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【结 构 式】 
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【分子编号】26093 【品名】2-Furoyl chloride 【CA登记号】527-69-5 |
【 分 子 式 】C5H3ClO2 【 分 子 量 】130.53032 【元素组成】C 46.01% H 2.32% Cl 27.16% O 24.51% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of furoyl chloride (I) with piperazine (II) by means of NaOH in water gives N-(2-furoyl)piperazin (III), which is reduced with H2 over Raney-Ni in methanol to afford N-(tetrahydro-2-furoyl)piperazine (IV) . Finally, this compound is condensed with 2-chloro-4-amino-6,7-dimethoxyquinazoline (V) in refluxing methoxyethanol.
| 【1】 Winn, M.; Kyncl, J.; Dunnigan, D.A.; Jones, P.H. (Abbott Laboratories Inc.); Antihypertensive agents. CA 1057754; CH 602712; DE 2646186; FR 2327787; GB 1517403; JP 52048678; US 4026894; US 4112097 . |
| 【2】 Roteman, R. (Abbott Laboratories Inc.); 1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-tetrahydrofuroyl)piperazine hydrochloride dihydrate. CA 1081229; DE 2831112; FR 2399430; JP 54027588 . |
| 【3】 Thorpe, P.; Castaner, J.; Serradell, M.N.; Blancafort, P.; Terazosin Hydrochloride. Drugs Fut 1983, 8, 1, 45. |
| 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) | 26093 | 2-Furoyl chloride | 527-69-5 | C5H3ClO2 | 详情 | 详情 |
| (II) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (III) | 30751 | 2-furyl(1-piperazinyl)methanone; 2-Furoyl-1-piperazine | 40172-95-0 | C9H12N2O2 | 详情 | 详情 |
| (IV) | 30752 | 1-piperazinyl(tetrahydro-2-furanyl)methanone; 1-(Tetrahydro-2-furoyl)piperazine | 63074-07-7 | C9H16N2O2 | 详情 | 详情 |
| (V) | 10443 | 2-Chloro-6,7-dimethoxy-4-quinazolinamine; 4-Amino-2-chloro-6,7-dimethoxyquinazoline; 2-Chloro-6,7-dimethoxy-4-quinazolinylamine | 23680-84-4 | C10H10ClN3O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)By esterification of mometasone (I) with 2-furoyl chloride (II) by means of TEA in dichloromethane.
| 【1】 Heggie, W.; Bandarra, J. (Hovione Sociedade Quimica SA); Process for the preparation of mometasone furoate. EP 1074558; JP 2001048897 . |
合成路线3
该中间体在本合成路线中的序号：(IV)The reaction of 9beta,11beta-epoxy-17alpha,21-dihydroxy-16alpha-methyl-1,4-pregnadiene-3,20-dione (I) with MsCl in pyridine gives the corresponding 21-mesylate (II), which is treated with LiCl in the same solvent to yield 21-chloro-9beta,11beta-epoxy-17alpha-hydroxy-16alpha-methyl-1,4-pregnadiene-3,20-dione (III). The esterification of (III) with 2-furoyl chloride (IV) and TEA affords the expected ester (IV), which is finally treated with anhydrous HCl in acetic acid in order to open the epoxide ring to provide the target mometasone furoate. A similar reaction sequence can be performed using p-toluenesulfonyl chloride instead of mesyl chloride in the first step of the sequence.
| 【1】 Shapiro, E.L. (Schering Corp.); 3,20-Dioxo-1,4-pregnanediene-17alpha-ol 17-aromatic heterocycle carboxylates. EP 0057401; US 4472393 . |
| 【2】 Tann, C.-H.; Tsai, D.J.S.; Kwok, D.-I.; Fu, X. (Schering Corp.); Process for the preparation of 17-esters of 9alpha,21-dihalo-pregnane-11beta,17alpha-diol-20-ones. WO 9800437 . |
| 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) | 45430 | (4aS,4bS,5aS,6aS,7R,8R)-7-glycoloyl-7-hydroxy-4a,6a,8-trimethyl-5a,6,6a,7,8,9,9a,9b,10,11-decahydrocyclopenta[7,8]phenanthro[4b,5-b]oxiren-2(4aH)-one | C22H28O5 | 详情 | 详情 | |
| (II) | 45431 | (4aS,4bS,5aS,6aS,7R,8R)-7-hydroxy-4a,6a,8-trimethyl-7-(2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]acetyl)-5a,6,6a,7,8,9,9a,9b,10,11-decahydrocyclopenta[7,8]phenanthro[4b,5-b]oxiren-2(4aH)-one | C25H34O5S | 详情 | 详情 | |
| (III) | 45432 | (4aS,4bS,5aS,6aS,7R,8R)-7-(2-chloroacetyl)-7-hydroxy-4a,6a,8-trimethyl-5a,6,6a,7,8,9,9a,9b,10,11-decahydrocyclopenta[7,8]phenanthro[4b,5-b]oxiren-2(4aH)-one | C22H27ClO4 | 详情 | 详情 | |
| (IV) | 26093 | 2-Furoyl chloride | 527-69-5 | C5H3ClO2 | 详情 | 详情 |
| (V) | 45433 | (4aS,4bS,5aS,6aS,7R,8R)-7-(2-chloroacetyl)-4a,6a,8-trimethyl-2-oxo-2,4a,5a,6,6a,7,8,9,9a,9b,10,11-dodecahydrocyclopenta[7,8]phenanthro[4b,5-b]oxiren-7-yl 2-furoate | 103213-32-7 | C27H29ClO6 | 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 esterification of 21-chloro-17alpha-hydroxy-16alpha-methyl-1,4,9(11)-pregnatriene-3,20-dione (I) with 2-furoyl chloride (II) by means of TEA gives the corresponding ester (III), which is then treated with HClO4 and 1,3-dichloro-5,5-dimethylhydantoin (DDH) in THF/water in order to add Cl-OH to the 9(11)-double bond of ester (III).
| 【1】 Shapiro, E.L. (Schering Corp.); 3,20-Dioxo-1,4-pregnanediene-17alpha-ol 17-aromatic heterocycle carboxylates. EP 0057401; US 4472393 . |
| 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) | 45434 | (10R,13S,16R,17R)-17-(2-chloroacetyl)-17-hydroxy-10,13,16-trimethyl-6,7,8,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-3-one | C22H27ClO3 | 详情 | 详情 | |
| (II) | 26093 | 2-Furoyl chloride | 527-69-5 | C5H3ClO2 | 详情 | 详情 |
| (III) | 45435 | (10R,13S,16R,17R)-17-(2-chloroacetyl)-10,13,16-trimethyl-3-oxo-6,7,8,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl 2-furoate | 83880-65-3 | C27H29ClO5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：4-Amino-1-phenethylpiperidine (I) is stirred with chloropyrazine (II) and copper powder in phenyl ether at 170-175 C to obtain 1-phenethyl-4-[N-(pyrazinyl)amino]piperidine (III). Subsequent acylation of (III) with 2-furoyl chloride in 1,2-dichloroethane yields mirfentanil as the hydrochloride salt after cooling and filtration. Further purification is achieved by recrystallization from n-propanol.
| 【1】 Bagley, J.R.; Doorley, B.M.; Ossipov, M.H.; Knight, V.V.; Jerussi, T.P.; Benvenga, M.J.; Wilhelm, J.A.; Waters, S.J.; Spaulding, T.C.; Wynn, R.L.; Rudo, F.G.; Glass, P.S.A.; MIRFENTANIL HYDROCHLORIDE. Drugs Fut 1990, 15, 8, 798. |
| 【2】 Bagley, J.R.; Wynn, R.L.; Rudo, F.G.; Doorley, B.M.; Spender, H.K.; Spaulding, T.; New 4-(heteroanilido)-piperidines structurally related to the pure opioid agonist, fentanyl, with agonist and/or antagonist properties. J Med Chem 1989, 32, 3, 663-671. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 26093 | 2-Furoyl chloride | 527-69-5 | C5H3ClO2 | 详情 | 详情 | |
| (I) | 31167 | 1-phenethyl-4-piperidinylamine; 1-phenethyl-4-piperidinamine; N-(Phenethyl)-4-aminopiperidine | 51448-56-7 | C13H20N2 | 详情 | 详情 |
| (II) | 24075 | 2-chloropyrazine | 14508-49-7 | C4H3ClN2 | 详情 | 详情 |
| (III) | 31168 | N-(1-phenethyl-4-piperidinyl)-N-(2-pyrazinyl)amine; N-(1-phenethyl-4-piperidinyl)-2-pyrazinamine | C17H22N4 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)The monoacylation of disulfide (I) with 2-furylcarbonyl chloride (II) by means of 48% HBr in ethanol/water at 80 C gives the monoamide (III), which is then condensed with 2-chloro-6,7-dimethoxyquinazoline-4-amine (IV) in refluxing isoamyl alcohol.
| 【1】 Minarini, A.; Budriesi, R.; Chiarini, A.; Leonardi, A.; Melchiorre, C.; Search for alpha1-adrenoceptor subtypes selective antagonists: Design, synthesis and biological activity of cystazosin, an alpha1D-adrenoceptor antagonist. Bioorg Med Chem Lett 1998, 8, 11, 1353. |
| 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) | 26092 | N-methyl-2-[[2-(methylamino)ethyl]disulfanyl]-1-ethanamine; N-methyl-N-(2-[[2-(methylamino)ethyl]disulfanyl]ethyl)amine | C6H16N2S2 | 详情 | 详情 | |
| (II) | 26093 | 2-Furoyl chloride | 527-69-5 | C5H3ClO2 | 详情 | 详情 |
| (III) | 26094 | N-methyl-N-(2-[[2-(methylamino)ethyl]disulfanyl]ethyl)-2-furamide | C11H18N2O2S2 | 详情 | 详情 | |
| (IV) | 10143 | benzyl (2S)-2-aminopropanoate | C10H13NO2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)Cystamine (I) was acylated with 2-furoyl chloride (II) in the presence of a catalytic amount of HBr to give amide (III). This was then condensed with chloroquinazoline (IV) in refluxing isoamyl alcohol to yield the title compound.
| 【1】 Minarini, A.; Budriesi, R.; Chiarini, A.; Leonardi, A.; Melchiorre, C.; Search for alpha1-adrenoceptor subtypes selective antagonists: Design, synthesis and biological activity of cystazosin, an alpha1D-adrenoceptor antagonist. Bioorg Med Chem Lett 1998, 8, 11, 1353. |
| 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) | 27502 | 2-[(2-aminoethyl)disulfanyl]-1-ethanamine | 56-17-7 | C4H12N2S2 | 详情 | 详情 |
| (II) | 26093 | 2-Furoyl chloride | 527-69-5 | C5H3ClO2 | 详情 | 详情 |
| (III) | 27503 | N-[2-[(2-aminoethyl)disulfanyl]ethyl]-2-furamide | C9H14N2O2S2 | 详情 | 详情 | |
| (IV) | 10443 | 2-Chloro-6,7-dimethoxy-4-quinazolinamine; 4-Amino-2-chloro-6,7-dimethoxyquinazoline; 2-Chloro-6,7-dimethoxy-4-quinazolinylamine | 23680-84-4 | C10H10ClN3O2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(V)The reaction of 4-hydroxybenzaldehyde (I) with cyanacetic acid (II) by means of pyridine in toluene gives the 3-(4-hydroxyphenyl)propenenitrile (III), which by reaction first with methanolic HCl and then with methanolic ammonia is converted into the amidine (IV). Finally, this compound is condensed with 2-furylcarbonyl chloride (V) in pyridine and treated with methanesulfonic acid to afford the target sulfonate.
| 【1】 Niwas, S.; Moore, R.; Kilpatrick, J.M.; Babu, Y.S.; Johnson, H.; Kellogg, D.; Development of novel inhibitors of complement and coagulation serine proteases. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 088. |
| 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) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (II) | 12591 | Cyanoacetic Acid; 2-Cyanoacetic acid | 372-09-8 | C3H3NO2 | 详情 | 详情 |
| (III) | 27819 | (E)-3-(4-hydroxyphenyl)-2-propenenitrile | C9H7NO | 详情 | 详情 | |
| (IV) | 27820 | (E)-3-(4-hydroxyphenyl)-2-propenimidamide | C9H10N2O | 详情 | 详情 | |
| (V) | 26093 | 2-Furoyl chloride | 527-69-5 | C5H3ClO2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(V)The acylation of (E)-3-(4-hydroxyphenyl)-2-propenamide (VI) with acetic anhydride gives the 4[(E)-3-amino-3-oxo-1-propenyl]phenyl acetate (VII), which by reaction first with BF3 ethearate and then with ammonia is converted into the amidine (IV). Finally, this compound is condensed with 2-furylcarbonyl chloride (V) in pyridine and treated with methanesulfonic acid to afford the target sulfonate.
| 【1】 Niwas, S.; Moore, R.; Kilpatrick, J.M.; Babu, Y.S.; Johnson, H.; Kellogg, D.; Development of novel inhibitors of complement and coagulation serine proteases. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 088. |
合成路线10
该中间体在本合成路线中的序号：(X)Acidic cleavage of the N-Boc group of (VIII) furnishes amine (IX). Finally, acylation of (IX) with 2-furoyl chloride (X) leads to the title compound. (1,2)
| 【1】 Curtis, M.P.; Dwight, W.; Fox, G.B.; Esbenshade, T.A.; Pan, J-B.; Bennani, Y.L.; Hancock, A.A.; Faghih, R.; A-320436: Potent human non-imidazole histamine H3 receptor antagonist. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 240. |
| 【2】 Black, L.A.; Faghih, R.; Bennani, Y.L.; Liu, H.; Zhang, H.Q.; Dwight, W.J.; Gentles, R.G.; Phelan, K.M.; Vasudevan, A. (Abbott Laboratories Inc.); Cyclic and bicyclic diamino histamine-3 receptor antagonists. WO 0166534 . |
| 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) | 64055 | 1,1-dimethylethyl 2-(4-{3-[(4'-cyano[1,1'-biphenyl]-4-yl)oxy]propyl}-1,4-diazepan-1-yl)-2-oxo-1-(1,3-thiazol-4-ylmethyl)ethylcarbamate | C32H39N5O4S | 详情 | 详情 | |
| (IX) | 64056 | 4'-[(3-{4-[2-amino-3-(1,3-thiazol-4-yl)propanoyl]-1,4-diazepan-1-yl}propyl)oxy][1,1'-biphenyl]-4-carbonitrile | C27H31N5O2S | 详情 | 详情 | |
| (X) | 26093 | 2-Furoyl chloride | 527-69-5 | C5H3ClO2 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(X)Intramolecular cyclization of p-hydroxy-4-chlorobutyrophenone (I) under alkaline conditions yields cyclopropyl(4-hydroxyphenyl) ketone (II). The phenolic hydroxyl group is then alkylated by 1-bromo-3-chloropropane (III) to furnish the chloropropyl ether (IV). Subsequent condensation of alkyl chloride (IV) with piperazine (V) gives rise to the N-substituted piperazine (VI). This is then coupled with N-Boc-L-alanine (VII) in the presence of EDC/DMAP to afford amide (VIII) (1, 2). After acidic cleavage of the N-Boc protecting group, the resultant monosubstituted piperazine (IX) is acylated by furanoyl chloride (X) to furnish the target furamide derivative
| 【1】 Black, L.A.; Faghih, R.; Liu, H.; et al.; Acyl-D-alanine amides: Selective histamine H3 receptor antagonists. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 323. |
| 【2】 Black, L.A.; Faghih, R.; Bennani, Y.L.; Liu, H.; Zhang, H.Q.; Dwight, W.J.; Gentles, R.G.; Phelan, K.M.; Vasudevan, A. (Abbott Laboratories Inc.); Cyclic and bicyclic diamino histamine-3 receptor antagonists. WO 0166534 . |
| 【3】 Black, L.A.; Faghih, R.; Bennani, Y.L.; Liu, H.; Zhang, H.Q.; Dwight, W.J.; Gentles, R.G.; Phelan, K.M.; Vasudevan, A. (Abbott Laboratories Inc.); Cyclic and bicyclic diamino histamine-3 receptor antagonists. US 2001049367; US 6559140 . |
| 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) | 62995 | C10H11ClO2 | 详情 | 详情 | ||
| (II) | 27425 | cyclopropyl(4-hydroxyphenyl)methanone | C10H10O2 | 详情 | 详情 | |
| (III) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (IV) | 62988 | 5-bromo-N-(1H-imidazol-2-yl)-6-quinoxalinamine; N-(5-bromo-6-quinoxalinyl)-N-(1H-imidazol-2-yl)amine | C11H8BrN5 | 详情 | 详情 | |
| (V) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (VI) | 62996 | C17H24N2O2 | 详情 | 详情 | ||
| (VII) | 15859 | Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid | 7764-95-6 | C8H15NO4 | 详情 | 详情 |
| (VIII) | 63042 | C28H23ClN2O2 | 详情 | 详情 | ||
| (IX) | 63043 | C17H15ClN2O2 | 详情 | 详情 | ||
| (X) | 26093 | 2-Furoyl chloride | 527-69-5 | C5H3ClO2 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(III)The starting 6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylic acid (I) is converted to the analogous carbothioic acid (II) via activation with carbonyl diimidazole, followed by reaction with hydrogen sulfide gas (1). The α-hydroxyl group of (II) is then selectively acylated with 2-furoyl chloride (III) to give the 17-furoate ester (IV) (2, 3). Finally, condensation of thioacid (IV) with bromofluoromethane under basic conditions provides the target fluoromethyl thioester (2-4).
| 【1】 Phillipps, G.H., Bain, B.M., Williamson, C., Steeples, I.P., Laing, S.B. (Glaxo Group, Ltd.). Androstane 17β-carbothioates. GB 2088877. |
| 【2】 Biggadike, K., Jones, P., Payne, J.J. (Glaxo Group, Ltd.). 17beta-Carbothioate 17alpha-arylcarbonyloxyoxy androstane derivative as anti-inflammatory agents. EP 1305330, JP 2004505990, US 6537983, US 2003045512, WO 0212266. |
| 【3】 Biggadike, K., Coote, S.J., Noga, B., Van Oort, M.M. (Glaxo Group, Ltd.). Amorphous fluticasone 2-furoate, pharmaceutical compositions thereof and its conversion to the crystalline unsolvated form. EP 1480996, JP 2005522442, US 2005152845, WO 03066655. |
| 【4】 Partridge, J.J., Walker, D.S. (SmithKline Beecham Corp.). A method for preparing fluticasone derivatives. WO 03013427. 5. Prous Science Disease Briefings: Allergic Rhinitis (online publication). Updated 2007. |
| 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) | 14476 | (6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic acid | C21H26F2O5 | 详情 | 详情 | |
| (II) | 14481 | (6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carbothioic S-acid | C21H26F2O4S | 详情 | 详情 | |
| (III) | 26093 | 2-Furoyl chloride | 527-69-5 | C5H3ClO2 | 详情 | 详情 |
| (IV) | 65207 | (6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11-hydroxy-17-furoyloxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carbothioic S-acid | C26H26F2O6S | 详情 | 详情 |