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【结 构 式】

【分子编号】12132

【品名】2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether

【CA登记号】696-59-3

【 分 子 式 】C6H12O3

【 分 子 量 】132.15948

【元素组成】C 54.53% H 9.15% O 36.32%
与该中间体有关的原料药合成路线共 22 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20合成路线21合成路线22

合成路线1

该中间体在本合成路线中的序号：(VII)

The reduction of 4-fluoro-3-nitroaniline (I) with SnCl2.2H20 in concentrated aqueous HCl gives 4 fluoro-m-phenylenediamine (II), which is condensed with diethyl ethoxymethylenemalonate (III) in refluxing ethanol to afford diethyl 4-fluoro-3-aminoanilinomethylenemalonate (IV). The cyclization of (IV) by means of acetic anhydride in diphenyl oxide at 250 C yields ethyl 7-acetamido-4-hydroxy-6-fluoroquinoline-3-carboxylate (V), which is alkyiated with ethyl bromide and NaOH in refluxing ethanol to give 7-amino-6-fluoro-1-ethyl-1,4 dihydro-4-oxoquinoline-3-carboxylic acid (VI). Finally, this compound is condensed with 2,5-dimethoxytetrahydrofuran (VII) in hot acetic acid.

参考文献 中间体
合成目标
【1】 Esteve Soler, J. (Provesan SA); 7-(1-Pyrrolyl) derivs. of 1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids and 1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids and their use as antimicrobial agents. EP 0134165; FR 2548664; FR 2559484; US 4552882 .
【2】 Prous, J.; Castaner, J.; Irloxafin. Drugs Fut 1986, 11, 10, 839.
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) 24710 4-fluoro-3-nitroaniline 364-76-1 C6H5FN2O2 详情 详情
(II) 24711 3-amino-4-fluorophenylamine C6H7FN2 详情 详情
(III) 14088 Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate 87-13-8 C10H16O5 详情 详情
(IV) 24713 diethyl 2-[(3-amino-4-fluoroanilino)methylene]malonate C14H17FN2O4 详情 详情
(V) 24714 ethyl 7-(acetamido)-6-fluoro-4-hydroxy-3-quinolinecarboxylate C14H13FN2O4 详情 详情
(VI) 24715 7-amino-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C12H11FN2O3 详情 详情
(VII) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

The cyclization of methyl 2-aminobenzoate (I) with 2,5-dimethoxytetrahydrofuran (II) in refluxing acetic acid gives methyl 2-(pyrrol-1-yl)benzoate (III), which by reduction with LiAlH4 in ether is converted into 2-(pyrrol-1-yl)benzyl alcohol (IV). The cyclization of (IV) with ethyl 2-oxopropionate (V) by means of butyllithium and tetramethylethylenediamine (TMEDA) in THF affords 4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepine-4-carboxylic acid ethyl ester (VI), which is hydrolyzed with NaOH in refluxing ethanol to the corresponding free acid (VII). The condensation of (VII) with 1-(piperidin-4-yl)-2,3-dihydro-1H-benzimidazol-2-one (VIII) by means of carbonyldiimidazol (CDI) in THF gives 1-[1-(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-ylcarbonyl) piperidin-4-yl]-2,3-dihydro-1H-benzimidazol-2-one (IX), which is finally reduced with LiAlH4 in THF, and treated with maleic acid in acetone.

参考文献 中间体
合成目标
【1】 Robinson, C.; Robinson, K.; Castaner, J.; Zaldaride Maleate. Drugs Fut 1996, 21, 7, 719.
【2】 Wasley, J.W.F.; Norman, J. (Novartis AG); Pyrrolo[1,2-a][4,1]benzoxazepins, process for their preparation, pharmaceutical compsns. containing them as well as therapeutic use. EP 0233483; JP 1987169791; JP 1995089966; US 4758559 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11161 methyl 2-aminobenzoate; Methyl anthranilate 134-20-3 C8H9NO2 详情 详情
(II) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(III) 12133 methyl 2-(1H-pyrrol-1-yl)benzoate C12H11NO2 详情 详情
(IV) 12134 [2-(1H-Pyrrol-1-yl)phenyl]methanol C11H11NO 详情 详情
(V) 12135 ethyl 2-oxopropanoate; Ethyl pyruvate 617-35-6 C5H8O3 详情 详情
(VI) 12136 ethyl 4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepine-4-carboxylate C16H17NO3 详情 详情
(VII) 12137 4-Methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepine-4-carboxylic acid C14H13NO3 详情 详情
(VIII) 12138 1-(4-Piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one; 4-(2-Keto-1-benzimidazolinyl)piperidine 20662-53-7 C12H15N3O 详情 详情
(IX) 12139 1-[1-[(4-Methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl)carbonyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one C26H26N4O3 详情 详情

合成路线3

该中间体在本合成路线中的序号：(X)

The reaction of 5-chloro-2-hydroxybenzoic acid (I) with 2-methyl-2-propenyl chloride (II) by means of K2CO3 and KI in hot DMF gives 5-chloro-2-(2-methyl-2-propenyloxy)benzoic acid 2-methyl-2-propenyl ester (III), which is rearranged by heating at 190 C yielding 5-chloro-2-hydroxy-3-(2-methyl-2-propenyl)benzoic acid 2-methyl-2-propenyl ester (IV). The cyclization of (IV) with refluxing 90% formic acid affords 5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid (V), which is treated with SOCl2 in DMF and condensed with endo-8-methyl-8-azabicyclo[3.2.1]octan-3-amine (VI). The acid intermediate (V) can also be obtained by hydrolysis of the ester (III) with NaOH and tetrabutylammonium bisulfate in refluxing water to give 5-chloro-2-(2-methyl-2-propenyloxy)benzoic acid (VII), which is rearranged by heating at 170 C yielding 5-chloro-2-hydroxy-3-(2-methyl-2-propenyl)benzoic acid (VIII). Finally, (VIII) is cyclized to acid intermediate (V) by a treatment with aqueous refluxing 2.7N HCl. The intermediate endo-8-methyl-8-azabicyclo[3.2.1]octan-3-amine (VI) has been obtained as follows: 2,5-dihydroxytetrahydrofuran (IX) or 2,5-dimethoxytetra-hydrofuran (X) with HCl give butanedialdehyde (XI), which, without isolation, is cyclized with 3-oxoglutaric acid (XII) and methylamine by means of NaOAc and HCl in hot water yielding 8-methyl-8-azabicyclo[3.2.1]octan-3-one (XIII). The reductocondensation of (XIII) with benzylamine by means of NaBH(OAc)3, followed by hydrogenolysis with H2 over Pd/C in basic water gives directly the amine (VI). The intermediate amine (VI) can also be obtained by condensation of bicyclooctanone (XIII) with benzylamine(A) to give the imine (XIV), which is reduced to the benzylamine (XV) with H2 over PtO2 in ethanol. Finally, this compound is debenzylated by hydrogenation over Pd/C in the same solvent yielding amine (VI).

参考文献 中间体
合成目标
【1】 Burks, J.E.; et al.; Development of a manufacturing process for zatosetron maleate. Org Process Res Dev 1997, 1, 3, 198.
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) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(I) 13895 5-Chloro-2-hydroxybenzoic acid; 5-Chlorosalicylic acid 321-14-2 C7H5ClO3 详情 详情
(II) 12127 3-Chloro-2-methyl-1-propene; Isobutenyl chloride 563-47-3 C4H7Cl 详情 详情
(III) 36355 2-methyl-2-propenyl 5-chloro-2-[(2-methyl-2-propenyl)oxy]benzoate C15H17ClO3 详情 详情
(IV) 36356 2-methyl-2-propenyl 5-chloro-2-hydroxy-3-(2-methyl-2-propenyl)benzoate C15H17ClO3 详情 详情
(V) 13900 5-Chloro-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylic acid C11H11ClO3 详情 详情
(VI) 12412 (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-amine; (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]oct-3-ylamine C8H16N2 详情 详情
(VII) 36357 5-chloro-2-[(2-methyl-2-propenyl)oxy]benzoic acid C11H11ClO3 详情 详情
(VIII) 36358 5-chloro-2-hydroxy-3-(2-methyl-2-propenyl)benzoic acid C11H11ClO3 详情 详情
(IX) 36359 tetrahydro-2,5-furandiol C4H8O3 详情 详情
(X) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(XI) 36360 succinaldehyde C4H6O2 详情 详情
(XII) 15530 1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid 542-05-2 C5H6O5 详情 详情
(XIII) 16443 (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-one C8H13NO 详情 详情
(XIV) 36361 N-benzyl-N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ylidene]amine; N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ylidene](phenyl)methanamine C15H20N2 详情 详情
(XV) 12413 N-Benzyl-N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amine; (1R,5S)-N-Benzyl-8-methyl-8-azabicyclo[3.2.1]octan-3-amine C15H22N2 详情 详情

合成路线4

该中间体在本合成路线中的序号：(II)

The condensation of ethyl 4-aminobenzoate (I) with 2,5-dimethoxytetrahydrofuran (II) in refluxing acetic acid/toluene gives ethyl 4-(1-pyrrolyl)benzoate (III), which by a Mannich reaction with formaldehyde and dimethylamine, followed by quaternization with methyl iodide in N,N'-dimethylimidazolidininone (DMI) yields the trimethylammonium salt (IV). The reduction of (IV) with borane/pyridine complex in DMI affords ethyl 4-(2-methyl-1-pyrrolyl)benzoate (V), which is treated with chlorosulfonyl isocyanate in heptane/toluene affording ethyl 4-(2-cyano-5-methyl-1-pyrrolyl)benzoate (VI). The reduction of (VI) with NaBH4 in methanol gives the benzyl alcohol (VII), which is treated with Ms-Cl and triethylamine to yield the mesylate (VIII). The condensation of (VIII) with N-(4-methyl-3-nitropyridin-2-yl)butyramide (IX) by means of NaOH and K2CO3 affords the disubstituted amide (X), which is cyclized by reduction of its nitro group with Fe and AcOH giving the imidazo[4,5-b]pyridine (XI). Finally, this compound is condensed with sodium azide and triethylamine in hot DMI in order to form the tetrazole ring of the target compound, which is salified with HCl in isopropanol/water.

参考文献 中间体
合成目标
【1】 Zanka, A.; et al.; Pilot scale synthesis of a novel nonpeptide angiotensin II receptor antagonist. Org Process Res Dev 1998, 2, 4, 230.
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) 16498 Benzocaine; ethyl 4-aminobenzoate 94-09-7 C9H11NO2 详情 详情
(II) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(III) 35440 ethyl 4-(1H-pyrrol-1-yl)benzoate C13H13NO2 详情 详情
(IV) 35448 [1-[4-(ethoxycarbonyl)phenyl]-1H-pyrrol-2-yl]-N,N,N-trimethylmethanaminium iodide C17H23IN2O2 详情 详情
(V) 35441 ethyl 4-(2-methyl-1H-pyrrol-1-yl)benzoate C14H15NO2 详情 详情
(VI) 35442 ethyl 4-(2-cyano-5-methyl-1H-pyrrol-1-yl)benzoate C15H14N2O2 详情 详情
(VII) 35443 1-[4-(hydroxymethyl)phenyl]-5-methyl-1H-pyrrole-2-carbonitrile C13H12N2O 详情 详情
(VIII) 35444 5-methyl-1-[4-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)phenyl]-1H-pyrrole-2-carbonitrile C16H18N2OS 详情 详情
(IX) 35445 N-(4-methyl-3-nitro-2-pyridinyl)butanamide C10H13N3O3 详情 详情
(X) 35446 N-[4-(2-cyano-5-methyl-1H-pyrrol-1-yl)benzyl]-N-(4-methyl-3-nitro-2-pyridinyl)butanamide C23H23N5O3 详情 详情
(XI) 35447 5-methyl-1-[4-[(7-methyl-2-propyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]phenyl]-1H-pyrrole-2-carbonitrile C23H23N5 详情 详情

合成路线5

该中间体在本合成路线中的序号：

3,5-Dihydroxybenzoic acid (I) was carboxylated under CO2-pressure in aqueous KOH solution. Acidification in situ directly precipitated 2,6-dihydroxyterephthalic acid (II), which was per-ethylated with diethyl sulfate in acetone to afford diethyl 2,6-diethoxyterephthalate (III). The sterically more hindered 1-ester group of di-ester (III) underwent Lossen rearrangement upon treatment with hydroxylamine sulfate in polyphosphoric acid. The resulting ethyl 4-amino-3,5-diethoxybenzoate (IV) was condensed with 2,5-dimethoxytetrahydrofuran in hexane under acetic acid catalysis and water removal yielding ethyl 3,5-diethoxy-4-(pyrrol-1-yl)benzoate (V), which was reduced with diisobutylaluminum hydride in toluene. The intermediate benzyl alcohol was oxidized in situ with activated manganese(IV) oxide to yield 3,5-diethoxy-4-(pyrrol-1-yl)benzaldehyde (VI). The following steps achieved the construction of the 2,4-diaminopyrimidine moiety of the title drug and reflect well established methodology. The benzaldehyde (VI) was condensed with 3-morpholinopropionitrile under potassium tert-butylate catalysis in N,N-dimethylformamide. The crude acrylonitrile intermediate was treated with aniline hydrochloride in 2-propanol in order to provide a better leaving group for the final cyclization, which was carried out by heating with an excess of guanidine in methyl sulfoxide.

参考文献 中间体
合成目标
【1】 Stockel, K.; Kompis, I.; Then, R.L.; Stephan-Guldner, M.; Hartman, P.G.; Epiroprim. Drugs Fut 1994, 19, 5, 446.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(I) 16230 resorcylic acid; 3,5-dihydroxybenzoic acid 99-10-5 C7H6O4 详情 详情
(II) 16231 2,6-dihydroxyterephthalic acid C8H6O6 详情 详情
(III) 16232 diethyl 2,6-diethoxyterephthalate C16H22O6 详情 详情
(IV) 16233 ethyl 4-amino-3,5-diethoxybenzoate C13H19NO4 详情 详情
(V) 16234 ethyl 3,5-diethoxy-4-(1H-pyrrol-1-yl)benzoate C17H21NO4 详情 详情
(VI) 16235 3,5-diethoxy-4-(1H-pyrrol-1-yl)benzaldehyde C15H17NO3 详情 详情

合成路线6

该中间体在本合成路线中的序号：

The alkylation of ethyl 2-(benzyloxycarbonylamino)cyanoacetate (I) with ethyl bromoacetate and anhydrous potassium carbonate in acetone gives diethyl 2-(benzyloxycarbonylamino)-2-cyanosuccinate (II), which is hydrolyzed by means of hydrogen peroxide and sodium carbonate in acetone/water, yielding 3-(benzyloxycarbonylamino)-3-(ethoxycarbonyl)pyrrolidine-2,5-dione (III). Racemic (III) is then resolved by means of crystallization with cinchonidine in ethanol to give the (-)-enantiomer (IV) (>99.5% e.e.). Hydrogenolysis of (IV) over Pd/C in ethanol, followed by treatment with 2,5-dimethoxytetrahydrofuran in acetic acid, affords (-)-3-(ethoxycarbonyl)-3-(pyrrol-1-yl)pyrrolidine-2,5-dione (VI). Treatment of (VI) with trichloroacetyl chloride in ethyl acetate, followed by condensation with 4-bromo-2-fluorobenzylamine in the presence of triethylamine, gives AS-3201 (>99.4% e.e.).

参考文献 中间体
合成目标
【1】 Negoro, T.; Murata, M.; Ueda, S.; Fujitani, B.; Ono, Y.; Kuromiya, A.; Komiya, M.; Suzuki, M.; Matsumoto, J.; Novel, highly potent aldose reductase inhibitors: (R)-(-)-2-(4-Bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3'-pyrrolidine-1,2',3,5'-tetrone (AS-3201) and its congeners. J Med Chem 1998, 41, 21, 4118-29.
【2】 Negoro, T.; Komiya, M.; Ono, Y.; AS-3201. Drugs Fut 2000, 25, 2, 131.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
19560 (4-bromo-2-fluorophenyl)methanamine; 4-bromo-2-fluorobenzylamine 112734-22-2 C7H7BrFN 详情 详情
(I) 32863 ethyl 2-[[(benzyloxy)carbonyl]amino]-2-cyanoacetate C13H14N2O4 详情 详情
(II) 32864 diethyl 2-[[(benzyloxy)carbonyl]amino]-2-cyanosuccinate C17H20N2O6 详情 详情
(III) 32865 ethyl 3-[[(benzyloxy)carbonyl]amino]-2,5-dioxo-3-pyrrolidinecarboxylate C15H16N2O6 详情 详情
(IV) 32866 ethyl (3R)-3-[[(benzyloxy)carbonyl]amino]-2,5-dioxo-3-pyrrolidinecarboxylate C15H16N2O6 详情 详情
(V) 32867 ethyl (3R)-3-amino-2,5-dioxo-3-pyrrolidinecarboxylate C7H10N2O4 详情 详情
(VI) 32868 ethyl (3R)-2,5-dioxo-3-(1H-pyrrol-1-yl)-3-pyrrolidinecarboxylate C11H12N2O4 详情 详情
(VII) 32869 ethyl (3R)-2,5-dioxo-3-[2-(2,2,2-trichloroacetyl)-1H-pyrrol-1-yl]-3-pyrrolidinecarboxylate C13H11Cl3N2O5 详情 详情

合成路线7

该中间体在本合成路线中的序号：(II)

Phenyl pyrrole (III) was prepared by Clauson-Kaas reaction of 4-methoxy-2-nitroaniline (I) with 2,5-dimethoxytetrahydrofuran (II). Subsequent reduction of the nitro group of (III) using hydrazine and Raney Nickel provided aniline (IV), which was cyclized with phosgene in refluxing toluene to furnish the pyrroloquinoxaline (V). This was chlorinated with POCl3 to obtain the chloroquinoxaline (VI). Finally, nucleophilic substitution in (VI) with N-(4-fluorobenzyl)piperazine (VII) yielded the title compound.

参考文献 中间体
合成目标
【1】 Katounina, T.; et al.; Synthesis of [18F]MR 18445 and its in vivo evaluat. J Label Compd Radiopharm 1997, 40, 542.
【2】 Lancelot, J.-C.; Prunier, H.; Rault, S.; et al.; Novel and selective partial agonists of 5-HT3 rece. J Med Chem 1997, 40, 12, 1808.
【3】 Katounina, T.; et al.; Synthesis and biological investigations of [18F]MR. Bioorg Med Chem 1998, 6, 6, 789.
【4】 Rault, S.; Lancelot, J.-C.; Prunier, H.; Robba, M.; Delagrange, P.; Renard, P.; Adam, G. (ADIR et Cie.); Pyrrolopyrazine derivs. with 5-HT3 activity. CA 2122890; EP 0623620; FR 2704547; JP 1994340666; US 5599812 .
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) 23592 4-methoxy-2-nitrophenylamine; 4-methoxy-2-nitroaniline 96-96-8 C7H8N2O3 详情 详情
(II) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(III) 23594 1-(4-methoxy-2-nitrophenyl)-1H-pyrrole; methyl 3-nitro-4-(1H-pyrrol-1-yl)phenyl ether C11H10N2O3 详情 详情
(IV) 23595 5-methoxy-2-(1H-pyrrol-1-yl)phenylamine; 5-methoxy-2-(1H-pyrrol-1-yl)aniline C11H12N2O 详情 详情
(V) 23596 7-methoxypyrrolo[1,2-a]quinoxalin-4(5H)-one C12H10N2O2 详情 详情
(VI) 23597 4-chloropyrrolo[1,2-a]quinoxalin-7-yl methyl ether; 4-chloro-7-methoxypyrrolo[1,2-a]quinoxaline C12H9ClN2O 详情 详情
(VII) 23598 1-(4-fluorobenzyl)piperazine C11H15FN2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(IX)

The synthesis of IY-81149 can be obtained according to Scheme 22875502a. The oxidation of 2,3-lutidine (I) with hydrogen peroxide in acetic acid affords 2,3-dimethylpyridine-N-oxide (II), which is treated with sulfuric acid and nitric acid to give the corresponding nitro compound (III). The treatment of (III) with NaOH in methanol gives 2,3-dimethyl-4-methoxypyridine-N-oxide (IV), which is reacted with acetic acid and acetic anhydride and oxidized in refluxing NaOH, yielding 3-methyl-4-methoxypyridine-2-methanol (V). The chlorination of (V) with thionylchloride in CH2Cl2 affords 3-methyl-4-methoxy-2-chloromethylpyridine (VI). The reaction of 2-mercapto-5-nitrobenzimidazole (VII) with iron and concentrated HCl in refluxing ethanol and water gives monoamine (VIII), which by condensation with 2,5-dimethoxytetrahydrofuran (IX) in acetic acid yields 2-mercapto-5-(1-pyrrolyl)benzimidazole (X). The condensation of (VI) with (X) by means of NaOH in methanol gives 2-[(4-methoxy-3-methyl-2-pyridinyl)methylsulfanyl]-5-(1H-pyrrol-1-yl)-1H-benzimidazole (XI), which is finally treated with m-chloroperoxybenzoic acid (m-CPBA) in chloroform.

参考文献 中间体
合成目标
【1】 Lee, S.M.; Jung, W.T.; Kim, D.Y.; IY-81149. Drugs Fut 1999, 24, 6, 618.
【2】 Kohl, B.; Sturm, E.; Senn-Bilfinger, J.; Simon, W.A.; Krüger, U.; Schaefer, H.; Rainer, G.; Figala, V.; Klemm, K.; (H+,K+)-ATPase inhibiting 2-[(2-pyridylmethyl)sulfinyl]benzimidazoles. 4. A novel series of dimethoxypyridyl-substituted inhibitors with enhanced selectivity. The selection of pantoprazole as a clinical candidate. J Med Chem 1992, 35, 6, 1049.
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) 26309 2,3-Dimethylpyridine 583-61-9 C7H9N 详情 详情
(II) 26310 2,3-dimethyl-1-pyridiniumolate C7H9NO 详情 详情
(III) 19482 2,3-dimethyl-4-nitro-1-pyridiniumolate 37699-43-7 C7H8N2O3 详情 详情
(IV) 26311 4-methoxy-2,3-dimethyl-1-pyridiniumolate C8H11NO2 详情 详情
(V) 26312 (4-methoxy-3-methyl-2-pyridinyl)methanol C8H11NO2 详情 详情
(VI) 20172 2-(chloromethyl)-4-methoxy-3-methylpyridine; 2-(chloromethyl)-3-methyl-4-pyridinyl methyl ether C8H10ClNO 详情 详情
(VII) 26313 5-nitro-1H-benzimidazol-2-ylhydrosulfide; 2-Mercapto-5-nitrobenzimidazole; 5-nitro-1H-benzimidazole-2-thiol 34202-69-2 C7H5N3O2S 详情 详情
(VIII) 26314 5-amino-1H-benzimidazol-2-ylhydrosulfide; 5-amino-1H-benzimidazole-2-thiol C7H7N3S 详情 详情
(IX) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(X) 20173 5-(1H-pyrrol-1-yl)-1H-benzimidazol-2-ylhydrosulfide; 5-(1H-pyrrol-1-yl)-1H-benzimidazole-2-thiol C11H9N3S 详情 详情
(XI) 20174 2-[[(4-methoxy-3-methyl-2-pyridinyl)methyl]sulfanyl]-5-(1H-pyrrol-1-yl)-1H-benzimidazole; methyl 3-methyl-2-([[5-(1H-pyrrol-1-yl)-1H-benzimidazol-2-yl]sulfanyl]methyl)-4-pyridinyl ether C19H18N4OS 详情 详情

合成路线9

该中间体在本合成路线中的序号：(II)

The condensation of dimethyl 5-aminoisophthalate (I) with 2,5-dimethoxytetrahydrofuran (II) in refluxing AcOH provided the pyrrolyl derivative (III). Partial hydrolysis of (III) with methanolic KOH then gave mono ester (IV). After activation of the carboxy group of (IV) as the corresponding mixed anhydride with isobutyl chloroformate, reduction employing NaBH4 furnished alcohol (V). The ester group of (V) was then displaced with guanidine-HCl (VI) in the presence of NaOMe to yield the title benzoyl guanidine, which was isolated as the methanesulfonate salt.

参考文献 中间体
合成目标
【1】 Kuno, A.; Inoue, Y.; Takasugi, H.; Mizuno, H.; Yamasaki, K. (Fujisawa Pharmaceutical Co., Ltd.); Guanidine derivs. as inhibitors of Na+/H+ exchange in cells. EP 0699185; JP 1996511243; US 5824691; WO 9426709 .
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) 35226 dimethyl 5-aminoisophthalate 99-27-4 C10H11NO4 详情 详情
(II) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(III) 35227 dimethyl 5-(1H-pyrrol-1-yl)isophthalate C14H13NO4 详情 详情
(IV) 35228 3-(methoxycarbonyl)-5-(1H-pyrrol-1-yl)benzoic acid C13H11NO4 详情 详情
(V) 35229 methyl 3-(hydroxymethyl)-5-(1H-pyrrol-1-yl)benzoate C13H13NO3 详情 详情
(VI) 14790 Guanidine 113-00-8 CH5N3 详情 详情

合成路线10

该中间体在本合成路线中的序号：(XIV)

Condensation between 2,5-dimethoxytetrahydrofuran (XIV), acetone-1,3-dicarboxylic acid (XV) and 3-amino-1-propanol (XVI), followed by acid decarboxylation of the intermediate adduct (XVII) furnished the tropinone analogue (XVIII). After conversion of (XVIII) to the corresponding oxime (XIX), its hydrogenation over PtO2 gave amine (XX). This was finally coupled with acid chloride (VIII) to give the title amide.

参考文献 中间体
合成目标
【1】 Yokomori, S.; Muramatsu, M.; Suzuki, M.; Ito, C.; Asanuma, H.; Isobe, Y.; Ohuchi, Y.; Kaneko, T.; Synthesis and evaluation of novel 2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives as potent and selective serotonin 5-HT4 receptor agonists. Chem Pharm Bull 2001, 49, 1, 29.
【2】 Ohuchi, Y.; Suzuki, M.; Asanuma, H.; Yokomori, S.; Hatayama, K. (Taisho Pharmaceutical Co., Ltd.); Quinolinecarboxylic acid deriv.. EP 0710662; JP 1996034784; US 5753673; WO 9531455 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 36336 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarbonyl chloride C13H12ClNO2 详情 详情
(XIV) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(XV) 15530 1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid 542-05-2 C5H6O5 详情 详情
(XVI) 18522 3-amino-1-propanol 156-87-6 C3H9NO 详情 详情
(XVII) 36340 (1R,5S)-8-(3-hydroxypropyl)-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylic acid C12H17NO6 详情 详情
(XVIII) 36341 (1R,5S)-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]octan-3-one C10H17NO2 详情 详情
(XIX) 36342 (1R,5S)-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]octan-3-one oxime C10H18N2O2 详情 详情
(XX) 36343 3-[(1R,5S)-3-amino-8-azabicyclo[3.2.1]oct-8-yl]-1-propanol C10H20N2O 详情 详情

合成路线11

该中间体在本合成路线中的序号：(VII)

Esterification of 4-nitro-D-phenylalanine (I) with HCl/MeOH provides the amino ester (II). This is subsequently acylated with 3,5-dimethylbenzoyl chloride (III), yielding amide (IV). Alkylation of amide (IV) by means of iodomethane and NaH affords the N-methyl amide (V). The nitro group of (V) is then reduced to amine (VI) by catalytic hydrogenation over Pd/C. Clauson-Kaas condensation of amine (VI) with 2,5-dimethoxytetrahydrofuran (VII) leads to the pyrrole derivative (VIII). The methyl ester function of (VIII) is then hydrolyzed with LiOH to provide the carboxylic acid (IX).

参考文献 中间体
合成目标
【1】 Ksander, G.M.; Kukkola, P.J.; Robinson, L.A. (Novartis AG); N-aroylamino acid amides as endothelin inhibitors. EP 0821670; JP 1999505522; WO 9633170 .
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) 57380 (2R)-2-amino-3-(4-nitrophenyl)propanoic acid C9H10N2O4 详情 详情
(II) 57381 methyl (2R)-2-amino-3-(4-nitrophenyl)propanoate C10H12N2O4 详情 详情
(III) 57374 3,5-dimethylbenzoyl chloride C9H9ClO 详情 详情
(IV) 57375 methyl (2R)-2-[(3,5-dimethylbenzoyl)amino]-3-(4-nitrophenyl)propanoate C19H20N2O5 详情 详情
(V) 57376 methyl (2R)-2-[(3,5-dimethylbenzoyl)(methyl)amino]-3-(4-nitrophenyl)propanoate C20H22N2O5 详情 详情
(VI) 57377 methyl (2R)-3-(4-aminophenyl)-2-[(3,5-dimethylbenzoyl)(methyl)amino]propanoate C20H24N2O3 详情 详情
(VII) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(VIII) 57378 methyl (2R)-2-[(3,5-dimethylbenzoyl)(methyl)amino]-3-[4-(1H-pyrrol-1-yl)phenyl]propanoate C24H26N2O3 详情 详情
(IX) 57379 (2R)-2-[(3,5-dimethylbenzoyl)(methyl)amino]-3-[4-(1H-pyrrol-1-yl)phenyl]propanoic acid C23H24N2O3 详情 详情

合成路线12

该中间体在本合成路线中的序号：(IX)

Ortho metalation of 4-chlorobenzoic acid (I) with 2 equivalents of sec-butyllithium in the presence of tetramethylethylenediamine (TMEDA) in THF at -90 C, followed by addition of methyl iodide at -80 C afforded 4-chloro-2-methylbenzoic acid (II). Chlorosulfonation of (II) with ClSO3H at 135 C provided (III), which was reduced to sulfinic acid (IV) by means of Na2SO3. Alkylation of the sodium salt of (IV) with methyl iodide in aqueous methanol yielded sulfone (V). Subsequent reaction with an excess of benzylamine at 160 C gave benzylaniline (VI), from which the benzyl group was removed by hydrogenolysis in the presence of Pd/C to afford primary amine (VII). Further esterification with a methanolic solution of HCl provided methyl ester (VIII). Conversion of amine (VIII) to pyrrolyl compound (X) was effected by treatment with 2,5-dimethoxytetrahydrofuran (IX) in the presence of 4-chloropyridine hydrochloride in refluxing dioxan. Finally, condensation with guanidine in methanol at 50 C furnished the title compound.

参考文献 中间体
合成目标
【1】 Baumgarth, M.; et al.; (2-Methyl-5-(methylsulfonyl)benzoyl)guanidine Na+/H+ antiporter inhibitors. J Med Chem 1997, 40, 13, 2017.
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) 18359 p-chlorobenzoic acid; 4-chlorobenzoic acid 74-11-3 C7H5ClO2 详情 详情
(II) 18360 4-chloro-2-methylbenzoic acid 7499-07-2 C8H7ClO2 详情 详情
(III) 18361 4-chloro-5-(chlorosulfonyl)-2-methylbenzoic acid C8H6Cl2O4S 详情 详情
(IV) 18362 4-chloro-2-methyl-5-sulfinobenzoic acid C8H7ClO4S 详情 详情
(V) 18363 4-chloro-2-methyl-5-(methylsulfonyl)benzoic acid C9H9ClO4S 详情 详情
(VI) 18364 4-(benzylamino)-2-methyl-5-(methylsulfonyl)benzoic acid C16H17NO4S 详情 详情
(VII) 18365 4-amino-2-methyl-5-(methylsulfonyl)benzoic acid C9H11NO4S 详情 详情
(VIII) 18366 methyl 4-amino-2-methyl-5-(methylsulfonyl)benzoate C10H13NO4S 详情 详情
(IX) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(X) 18368 methyl 2-methyl-5-(methylsulfonyl)-4-(1H-pyrrol-1-yl)benzoate C14H15NO4S 详情 详情

合成路线13

该中间体在本合成路线中的序号：(VI)

Benzyl alcohol (I) was treated with mesyl chloride and triethylamine in CH2Cl2 at 0 C, and the resulting mesylate (II) was subsequently coupled with 2-methyl-8-hydroxyquinoline (III) in the presence of NaH to afford ether (IV). Reduction of the nitro group of (IV) with hydrazine in the presence of FeCl3 and carbon gave aniline (V). Pyrrole (VII) was then obtained by heating (V) with 2,5-dimethoxy tetrahydrofuran (VI) in AcOH. Further reaction of (VII) with chlorosulfonylisocyanate (VIII) at low temperature provided the 2-cyanopyrrole (IX). The cyano group of (IX) was reduced with LiAlH4 to give amine (X). This was finally condensed with pyridinylacrylic acid (XI) using EDC and HOBt to yield the target amide, which was isolated as the dihydrochloride salt.

参考文献 中间体
合成目标
【1】 Abe, Y.; Kayakiri, H.; Satoh, S.; Inoue, T.; Sawada, Y.; Inamura, N.; Asano, M.; Aramori, I.; Hatori, C; Sawai, H.; Oku, T.; Tanaka, H.; A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 4. Discovery of novel frameworks mimicking the active conformation. J Med Chem 1998, 41, 23, 4587.
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) 18590 (2,6-dichloro-3-nitrophenyl)methanol C7H5Cl2NO3 详情 详情
(II) 19295 2,6-dichloro-3-nitrobenzyl methanesulfonate C8H7Cl2NO5S 详情 详情
(III) 18598 2-methyl-8-quinolinol 826-81-3 C10H9NO 详情 详情
(IV) 18926 (E)-3-[4-[(methylamino)carbonyl]phenyl]-2-propenoic acid C11H11NO3 详情 详情
(V) 18930 2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenylamine; 2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]aniline C17H14Cl2N2O 详情 详情
(VI) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(VII) 19300 2,6-dichloro-3-(1H-pyrrol-1-yl)benzyl 2-methyl-8-quinolinyl ether; 8-[[2,6-dichloro-3-(1H-pyrrol-1-yl)benzyl]oxy]-2-methylquinoline C21H16Cl2N2O 详情 详情
(VIII) 14010 ethyl 5-(2-chlorophenyl)-2-hydrazino-3,6,7,9-tetrahydro-8H-pyrido[4',3':4,5]thieno[2,3-e][1,4]diazepine-8-carboxylate C19H20ClN5O2S 详情 详情
(IX) 19302 1-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-1H-pyrrole-2-carbonitrile C22H15Cl2N3O 详情 详情
(X) 19303 [1-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-1H-pyrrol-2-yl]methanamine; [1-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-1H-pyrrol-2-yl]methylamine C22H19Cl2N3O 详情 详情
(XI) 19304 (E)-3-[6-(acetamido)-3-pyridinyl]-2-propenoic acid C10H10N2O3 详情 详情

合成路线14

该中间体在本合成路线中的序号：(II)

The cyclization of the amino group of 4-amino-3-(4-chlorophenyl)butyric acid (I) with 2,5-dimethoxytetrahydrofuran (II) by means of AcOH in THF gives the corresponding pyrrole (III), which is cyclized by means of TEA, ClCOOEt, pyrrolidine and POCl3 in toluene yielding the pyrrolopyridone (IV). Finally, this compound is condensed with pyridine-4-carbaldehyde (V) by means of tetrabutylammonium bisulfate and NaOH in water.

参考文献 中间体
合成目标
【1】 Moslemi, S.; Dallemagne, P.; Enguehard, C.; Sonnet, P.; Séralini, G.-E.; Bureau, R.; Auvray, P.; Sourdaine, P.; Guillon, J.; Rault, S.; MR 20492 and MR 20494: Two indolizinone derivatives that strongly inhibit human aromatase. J Steroid Biochem Mol Biol 1999, 70, 1-3, 59.
【2】 Sonnet, P.; Dallemagne, P.; Guillon, J.; et al.; New aromatase inhibitors. Synthesis and biological activity of aryl-substituted pyrrolizine and indolizine derivatives. Bioorg Med Chem 2000, 8, 5, 945.
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) 36490 4-amino-3-(4-chlorophenyl)butyric acid 1134-47-0 C10H12ClNO2 详情 详情
(II) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(III) 36491 3-(4-chlorophenyl)-4-(1H-pyrrol-1-yl)butyric acid C14H14ClNO2 详情 详情
(IV) 18742 6-(4-chlorophenyl)-6,7-dihydro-8(5H)-indolizinone C14H12ClNO 详情 详情
(V) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情

合成路线15

该中间体在本合成路线中的序号：(V)

Friedel-Crafts acetylation of 4-chlorothioanisole (I) gave acetophenone (II), which was then brominated to afford the corresponding bromoketone (III). Further reaction of (III) with hexamethylenetetramine, followed by acid hydrolysis yielded the aminoketone (IV). The Clauson-Kaas reaction of amine (IV) with 2,5-dimethoxytetrahydrofuran (V) in the presence of AcOH-AcONa provided pyrrole (VI), and then the thioether function of (VI) was oxidized to sulfoxide (VII) with sodium periodate. The subsequent Pummerer cyclization using trifluoroacetic anhydride produced an intermediate tricyclic sulfonium salt (VIII) that, upon losing a methyl group, yielded the pyrrolobenzothiazepine (IX). Reduction of the ketone function of (IX) to alcohol (X) with NaBH4, followed by treatment with PBr3, furnished bromide (XI). Finally, displacement of the bromide of (XI) at 130 C with N-methylpiperazine (XII) provided the title compound, which was isolated as the dihydrochloride salt on treating with methanolic HCl.

参考文献 中间体
合成目标
【1】 Campiani, G.; Nacci, V.; Bechelli, S.; Ciani, S.M.; Garofalo, A.; Fiorini, I.; Wikstrom, H.; de Boer, P.; Liao, Y.; Tepper, P.G.; Cagnotto, A.; Mennini, T.; New antipsychotic agents with serotonin and dopamine antagonist properties based on a pyrrolo[2,1-b][1,3]benzothiazepine structure. J Med Chem 1998, 41, 20, 3763.
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) 20423 4-chlorophenyl methyl sulfide; 1-chloro-4-(methylsulfanyl)benzene 123-09-1 C7H7ClS 详情 详情
(II) 20424 1-[5-chloro-2-(methylsulfanyl)phenyl]-1-ethanone C9H9ClOS 详情 详情
(III) 20425 2-bromo-1-[5-chloro-2-(methylsulfanyl)phenyl]-1-ethanone C9H8BrClOS 详情 详情
(IV) 20426 2-amino-1-[5-chloro-2-(methylsulfanyl)phenyl]-1-ethanone C9H10ClNOS 详情 详情
(V) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(VI) 20428 1-[5-chloro-2-(methylsulfanyl)phenyl]-2-(1H-pyrrol-1-yl)-1-ethanone C13H12ClNOS 详情 详情
(VII) 20429 1-[5-chloro-2-(methylsulfinyl)phenyl]-2-(1H-pyrrol-1-yl)-1-ethanone C13H12ClNO2S 详情 详情
(VIII) 20430 7-chloro-4-methyl-9-oxo-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepin-4-ium C13H11ClNOS 详情 详情
(IX) 20431 7-chloropyrrolo[2,1-b][1,3]benzothiazepin-9(10H)-one C12H8ClNOS 详情 详情
(X) 20432 7-chloro-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepin-9-ol C12H10ClNOS 详情 详情
(XI) 20433 9-bromo-7-chloro-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine C12H9BrClNS 详情 详情
(XII) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线16

该中间体在本合成路线中的序号：(II)

1-(3-Hydroxy-2-pyridyl)pyrrole (III) was prepared by Paal-Knorr condensation of 2-amino-3-hydroxypyridine (I) with 2,5-dimethoxytetrahydrofuran (II). The O-alkylation of (II) with ethyl alpha-bromophenylacetate (IV) in the presence of NaH in THF furnished ether (V). Subsequent saponification of the ethyl ester group of (IV) gave rise to carboxylic acid (VI), that was cyclized to tricyclic ketone (VII) upon treatment with phosphorus pentachloride. Finally, alkylation of the corresponding potassium enolate of (VII) with ethyl iodide yielded the title compound.

参考文献 中间体
合成目标
【1】 Morelli, E.; Campiani, G.; Fabbrini, M.; et al.; Pyrrolobenzoxazepinone derivatives as non-nucleoside HIV-1 RT inhibitors: Further structure-activity relationship studies and identification of more potent broad-spectrum HIV-1 RT inhibitors with antiviral activirty. J Med Chem 1999, 42, 21, 4462.
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) 37086 2-amino-3-pyridinol; 2-Amino-3-hydroxypyridine 16867-03-1 C5H6N2O 详情 详情
(II) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(III) 41979 2-(1H-pyrrol-1-yl)-3-pyridinol C9H8N2O 详情 详情
(IV) 41980 ethyl 2-bromo-2-phenylacetate 2882-19-1 C10H11BrO2 详情 详情
(V) 41981 ethyl 2-phenyl-2-[[2-(1H-pyrrol-1-yl)-3-pyridinyl]oxy]acetate C19H18N2O3 详情 详情
(VI) 41982 2-phenyl-2-[[2-(1H-pyrrol-1-yl)-3-pyridinyl]oxy]acetic acid C17H14N2O3 详情 详情
(VII) 41983 6-phenylpyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazepin-7(6H)-one C17H12N2O2 详情 详情

合成路线17

该中间体在本合成路线中的序号：(II)

The cyclization of the amino group of 4-amino-3-(4-chlorophenyl)butyric acid (I) with 2,5-dimethoxytetrahydrofuran (II) by means of AcOH in THF gives the corresponding pyrrole (III), which is cyclized by means of TEA, ClCOOEt, pyrrolidine and POCl3 in toluene yielding the pyrrolopyridone (IV). Finally, this compound is condensed with pyridine-3-carbaldehyde (V) by means of tetrabutylammonium bisulfate and NaOH in water.

参考文献 中间体
合成目标
【1】 Moslemi, S.; Dallemagne, P.; Enguehard, C.; Sonnet, P.; Séralini, G.-E.; Bureau, R.; Auvray, P.; Sourdaine, P.; Guillon, J.; Rault, S.; MR 20492 and MR 20494: Two indolizinone derivatives that strongly inhibit human aromatase. J Steroid Biochem Mol Biol 1999, 70, 1-3, 59.
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) 36490 4-amino-3-(4-chlorophenyl)butyric acid 1134-47-0 C10H12ClNO2 详情 详情
(II) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(III) 36491 3-(4-chlorophenyl)-4-(1H-pyrrol-1-yl)butyric acid C14H14ClNO2 详情 详情
(IV) 18742 6-(4-chlorophenyl)-6,7-dihydro-8(5H)-indolizinone C14H12ClNO 详情 详情
(V) 12849 Nicotinaldehyde; 3-Pyridinecarboxaldehyde 500-22-1 C6H5NO 详情 详情

合成路线18

该中间体在本合成路线中的序号：(II)

The N-arylpyrrole (III) was prepared by the Clauson-Kaas reaction of 2-nitroaniline (I) with 2,5-dimethoxytetrahydrofuran (II) in AcOH under microwave irradiation. Subsequent reduction of the nitro group of (III) using BiCl3 and NaBH4 provided aniline (IV), which was condensed with cinnamoyl chloride (V) in the presence of pyridine to give the corresponding amide (VI). Cyclization of (VI) using POCl3 and pyridine produced the pyrroloquinoxaline (VII), and further Vilsmeier-Haack formylation gave aldehyde (VIII). This was condensed with boiling 3-(dimethylamino)propylamine (IX), and the resulting imine (X) was finally reduced to the target amine with NaBH4 in MeOH. The title compound was finally converted to the trioxalate salt upon treatment with oxalic acid in isopropanol.

参考文献 中间体
合成目标
【1】 Guillon, J.; Rault, S.; Kervran, A.; Renard, P.; Manechez, D.; Pfeiffer, B.; Dallemagne, P.; Synthesis of new pyrrolo[1,2-a]quinoxalines: Potential non-peptide glucagon receptor antagonists. Eur J Med Chem 1998, 33, 4, 293.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
15713 Oxalic acid 144-62-7 C2H2O4 详情 详情
(I) 11608 o-Nitroaniline; 2-Nitroaniline; 2-Nitrophenylamine 88-74-4 C6H6N2O2 详情 详情
(II) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(III) 31487 1-(2-nitrophenyl)-1H-pyrrole 33265-60-0 C10H8N2O2 详情 详情
(IV) 31488 2-(1H-pyrrol-1-yl)aniline; 2-(1H-pyrrol-1-yl)phenylamine 6025-60-1 C10H10N2 详情 详情
(V) 11303 (E)-3-Phenyl-2-propenoyl chloride; 3-Phenyl-2-propenoyl chloride 102-92-1 C9H7ClO 详情 详情
(VI) 31489 (E)-3-phenyl-N-[2-(1H-pyrrol-1-yl)phenyl]-2-propenamide C19H16N2O 详情 详情
(VII) 31490 4-[(E)-2-phenylethenyl]pyrrolo[1,2-a]quinoxaline C19H14N2 详情 详情
(VIII) 31491 4-[(E)-2-phenylethenyl]pyrrolo[1,2-a]quinoxaline-1-carbaldehyde C20H14N2O 详情 详情
(IX) 25248 N-(3-aminopropyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,3-propanediamine 109-55-7 C5H14N2 详情 详情
(X) 31492 N-[3-(dimethylamino)propyl]-N-((E)-[4-[(E)-2-phenylethenyl]pyrrolo[1,2-a]quinoxalin-1-yl]methylidene)amine; N(1),N(1)-dimethyl-N(3)-((E)-[4-[(E)-2-phenylethenyl]pyrrolo[1,2-a]quinoxalin-1-yl]methylidene)-1,3-propanediamine C25H26N4 详情 详情

合成路线19

该中间体在本合成路线中的序号：(II)

Clauson-Kaas reaction between 2-fluoroaniline (I) and 2,5-dimethoxytetrahydrofuran (II) in refluxing HOAc affords pyrrolic compound (III), which is then converted into cyanopyrrole derivative (IV) through a one-pot sequence involving formylation with oxalyl chloride, oximation with NH2OH.HCl and dehydration with Ac2O. Cyclization of nitrile (IV) by treatment with KOH in ethylene glycol or in tert-butyl alcohol yields quinoxalinone derivative (V), which is then transformed into the hydrazine derivative (VI) by refluxing with POCl3 and catalytic N,N-dimethylaniline followed by treatment with hydrazine in MeOH. Finally, the desired product is obtained by reaction of (VI) with pyrazinecarboxylic acid (VII) in the presence of PPh3 and 2,2'-dipyridyl disulfide (Aldrithiol-2) in CH2Cl2.

参考文献 中间体
合成目标
【2】 Campiani, G.; et al.; Novel and highly potent 5-HT3 receptor agonists based on a pyrroloquinoxaline structure. J Med Chem 1997, 40, 22, 3670.
【1】 Campiani, G.; Fabbrini, M.; Aiello, F.; et al.; Quinoxalinylethylpyridylthioureas (QXPTs) as potent non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors. Further SAR studies and identification of a novel orally bioavailable hydrazine-based antiviral agent. J Med Chem 2001, 44, 3, 305.
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) 22296 2-fluorophenylamine; 2-fluoroaniline 348-54-9 C6H6FN 详情 详情
(II) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(III) 48110 1-(2-fluorophenyl)-1H-pyrrole C10H8FN 详情 详情
(IV) 48111 1-(2-fluorophenyl)-1H-pyrrole-2-carbonitrile C11H7FN2 详情 详情
(V) 48112 pyrrolo[1,2-a]quinoxalin-4(5H)-one C11H8N2O 详情 详情
(VI) 48113 4-hydrazinopyrrolo[1,2-a]quinoxaline C11H10N4 详情 详情
(VII) 37256 2-pyrazinecarboxylic acid; Pyrazinoic acid 98-97-5 C5H4N2O2 详情 详情

合成路线20

该中间体在本合成路线中的序号：(VI)

The title compound has been synthesized by two closely related methods. Claisen condensation of 3,4-dimethoxyphenylacetonitrile (I) with ethyl formate produced the cyano aldehyde sodium enolate (II), which was further O-acylated with benzenesulfonyl chloride to afford (III). The aminothiophene derivative (V) was prepared by cyclization of (III) with methyl thioglycolate (IV) under basic conditions. A pyrrole ring was then introduced in (V) through a Paal-Knorr synthesis employing 2,5-dimethoxytetrahydrofuran (VI) in the presence of 4-chloropyridinium chloride, yielding (VII). Refluxing of ester (VII) in pyrrolidine (VIII) gave rise to amide (IX). The intramolecular cyclization of (IX) under Vilsmeier conditions furnished the tricyclic system (X). Finally, regioselective cleavage of the meta methoxy group of (X) by means of AlCl3 yielded the target compound.

参考文献 中间体
合成目标
【1】 Caignard, D.-H.; Enghehard, C.; Robba, M.; Lancelot, J.-C.; Pierre, A.; Renard, P.; Rault, S.; Atassi, G. (ADIR et Cie.); Derivs. of the 8H-(2,3-b)-pyrrolizine-8-one, process for their preparation and pharmaceutical compsns. containing them. EP 0982308; FR 2781482; JP 2000044572; US 6071945 .
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) 25857 2-(3,4-dimethoxyphenyl)acetonitrile 93-17-4 C10H11NO2 详情 详情
(II) 52226 sodium (Z)-2-cyano-2-(3,4-dimethoxyphenyl)-1-ethenolate C11H10NNaO3 详情 详情
(III) 52227 (Z)-2-cyano-2-(3,4-dimethoxyphenyl)ethenyl benzenesulfonate C17H15NO5S 详情 详情
(IV) 18838 methyl 2-sulfanylacetate 2365-48-2 C3H6O2S 详情 详情
(V) 52228 methyl 3-amino-4-(3,4-dimethoxyphenyl)-2-thiophenecarboxylate C14H15NO4S 详情 详情
(VI) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(VII) 52229 methyl 4-(3,4-dimethoxyphenyl)-3-(1H-pyrrol-1-yl)-2-thiophenecarboxylate C18H17NO4S 详情 详情
(VIII) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情
(IX) 52230 [4-(3,4-dimethoxyphenyl)-3-(1H-pyrrol-1-yl)-2-thienyl](1-pyrrolidinyl)methanone C21H22N2O3S 详情 详情
(X) 52231 3-(3,4-dimethoxyphenyl)-8H-thieno[2,3-b]pyrrolizin-8-one C17H13NO3S 详情 详情

合成路线21

该中间体在本合成路线中的序号：(II)

Condensation of benzyl carbazate (I) with 2,5-dimethoxytetrahydrofuran (II) affords the N-benzyloxycarbonyl aminopyrrole (III). The lithiated derivative of (III) is condensed with (R)-glycidyl butyrate (IV) to furnish the chiral oxazolidinone (V). Alcohol (V) is converted to the corresponding mesylate (VI) with methanesulfonyl chloride and triethylamine. Finally, nucleophilic displacement of mesylate (VI) with sodium methoxide affords the target methyl ether.

参考文献 中间体
合成目标
【1】 Massa, S.; Befani, O.; Esposito, M.; Sbardella, g.; Mai, A.; Turini, P.; Giovannini, V.; Mondovi, B.; 3-(1H-Pyrrol-1-yl)-2-oxazolidinones as reversible, highly potent, and selective inhibitors of monoamine oxidase type A. J Med Chem 2002, 45, 6, 1180.
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) 36108 benzyl 1-hydrazinecarboxylate 5331-43-1 C8H10N2O2 详情 详情
(II) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(III) 57806 benzyl 1H-pyrrol-1-ylcarbamate C12H12N2O2 详情 详情
(IV) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(V) 57807 (5R)-5-(hydroxymethyl)-3-(1H-pyrrol-1-yl)-1,3-oxazolidin-2-one C8H10N2O3 详情 详情
(VI) 57808 [(5R)-2-oxo-3-(1H-pyrrol-1-yl)-1,3-oxazolidin-5-yl]methyl methanesulfonate C9H12N2O5S 详情 详情

合成路线22

该中间体在本合成路线中的序号：(XVIII)

Reaction of 2-aminobenzyl alcohol (I) with acetone in aqueous AcOH affords 2,2-dimethyl-1,4-dihydro-2H-3,1-benzoxazine, which is reduced with LiAlH4 in THF, producing 2-(isopropylamino)benzyl alcohol (II). After oxidation of alcohol (II) to the corresponding benzaldehyde (III) by means of MnO2 in toluene at 117 °C, Knoevenagel condensation with Meldrum’s acid (IV) in the presence of AcOH and ethylenediamine in MeOH gives 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (V) . Chlorination of acid (V) with SOCl2 in toluene at 95 °C and subsequent coupling of the resulting acid chloride with N-Boc-endo-3-aminotropane (VI) in the presence of NaOH in toluene/water affords the corresponding amide (VII). Deprotection of the N-Boc-tropane derivative (VII) by means of TFA in CH2Cl2 furnishes the corresponding amine TFA salt (VIII) (1-9), which is then N-alkylated with 1-chloro-3-(N-Boc-N-methylamino)propan-2(S)-ol (IX) [prepared by condensation of (S)-epichlorohydrin (X) with Nmethylbenzylamine in hexane and subsequent hydrogenolysis of the obtained benzylamine derivative (XI) in the presence of Pd(OH)2/C and Boc2O in EtOAc] in the presence of DIEA in MeOH at 80 °C to give the N-Boc-methylamine derivative (XII). Deprotection of this compound by means of TFA in CH2Cl2 and N-sulfonylation of the obtained free amine (XIII) with methanesulfonyl chloride (XIV) in the presence of DBU in CH2Cl2 then affords velusetrag. Alternatively, reaction of amine (VIII) with N-[(S)-glycidyl]-N-methylmethanesulfonamide (XV) [prepared by alkylation of N-methylmethanesulfonamide (XVI) with (S)-epichlorohydrin (XVII) using aqueous NaOH] in the presence of NaOH in MeOH yields velusetrag . N-Boc-endo-3-aminotropane (VI) is prepared by hydrolysis of 2,5-dimethoxytetrahydrofuran (XVIII) with aqueous HCl, followed by Mannich reaction of the resulting succinaldehyde with BnNH2 and 1,3-acetonedicarboxylic acid (XIX) in the presence of HCl in H2O to give N-benzyl-8-azabicyclo[3.2.1]octan-3-one (XX). Treatment of this compound with H2 over Pd(OH)2/C and Boc2O in EtOAc yields N-Boc-8-azabicyclo[3.2.1]octan-3-one (XXI), which is then converted to the desired amine (VI) by reductive amination with HCOONH4 in the presence of Pd/C in MeOH/H2O .
Velusetrag can be converted to its salts, including hydrochloride, citrate,adipate, phosphate, sulfate, tartrate, malate, hydrobromide and mesylate, by treatment with the respective acids .

参考文献 中间体
合成目标
【1】 Marquess, D., Fatheree, P.R., Turner, D.S., Long, D.D., Choi, S.-K., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4 receptor agonists. EP 1735304, JP 2007535546, JP 2008174569, US 2005228014, US 2007281970, US 7375114, US 7728006, WO 2005100350.
【2】 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4 receptor agonists. US 2007270457, US 7592355.
【3】 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4, receptor agonists. US 2008176895, US 7763637.
【4】 Choi, S.-K., Fatheree, P., Goldblum, A.A., Jiang, L., Long, D.D., Marquess, D., Turner, S.D. (Theravance, Inc.). 5-HT4 receptor agonist compounds. US 2008255187, US 7534889.
【5】 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S.-K., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4 receptor agonists. US 2010285519.
【6】 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S.-K., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolone-carboxamide compounds as 5-HT4 receptor agonists. US 2010311979.
【7】 Choi, S.-K., Fatheree, P., Goldblum, A.A., Jiang, L., Long, D.D., Marquess, D., Turner, S.D. (Theravance, Inc.). 5-HT4 receptor agonist compounds. EP 1807422, JP 2008518965, US 2006100236, US 7399862, WO 2006052640.
【8】 Fatheree, P.R., Turner, S.D., Goldblum, A., Chao, R., Genov, D. (Theravance, Inc.). Crystalline form of a quinolinone-carboxamide compound. EP 1874766, JP 2008535848, US 2006229332, US 7728004, WO 2006108127.
【9】 Genov, D., Lee, J., Liu, J. (Theravance, Inc.). Process for preparing intermediates to 5-HT4 receptor agonist compounds. EP 1984362, JP 2009526852, US 2007191355, WO 2007097976.
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) 18619 (2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol 5344-90-1 C7H9NO 详情 详情
(II) 36334 [2-(isopropylamino)phenyl]methanol；2-(isopropylamino)benzyl alcohol;(2-(isopropylamino)phenyl)methanol C10H15NO 详情 详情
(III) 36335 2-(isopropylamino)benzaldehyde C10H13NO 详情 详情
(IV) 14738 Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester 2033-24-1 C6H8O4 详情 详情
(V) 36333 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid C13H13NO3 详情 详情
(VI) 68799 (1R,3r,5R)-tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate C12H22N2O2 详情 详情
(VII) 68803 (1R,3R)-tert-butyl 3-(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylate C25H33N3O4 详情 详情
(VIII) 68804 N-((1R,3R)-8-azabicyclo[3.2.1]octan-3-yl)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide 2,2,2-trifluoroacetate C20H25N3O2.C2HF3O2 详情 详情
(IX) 68807 1-chloro-3-(N-Boc-N-methylamino)propan-2(S)-ol;(S)-tert-butyl (3-chloro-2-hydroxypropyl)(methyl)carbamate C9H18ClNO3 详情 详情
(X) 13917 (S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin 67843-74-7 C3H5ClO 详情 详情
(XI) 68808 (S)-1-(benzyl(methyl)amino)-3-chloropropan-2-ol C11H16ClNO 详情 详情
(XII) 68805 tert-butyl ((S)-2-hydroxy-3-((1R,3R,5S)-3-(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)-8-azabicyclo[3.2.1]octan-8-yl)propyl)(methyl)carbamate C29H42N4O5 详情 详情
(XIII) 68806 N-((1R,3R,5S)-8-((R)-2-hydroxy-3-(methylamino)propyl)-8-azabicyclo[3.2.1]octan-3-yl)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide 2,2,2-trifluoroacetate C24H34N4O3.C2HF3O2 详情 详情
(XIV) 13467 Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride 124-63-0 CH3ClO2S 详情 详情
(XV) 68802 N-[(S)-glycidyl]-N-methylmethanesulfonamide;(S)-N-methyl-N-(oxiran-2-ylmethyl)methanesulfonamide C5H11NO3S 详情 详情
(XVI) 67859 N-methylmethanesulfonamide 1184-85-6 C2H7NO2S 详情 详情
(XVII) 13917 (S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin 67843-74-7 C3H5ClO 详情 详情
(XVIII) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(XIX) 15530 1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid 542-05-2 C5H6O5 详情 详情
(XX) 68801 (1R,5R)-8-benzyl-8-azabicyclo[3.2.1]octan-3-one;N-benzyl-8-azabicyclo[3.2.1]octan-3-one C14H17NO 详情 详情
(XXI) 68800 N-Boc-8-azabicyclo[3.2.1]octan-3-one C12H19NO3 详情 详情
Extended Information