethyl acetate C15H19NO4 详情 详情
(VII) 61856 2-[2-(2-bromoacetyl)(methyl)anilino]-2-oxoethyl acetate C13H14BrNO4 详情 详情
(VIII) 61857 2-[2-(2-azidoacetyl)(methyl)anilino]-2-oxoethyl acetate C13H14N4O4 详情 详情
(IX) 61697 3-methoxy-4-(1,3-oxazol-5-yl)phenyl isothiocyanate; 5-(4-isothiocyanato-2-methoxyphenyl)-1,3-oxazole C11H8N2O2S 详情 详情
(X) 61858 2-[2-{2-[3-methoxy-4-(1,3-oxazol-5-yl)anilino]-1,3-oxazol-5-yl}(methyl)anilino]-2-oxoethyl acetate C24H22N4O6 详情 详情
(XI) 61859 2-hydroxy-N-(2-{2-[3-methoxy-4-(1,3-oxazol-5-yl)anilino]-1,3-oxazol-5-yl}phenyl)-N-methylacetamide C22H20N4O5 详情 详情
(XII) 61860 2-[2-{2-[3-methoxy-4-(1,3-oxazol-5-yl)anilino]-1,3-oxazol-5-yl}(methyl)anilino]-2-oxoethyl methanesulfonate C23H22N4O7S 详情 详情
(XIII) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线62

该中间体在本合成路线中的序号：(VII)

Fischer esterification of 4'-hydroxybiphenyl-4-carboxylic acid (I) with H2SO4/MeOH provides ester (II). The phenolic hydroxyl group is then alkylated with 1-bromo-3-chloropropane (III) in the presence of K2CO3 to furnish the chloropropyl ether (IV). Saponification of methyl ester (IV) with LiOH leads to carboxylic acid (V), which is further activated as the corresponding acid chloride (VI) upon heating in SOCl2. Acid chloride (VI) is subsequently coupled with morpholine (VII) to yield amide (VIII). Finally, alkyl chloride (VIII) is displaced with (R,R)-2,5-dimethylpyrrolidine (IX) in the presence of K2CO3 and KI to furnish the title compound.

参考文献 中间体
合成目标
【1】 Faghih, R.; Bennani, Y.L. (Abbott Laboratories Inc.); Aminoalkoxybiphenyl carboxamides as histamine-3 receptor ligands and their therapeutic applications. US 6316475; WO 0240461 .
【2】 Faghih, R.; Bennani, Y.; Aminoalkoxybiphenylcarboxamides as histamine-3 receptor ligands and their therapeutic applications. US 2002111340 .
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) 63280 4'-hydroxy[1,1'-biphenyl]-4-carboxylic acid C13H10O3 详情 详情
(II) 63281 methyl 4'-hydroxy[1,1'-biphenyl]-4-carboxylate C14H12O3 详情 详情
(III) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(IV) 63282 methyl 4'-(3-chloropropoxy)[1,1'-biphenyl]-4-carboxylate C17H17ClO3 详情 详情
(V) 63283 4'-(3-chloropropoxy)[1,1'-biphenyl]-4-carboxylic acid C16H15ClO3 详情 详情
(VI) 63284 4'-(3-chloropropoxy)[1,1'-biphenyl]-4-carbonyl chloride C16H14Cl2O2 详情 详情
(VII) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(VIII) 63285 [4'-(3-chloropropoxy)[1,1'-biphenyl]-4-yl](4-morpholinyl)methanone C20H22ClNO3 详情 详情
(IX) 63286 (2R,5R)-2,5-dimethylpyrrolidine C6H13N 详情 详情

合成路线63

该中间体在本合成路线中的序号：(II)

Reaction of 2,5-dibromopyridine (I) with morpholine (II) yields 5-bromo-2-(4-morpholinyl)pyridine (III). Palladium-catalyzed coupling of (III) with trimethylsilyl acetylene (IV) leads to the ethynylpyridine (V)

参考文献 中间体
合成目标
【1】 Gomtsyan, A.; et al.; Design, synthesis, and structure-activity relationship of 6-alkynylpyrimidines as potent adenosine kinase inhibitors. J Med Chem 2002, 45, 17, 3639.
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) 19330 2,5-dibromopyridine 624-28-2 C5H3Br2N 详情 详情
(II) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(III) 60887 4-(5-bromo-2-pyridinyl)morpholine C9H11BrN2O 详情 详情
(IV) 51602 1-Propyne C3H4 详情 详情
(V) 60888 4-(5-ethynyl-2-pyridinyl)morpholine C11H12N2O 详情 详情

合成路线64

该中间体在本合成路线中的序号：(XIV)

Alkylation of vanillic acid methyl ester (V) with 3-chloropropyl tosylate (VI) in the presence of K2CO3 and Aliquat 336 gives the chloropropyl ether (VII). Subsequent electrophilic nitration of (VII) in hot HOAc affords the ortho-nitrobenzoate (VIII), which is further reduced to the amino benzoate analogue (IX) employing Fe/NH4Cl. Condensation of amino ester (IX) with dimethylformamide dimethylacetal provides adduct (X). This is then converted to the key quinoline derivative (XI) upon condensation with acetonitrile in the presence of butyllithium. Chlorination of (XI) with boiling POCl3 leads to the 4-chloroquinoline (XII). This is then coupled with the (imidazolylsulfanyl)aniline (IV) using pyridinium chloride in refluxing ethoxyethanol to furnish the anilino quinoline adduct (XIII). Finally, displacement of the chloride group of (XIII) with morpholine (XIV) in DMF provides the title compound.

参考文献 中间体
合成目标
【1】 Dutia, M.; Powell, D.W.; Berger, D.M.; et al.; Synthesis and evaluation of 4-anilino substituted 3-quinolinecarbonitriles as inhibitors of kinases of the Ras-MAPK signaling cascade. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 105.
【2】 Frost, P.; Floyd, M.B. Jr.; Wissner, A.; Hamann, P.R.; Zhang, N.; Tsou, H.-R.; Berger, D.M.; Salvati, M.E. (Wyeth); Substd. 3-cyanoquinolines as protein tyrosine kinase inhibitors. EP 1117659; JP 2002525369; WO 0018761 .
【3】 Frost, P.; Floyd, M.B. Jr.; Wissner, A.; Hamann, P.R.; Zhang, N.; Tsou, H.-R.; Berger, D.M.; Salvati, M.E. (Wyeth); Substd. 3-cyanoquinolines. US 6288082 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 58443 3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]aniline; 3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenylamine C10H10ClN3S 详情 详情
(V) 29176 methyl 4-hydroxy-3-methoxybenzoate 3943-74-6 C9H10O4 详情 详情
(VI) 55581 3-Chloropropyl-p-toluenesulfonate C10H13ClO3S 详情 详情
(VII) 50008 methyl 4-(3-chloropropoxy)-3-methoxybenzoate C12H15ClO4 详情 详情
(VIII) 50009 methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate C12H14ClNO6 详情 详情
(IX) 50010 methyl 2-amino-4-(3-chloropropoxy)-5-methoxybenzoate C12H16ClNO4 详情 详情
(X) 50011 methyl 4-(3-chloropropoxy)-2-[[(E)-(dimethylamino)methylidene]amino]-5-methoxybenzoate C15H21ClN2O4 详情 详情
(XI) 50012 7-(3-chloropropoxy)-4-hydroxy-6-methoxy-3-quinolinecarbonitrile C14H13ClN2O3 详情 详情
(XII) 48519 4-chloro-7-(3-chloropropoxy)-6-methoxy-3-quinolinecarbonitrile C14H12Cl2N2O2 详情 详情
(XIII) 58444 4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(3-chloropropoxy)-6-methoxy-3-quinolinecarbonitrile C24H21Cl2N5O2S 详情 详情
(XIV) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线65

该中间体在本合成路线中的序号：(VII)

Condensation of N-Boc-tert-leucine pentafluorophenyl ester (I) with Grignard reagent (II) furnishes the trifluorophenyl ketone (III). After acidic N-Boc group cleavage in (III), the resultant amine (IV) is coupled with the N-formyl-N-(benzyloxy)aminoacid (V) to provide the corresponding amide (VI). Displacement of the 4-fluoro group of (VI) with morpholine (VII) gives rise to the morpholinophenyl ketone (VIII). The O-benzyl protecting group of (VIII) is finally removed by transfer hydrogenolysis in the presence of cyclohexene and Pd/C to afford the target hydroxylamine compound (1).

参考文献 中间体
合成目标
【1】 Ayscough, A.; Beckett, R.P.; Brookings, D.C.; Clements, J.M.; East, S.P.; Keavey, K.; Smith, K.H.; Thomas, W.; Thompson, A.J.; Todd, R.S.; A new series of potent PDF inhibitors displaying broad-spectrum antibacterial activity against respiratory tract infections. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1677.
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) 60284 2,3,4,5,6-pentafluorophenyl 2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3,3-dimethylbutanoate C17H20F5NO4 详情 详情
(II) 64474 bromo(2,4,5-trifluorophenyl)magnesium C6H2BrF3Mg 详情 详情
(III) 64475 tert-butyl (1S)-2,2-dimethyl-1-(2,4,5-trifluorobenzoyl)propylcarbamate C17H22F3NO3 详情 详情
(IV) 64476 (2S)-2-amino-3,3-dimethyl-1-(2,4,5-trifluorophenyl)-1-butanone C12H14F3NO 详情 详情
(V) 64477 (2R)-3-[(benzyloxy)(formyl)amino]-2-(cyclopentylmethyl)propanoic acid C17H23NO4 详情 详情
(VI) 64478 (2R)-3-[(benzyloxy)(formyl)amino]-2-(cyclopentylmethyl)-N-[(1S)-2,2-dimethyl-1-(2,4,5-trifluorobenzoyl)propyl]propanamide C29H35F3N2O4 详情 详情
(VII) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(VIII) 64479 (2R)-3-[(benzyloxy)(formyl)amino]-2-(cyclopentylmethyl)-N-{(1S)-1-[2,5-difluoro-4-(4-morpholinyl)benzoyl]-2,2-dimethylpropyl}propanamide C33H43F2N3O5 详情 详情

合成路线66

该中间体在本合成路线中的序号：(IV)

Alkaline hydrolysis of ester (I), followed by chlorination of the resulting carboxylic acid (II) by means of oxalyl chloride furnishes the acid chloride (III). This is then treated with morpholine (IV) to provide the corresponding amide (V). Displacement of the bromide group of (V) with 3-(aminomethyl)pyridine (VI) leads to the secondary amine (VII), which is further protected as the N-Boc derivative (VIII) employing di-tert-butyl dicarbonate. Addition of the 2-lithiated benzimidazole (IX) to the morpholine amide (VIII) gives rise to ketone (X). The N-Boc group of (X) is finally cleaved by treatment with trifluoroacetic acid in CH2Cl2.

参考文献 中间体
合成目标
【1】 Kawasaki, K.; Masubuchi, M.; Morikami, K.; Sogabe, S.; Aoyama, T.; Ebiike, H.; Niizuma, S.; Hayase, M.; Fujii, T.; Sakata, K.; Shindoh, H.; Shiratori, Y.; Aoki,Y.; Ohtsuka, T.; Shimma, N.; Design and synthesis of novel benzofurans as a new class of antifungal agents targeting fungal N-myristoyltransferase. Part 3. Bioorg Med Chem Lett 2003, 13, 1, 87.
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) 51127 6-phenyl-1-(1-piperazinyl)-1-hexanone C16H24N2O 详情 详情
(II) 63703 4-[(3-bromopropyl)oxy]-3-methyl-1-benzofuran-2-carboxylic acid C13H13BrO4 详情 详情
(III) 63704 4-[(3-bromopropyl)oxy]-3-methyl-1-benzofuran-2-carbonyl chloride C13H12BrClO3 详情 详情
(IV) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(V) 63705 {4-[(3-bromopropyl)oxy]-3-methyl-1-benzofuran-2-yl}(4-morpholinyl)methanone C17H20BrNO4 详情 详情
(VI) 18731 3-pyridinylmethanamine; 3-pyridinylmethylamine 3731-52-0 C6H8N2 详情 详情
(VII) 63706 [3-methyl-4-({3-[(3-pyridinylmethyl)amino]propyl}oxy)-1-benzofuran-2-yl](4-morpholinyl)methanone C23H27N3O4 详情 详情
(VIII) 63707 1,1-dimethylethyl 3-{[3-methyl-2-(4-morpholinylcarbonyl)-1-benzofuran-4-yl]oxy}propyl(3-pyridinylmethyl)carbamate C28H35N3O6 详情 详情
(IX) 63708 [1-(2-propenyl)-1H-benzimidazol-2-yl]lithium C10H9LiN2 详情 详情
(X) 63709 1,1-dimethylethyl 3-[(3-methyl-2-{[1-(2-propenyl)-1H-benzimidazol-2-yl]carbonyl}-1-benzofuran-4-yl)oxy]propyl(3-pyridinylmethyl)carbamate C34H36N4O5 详情 详情

合成路线67

该中间体在本合成路线中的序号：(XIX)

The precursor dihydropyridones (IIa) and (IIb) can be synthesized as follows. Acylation of either 4-nitroaniline (XVa) (1) or 4-iodoaniline (XVb) (2) with 5-bromovaleryl chloride (V) affords the corresponding bromoamides (XVIa) and (XVIb), which are cyclized to piperidones (XVIIa) and (XVIIb) upon treatment with potassium tert-butoxide or with potassium hydroxide under phase-transfer conditions. Piperidones (XVIIa/b) are then chlorinated by means of phosphorus pentachloride in chlorobenzene or chloroform to form the geminal dichlorides (XVIIIa) and (XVIIIb) (1, 2). Dehydrohalogenation of (XVIIIa) by means of lithium carbonate and lithium chloride in DMF at 105-110 °C then provides the chloro dihydropyridone (IIa) (1). Alternatively, the dichloro derivative (XVIIIb) is refluxed with neat morpholine (XIX) to furnish intermediate (IIb) (2). Scheme 3.

参考文献 中间体
合成目标
【1】 Shapiro, R., Rossano, L.T., Mudryk, B.M. et al. (Bristol-Myers Squibb Co.). Process for preparing 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones. WO 2007001385.
【2】 Pinto, D., Quan, M., Orwat, M. et al. (Bristol-Myers Squibb Co.). Lactam-containing compounds and derivatives thereof as factor Xa inhibitors. EP 1427415, JP 2005507889, WO 03026652.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVA) 15547 4-nitrophenylamine; p-Nitroaniline; 4-nitroaniline 100-01-6 C6H6N2O2 详情 详情
(XVB) 26393 4-iodoaniline; 4-iodophenylamine 540-37-4 C6H6IN 详情 详情
(XVIa) 65620 　 　 C11H13BrN2O3 详情 详情
(XVIb) 65621 　 　 C11H13BrINO 详情 详情
(XVIIa) 65622 1-(4-Nitrophenyl)-2-piperidinone 38560-30-4 C11H12N2O3 详情 详情
(XVIIb) 65618 1-(4-Iodophenyl)-2-piperidinone 385425-15-0 C11H12INO 详情 详情
(XVIIIa) 65623 3,3-Dichloro-1-(4-nitrophenyl)-2-piperidinone 881386-01-2 C11H10Cl2N2O3 详情 详情
(XVIIIb) 65624 3,3-Dichloro-1-(4-iodophenyl)piperidin-2-one 545445-10-1 C11H10Cl2INO 详情 详情
(IIA) 65610 3-Chloro-5,6-dihydro-1-(4-nitrophenyl)-2(1H)-pyridinone 536760-29-9 C11H9ClN2O3 详情 详情
(IIB) 65611 1-(4-Iodophenyl)-3-morpholino-5,6-dihydropyridin-2(1H)-one; N-(4-Iodophenyl)-3-morpholino-5,6-dihydro-2H-pyridin-2-one 473927-69-4 C15H17IN2O2 详情 详情
(V) 39700 5-bromopentanoyl chloride 4509-90-4 C5H8BrClO 详情 详情
(XIX) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线68

该中间体在本合成路线中的序号：(II)

Ring opening of 3(R)-(benzyloxycarbonylamino)-γ-butyrolactone (I) with morpholine (II) in dioxane at 65 °C provides the morpholide (III), which is condensed with diphenyl disulfide in the presence of Bu3P in hot toluene, yielding the phenyl thioether (IV). Then, the benzyloxycarbonyl protecting group is removed with 30% HBr in AcOH, and the resulting deprotected amino-amide (V) is reduced to diamine (VI) using a solution of borane in tetrahydrofuran (1). Subsequent coupling of diamine (VI) with 4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (VII) in the presence of DIEA in THF or DMSO gives the sulfanilamide (VIII) (1-3), which is finally acylated with the piperazinylbenzoic acid derivative (IX) by means of EDC and DMAP in CH2Cl 2 (1-4). Scheme 1.

参考文献 中间体
合成目标
【1】 Bruncko, M., Ding, H., Elmore, S.W. et al. (Abbott Laboratories Inc.). Apoptosis promoters. EP 1888550, US 2007027135, US 7390799, WO 2007040650.
【2】 Ding, H., Park, C.-M., Bruncko, M. et al. ABT-263, an orally bioavailable inhibitor of Bcl-2 family proteins. 235th ACS Natl Meet (April 6-10, New Orleans) 2008, Abst MEDI 110.
【3】 Zhang, H., Zhou, J., Ha, C., Pei, D., Ding, K. An efficient synthesis of ABT-263, a novel inhibitor of antiapoptotic Bcl-2 proteins. Synthesis 2008, (15): 2398-404.
【4】 Song, X., Bruncko, M., Ding, H. et al. P2 site SAR development toward ABT-263, an orally bioavailable inhibitor of Bcl-2 family proteins. 235th ACS Natl Meet (April 6-10, New Orleans) 2008, Abst MEDI 78.
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) 65752 3(R )-(benzyloxycarbonylamino)-γ-butyrolactone; Benzyl (R)-5-oxotetrahydrofuran-3-ylcarbamate; N-[(3R)-Tetrahydro-5-oxo-3-furanyl]carbamic acid phenylmethyl ester 118399-28-3 C12H13NO4 详情 详情
(II) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(III) 65753 　 　 C16H22N2O5 详情 详情
(IV) 65754 　 　 C22H26N2O4S 详情 详情
(V) 65755 　 　 C14H20N2O2S 详情 详情
(VI) 65756 　 　 C14H22N2OS 详情 详情
(VII) 65757 4-Fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide 1027345-08-9 C7H5F4NO4S2 详情 详情
(VIII) 65758 　 　 C21H26F3N3O5S3 详情 详情
(IX) 65759 　 　 C26H31ClN2O2 详情 详情

合成路线69

该中间体在本合成路线中的序号：(V)

　

参考文献 中间体
合成目标
【1】 Yu DS,Wang ZQ,XiongY. et aL 2005. New synthetic method of linezolid．中国药物他学杂志，15(2): 89～90, 93
【2】 Yu DS, Huang L, Liang H, et aL 2005. A new and dficient synthetic metbod and antibacterial activities of oxazolidinone analogs Chinese Chem Lett, 16 (7)t 875～ 878
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 66506 (S)-N-((3-(4-bromo-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide 　 C12H12BrFN2O3 详情 详情
(I) 66505 (R)-5-(chloromethyl)-3-(3-fluorophenyl)oxazolidin-2-one 149524-44-7 C10H9ClFNO2 详情 详情
(II) 60317 (R)-5-(azidomethyl)-3-(3-fluorophenyl)oxazolidin-2-one C10H9FN4O2 详情 详情
(III) 60319 N-{[3-(3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide C12H13FN2O3 详情 详情
(V) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线70

该中间体在本合成路线中的序号：(V)

Cyclization of morpholine-4-carboximidamide hydrobromide (I) with diethyl malonate (II) by means of naoEt in refluxing EtoH gives 2-(morpholin-4-yl)pyrimidine-4,6-diol (III), which by chlorination with PoCl3 at 120 °C affords 4,6-dichloro-2-(morpholin-4-yl)pyrimidine (IV). nucleophilic substitution of the dichloropyrimidine (IV) with morpholine (V) in the presence of Et3n in refluxing N-methyl-2-pyrrolidone provides 2,4-di(morpholin-4-yl)-6-chloropyrimidine (VI) . Alternatively, dimorpholinopyrimidine (VI) is prepared by reaction of 2,4,6-trichloropyrimidine (VII) with morpholine (V) in THF, followed by chromatographic separation . Finally, chloropyrimidine derivative (VI) is submitted to a Suzuki cross-coupling reaction with boronate ester (VIII) in the presence of Pd(dppf)2Cl2·CH2Cl2 or Pd(dppf)2Cl2 and na2Co3 in 1,2-dimethoxyethane at 90-95 °C .
Alternatively, iodination of chloride (VI) with HI and naI yields the corresponding iodide (IX) , which is also coupled with boronate (VIII) in the presence of Pd(dppf)Cl2·CH2Cl2 and K2Co3 in 1,4-dioxane/H2o at 100 °C .
Boronate ester (VIII) is obtained by bromination of 4-(trifluoromethyl) pyridin-2-amine (X) with nBS in CHCl3 or CH2Cl2 to afford 5-bromo-4-(trifluoromethyl)pyrimidin-2-amine (XI), which is finally condensed with bis(pinacolato)diboron (XII) in the presence of Pd(dppf)2Cl2·CH2Cl2 and KoAc in refluxing dioxane or DMSO .

参考文献 中间体
合成目标
【1】 Pick, T., Barsanti, P., Iwanowicz, E. et al. (novartis AG). Pyrimidine derivatives used as PI-3 kinase inhibitors. EP 1984350, EP 2261223, JP 200952764, US 2010249126, US 8217035, US 2012225859, Wo 2007084786.
【2】 Burger, M.T., Pecchi, S., Wagman, A. et al. Discovery of BKM120, a pan class I PI3 kinase inhibitor in phase I/II clinical trials. 240th ACS natl Meet (Aug 22-26, Boston) 2010, Abst MEDI 489.
【3】 Vu, A.T., Morris, J. Malhotra, S.V. Efficient and improved synthesis of a PI3K inhibitor anticancer agent. 241st ACS natl Meet (March 27-31, Anaheim) 2011, Abst oRGn 115.
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) 67957 morpholine-4-carboximidamide hydrobromide 　 C5H11N3O.HBr 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(III) 67958 2-morpholinopyrimidine-4,6-diol 　 C8H11N3O3 详情 详情
(IV) 67959 4,6-dichloro-2-(morpholin-4-yl)pyrimidine 10397-13-4 C8H9Cl2N3O 详情 详情
(V) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(VI) 67960 4,4'-(6-chloropyrimidine-2,4-diyl)dimorpholine 　 C12H17ClN4O2 详情 详情
(VII) 43734 2,4,6-trichloropyrimidine 3764-01-0 C4HCl3N2 详情 详情
(VIII) 67961 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridin-2-amine 　 C12H16BF3N2O2 详情 详情
(IX) 67962 4,4'-(6-iodopyrimidine-2,4-diyl)dimorpholine 　 C12H17IN4O2 详情 详情
(X) 67963 4-(trifluoromethyl)pyridin-2-amine 106447-97-6 C6H5F3N2 详情 详情
(XI) 67964 5-bromo-4-(trifluoromethyl)pyridin-2-amine 　 C6H4BrF3N2 详情 详情
(XII) 53342 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1,3,2-dioxaborolane; Bis(pinacolato)diboron; Diboron pinacol ester 73183-34-3 C12H24B2O4 详情 详情

合成路线71

该中间体在本合成路线中的序号：(V)

Cyclocondensation of ethyl 3-amino-4-methyl-2-thiophenecarboxylate (I) with urea (II) at 190 °C gives 7-methylthieno[3,2-d]pyrimidine-2,4-dione (III), which is chlorinated with POCl3 at reflux to yield 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine (IV). Condensation of compound (IV) with morpholine (V) in MeoH affords 2-chloro-7-methyl-4-(4-morpholinyl)thieno[3,2-d]pyrimidine (VI) , which, after metalation with BuLi in THF, is formylated with DMF, providing the thieno[3,2-d]pyrimidine-6-carbaldehyde derivative (VII) . Reductive amination of aldehyde (VII) with N-Boc-piperazine (VIII) in the presence of HC(oMe)3, AcoH and naBH(oAc)3 in dichloroethane gives the piperazinylmethyl derivative (IX) , which by cleavage of the Boc moiety by means of HCl in CH2Cl2 produces the N-deprotected piperazine derivative (X). N-Acylation of compound (X) with (S)-lactic acid (XI) in the presence of HATU and DIEA in DMF generates the corresponding amide (XII), which is finally submitted to Suzuki coupling with the boronate ester (XIII) in the presence of PdCl2(PPh3)4 and Na2CO3 or K2CO3 in acetonitrile .
Alternatively, Suzuki coupling of chloro intermediate (IX) with boronate ester (XIII) in the presence of PdCl2(PPh3)2 and Na2CO3 in acetonitrile under microwave irradiation produces the 2-aminopyrimidine derivative (XIV), which is then N-deprotected by means of HCl in CH2Cl2 to yield the free piperazine derivative (XV). Finally, piperazine derivative (XV) is condensed with (S)-lactic acid (XI) in the presence of DIEA and HATU in DMF .

参考文献 中间体
合成目标
【1】 Belvin, M., Friedman, L., Hoeflich, K. et al. (Genentech, Inc.; F. Hoffmann-La Roche AG). Combinations of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic agents, and methods of use. Cn 101939006, EP 2205242, JP 2010539177, KR 2010085912, US 2011223619, US 8247397, Wo 2009036082.
【2】 Ebens, A.J. Jr., Friedman, L. (Genentech, Inc.). Combination of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic a gents for the treatment of hematopoietic malignancies. Cn 102369011, EP 2405916, JP 2012520313, KR 2011132442, US 2010233164, US 8536161, Wo 2010105008.
【3】 Sutherlin, D.P., Bao, L., Berry, M. et al. Discovery of a potent, selective, and orally available class I phosphatidylinositol 3-kinase (PI3K)/Mammalian target of rapamycin (mTOR) kinase inhibitor. J Med Chem 2011, 54(21): 7579-87.
【4】 Bayliss, T., Chuckowree, I., Folkes, A. et al. (Genentech, Inc.; F. Hoffmann-La Roche AG). Phosphoinositide 3-kinase inhibitor compounds and methods of use. CA 2671782, EP 2114949, EP 2518074, JP 2010512338, US 2008242665, US 7888352, US 8383620, US 2013129820, WO 2008070740.
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) 68092 ethyl 3-amino-4-methyl-2-thiophenecarboxylate 　 C8H11NO2S 详情 详情
(II) 19310 urea 57-13-6 CH4N2O 详情 详情
(III) 68093 7-methylthieno[3,2-d]pyrimidine-2,4-dione 35265-81-7 C7H6N2O2S 详情 详情
(IV) 68094 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine 35265-83-9 C7H4Cl2N2S 详情 详情
(V) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(VI) 68095 4-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)morpholine;2-chloro-7-methyl-4-(4-morpholinyl)thieno[3,2-d]pyrimidine 　 C11H12ClN3OS 详情 详情
(VII) 68096 2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde 　 C12H12ClN3O2S 详情 详情
(VIII) 68097 tert-butyl piperazine-1-carboxylate 143238-38-4 C9H18NO2 详情 详情
(IX) 68098 tert-butyl 4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate 　 C21H30ClN5O3S 详情 详情
(X) 68099 4-(2-chloro-7-methyl-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-4-yl)morpholine hydrochloride 　 C16H22ClN5OS.HCl 详情 详情
(XI) 68100 (S)-lactic acid;(S)-2-hydroxypropanoic acid 　 C3H6O3 详情 详情
(XII) 68101 (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one 　 C19H26ClN5O3S 详情 详情
(XIII) 68102 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine 402960-38-7 C10H16BN3O2 详情 详情
(XIV) 68103 tert-butyl 4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate 　 C25H34N8O3S 详情 详情
(XV) 68104 5-(7-methyl-4-morpholino-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine 　 C20H26N8OS 详情 详情

合成路线72

该中间体在本合成路线中的序号：(XIX)

Reaction of 2-nitrovanillin (III) with NH4OH and I2 in H2O/THF yields nitrile (XVIII), which is then condensed with 4-(3-chloropropyl)morpholine hydrochloride (XII) —prepared by alkylation of morpholine (XIX) with 1-bromo-3-chloropropane (XX) in toluene at 84 °C— by means of Cs2CO3 in DMF at 75 °C to give the morpholinopropyl ether (XXI). Reduction of the nitro group in compound (XXI) with Fe and AcOH affords amine (XXII), which by cyclization with ethylenediamine (VII) and sulfur at 100 °C produces the imidazoline derivative (XXIII). Finally, aminoimidazoline (XXIII) is then subjected to ring closure with cyanogen bromide (IX) in the presence of Et3N in CH2Cl2 .

参考文献 中间体
合成目标
【1】 Hentemann, M., Wood, J., Scott, W. et al. (Bayer Pharmaceuticals Corp.). Substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis. EP 2096919, JP 2010511718, US 2011083984, US 8466283, US 201326113, WO 2008070150.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 68129 2-nitrovanillin；4-Hydroxy-3-methoxy-2-nitrobenzaldehyde 　 C8H7NO5 详情 详情
(VII) 14754 ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine 107-15-3 C2H8N2 详情 详情
(IX) 28017 cyanic bromide；cyanogen bromide 506-68-3 CBrN 详情 详情
(XII) 18691 4-(3-chloropropyl)morpholine;N-(3-Chloropropyl)morpholine 7357-67-7 C7H14ClNO 详情 详情
(XIII) 68137 7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine 　 C18H25N5O3 详情 详情
(XVIII) 68140 4-hydroxy-3-methoxy-2-nitrobenzonitrile 　 C8H6N2O4 详情 详情
(XIX) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(XX) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(XXI) 66434 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzonitrile 675126-26-8 C15H19N3O5 详情 详情
(XXII) 66435 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzonitrile 675126-27-9 C15H21N3O3 详情 详情
(XXIII) 68141 6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxy-3-(3-morpholinopropoxy)aniline 　 C17H26N4O3 详情 详情

合成路线73

该中间体在本合成路线中的序号：(XXXIV)

参考文献 中间体
合成目标
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成

合成路线74

该中间体在本合成路线中的序号：(XXIX)

Bromination of 1-(3-tert-butyl-4-hydroxyphenyl)ethanone (III) with NBS in acetonitrile yields 1-(3-bromo-5-tert-butyl-4-hydroxyphenyl)ethanone (XXV), which by protection with trimethyl orthoformate (XXVI) in the presence of (±)-CSA in MeOH affords the dimethyl acetal (XXVII). O-Methylation of phenol (XXVII) with MeI by means of K2CO3 in DMF provides 1-bromo-3-tert-butyl-5-(1,1-dimethoxyethyl)-2-methoxybenzene (XXVIII), which by Buchwald–Hartwig condensation with morpholine (XXIX) in the presence of Pd(OAc)2, BINAP and t-BuONa in DME leads to the Narylmorpholine (XXX). Bromination of compound (XXX) with PhNMe3Br3 in THF/MeOH generates the α-bromoacetal (XXXI), which, without isolation, is finally hydrolyzed by quenching in aqueous Na2S2O3 to give bromo ketone (IX) .

参考文献 中间体
合成目标
【1】 Shimomura, N., Sasho, M., Kayano, A., Yoshizawa, K., Tsujii, M., Kuroda,H., Furukawa, K. (Eisai R&D Management Co., Ltd.). Processes for producing cyclic benzamidine derivative. CA 2515715, EP 1602646, US 2006058370, US 7375236, WO 2004078721.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXX） 68422 4-(3-(tert-butyl)-5-(1,1-dimethoxyethyl)-2-methoxyphenyl)morpholine 　 C19H31NO4 详情 详情
(III) 68400 1-(3-tert-butyl-4-hydroxyphenyl)ethanone 　 C12H16O2 详情 详情
(IX) 68405 2-bromo-1-(3-(tert-butyl)-4-methoxy-5-morpholinophenyl)ethanone 　 C17H24BrNO3 详情 详情
(XXV) 68419 1-(3-bromo-5-(tert-butyl)-4-hydroxyphenyl)ethanone 　 C12H15BrO2 详情 详情
(XXVI) 27311 trimethoxymethane;Trimethyl orthoformate;Methyl orthoformate 149-73-5 C4H10O3 详情 详情
(XXVII) 68420 2-bromo-6-(tert-butyl)-4-(1,1-dimethoxyethyl)phenol 　 C14H21BrO3 详情 详情
(XXVIII) 68421 1-bromo-3-(tert-butyl)-5-(1,1-dimethoxyethyl)-2-methoxybenzene;1-bromo-3-tert-butyl-5-(1,1-dimethoxyethyl)-2-methoxybenzene 　 C15H23BrO3 详情 详情
(XXIX) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(XXXI) 68423 4-(5-(2-bromo-1,1-dimethoxyethyl)-3-(tert-butyl)-2-methoxyphenyl)morpholine 　 C19H30BrNO4 详情 详情

合成路线75

该中间体在本合成路线中的序号：(XXVI)

Alkylation of 4’-hydroxy-3’-methoxyacetophenone (XVII) with benzyl bromide by means of K2CO3 in DMF gives benzyl ether (XVIII), which is reacted with fuming HNO3 and concentrated H2SO4 in cold CH2Cl2 to afford 4’-benzyloxy-5’-methoxy-2’-nitroacetophenone (XIX). After reduction of the nitro group of compound (XIX) using iron powder and ammonium formate in refluxing H2O/toluene, the resulting 2-aminoacetophenone derivative (XX) cyclizes with ethyl formate (XXI) in the presence of NaOEt in DME, providing 7-benzyloxy-6-methoxy-4-quinolinol (XXII). Finally, quinolinol (XXII) is treated with trifluoromethanesulfonyl chloride in the presence of DMAP and 2,6-lutidine in cold CH2Cl2 .

参考文献 中间体
合成目标
【1】 Deschamps, N.M., Martin, M.T., Monteith, M.J., Zhou, X. (GlaxoSmithKline Inc.). Preparation of a quinolinyloxydiphenylcyclopropanedicarboxamide. US 2010081805, WO 010036831.
【2】 Wilson, J., Zuberi, S., Naganathan, S., Goldman, E., Kanter, J. (Exelixis, Inc.). Methods of preparing quinoline derivatives. WO 2010056960.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXIVa) 22605 4-(3-Chloropropoxy)-3-Methoxyacetophenone;3-(4-Acetyl-2-methoxyphenoxy)propyl chloride;1-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone;1-[4-(3-chloropropoxy)-3-methoxyphenyl]-1-ethanone 58113-30-7 C12H15ClO3 详情 详情
(XXIVb) 69115 1-(4-(3-bromopropoxy)-3-methoxyphenyl)ethanone 　 C12H15BrO3 详情 详情
(XXVa) 69117 1-(4-(3-chloropropoxy)-5-methoxy-2-nitrophenyl)ethanone 　 C12H14ClNO5 详情 详情
(XXVb) 69116 1-(4-(3-bromopropoxy)-5-methoxy-2-nitrophenyl)ethanone C12H14BrNO5 详情 详情
(VI) 69105 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinoline;4-(3-((4-chloro-6-methoxyquinolin-7-yl)oxy)propyl)morpholine 　 C17H21ClN2O3 详情 详情
(XVII) 22604 1-(4-hydroxy-3-methoxyphenyl)-1-ethanone；Acetovanillone;4’-hydroxy-3’-methoxyacetophenone;1-(4-hydroxy-3-methoxyphenyl)ethanone 498-02-2 C9H10O3 详情 详情
(XXI) 16602 ethyl formate 109-94-4 C3H6O2 详情 详情
(XXIII) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(XXVI) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(XXVII) 69118 1-(5-methoxy-4-(3-morpholinopropoxy)-2-nitrophenyl)ethanone 　 C16H22N2O6 详情 详情
(XXVIII) 56891 1,3-propanediol cyclic sulfate;1,3,2-dioxathiane 2,2-dioxide;1,3-Propylene sulfate 1073-05-8 C3H6O4S 详情 详情
(XXIX) 69119 4’-(morpholinopropoxy)acetophenone;1-(3-methoxy-4-(3-morpholinopropoxy)phenyl)ethanone 　 C16H23NO4 详情 详情
(XXX) 69120 1-(2-amino-5-methoxy-4-(3-morpholinopropoxy)phenyl)ethanone 　 C16H24N2O4 详情 详情
(XXXI) 69121 6-methoxy-7-(3-morpholinopropoxy)quinolin-4-ol 　 C17H22N2O4 详情 详情
(XXXII) 20360 methyl(phenyl)formamide;N-Methylformanilide;N-Formyl-N-methylaniline;Methylphenylformamide;N-methyl-N-phenylformamide;N-Methyl-N-formylaniline;N-Formyl-N-methylaniline 93-61-8 C8H9NO 详情 详情

合成路线76

该中间体在本合成路线中的序号：(XXVII)

N-Protection of 2-amino-5-nitrophenol (XVII) with Ac2O in the presence of AcOH gives N-(2-hydroxy-4-nitrophenyl)acetamide (XXI), which upon O-alkylation with ethyl bromide (XX) in the presence of K2CO3 in DMF at 60 °C affords N-(2-ethoxy-4-nitrophenyl) acetamide (XXII). Reduction of the nitro derivative (XXII) with H2 over Pd/C in THF furnishes the corresponding aniline (XXIII), which by condensation with ethyl 2-cyano-3-ethoxy-2-propenoate (XXIV) at reflux produces enamine (XXV). Thermal cyclization of enamino ester (XXV) in Dowtherm at 250 °C then yields 4-hydroxyquinoline derivative (XXVI) , which upon chlorination with POCl3 in 1,2-diethoxyethane at 80-85 °C affords N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide (VII) . Alternatively, condensation of ethyl cyanoacetate (II) with morpholine (XXVII) at 100-110 °C gives 4-(cyanoacetyl)morpholine (XXVIII), which after coupling with 4-acetamido-3-ethoxyaniline (XXIII) in the presence of triethyl orthoformate in i-PrOH at 50-60 °C produces the arylamino propenamide (XXIX). Finally, cyclization of (XXIX) in the presence of POCl3 in acetonitrile at 60-65 °C then leads to the target intermediate (VII) .

参考文献 中间体
合成目标
【1】 Wissner, A., Rabindran, S.K., Tsou, H.-R. (Wyeth). Substituted quinolines as protein tyrosine kinase enzyme inhibitors. EP 1670473, WO 2005034955.
【2】 Rabindran, S.K., Tsou, H.-R., Wissner, A. (Wyeth). Protein tyrosine kinase enzyme inhibitors. US 2005059678, US 7399865, WO 2005028443.
【3】 Bernier, C., Shaw, C.-C. (Wyeth). Method of preparing 4-halogenated quinoline intermediates. WO 2009139797.
【4】 Wang, Y., Warren, C. Papamichelakis, M. (Wyeth). Quinoline intermediates of receptor tyrosine kinase inhibitors and the synthesis thereof. WO 2005070890.
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) 11877 Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate 105-56-6 C5H7NO2 详情 详情
(VII) 69196 6-acetamido-4-chloro-7-ethoxyquinoline-3-carbonitrile;4-Chloro-3-cyano-7-ethoxy-6-(acetylamino)quinoline 848133-76-6 C14H12ClN3O2 详情 详情
(XVII) 33067 2-amino-5-nitrophenol 121-88-0 C6H6N2O3 详情 详情
(XX) 30344 1-bromoethane；ethyl bromide 74-96-4 C2H5Br 详情 详情
(XXI) 69203 N-(2-hydroxy-4-nitrophenyl)acetamide 　 C8H8N2O4 详情 详情
(XXII) 69204 N-(2-ethoxy-4-nitrophenyl)acetamide 　 C10H12N2O4 详情 详情
(XXIII) 69205 N-(4-amino-2-ethoxyphenyl)acetamide 　 C10H14N2O2 详情 详情
(XXIV) 43563 ethyl (E)-2-cyano-3-ethoxy-2-propenoate；(E)-ethyl 2-cyano-3-ethoxyacrylate 94-05-3 C8H11NO3 详情 详情
(XXV) 69206 (E)-ethyl 3-((4-acetamido-3-ethoxyphenyl)amino)-2-cyanoacrylate 　 C16H19N3O4 详情 详情
(XXVI) 69207 N-(3-cyano-7-ethoxy-4-hydroxyquinolin-6-yl)acetamide 　 C14H13N3O3 详情 详情
(XXVII) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(XXVIII) 69208 4-(cyanoacetyl)morpholine;Cyanoacetic acid morpholide;N-(Cyanoacetyl)morpholine;3-Morpholin-4-yl-3-oxopropionitrile;3-(4-Morpholinyl)-3-oxopropanenitrile;(Morpholinocarbonyl)acetonitrile;(Morpholin-4-ylcarbonyl)acetonitrile 15029-32-0 C7H10N2O2 详情 详情
(XXIX) 69209 (E)-N-(4-((2-cyano-3-morpholino-3-oxoprop-1-en-1-yl)amino)-2-ethoxyphenyl)acetamide 　 C18H22N4O4 详情 详情

合成路线77

该中间体在本合成路线中的序号：(II)

Condensation of the chloroacetyl tripeptide (I) with morpholine (II) by means of KI in THF gives the tetrapeptide derivative (III), which is hydrolyzed with LiOH in MeOH/H2O to yield the corresponding carboxylic acid (IV) . Alternatively, reaction of the trifluoroacetate salt of tripeptide (V) with 4-morpholinoacetic acid (VI) in the presence of DIEA and PyBOP in DMF affords the tetrapeptide benzyl ester (VII), which is then debenzylated by means of H2 over Pd/C in MeOH/EtOAc to give the carboxylic acid (IV) . Finally, the carboxylic acid building block (IV) is coupled with either 2(S)-amino-4-methyl-1-[2(R)-methyloxiran-2-yl]pentan-1-one trifluoroacetate salt (VIII) in the presence of DIEA, HOBt and PyBOP in acetonitrile , or BOP in DMF, or HBTU in DMF or acetonitrile , or with the formic acid salt (IX) by means of DIEA, HOBt and HBTU in acetonitrile . The corresponding citrate salt is prepared by treatment of carfilzomib with citric acid in THF .

参考文献 中间体
合成目标
【1】 Phiasivongsa, P., Sehl, L.C., Fuller, W.D., Laidig, G.J. (Proteolix, Inc.). Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides. WO 2009045497.
【2】 Smyth, M.S., Laidig, G.J. (Proteolix, Inc.). Compounds for proteasome enzyme inhibition. CA 2589765, EP 1781688, JP 2008509166, US 2009131421, WO 2006017842.
【4】 Smyth, M.S., Laidig, G.J. (Proteolix, Inc.). Compounds for enzyme inhibition. US 2006030533, US 7417042.
【3】 Smyth, M.S., Laidig, G.J., Borchardt, R.T. et al. (Proteolix, Inc.). Compounds for proteasome enzyme inhibition. EP 1745064, JP 2008501637, US 2005245435, US 2008200398, US 7232818, WO 2005105827.
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) 69390 (R)-methyl 2-((S)-2-((R)-2-(2-chloroacetamido)-4-phenylbutanamido)-4-methylpentanamido)-3-phenylpropanoate C28H36ClN3O5 详情 详情
(II) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(III) 69391 (R)-methyl 2-((S)-4-methyl-2-((R)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamido)-3-phenylpropanoate C32H44N4O6 详情 详情
(IV) 69392 (R)-2-((S)-4-methyl-2-((R)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamido)-3-phenylpropanoic acid C31H42N4O6 详情 详情
(V) 69393 (R)-benzyl 2-((S)-2-((R)-2-amino-4-phenylbutanamido)-4-methylpentanamido)-3-phenylpropanoate 2,2,2-trifluoroacetate C32H39N3O4.C2HF3O2 详情 详情
(VI) 69394 4-morpholinoacetic acid;2-(4-Morpholinyl)aceticacid;2-(Morpholino)acetic acid;Morpholin-4-ylaceticacid;Morpholinoacetic acid;N-(Carboxymethyl)morpholine 3235-69-6 C6H11NO3 详情 详情
(VII) 69395 (R)-benzyl 2-((S)-4-methyl-2-((R)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamido)-3-phenylpropanoate C38H48N4O6 详情 详情
(VIII) 69396 2(S)-amino-4-methyl-1-[2(R)-methyloxiran-2-yl]pentan-1-one trifluoroacetate salt C9H17NO2.C2HF3O2 详情 详情
(IX) 69397 (S)-2-amino-4-methyl-1-((R)-2-methyloxiran-2-yl)pentan-1-one formate C9H17NO2.CH2O2 详情 详情
Extended Information