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【结 构 式】

【分子编号】20095

【品名】propionic anhydride

【CA登记号】123-62-6

【 分 子 式 】C6H10O3

【 分 子 量 】130.1436

【元素组成】C 55.37% H 7.74% O 36.88%
与该中间体有关的原料药合成路线共 17 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1

该中间体在本合成路线中的序号：(II)

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

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

合成路线2

该中间体在本合成路线中的序号：(A)

The reaction of cyclopentene oxide (I) with dimethylamine (II) gives 2-(dimethylamino)cyclopentanol (III), which is treated with methanesulfonyl chloride and NaH in THF to afford the corresponding methasulfonyl ester (IV). The condensation of (IV) with 3,4-dichloroaniline (V) in THF yields N,N-dimethyl-N'-(3,4-dichlorophenyl)cyclopentane-1,2-diamine (VI), which is acylated with propionic anhydride (A) and treated finally with maleic acid (B).

参考文献 中间体
合成目标
【1】 Szmuszkovicz, J.; N-(2-Aminocyclopentyl)acylanilides and treating depression. BE 0861351; BE 0861355; US 4156015 .
【2】 Szmuszkovicz, J.; Composes alcanoylanilides et leur preparation. BE 0875461 .
【3】 Szmuszkovicz, J.; N-(2-aminocyclopentyl)amides. BE 0867554; DE 2817112; FR 2416882; GB 1581914; JP 54106451; NL 7803442 .
【4】 Szmuszkovicz, J.; Anilide derivatives as antidepressants. US 4128663; US 4148913 .
【5】 Szmuszkovicz, J.; N-(2-Aminocyclopentyl)acylanilides and treating depression. US 4156733; US 4157398 .
【6】 Szmuszkovicz, J.; Kane, M.P.; von Voigtlander, P.F.; A new non-tricyclic antidepressant agent. Synthesis and activity of N-[trans-2-(dimethyamino)cyclopentyl]-N-(3,4-dichlorophenyl)propanamide and related compounds. J Med Chem 1981, 24, 10, 1230-36.
【7】 Owen, R.T.; Serradell, M.N.; Castaner, J.; U-48753 E. Drugs Fut 1984, 9, 11, 846.
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) 20095 propionic anhydride 123-62-6 C6H10O3 详情 详情
(B) 23808 Fumaric acid; (E)-2-butenedioic acid 110-17-8 C4H4O4 详情 详情
(I) 34274 (1R,5S)-6-oxabicyclo[3.1.0]hexane C5H8O 详情 详情
(II) 19443 N-methylmethanamine; N,N-dimethylamine 124-40-3 C2H7N 详情 详情
(III) 34275 (1S,2S)-2-(dimethylamino)cyclopentanol C7H15NO 详情 详情
(IV) 34276 N,N-dimethyl-N-((1S,2S)-2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]cyclopentyl)amine; (1S,2S)-N,N-dimethyl-2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]cyclopentanamine C10H21NOS 详情 详情
(V) 23629 3,4-dichloroaniline 95-76-1 C6H5Cl2N 详情 详情
(VI) 34277 N-[(1S,2S)-2-(3,4-dichloroanilino)cyclopentyl]-N,N-dimethylamine; (1S,2S)-N(1)-(3,4-dichlorophenyl)-N(2),N(2)-dimethyl-1,2-cyclopentanediamine C13H18Cl2N2 详情 详情

合成路线3

该中间体在本合成路线中的序号：(A)

This compound can be obtained in two different ways: 1) The acylation of 5-amino-1-beta-D-ribofuranosylimidazole-4-carboxamide (I) with propionic anhydride (A) in pyridine gives the corresponding tri-O-propionyl derivative (II), which by treatment with POCl3 and triethylamine in CHCl3 is converted into 5-amino-4-cyano-1-(2,3,5-tri-O-propionyl-beta-D-ribofuranosyl)imidazole (III). The hydrolysis of (III) with methanolic ammonia yields 5-amino-4-cyano-1-beta-D-ribofuranosylimidazole (IV), which is finally cyclized with phenylcyanamide (V) in methanolic ammonia at 180 C in a pressure vessel. This cyclization can also be performed with (III) and (V) directly, using the same procedure. 2) By reaction of 2-bromoadenosine (VI) with aniline (VII) in 2-methoxyethanol at 120 C.

参考文献 中间体
合成目标
【1】 Marumoto, R.; et al.; Synthesis and coronary vasodilating activity of 2-substituted adenosines. Chem Pharm Bull 1975, 23, 4, 759-774.
【2】 Marumoto, R.; et al. (Takeda Chemical Industries, Ltd.); 2,6-Diaminonebularine derivs.. US 3936439 .
【3】 Marumoto, R.; et al. (Takeda Chemical Industries, Ltd.); Production of 2,6-diaminonebularines. DE 2845435 .
【4】 Castaner, J.; Serradell, M.N.; Blancafort, P.; Thorpe, P.J.; CV-1808. Drugs Fut 1981, 6, 4, 222.
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) 20095 propionic anhydride 123-62-6 C6H10O3 详情 详情
(I) 37427 5-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1H-imidazole-4-carboxamide C9H14N4O5 详情 详情
(II) 37428 [(2R,3R,4R,5R)-5-[5-amino-4-(aminocarbonyl)-1H-imidazol-1-yl]-3,4-bis(propionyloxy)tetrahydro-2-furanyl]methyl propionate C18H26N4O8 详情 详情
(III) 37429 [(2R,3R,4R,5R)-5-(5-amino-4-cyano-1H-imidazol-1-yl)-3,4-bis(propionyloxy)tetrahydro-2-furanyl]methyl propionate C18H24N4O7 详情 详情
(IV) 37430 5-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1H-imidazole-4-carbonitrile C9H12N4O4 详情 详情
(V) 37431 phenylcyanamide C7H6N2 详情 详情
(VI) 37432 (2R,3R,4S,5R)-2-(6-amino-2-bromo-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol C10H12BrN5O4 详情 详情
(VII) 12294 Aniline; Phenylamine 62-53-3 C6H7N 详情 详情

合成路线4

该中间体在本合成路线中的序号：(VIII)

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

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

合成路线5

该中间体在本合成路线中的序号：(A)

The esterification of 1-benzyl-4-(phenylamino)piperidine-4-carboxylic acid (I) with ethanol and H2SO4 gives the corresponding ethyl ester (II), which is reduced with LiAlH2(OCH2CH2OCH3)2 in benzene affording 1-benzyl-4-(phenylamino)piperidine-4-methanol (III) The methylation of (III) with methyl iodide and NaH in HMPA yields 1-benzyl-4-methoxymethyl-4-(phenylamino)piperidine (IV), which is refluxed with propionic anhydride (A) to give N-[4-(methoxymethyl)-1-benzyl-4-piperidyl]propionanilide (V). The hydrogenolysis of (V) with H2 over Raney-Ni in methanol yields N-[4-(methoxymethyl)-4-piperidyl]propionanilide (VI), which is finally condensed with 2-thiopheneethanol methanesulfonate (B) by means of Na2CO3 in methyl isobutyl ketone.

参考文献 中间体
合成目标
【1】 Van Daele, P.G.H.; et al.; Synthetic analgesics: N-(1-[2-arylethyl]-4-substituted-4-piperidinyl)-N-arylalkanamides. Arzneim-Forsch Drug Res 1976, 26, 8, 1521.
【2】 Castaner, J.; Arrigoni-Martelli, E.; Sufentanil. Drugs Fut 1977, 2, 5, 334.
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) 20095 propionic anhydride 123-62-6 C6H10O3 详情 详情
(B) 33889 2-(2-thienyl)-1-ethanol; Thiophene-2-ethanol 5402-55-1 C6H8OS 详情 详情
(I) 33884 4-anilino-1-benzyl-4-piperidinecarboxylic acid C19H22N2O2 详情 详情
(II) 33885 ethyl 4-anilino-1-benzyl-4-piperidinecarboxylate C21H26N2O2 详情 详情
(III) 33886 (4-anilino-1-benzyl-4-piperidinyl)methanol C19H24N2O 详情 详情
(IV) 33887 N-[1-benzyl-4-(methoxymethyl)-4-piperidinyl]-N-phenylamine; 1-benzyl-4-(methoxymethyl)-N-phenyl-4-piperidinamine C20H26N2O 详情 详情
(V) 33888 N-[1-benzyl-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide C23H30N2O2 详情 详情
(VI) 32220 N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide C16H24N2O2 详情 详情

合成路线6

该中间体在本合成路线中的序号：

The dehydrogenation of 16alpha-methyl-11beta,17alpha,21-trihydroxypregna-1,4-diene-3,20-dione-21-acetate (I) with dichlorodicyanobenzoquinone (II) in dioxane HCl gives 16alpha-methyl-11beta,17alpha,21-trihydroxypregna-1,4,6-triene-3,20-dione-21-acetate (III), which is hydrolyzed with aqueous NaHCO3 to the corresponding free triol (IV). The reaction of (IV) with triethyl orthopropionate (A) by means of p-toluenesulfonic acid in DMSO yields 16alpha-methyl-11beta,17alpha,21-trihydroxypregna-1,4,6-triene-3,20-dione-17,21-ethylorthopropionate (V), which is hydrolyzed partially with acetic acid to 16alpha-methyl-11beta,17alpha,21-trihydroxypregna-1,4,6-triene-3,20-dione-17-propionate (VI). The acylation of (VI) with propionic anhydride affords 16alpha-methyl-11beta,17alpha,21-trihydroxypregna-1,4,6-triene-3,20-dione-17,21-dipropionate (VII), which is finally treated with dry HCl in dioxane.

参考文献 中间体
合成目标
【1】 Green, M.J.; et al. (Schering Corp.); 7alpha-Halogeno-3,20-dioxo-1,4-pregnadienes, methods for their manufacture, their use as anti-inflammatory agents, and pharmaceutical formulations useful therefor. US 4124707 .
【2】 Green, M.J.; et al. (Schering Corp.); Process for the preparation of 7{60 -halogeno-3-oxo-4-dehydro steroids and novel 7{60 -halogeno derivatives produced thereby. CA 1099254; US 4076708 .
【3】 Van Wagenen, B.C.; Barmore, R.M. (NPS Pharmaceuticals, Inc.); Chiral reductions of imines leading to the syntheses of optically active amines. WO 9711934 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
20095 propionic anhydride 123-62-6 C6H10O3 详情 详情
(A) 10395 1,1,1-Triethoxypropane; 1,1-Diethoxypropyl ethyl ether; Triethyl orthopropionate 115-80-0 C9H20O3 详情 详情
(I) 32645 2-[(8S,9S,10R,11S,13S,14S,16R,17R)-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate C24H32O6 详情 详情
(II) 21890 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 4,5-dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile 84-58-2 C8Cl2N2O2 详情 详情
(III) 32646 2-[(8S,9S,10R,11S,13S,14S,16R,17R)-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate 13796-64-0 C24H30O6 详情 详情
(IV) 32647 (8S,9S,10R,11S,13S,14S,16R,17R)-17-glycoloyl-11,17-dihydroxy-10,13,16-trimethyl-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-3-one 13954-10-4 C22H28O5 详情 详情
(V) 32648 2'-Ethoxy-2'-ethyl-11beta-hydroxy-16alpha-methylspiro[androsta-1,4,6-triene-17(R),4'-[1,3]dioxane]-3,5'-dione 67212-72-0 C27H36O6 详情 详情
(VI) 32649 (8S,9S,10R,11S,13S,14S,16R,17R)-17-glycoloyl-11-hydroxy-10,13,16-trimethyl-3-oxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl propionate C25H32O6 详情 详情
(VII) 32650 (8S,9S,10R,11S,13S,14S,16R,17R)-11-hydroxy-10,13,16-trimethyl-3-oxo-17-[2-(propionyloxy)acetyl]-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl propionate 67212-74-2 C28H36O7 详情 详情

合成路线7

该中间体在本合成路线中的序号：

The dehydrogenation of 16alpha-methyl-17alpha,21-dihydroxypregna-1,4-diene-3,11,20-trione-21-acetate (VIII) with (II) in dioxane-HCl gives 16alpha-methyl-17alpha,21-dihydroxypregna-1,4,6-triene-3,11,20-trione-21-acetate (IX), which is hydrolyzed with aqueous NaHCO3 to the corresponding free diol (X). The reaction of (X) with triethyl orthopropionate (A) as before yields 16alpha-methyl-17alpha,21-dihydroxypregna-1,4,6-triene-3,11,20-trione-17,21-ethylorthopropionate (XI), which is hydrolyzed partially with acetic acid to 16alpha-methyl-17alpha,21-dihydroxypregna-1,4,6-triene-3,11,20-trione-17-propionate (XII). The acylation of (XII) with propionic anhydride yields the corresponding dipropionate (XIII), which is treated with dry HCl in dioxane to afford 16alpha-methyl-17alpha,21-dihydroxy-7alpha-chloropregna-1,4-diene-3,11,20-trione 17,21-dipropionate (XIV). Finally, this compound is reduced with NaSH4 in methanol - THF.

参考文献 中间体
合成目标
【1】 Green, M.J.; et al. (Schering Corp.); 7alpha-Halogeno-3,20-dioxo-1,4-pregnadienes, methods for their manufacture, their use as anti-inflammatory agents, and pharmaceutical formulations useful therefor. US 4124707 .
【2】 Green, M.J.; et al. (Schering Corp.); Process for the preparation of 7{60 -halogeno-3-oxo-4-dehydro steroids and novel 7{60 -halogeno derivatives produced thereby. CA 1099254; US 4076708 .
【3】 Van Wagenen, B.C.; Barmore, R.M. (NPS Pharmaceuticals, Inc.); Chiral reductions of imines leading to the syntheses of optically active amines. WO 9711934 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
20095 propionic anhydride 123-62-6 C6H10O3 详情 详情
(A) 10395 1,1,1-Triethoxypropane; 1,1-Diethoxypropyl ethyl ether; Triethyl orthopropionate 115-80-0 C9H20O3 详情 详情
(II) 21890 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 4,5-dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile 84-58-2 C8Cl2N2O2 详情 详情
(VIII) 32651 2-[(8S,9S,10R,13S,14S,16R,17R)-17-hydroxy-10,13,16-trimethyl-3,11-dioxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate C24H30O6 详情 详情
(IX) 32652 2-[(8S,9S,10R,13S,14S,16R,17R)-17-hydroxy-10,13,16-trimethyl-3,11-dioxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate C24H28O6 详情 详情
(X) 32653 (8S,9S,10R,13S,14S,16R,17R)-17-glycoloyl-17-hydroxy-10,13,16-trimethyl-9,10,12,13,14,15,16,17-octahydro-3H-cyclopenta[a]phenanthrene-3,11(8H)-dione C22H26O5 详情 详情
(XI) 32654 2'-Ethoxy-2'-ethyl-16alpha-methylspiro[androsta-1,4,6-triene-17(R),4'-[1,3]dioxane]-3,5',11-trione C27H34O6 详情 详情
(XII) 32655 (8S,9S,10R,13S,14S,16R,17R)-17-glycoloyl-10,13,16-trimethyl-3,11-dioxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl propionate C25H30O6 详情 详情
(XIII) 32656 2-oxo-2-[(8S,9S,10R,13S,14S,16R,17R)-10,13,16-trimethyl-3,11-dioxo-17-(propionyloxy)-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl]ethyl propionate C28H34O7 详情 详情
(XIV) 32657 (7R,8S,9S,10R,13S,14S,16R,17R)-7-chloro-10,13,16-trimethyl-3,11-dioxo-17-[2-(propionyloxy)acetyl]-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl propionate C28H35ClO7 详情 详情

合成路线8

该中间体在本合成路线中的序号：(II)

The acylation of benzoxazolin-2-one (I) with propionic anhydride (II) by means of P2O5 and MsOH gives 6-propionylbenzoxazolin-2-one (III), which is treated with chloroacetyl chloride to yield 7-propionyl-3,4-dihydro-2H-1,4-benzoxazin-3-one (IV). The Mannich condensation of (IV) with CH2O and NH3 followed by methylation with methyl iodide affords the trimethylammonium compound (V), which by reaction with KCN, followed by hydrolysis with HCl gives 3-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-ylcarbonyl)butyric acid (VI). Finally this compound is cyclized with hydrazine to furnish the target pyridazinone.

参考文献 中间体
合成目标
【1】 Bonte, J.P.; Lesier, D.; Lespagnol, C.; et al.; 6-Acyl benzoxazolinones. I. Eur J Med Chem - Chim Ther 1974, 9, 491.
【2】 Kryvenko, M.; Techer, H.; Lavergne, M.; et al.; Electrophilic substitutions of 2H-1,4-benzoxazine-3-one: Acylation and chlorosulfonation. CR Acad Sci Paris Ser C 1970, 270, 19, 1601.
【3】 Lesier, D.; Lespagnol, C.; Bonte, J.P.; et al.; 6-Acyl benzoxazolinones. II. Preparation of some transformation products. Eur J Med Chem - Chim Ther 1974, 9, 497-500.
【4】 Thyes, M.; Lehmann, H.D.; Gries, J.; et al.; 6-Aryl-4,5-dihydro-3(2H)-pyridazinones. A new class of compounds with platelet aggregation inhibiting and hypotensive activities. J Med Chem 1983, 26, 6, 800.
【5】 Moussavi, Z.; Lesieur, D.; Depreux, P.; An aternative synthesis of cardiotonic 6-(3,4-dihydro-3-oxo-1,4[2H]benzoxazin-7-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-ones. Synth Commun 1991, 21, 2, 271.
【6】 Combs, D.W.; Bemoradan and related pyridazinone cardiotonics. Drugs Fut 1993, 18, 2, 139.
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) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(I) 41299 2-Benzoxazolinone; 2(3H)-benzoxazolone; 1,3-benzoxazol-2(3H)-one 59-49-4 C7H5NO2 详情 详情
(II) 20095 propionic anhydride 123-62-6 C6H10O3 详情 详情
(III) 41300 6-propionyl-1,3-benzoxazol-2(3H)-one C10H9NO3 详情 详情
(IV) 41301 7-propionyl-2H-1,4-benzoxazin-3(4H)-one C11H11NO3 详情 详情
(V) 41302 N,N,N,2-tetramethyl-3-oxo-3-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-1-propanaminium C15H21N2O3 详情 详情
(VI) 41303 3-methyl-4-oxo-4-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)butyric acid C13H13NO5 详情 详情

合成路线9

该中间体在本合成路线中的序号：(VII)

The reaction of 1-benzyl-4-piperidone (I) with aniline (II) and KCN in acetic acid gives the aminonitrile (III), which is treated with H2SO4 at room temperature to yield the carboxamide (IV). The hydrolysis of (IV) with refluxing aqueous HCl affords the carboxylic acid (V), which is esterified with Ms-OH and methanol to provide the methyl ester (VI). Acylation of the NH group of (VI) with propionic anhydride (VII) gives the propionamide (VIII), which is debenzylated with H2 over Pd/C to yield the piperidine (IX). Finally, this compound is condensed with methyl acrylate (XI) in acetonitrile to afford the target compound.

参考文献 中间体
合成目标
【1】 Killgore, J.K.; Jacob, M. (Mallinckrodt Medical Inc.); New methods for the syntheses of alfentanil, sufentanil and remifentanil. WO 0140184 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 15720 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one 3612-20-2 C12H15NO 详情 详情
(II) 12294 Aniline; Phenylamine 62-53-3 C6H7N 详情 详情
(III) 49674 4-Anilino-1-benzyl-4-cyanopiperidine C19H21N3 详情 详情
(IV) 49675 4-Anilino-1-benzylisonipecotamide C19H23N3O 详情 详情
(V) 33884 4-anilino-1-benzyl-4-piperidinecarboxylic acid C19H22N2O2 详情 详情
(VI) 49676 methyl 4-anilino-1-benzyl-4-piperidinecarboxylate C20H24N2O2 详情 详情
(VII) 20095 propionic anhydride 123-62-6 C6H10O3 详情 详情
(VIII) 49677 methyl 1-benzyl-4-(propionylanilino)-4-piperidinecarboxylate C23H28N2O3 详情 详情
(IX) 15668 methyl 4-(propionylanilino)-4-piperidinecarboxylate C16H22N2O3 详情 详情
(X) 14156 methyl acrylate 96-33-3 C4H6O2 详情 详情

合成路线10

该中间体在本合成路线中的序号：(II)

An improved synthesis of 5,7-dihydroxy-8-propionyl-4-propyl-2H-1-benzopyran-2-one, a key intermediate in the synthesis of (+)-calanolide A, has been reported: Friedel-Crafts acylation of 5,7-dihydroxy-4-propyl-2H-1-benzopyran-2-one (I) with propionic anhydride (II) by means of AlCl3 in refluxing nitromethane.

参考文献 中间体
合成目标
【1】 Xu, Z.-Q.; Zembower, D.E.; Flavin, M.T.; Jimenez, N.; Kirchhoff, E.W.; Zhang, J.; Sen, P.; Automated process research. An example of accelerated optimization of the friedel-grafts acylation reaction, a key step for the synthesis of anti-HIV (+)-calanolide A. Org Process Res Dev 2000, 4, 6, 577.
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) 22405 5,7-dihydroxy-4-propyl-2H-chromen-2-one C12H12O4 详情 详情
(II) 20095 propionic anhydride 123-62-6 C6H10O3 详情 详情
(III) 22407 5,7-dihydroxy-8-propionyl-4-propyl-2H-chromen-2-one C15H16O5 详情 详情

合成路线11

该中间体在本合成路线中的序号：(II)

Condensation of p-fluorobenzaldehyde (I) with propionic anhydride (II) by means of sodium propionate at 140 C affords p-fluoro-alpha-methylcinnamic acid (III), which is then hydrogenated over Pd/C in EtOH to provide p-fluoro-alpha-methylhydrocinnamic acid (IV). Derivative (IV) is subjected to cyclization by treatment with polyphosphoric acid (PPA) to give 6-fluoro-2-methylindanone (V), which is converted into 5-fluoro-2-methylindenyl-3-acetic acid (VII) by first condensation with cyanoacetic acid (VI) by means of acetic acid and ammonium acetate in refluxing toluene, followed by hydrolysis with KOH in hot ethanol. Condensation of derivative (VII) with p-methylthiobenzaldehyde (VIII) by means of sodium methoxide in hot MeOH affords 5-fluoro-2-methyl-1-[p-(methylsulfanyl)benzylidene]-3-indenyl acetic acid (IX), which is then oxidized in MeOH/acetone by means of an aqueous solution of sodium periodate to yield methylsulfinylbenzylidene derivative (X). Finally, the target product is obtained by further oxidation of (X) with H2O2 in the presence of sodium methoxide and sodium bicarbonate in MeOH/acetonitrile at -10 C.

参考文献 中间体
合成目标
【1】 Mayle, M.J.; Menander, K.B. (Cell Pathways, Inc.); A method for treating patients with acne by administering a cyclic GMP PDE inhibitor. WO 0044372 .
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) 12337 4-fluorobenzaldehyde 459-57-4 C7H5FO 详情 详情
(II) 20095 propionic anhydride 123-62-6 C6H10O3 详情 详情
(III) 48870 (Z)-3-(4-fluorophenyl)-2-methyl-2-propenoic acid C10H9FO2 详情 详情
(IV) 48871 3-(4-fluorophenyl)-2-methylpropionic acid C10H11FO2 详情 详情
(V) 48872 6-Fluoro-2-methylindanone C10H9FO 详情 详情
(VI) 12591 Cyanoacetic Acid; 2-Cyanoacetic acid 372-09-8 C3H3NO2 详情 详情
(VII) 48874 2-(5-fluoro-2-methyl-1H-inden-3-yl)acetic acid C12H11FO2 详情 详情
(VIII) 18815 4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde 3446-89-7 C8H8OS 详情 详情
(IX) 51940 2-(5-fluoro-2-methyl-1-[(E)-[4-(methylsulfanyl)phenyl]methylidene]-1H-inden-3-yl)acetic acid C20H17FO2S 详情 详情
(X) 51941 2-(5-fluoro-2-methyl-1-[(E)-[4-(methylsulfinyl)phenyl]methylidene]-1H-inden-3-yl)acetic acid C20H17FO3S 详情 详情

合成路线12

该中间体在本合成路线中的序号：(II)

The acylation of 4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide, valdecoxib (I), with propionic anhydride (II) by means of TEA and DMAP in THF gives N-[4-(5-methyl-3-phenylisoxazol-4-yl)phenylsulfonyl]propionamide (III), which is then treated with NaOH in ethanol.

参考文献 中间体
合成目标
【1】 Leeson, P.; Castaner, J.; Castaner, R.M.; Sorbera, L.A.; Valdecoxib and Parecoxib Sodium. Drugs Fut 2001, 26, 2, 133.
【2】 Koboldt, C.M.; Talley, J.J.; Seibert, K.; Carter, J.S.; Yuan, J.; Kellog, M.S.; Bertenshaw, S.R.; Brown, D.L.; Zhang, Y.Y.; Graneto, M.J.; N-[[(5-Methyl-3-phenylisoxazol-4-yl)-phenyl]sulfonyl]propanamide, sodium salt, parecoxib sodium: A potent and selective inhibitor of COX-2 for parenteral administration. J Med Chem 2000, 43, 9, 1661.
【3】 Talley, J.J.; Malecha, J.W.; Bertenshaw, S.; Graneto, M.J.; Carter, J.S.; Li, J.; Nagarajan, S.; Brown, D.L.; Rogier, D.J. Jr.; Penning, T.D.; Khanna, I.K.; Xu, X.; Weier, R.M. (Pharmacia Corp.); Substd. benzenesulfonamide derivs. as prodrugs of COX-2 inhibitors. EP 0892791; JP 2000509029; US 5932598; WO 9738986 .
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) 44350 4-(5-methyl-3-phenyl-4-isoxazolyl)benzenesulfonamide C16H14N2O3S 详情 详情
(II) 20095 propionic anhydride 123-62-6 C6H10O3 详情 详情
(III) 44351 4-(5-methyl-3-phenyl-4-isoxazolyl)-N-propionylbenzenesulfonamide C19H18N2O4S 详情 详情

合成路线13

该中间体在本合成路线中的序号：(II)

Heating p-fluorobenzaldehyde (I) with propionic anhydride (II) in the presence of sodium propionate affords methyl cinnamic acid derivative (III), which is then hydrogenated over Pd/C in EtOH to provide methyl hydrocinnamic acid derivative (IV). Ring closure of (IV) is then performed by heating with polyphosphoric acid to yield methylindanone derivative (V). Condensation of (V) with cyanoacetic acid (VI) by means of ammonium acetate and HOAc in refluxing toluene, followed by treatment with KOH in refluxing EtOH, provides acetic acid derivative (VII), which is then condensed with 3,4,5-trimethoxybenzaldehyde (VIII) by heating with NaOMe in MeOH to give substituted benzylidene derivative (IX). The target product can be finally obtained either by direct condensation of (IX) with benzylamine (XI) by means of DMAP and EDC in DMA or by first conversion of (IX) into the corresponding acetyl chloride by reaction with oxalyl chloride in refluxing THF, followed by coupling with benzylamine (XI) in CH2Cl2. Alternatively, the desired compound can also be obtained by coupling of acetic acid derivative (VII) with benzylamine (XI) by means of DMAP, EDC in DMA to afford N-benzyl acetamide derivative (XII), followed by condensation with 3,4,5-trimethoxybenzaldehyde (VIII) by heating with NaOMe in MeOH.

参考文献 中间体
合成目标
【1】 Sperl, G.; Gross, P.; Brendel, K.; Pamucku, R.; Piazza, G.A. (University of Arizona); Substd. benzylidene indenyl formamides, acetamides and propionamides. WO 9747303 .
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) 12337 4-fluorobenzaldehyde 459-57-4 C7H5FO 详情 详情
(II) 20095 propionic anhydride 123-62-6 C6H10O3 详情 详情
(III) 48870 (Z)-3-(4-fluorophenyl)-2-methyl-2-propenoic acid C10H9FO2 详情 详情
(IV) 48871 3-(4-fluorophenyl)-2-methylpropionic acid C10H11FO2 详情 详情
(V) 48872 6-Fluoro-2-methylindanone C10H9FO 详情 详情
(VI) 48873 2-Oxopropionitrile; Acetylcyanide; Pyruvonitrile C3H3NO 详情 详情
(VII) 48874 2-(5-fluoro-2-methyl-1H-inden-3-yl)acetic acid C12H11FO2 详情 详情
(VIII) 11136 3,4,5-Trimethoxybenzaldehyde 86-81-7 C10H12O4 详情 详情
(IX) 48875 2-[5-fluoro-2-methyl-1-[(E)-(3,4,5-trimethoxyphenyl)methylidene]-1H-inden-3-yl]acetic acid C22H21FO5 详情 详情
(X) 48876 2-[5-fluoro-2-methyl-1-[(E)-(3,4,5-trimethoxyphenyl)methylidene]-1H-inden-3-yl]acetyl chloride C22H20ClFO4 详情 详情
(XI) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(XII) 48877 N-benzyl-2-(5-fluoro-2-methyl-1H-inden-3-yl)acetamide C19H18FNO 详情 详情

合成路线14

该中间体在本合成路线中的序号：(A)

By esBy esterification of camptothecin (I) with propionic anhydride in pyridine. terification of camptothecin (I) with propionic anhydride in pyridine.

参考文献 中间体
合成目标
【1】 Cao, Z.; et al.; Alkyl esters of camptothecin and 9-nitrocamptothecin: Synthesis, in vitro pharmacokinetics, toxicity, and antitumor activity. J Med Chem 1998, 41, 1, 31.
【2】 Ciovanella, B.C.; Zhisong, C. (The Stehlin Foundation for Cancer Research); Derivs. of camptothecin for use in treating cancer. EP 0879236; WO 9728165 .
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) 20095 propionic anhydride 123-62-6 C6H10O3 详情 详情
(I) 25916 (4S)-4-hydroxy-4-methyl-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione C20H16N2O4 详情 详情

合成路线15

该中间体在本合成路线中的序号：(II)

7-Hydroxy-3-methylcoumarin (III) was obtained by Perkin reaction of 2,4-dihydroxybenzaldehyde (I) and propionic anhydride (II) in the presence of sodium propionate in pyridine. Alkylation of N-phenylpiperazine (IV) with 1-bromo-3-chloropropane (V) and NaOH in acetone provided the chloropropyl compond (VI), which was finally condensed with coumarin (III) using NaH in DMF.

参考文献 中间体
合成目标
【1】 Antonello, C.; et al.; Synthesis and characterization of new methylpsoralens as potential photochemotherapeutic agents. Farmaco 1994, 49, 4, 277.
【2】 Teran, C.; Santana, L.; Uriarte, E.; Fall, Y.; Unelius, L.; Tolf, B.R.; Phenylpiperazine derivatives with strong affinity for 5HT1A, D2A and D3 receptors. Bioorg Med Chem Lett 1998, 8, 24, 3567.
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) 20094 2,4-dihydroxybenzaldehyde 95-01-2 C7H6O3 详情 详情
(II) 20095 propionic anhydride 123-62-6 C6H10O3 详情 详情
(III) 20096 7-hydroxy-3-methyl-2H-chromen-2-one C10H8O3 详情 详情
(IV) 10756 N-Phenylpiperazine; 1-Phenylpiperazine; Phenyl piperazine 92-54-6 C10H14N2 详情 详情
(V) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(VI) 20099 1-(3-chloropropyl)-4-phenylpiperazine C13H19ClN2 详情 详情

合成路线16

该中间体在本合成路线中的序号：(II)

Heating p-fluorobenzaldehyde (I) with propionic anhydride (II) in the presence of sodium propionate affords methyl cinnamic acid derivative (III), which is then hydrogenated over Pd/C in EtOH to provide methyl hydrocinnamic acid derivative (IV). Ring closure of (IV) is then performed by heating with polyphosphoric acid to yield methylindanone derivative (V). Condensation of (V) with cyanoacetic acid (VI) by means of ammonium acetate and HOAc in refluxing toluene followed by treatment with KOH in refluxing EtOH provides acetic acid derivative (VII), which is then converted into acetyl chloride compound (VIII) by reaction with oxalyl chloride in refluxing THF. Coupling of (VIII) with benzylamine (IX) in refluxing CH2Cl2 gives indenylacetamide derivative (X), which is finally condensed with 4-pyridinecarboxaldehyde (XI) by means of NaOMe in MeOH to furnish the desired compound.

参考文献 中间体
合成目标
【1】 Piazza, G.; Gross, P.; Brendel, K.; Sperl, G.; Pamukcu, R. (Cell Pathways, Inc.; University of Arizona); N-Benzyl-3-indenylacetamides derivs. for treating neoplasia. EP 1044187; US 5948779; US 6066634; WO 9931065 .
【2】 Mayle, M.J.; Menander, K.B. (Cell Pathways, Inc.); A method for treating patients with acne by administering a cyclic GMP PDE inhibitor. WO 0044372 .
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) 12337 4-fluorobenzaldehyde 459-57-4 C7H5FO 详情 详情
(II) 20095 propionic anhydride 123-62-6 C6H10O3 详情 详情
(III) 48870 (Z)-3-(4-fluorophenyl)-2-methyl-2-propenoic acid C10H9FO2 详情 详情
(IV) 48871 3-(4-fluorophenyl)-2-methylpropionic acid C10H11FO2 详情 详情
(V) 48872 6-Fluoro-2-methylindanone C10H9FO 详情 详情
(VI) 48873 2-Oxopropionitrile; Acetylcyanide; Pyruvonitrile C3H3NO 详情 详情
(VII) 48874 2-(5-fluoro-2-methyl-1H-inden-3-yl)acetic acid C12H11FO2 详情 详情
(VIII) 48878 2-(5-fluoro-2-methyl-1H-inden-3-yl)acetyl chloride C12H10ClFO 详情 详情
(IX) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(X) 48877 N-benzyl-2-(5-fluoro-2-methyl-1H-inden-3-yl)acetamide C19H18FNO 详情 详情
(XI) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情

合成路线17

该中间体在本合成路线中的序号：(XIV)

The precursor 4-bromo-2,6-diethylpyridine (V) can be prepared by several methods. Condensation of 3-oxoglutaric acid (XIII) with propionic anhydride (XIV) in the presence of H2SO4, followed by cyclization with HCl at 100 °C leads to 2,6-diethyl-4-pyranone (XV). Subsequent treatment of pyranone (XV) with NH4OH at 50 °C yields 2,6-diethyl-4-pyridinol (XVI) , which is finally brominated with PBr5 in CHCl3 or POBr3 in DMF at 120 °C .
Alternatively, substitution of 2,6-dichloropyridine (XVII) with ethylmagnesium bromide (XVIII) in the presence of NiCl2(dppp) in Et2O gives 2,6-diethylpyridine (XIX), which can also be obtained by Wolff- Kishner reduction of 2,6-diacetylpyridine (XX) with NH2NH2 in the presence of NaOH in diethylene glycol at 120 °C. Oxidation of 2,6-diethylpyridine (XIX) with mCPBA in CHCl3, followed by nitration of the resulting 2,6-diethylpyridine-1-oxide (XXI) with HNO3 and H2SO4 at 90 °C provides the 4-nitro derivative (XXII). Substitution of nitropyridine (XXII) using AcBr in AcOH at 90 °C affords 4-bromo-2,6-diethylpyridin-1-oxide (XXIII), which is finally reduced with PBr3 in CH2Cl2 .

参考文献 中间体
合成目标
【1】 Gonzalez, J., Jewell, T.M., Li, H., Linton, A., Tatlock, J.H. (Pfizer, Inc.; Agouron Pharmaceuticals, Inc.). Inhibitors of hepatitis C virus RNAdependent RNA polymerase, and compositions and treatments using the same. EP 1781662, JP 2008509984, US 2006122399, US 7151105, US 8268835, WO 2006018725.
【2】 Li, H., Tatlock, J., Linton, A. et al. Discovery of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-(1,2,4)triazolo(1,5-a)pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (PF-00868554) as a potent and orally available hepatitis C virus polymerase inhibitor. J Med Chem 2009, 52(5): 1255-8.
【3】 Johnson, S., Drowns, M., Tatlock, J. et al. Synthetic route optimization of PF-00868554, an HCV polymerase inhibitor in clinical evaluation. Synlett 2010(5): 796-800.
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) 68333 4-bromo-2,6-diethylpyridine 877133-54-5 C9H12BrN 详情 详情
(XIII) 15530 1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid 542-05-2 C5H6O5 详情 详情
(XIV) 20095 propionic anhydride 123-62-6 C6H10O3 详情 详情
(XV) 68342 2,6-diethyl-4H-pyran-4-one 　 C9H12O2 详情 详情
(XVI) 68343 2,6-diethyl-4-pyridinol;2,6-diethylpyridin-4-ol 　 C9H13NO 详情 详情
(XVII) 13573 2,6-Dichloropyridine 2402-78-0 C5H3Cl2N 详情 详情
(XVIII) 24239 bromo(ethyl)magnesium；ethylmagnesium bromide 925-90-6 C2H5BrMg 详情 详情
(XIX) 68344 2,6-diethylpyridine 935-28-4 C9H13N 详情 详情
(XX) 48515 2,6-Diacetylpyridine 1129-30-2 C9H9NO2 详情 详情
(XXI) 68345 2,6-diethylpyridine-1-oxide 　 C9H13NO 详情 详情
(XXII) 68346 2,6-diethyl-4-nitropyridine 1-oxide 　 C9H12N2O3 详情 详情
(XXIII) 68347 4-bromo-2,6-diethylpyridin-1-oxide 　 C9H12BrNO 详情 详情
Extended Information