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【结 构 式】 
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【分子编号】33862 【品名】trifluoroacetic anhydride 【CA登记号】407-25-0 |
【 分 子 式 】C4F6O3 【 分 子 量 】210.0326192 【元素组成】C 22.87% F 54.27% O 22.85% |
合成路线1
该中间体在本合成路线中的序号：(B)The condensation of 7-methoxy-3,4-dihydro-1(2H)-naphthalenone (I) with tetramethylene dibromide (A) by means of NaH in benzene gives 3,4-dihydro-7-methoxy-2,2-tetramethylene-1(2H)-naphthalenone (II), b.p.(0.05) = 120-3 C, which is treated with acetonitrile and butyllithium in THF yielding 1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2,2-tetramethylene-1-naphthaleneacetonitrile (III), m.p. 140-2 C. This compound is reduced with LiAlH4 in THF to afford hydro-2,2-tetramethylene-1-naphthol (IV), m.p 178-80 C, and isomerized to 4a-(2-aminoethyl)-1,2,3,4,4a,9-hexahydro-6-methoxy-phenantrene (V), m.p. 187 C. This amine is cyclized by reaction with bromine in CHCl3 giving 3-methoxy-9a-bromonrhasybanan hydrobromide (VI), m.p. 207.0-8.5 C (decomp.), and isomerized with dehydrobromination by treatment with NaHCO3 in DMF affording 3-methoxy-DELTA(8,14)-morphinan (VII), m.p. 180-4 C. The acetylation of (VII) with trifluoroacetic anhydride (B) yields 3-methoxy-N-trifluoroacetyl-DELTA(8,14)-morphinan (VIII), m.p. 94-6 C, which is epoxidized with m-chloroperbenzoic acid in methylene chloride giving 8,14-epoxy-3-methoxy-N-trifluoroacetylmorphinan (IX), m.p. 102-5 C. The deacetylation of (IX) with NaSH4 in ethanol gives 8,14-epoxy-3-methoxymorphinan (X), oily product that is treated with LiAlH4 in THF to open the epoxide ring and yield 14-hydroxy-3-methoxymorphinan (XI) (HCl salt, m.p. 243-4 C (decomp.)). The condensation of (Xl) with cyclobutylcarbonyl chloride (C) by means of pyridine in CH2Cl2 affords N-cyclobutylcarbonyl-14-hydroxy-3-methoxymorphinan (XII), m.p. 183-5 C, which is reduced with LiAlH4 in refluxing THF giving N-cyclobutylmethyl-14-hydroxy-3-methoxymorphinan (XIII) (HCl salt, mp. 248-50 C (decomp.)). Finally, (XIII) is demethylated by treatment with refluxing 48% HBr.
| 【1】 Conway, T.T.; Monkovic, I.; J Am Chem Soc 1973, 95, 23, 7910-12. |
| 【2】 Pachter, I.; et al.; 14-Hydroxymorphinan derivatives. DE 2243961; FR 2154481; GB 1412129; GB 1412130; US 3819635 . |
| 【3】 Monkovic, I.; Conway, T.T.; Process for the preparation of 14-hydroxymorphinan derivatives. JP 49061169; NL 7306344; US 3775414 . |
| 【4】 Paton, D.M.; Castaner, J.; Butorphanol. Drugs Fut 1977, 2, 4, 231. |
| 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) | 11883 | 1,4-Dibromobutane; 1,4-Butylene bromide | 110-52-1 | C4H8Br2 | 详情 | 详情 |
| (B) | 33862 | trifluoroacetic anhydride | 407-25-0 | C4F6O3 | 详情 | 详情 |
| (I) | 21385 | 7-methoxy-3,4-dihydro-1(2H)-naphthalenone | 6836-19-7 | C11H12O2 | 详情 | 详情 |
| (II) | 33856 | C15H18O2 | 详情 | 详情 | ||
| (III) | 33857 | RCL R15,507-1 | C17H21NO2 | 详情 | 详情 | |
| (IV) | 33858 | C17H25NO2 | 详情 | 详情 | ||
| (V) | 33859 | 2-[6-methoxy-1,3,4,9-tetrahydro-4(2H)-phenanthrenyl]ethylamine; 2-[6-methoxy-1,3,4,9-tetrahydro-4(2H)-phenanthrenyl]-1-ethanamine | C17H23NO | 详情 | 详情 | |
| (VI) | 33860 | C17H22BrNO | 详情 | 详情 | ||
| (VII) | 33861 | (1S,9R)-4-methoxy-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6,10-tetraene; (1S,9R)-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6,10-tetraen-4-yl methyl ether | C17H21NO | 详情 | 详情 | |
| (VIII) | 33863 | 2,2,2-trifluoro-1-[(1S,9R)-4-methoxy-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6,10-tetraen-17-yl]-1-ethanone | C19H20F3NO2 | 详情 | 详情 | |
| (IX) | 33864 | 2,2,2-trifluoro-1-[(1S,9R,10S,12S)-4-methoxy-11-oxa-18-azapentacyclo[7.6.3.0(1,10).0(2,7).0(10,12)]octadeca-2,4,6-trien-18-yl]-1-ethanone | C19H20F3NO3 | 详情 | 详情 | |
| (X) | 33865 | (1S,9R,10S,12S)-4-methoxy-11-oxa-18-azapentacyclo[7.6.3.0(1,10).0(2,7).0(10,12)]octadeca-2,4,6-triene; methyl (1S,9R,10S,12S)-11-oxa-18-azapentacyclo[7.6.3.0(1,10).0(2,7).0(10,12)]octadeca-2,4,6-trien-4-yl ether | C17H21NO2 | 详情 | 详情 | |
| (XI) | 33866 | (1S,9R,10S)-4-methoxy-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6-trien-10-ol | C17H23NO2 | 详情 | 详情 | |
| (XII) | 33867 | cyclobutyl[(1S,9R,10S)-10-hydroxy-4-methoxy-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6-trien-17-yl]methanone | C22H29NO3 | 详情 | 详情 | |
| (XIII) | 33868 | (1S,9R,10S)-17-(cyclobutylmethyl)-4-methoxy-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6-trien-10-ol | C22H31NO2 | 详情 | 详情 | |
| (C) | 18589 | cyclobutanecarbonyl chloride | 5006-22-4 | C5H7ClO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：Treatment of 2-methyl-3-butyn-2-ol (I) with trifluoroacetic anhydride and DBU gave trifluoroacetate (II), which was condensed with 4-bromophenol (III) in the presence of CuCl2 to afford propargyl ether (IV). Cyclization of (IV) in N,N-diethylaniline at 185 C produced benzopyran (V). The required sulfonyl group was introduced in (V) by lithium-bromine exchange, followed by reaction with sulfur dioxide to give the lithium sulfinate (VI), and then oxidation to the sulfonyl chloride (VII) by means of sulfuryl chloride (1). Subsequent treatment of (VII) with diisobutylamine yielded sulfonamide (VIII). Asymmetric epoxidation of (VIII) using sodium hypochlorite and (S,S)(+)-N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamino-manganese(III) chloride (Jacobsen's catalyst) gave rise to epoxide (IX), which was opened with ammonium hydroxide to furnish the trans aminoalcohol (X). Finally, coupling of (X) with N-chlorophenyl-N'-cyanothiourea (XI) in the presence of EDC provided the title cyanoguanidine derivative.
| 【1】 Grover, G.J.; Ding, C.Z.; Miller, A.V.; Rovnyak, G.C.; Ahmed, S.Z.; Misra, R.N.; Normandin, D.E.; Atwal, K.S.; Kelly, Y.; Sleph, P.G.; Cardioselective antiischemic ATP-sensitive potassium channel (KATP) openers. 6. Effect of modifications at C6 of benzopyranyl cyanoguanidines. J Med Chem 1999, 42, 18, 3711. |
| 【2】 Ding, C.Z.; Atwal, K.S. (Bristol-Myers Squibb Co.); Sulfonamido substd. benzopyran potassium channel activators. CA 2178353; EP 0747374; JP 1997003035; US 5869478 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 33862 | trifluoroacetic anhydride | 407-25-0 | C4F6O3 | 详情 | 详情 | |
| (I) | 17922 | 2-methyl-3-butyn-2-ol; 3-Methyl butynol | 115-19-5 | C5H8O | 详情 | 详情 |
| (II) | 34888 | 1,1-dimethyl-2-propynyl 2,2,2-trifluoroacetate | C7H7F3O2 | 详情 | 详情 | |
| (III) | 25313 | 4-bromophenol | 106-41-2 | C6H5BrO | 详情 | 详情 |
| (IV) | 34889 | 1-bromo-4-[(1,1-dimethyl-2-propynyl)oxy]benzene; 4-bromophenyl 1,1-dimethyl-2-propynyl ether | C11H11BrO | 详情 | 详情 | |
| (V) | 34890 | 6-bromo-2,2-dimethyl-2H-chromene | C11H11BrO | 详情 | 详情 | |
| (VI) | 34891 | lithium 2,2-dimethyl-2H-chromene-6-sulfinate | C11H11LiO3S | 详情 | 详情 | |
| (VII) | 34892 | 2,2-dimethyl-2H-chromene-6-sulfonyl chloride | C11H11ClO3S | 详情 | 详情 | |
| (VIII) | 34893 | N,N-diisobutyl-2,2-dimethyl-2H-chromene-6-sulfonamide | C19H29NO3S | 详情 | 详情 | |
| (IX) | 34894 | (1aS,7bS)-N,N-diisobutyl-2,2-dimethyl-1a,7b-dihydro-2H-oxireno[2,3-c]chromene-6-sulfonamide | C19H29NO4S | 详情 | 详情 | |
| (X) | 34895 | (3S,4R)-4-amino-3-hydroxy-N,N-diisobutyl-2,2-dimethyl-3,4-dihydro-2H-chromene-6-sulfonamide | C19H32N2O4S | 详情 | 详情 | |
| (XI) | 34896 | N-(4-chlorophenyl)-N'-cyanothiourea | C8H6ClN3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)Introduction of a Boc protecting group on derivative (I) by treatment with tert-butyldicarbonate and DMAP in dioxane affords 5-N-Boc derivative (II), which is then deacetylated by reaction with NaOMe in MeOH to provide compound (III). Conversion of trihydroxy derivative (III) into carboxylic acid (IV) is performed by first oxidation with sodium periodate in MeOH/H2O followed by treatment with sodium chlorite/potassium dihydrogen orthophosphate in tert-BuOH. Coupling of (IV) with secondary amine (V) by means of TBTU in THF yields phenethylpropyl carbamoyl derivative (VI), whose Boc group is removed by means of HCl in dioxane to give primary amine (VII). Condensation of (VII) with trifluoroacetic anhydride (VIII) in pyridine furnishes trifluoroacetylamino derivative (IX), whose azide group is reduced by means of PPh3 and Et3N in THF/H2O to yield 4-amino derivative (X). Finally, the desired product is obtained by saponification of the methyl ester group of (X) by heating with Et3N in H2O.
| 【1】 Smith, P.W.; et al.; Synthesis and influenza virus sialidase inhibitory activity of analogues of 4-guanidino-Neu5Ac2en (GG167) with modified 5-substituents. Eur J Med Chem 1996, 31, 2, 143. |
| 【2】 Fulton, H.E.; Jack, T.I.; Coomber, B.A.; Colman, P.; Wonacott, A.J.; Varghese, J.; Evans, D.N.; Wyatt, P.G.; Sialidase inhibitors related to zanamivir. Further SAR studies of 4-amino-4H-pyran-2-carboxylic acid-6-propylamides. Bioorg Med Chem Lett 2001, 11, 5, 669. |
| 【3】 Smith, P.; Sollis, S.; Cherry, P.; Howes, P. (Biota Scientific Management Pty Ltd.); 6-Carboxamido dihydropyran derivs.. US 5990156; WO 9636628 . |
| 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) | 15979 | methyl (2R,3R,4S)-3-(acetamido)-4-azido-2-[(1S,2R)-1,2,3-tris(acetoxy)propyl]-3,4-dihydro-2H-pyran-6-carboxylate | C18H24N4O10 | 详情 | 详情 | |
| (II) | 50043 | methyl (2R,3R,4S)-3-[acetyl(tert-butoxycarbonyl)amino]-4-azido-2-[(1S,2R)-1,2,3-tris(acetoxy)propyl]-3,4-dihydro-2H-pyran-6-carboxylate | C23H32N4O12 | 详情 | 详情 | |
| (III) | 50044 | methyl (2R,3R,4S)-4-azido-3-[(tert-butoxycarbonyl)amino]-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylate | C15H24N4O8 | 详情 | 详情 | |
| (IV) | 50045 | (2R,3R,4S)-4-azido-3-[(tert-butoxycarbonyl)amino]-6-(methoxycarbonyl)-3,4-dihydro-2H-pyran-2-carboxylic acid | C13H18N4O7 | 详情 | 详情 | |
| (V) | 50046 | N-phenethyl-1-propanamine; N-phenethyl-N-propylamine | C11H17N | 详情 | 详情 | |
| (VI) | 50047 | methyl (2R,3R,4S)-4-azido-3-[(tert-butoxycarbonyl)amino]-2-[[phenethyl(propyl)amino]carbonyl]-3,4-dihydro-2H-pyran-6-carboxylate | C24H33N5O6 | 详情 | 详情 | |
| (VII) | 50048 | methyl (2R,3R,4S)-3-amino-4-azido-2-[[phenethyl(propyl)amino]carbonyl]-3,4-dihydro-2H-pyran-6-carboxylate | C19H25N5O4 | 详情 | 详情 | |
| (VIII) | 33862 | trifluoroacetic anhydride | 407-25-0 | C4F6O3 | 详情 | 详情 |
| (IX) | 50049 | methyl (2R,3R,4S)-4-azido-2-[[phenethyl(propyl)amino]carbonyl]-3-[(2,2,2-trifluoroacetyl)amino]-3,4-dihydro-2H-pyran-6-carboxylate | C21H24F3N5O5 | 详情 | 详情 | |
| (X) | 50050 | methyl (2R,3R,4S)-4-amino-2-[[phenethyl(propyl)amino]carbonyl]-3-[(2,2,2-trifluoroacetyl)amino]-3,4-dihydro-2H-pyran-6-carboxylate | C21H26F3N3O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)Treatment of aniline (I) with hexafluoroacetone trihydrate (II) and p-toluenesulfonic acid affords derivative (III), which is then derivatized with trifluoroacetic anhydride (IV) to provide trifluoroacetanilide derivative (V). Reduction of (V) by means of LiAlH4 in refluxing THF yields N-trifluoroethylaniline derivative (VI), which is finally converted into the target sulfonamide by reaction with benzenesulfonyl chloride (VII) in pyridine.
| 【1】 Shan, B. (Tularik Inc.); Compsns. and methods for raising HDL cholesterol levels. WO 0103705 . |
| 【2】 Liu, J.; Li, L.; Cutler, S.T.; Zhu, L.; Shan, B.; Medina, J.C.; Hasegawa, H.; Lustig, K. (Tularik Inc.); LXR modulators. EP 1161233; WO 0054759 . |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 44260 | 1,1,1,3,3,3-hexafluoroacetone | 684-16-2 | C3F6O | 详情 | 详情 |
| (III) | 50005 | 2-(4-Aminophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 4-(Hexafluoro-2-hydroxyisopropyl)aniline | 722-92-9 | C9H7F6NO | 详情 | 详情 |
| (IV) | 33862 | trifluoroacetic anhydride | 407-25-0 | C4F6O3 | 详情 | 详情 |
| (V) | 50006 | 2,2,2-trifluoro-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide | C11H6F9NO2 | 详情 | 详情 | |
| (VI) | 50007 | 1,1,1,3,3,3-hexafluoro-2-[4-[(2,2,2-trifluoroethyl)amino]phenyl]-2-propanol | C11H8F9NO | 详情 | 详情 | |
| (VII) | 14713 | benzenesulfonyl chloride | 98-09-9 | C6H5ClO2S | 详情 | 详情 |