|
【结 构 式】 
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【分子编号】14101 【品名】Chlorosulfonyl isocyanate 【CA登记号】1189-71-5 |
【 分 子 式 】CClNO3S 【 分 子 量 】141.53464 【元素组成】C 8.49% Cl 25.05% N 9.9% O 33.91% S 22.66% |
合成路线1
该中间体在本合成路线中的序号：(V)A new method for the synthesis of sorbinil has been reported: The condensation of 2,3-dihydro-6-fluoro-4H-1-benzopyran-4-one (I) with methylbenzylamine (II) by means of TiCl4 in benzene gives 2,3-dihydro-6-fluoro-4-(1-phenylethylimino)-4H-1-benzopyran (III), which by reaction with HCN in ethanol is converted to 4-cyano-2,3-dihydro-6-fluoro-4-(1-phenylethylamino)-4H-1-benzopyran (IV). The cyclization of (IV) with chlorosulfonyl isocyanate (V) in methylene chloride affords 2,3-dihydro-6-fluoro-3'-(1-phenylethyl)spiro(4H-1-benzopyran-4,4'-imidazolidine)-2',5'-dione (VI), which is finally treated with 48% HBr in refluxing acetic acid.
| 【1】 Kelbaugh, P.R.; Sarges, R.; Howard, H.R. Jr.; Synthesis of optically active spirohydantoins by asymmetric induction. Hydantoin formation from amino nitriles and chlorosulfonyl isocyanate. J Org Chem 1982, 47, 21, 4081-85. |
| 【2】 Sarges, R. (Pfizer Inc.); Intermediates in the preparation of chiral hydantoins. US 4348526 . |
| 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) | 10056 | 6-Fluoro-2,3-dihydro-4H-chromen-4-one; 6-Fluoro-4-chromanone | 66892-34-0 | C9H7FO2 | 详情 | 详情 |
| (II) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (III) | 29153 | N-(6-fluoro-2,3-dihydro-4H-chromen-4-ylidene)-1-phenyl-1-ethanamine | C17H16FNO | 详情 | 详情 | |
| (IV) | 29154 | 6-fluoro-4-[(1-phenylethyl)amino]-4-chromanecarbonitrile | C18H17FN2O | 详情 | 详情 | |
| (V) | 14101 | Chlorosulfonyl isocyanate | 1189-71-5 | CClNO3S | 详情 | 详情 |
| (VI) | 29155 | (4S)-6-Fluoro-3'-(1-phenylethyl)-3,4-dihydro-2H-spiro[1-benzopyran-4-4'-imidazolidine]-2',5'-dione | C19H17FN2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)The acetylation of 1,2,3,4-tetrahydroisoquinoline (I) with acetic anhydride gives 2-acetyl-1,2,3,4-tetrahydroisoquinoline (II), which is sulfonated with chloro sulfonic acid in methylene chloride yielding 2-acetyl-7-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline (III). The reaction of (III) with 3-chloroaniline (IV) and triethylamine in refluxing acetone affords 2-acetyl-7-(3-chlorophenylamino sulfonyl)-1,2,3,4-tetrahydroisoquinoline (V), which is deacetylated by a treatment with HCl in refluxing butanol to 7-(3-chlorophenylaminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (VI). Finally, this compound is condensed with bis(chlorosulfonyl)imide (VII) [prepared with chlorosulfonic acid (VIII) and chlorosulfonyl isocyanate (IX)] in acetonitrile containing triethylamine.
| 【1】 Ali Fadia E. (SmithKline Beecham Corp.); N,N'-Bis[substituted-1,2,3,4-tetrahydroisoquinolino]disulfonylimides and antiallergic compositions and method of use. DD 158240; EP 0038177; US 4135935 . |
| 【2】 Serradell, M.N.; Chu, S.S.; Castaner, J.; SKF-88046. Drugs Fut 1985, 10, 1, 42. |
| 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) | 14124 | 1,2,3,4-Tetrahydroisoquinoline | 91-21-4 | C9H11N | 详情 | 详情 |
| (II) | 29003 | 1-[3,4-dihydro-2(1H)-isoquinolinyl]-1-ethanone | C11H13NO | 详情 | 详情 | |
| (III) | 29004 | 2-acetyl-1,2,3,4-tetrahydro-7-isoquinolinesulfonyl chloride | C11H12ClNO3S | 详情 | 详情 | |
| (IV) | 25239 | 3-chloroaniline; 3-chlorophenylamine | 108-42-9 | C6H6ClN | 详情 | 详情 |
| (V) | 29005 | 2-acetyl-N-(3-chlorophenyl)-1,2,3,4-tetrahydro-7-isoquinolinesulfonamide | C17H17ClN2O3S | 详情 | 详情 | |
| (VI) | 29006 | N-(3-chlorophenyl)-1,2,3,4-tetrahydro-7-isoquinolinesulfonamide | C15H15ClN2O2S | 详情 | 详情 | |
| (VII) | 29007 | Bis(chlorosulfonyl)imide | HCl2NO4S2 | 详情 | 详情 | |
| (VIII) | 29008 | Chlorosulfonic acid | 7790-94-5 | HClO3S | 详情 | 详情 |
| (IX) | 14101 | Chlorosulfonyl isocyanate | 1189-71-5 | CClNO3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(A)16-Methylprostaglandin PGF2alpha methyl ester (Ia-b) is cyclized with iodine/sodium bicarbonate to give (IIa-b), which is acetylated with acetic anhydride/pyridine to (IIIa-b). Dehydrohalogenation with DBN generates the protected PGI2 analogue (IVa-b), which reacts smoothly with chlorosulfonyl isocyanate (A) to afford the adduct (Va-b). Without isolation (Va-b) gives on treatment with triethylamine in acetonitrile or solvolysis with N,N-dimethylformamide (DMF) the stable protected 5-cyano analoque (VIa-b), which contains up to ca. 5% Z-isomer, readily removed by chromatography. Finally, saponification affords the free ZK-34,798 (nileprost).
| 【1】 Lohaus, G.; Nitrilsynthesen mit chlorsulfonylisocyanat. Chem Ber 1967, 100, 2719-29. |
| 【2】 Vorbruggen, H.; Reaktive isocyanate I. Sie direkte einfuehrung von nitrilgruppen in ungesattigte systeme. Eine einfache umwandlung von carbosauren in ihre nitrile. Tetrahedron Lett 1968, 1631-34. |
| 【3】 Tanouchi, T.; Miyake, H.; Igushi, Y.; Hayashi, M.; Iguchi, S.; The synthesis of 16(R)- or 16(S)-methylprostaglandins. J Org Chem 1973, 38, 1250-51. |
| 【4】 Whittaker, N.; A synthesis of prostaglandin sodium salt. Tetrahedron Lett 1977, 2805-08. |
| 【5】 Vorbruggen, H.; Skuballa, W.; Raduchel, B.; Losert, W.; Loge, P.; Muller, B.; Mannesmann, G. (Schering AG); 5-Cyano-prostacyclin derivs.. US 4219479 . |
| 【6】 Hashimoto, S.; Nileprost. Drugs Fut 1982, 7, 9, 643. |
| 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) | 14101 | Chlorosulfonyl isocyanate | 1189-71-5 | CClNO3S | 详情 | 详情 |
| (Ia) | 37110 | methyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R,4S)-3-hydroxy-4-methyloctyl]cyclopentyl]-5-heptenoate | C22H40O5 | 详情 | 详情 | |
| (Ib) | 37111 | methyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R,4R)-3-hydroxy-4-methyloctyl]cyclopentyl]-5-heptenoate | C22H40O5 | 详情 | 详情 | |
| (IIa) | 37112 | methyl 5-[(3aR,4R,5R,6aS)-5-hydroxy-4-[(E,3S,4S)-3-hydroxy-4-methyl-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-yl]-5-iodopentanoate | C22H37IO5 | 详情 | 详情 | |
| (IIb) | 37113 | methyl 5-[(3aR,4R,5R,6aS)-5-hydroxy-4-[(E,3S,4R)-3-hydroxy-4-methyl-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-yl]-5-iodopentanoate | C22H37IO5 | 详情 | 详情 | |
| (IIIa) | 37114 | methyl 5-[(3aR,4R,5R,6aS)-5-(acetoxy)-4-[(E,3S,4S)-3-(acetoxy)-4-methyl-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-yl]-5-iodopentanoate | C26H41IO7 | 详情 | 详情 | |
| (IIIb) | 37115 | methyl 5-[(3aR,4R,5R,6aS)-5-(acetoxy)-4-[(E,3S,4R)-3-(acetoxy)-4-methyl-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-yl]-5-iodopentanoate | C26H41IO7 | 详情 | 详情 | |
| (IVa) | 37116 | methyl 5-[(3aR,4R,5R,6aS)-5-(acetoxy)-4-[(E,3S,4S)-3-(acetoxy)-4-methyl-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-ylidene]pentanoate | C26H40O7 | 详情 | 详情 | |
| (IVb) | 37117 | methyl 5-[(3aR,4R,5R,6aS)-5-(acetoxy)-4-[(E,3S,4R)-3-(acetoxy)-4-methyl-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-ylidene]pentanoate | C26H40O7 | 详情 | 详情 | |
| (Va) | 37118 | methyl 5-[(3aR,4R,5R,6aS)-5-(acetoxy)-4-[(E,3S,4S)-3-(acetoxy)-4-methyl-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-ylidene]-6-[(chlorosulfonyl)amino]-6-oxohexanoate | C27H40ClNO10S | 详情 | 详情 | |
| (Vb) | 37119 | methyl 5-[(3aR,4R,5R,6aS)-5-(acetoxy)-4-[(E,3S,4R)-3-(acetoxy)-4-methyl-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-ylidene]-6-[(chlorosulfonyl)amino]-6-oxohexanoate | C27H40ClNO10S | 详情 | 详情 | |
| (VIa) | 37120 | methyl 5-[(3aR,4R,5R,6aS)-5-(acetoxy)-4-[(E,3S,4S)-3-(acetoxy)-4-methyl-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-ylidene]-5-cyanopentanoate | C27H39NO7 | 详情 | 详情 | |
| (VIb) | 37121 | methyl 5-[(3aR,4R,5R,6aS)-5-(acetoxy)-4-[(E,3S,4R)-3-(acetoxy)-4-methyl-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-ylidene]-5-cyanopentanoate | C27H39NO7 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)The synthesis of [14C]-labeled tenidap sodium has been reported: The chlorination of [14C]-2,3-dihydro-1H-indole-2,3-dione (I) with sulfuryl chloride and triethylamine in hot acetonitrile gives the 5-chloro derivative (II), which is partially reduced by treatment with hydrazine hydrate in refluxing ethanol, followed by a treatment with KOH in the same refluxing solvent, to yield 5-chloro-2,3-dihydro-1H-indol-2-one (III). The reaction of (III) with chlorosulfonyl isocyanate (IV) in refluxing dichloromethane affords 5-chloro-2-oxo-2,3-dihydro-1H-indole-1-carboxamide (V), which is condensed with 2-thienylcarbonyl chloride (VI) by means of dimethylaminopyridine (DMAP) and triethylamine (TEA) in DMF, giving tenidap (VII). Finally, this compound is treated with NaHCO3 in hot acetone.
| 【1】 Hale, K.J.; Lennon, J.A.; Hobbs, C.J.; Javaid, M.H.; Manaviazar, S.; Asymmetric synthesis of the C17-C27 segment of the antineoplasticmacrolide bryostatin 1. J Label Compd Radiopharm 1995, 36, 8, 1359. |
| 【2】 Johnson, D.L.; Melvin, L.S.; Falkner, F.C.; Rusek, F.W.; Robinson, R.P.; Synthesis of C-14 isotopic isomers of tenidap - A novel antiinflammatory agent. J Label Compd Radiopharm 1996, 38, 3, 207. |
| 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) | 14098 | 2,3-Indolinedione; 1H-Indole-2,3-dione; Isatin | 91-56-5 | C8H5NO2 | 详情 | 详情 |
| (I) | 45196 | C8H5NO2 | 详情 | 详情 | ||
| (II) | 14099 | 5-Chloro-1H-indole-2,3-dione; 5-Chloroisatin | 17630-76-1 | C8H4ClNO2 | 详情 | 详情 |
| (II) | 45197 | C8H4ClNO2 | 详情 | 详情 | ||
| (III) | 14100 | 5-Chlorooxindole; 5-Chloro-1,3-dihydro-2H-indol-2-one | 17630-75-0 | C8H6ClNO | 详情 | 详情 |
| (III) | 45198 | C8H6ClNO | 详情 | 详情 | ||
| (IV) | 14101 | Chlorosulfonyl isocyanate | 1189-71-5 | CClNO3S | 详情 | 详情 |
| (V) | 14096 | 5-Chloro-2-oxo-1-indolinecarboxamide | C9H7ClN2O2 | 详情 | 详情 | |
| (V) | 45199 | C9H7ClN2O2 | 详情 | 详情 | ||
| (VI) | 14103 | 2-Thiophenecarbonyl chloride | 5271-67-0 | C5H3ClOS | 详情 | 详情 |
| (VII) | 14104 | 5-Chloro-3-[(Z)-hydroxy(2-thienyl)methylidene]-2-oxo-1H-indole-1(2H)-carboxamide | C14H9ClN2O3S | 详情 | 详情 | |
| (VII) | 45200 | C14H9ClN2O3S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VII)5-Chloro-2-oxo-2,3-dihydro-1H-indole-1-carboxamide (X), a key intermediate in the synthesis of tenidap, has been obtained by several different ways, all of them starting from 5-chloro-2,3-dihydro-1H-indol-2-one (I). 1. The reaction of indolone (I) with cyclohexylcarbonyl isocyanate (II) gives the N-acyl carboxamide (III), which is treated with KOH to yield 2-(5-chloro-2-ureidophenyl)acetic acid (IV). Finally, this compound is cyclized to the target carboxamide by treatment with trifluoroacetic anhydride and trifluoroacetic acid. 2. The reaction of indolone (I) with isobutyryl isocyanate (XI) gives the N-acyl carboxamide (V), which is treated with KOH to yield 2-(5-chloro-2-ureidophenyl)acetic acid (III). Finally, this compound is cyclized to the target carboxamide as before. 3. The reaction of indolone (I) with trichloroacetyl isocyanate (VI) in hot toluene gives the target carboxamide in one step. 4. The reaction of indolone (I) with chlorosulfonyl isocyanate (VII) gives the N-chlorosulfonyl carboxamide (VIII), which is hydrolyzed to the target carboxamide with aqueous acetic acid. 5. The reaction of indolone (I) with NaOH and then with H2SO4 gives 2-(2-amino-5-chlorophenyl)acetic acid (IX), which is treated with potassium isocyanate and AcOH to yield 2-(5-chloro-2-ureidophenyl)acetic acid (III). Finally, this compound can be cyclized to the target intermediate by means of AcOH and NaOAc.
| 【1】 Sarma, M.R.; Goud, P.S.; Sailaja, M.; Kumar, P.R.; Reddy, G.O.; Raju, S.; Synthesis of tenidap: An improved process for the preparation of 5-chloro-2-oxindole-1-carboxamide. Org Process Res Dev 2001, 5, 1, 61. |
| 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) | 14100 | 5-Chlorooxindole; 5-Chloro-1,3-dihydro-2H-indol-2-one | 17630-75-0 | C8H6ClNO | 详情 | 详情 |
| (II) | 47903 | cyclohexanecarbonyl isocyanate | C8H11NO2 | 详情 | 详情 | |
| (III) | 47904 | 5-chloro-N-(cyclohexylcarbonyl)-2-oxo-1-indolinecarboxamide | C16H17ClN2O3 | 详情 | 详情 | |
| (IV) | 47905 | 2-[2-[(aminocarbonyl)amino]-5-chlorophenyl]acetic acid | C9H9ClN2O3 | 详情 | 详情 | |
| (V) | 47906 | 5-chloro-N-isobutyryl-2-oxo-1-indolinecarboxamide | C13H13ClN2O3 | 详情 | 详情 | |
| (VI) | 40725 | 2,2,2-trichloroacetyl isocyanate | 3019-71-4 | C3Cl3NO2 | 详情 | 详情 |
| (VII) | 14101 | Chlorosulfonyl isocyanate | 1189-71-5 | CClNO3S | 详情 | 详情 |
| (VIII) | 47907 | 5-chloro-1-[[(chlorosulfonyl)amino]carbonyl]-2-oxoindoline | C9H6Cl2N2O4S | 详情 | 详情 | |
| (IX) | 47908 | 2-(2-amino-5-chlorophenyl)acetic acid | C8H8ClNO2 | 详情 | 详情 | |
| (X) | 14096 | 5-Chloro-2-oxo-1-indolinecarboxamide | C9H7ClN2O2 | 详情 | 详情 | |
| (XI) | 47909 | 2-methylpropanoyl isocyanate | C5H7NO2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)A synthesis of L-692429 has been reported: The cyclization of isobutene (I) with chlorosulfonyl isocyanate (II) gives 1-(chlorosulfonyl)-4,4-dimethylazetidin-2-one (III), which is condensed with 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (IV) by means of triethylamine in methanol to yield 3-methyl-3-(methylsulfonamido)-N-[2-oxo-2,3,4,5-tetrahydro-1H-1-benzaze pin-3(R)-yl]butyramide (V). The reaction of (V) with 2'-[1-(triphenylmethyl)tetrazol-5-yl]biphenyl-4-ylmethyl bromide (VI) by means of NaH in THF/DMF affords protected L-692429, which is finally deprotected by a treatment with 5N HCl.
| 【1】 Bergan, J.J.; Reider, P.J.; McNamara, J.M.; Volante, R.P.; Bhupathy, M.; A convergent synthesis of a novel non-peptidyl growth hormone secretagogue, L-692,429. Tetrahedron Lett 1995, 36, 52, 9445. |
| 【2】 Schoen, W.R.; et al.; A novel 3-substituted benzazepinone growth hormone secretagogue (L-692,429). J Med Chem 1994, 37, 7, 897. |
| 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) | 15926 | 2-methyl-1-propene; isobutylene | 115-11-7 | C4H8 | 详情 | 详情 |
| (II) | 14101 | Chlorosulfonyl isocyanate | 1189-71-5 | CClNO3S | 详情 | 详情 |
| (III) | 15928 | 2,2-dimethyl-4-oxo-1-azetanesulfonyl chloride | C5H8ClNO3S | 详情 | 详情 | |
| (IV) | 15929 | (3R)-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H12N2O | 详情 | 详情 | |
| (V) | 15930 | 3-methyl-3-[(methylsulfonyl)amino]-N-[(3R)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]butanamide | C16H23N3O4S | 详情 | 详情 | |
| (VI) | 15538 | 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-2-trityl-2H-1,2,3,4-tetraazole | 124750-51-2 | C33H25BrN4 | 详情 | 详情 |
| (VII) | 15932 | 3-methyl-3-[(methylsulfonyl)amino]-N-((3R)-2-oxo-1-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)butanamide | C49H47N7O4S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IX)1) The reaction of (V) with SOCl2 or (COCl)2 in DMF affords the expected acyl chloride (VI), which is finally condensed with 2,6-diisopropylphenyl sulfamate (VII) by means of triethylamine in hot toluene to obtain Avasimibe. 2) The sulfamate (VII) can be obtained by condensation of 2,6-diisopropylphenol (VIII) with chlorosulfonyl isocyanate (IX) in refluxing toluene to give the isocyanate (X), which is hydrolyzed with water to the sulfamate (VII). compound is condensed with the previously described isocyanate (X) in refluxing THF to obtain Avasimibe. 3) Avasimibe can also be obtained by condensation of isocyanate (X) with Grignard reagent (XIII).
|
【1】
Sorbera, L.A.; Rabasseda, X.; Castañer, J.; Avasimibe |
| 【2】 Lee, H.T.; Picad, J.A.; Sliskovic, D.R.; Wierenga, W. (Pfizer Inc.); N-Acyl sulfamic acid esters (or thioesters), N-acyl sulfonamides, and N-sulfonyl carbamic acid esters (or thioesters) as hypercholesterolemic agents. EP 0698010; JP 1996510256; US 5491172; WO 9426702 . |
| 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) | 20240 | 2-(2,4,6-triisopropylphenyl)acetic acid | C17H26O2 | 详情 | 详情 | |
| (VI) | 20247 | 2-(2,4,6-triisopropylphenyl)acetyl chloride | C17H25ClO | 详情 | 详情 | |
| (VII) | 20248 | 2,6-diisopropylphenylsulfamate | C12H19NO3S | 详情 | 详情 | |
| (VIII) | 20249 | 2,6-Diisopropylphenol | 2078-54-8 | C12H18O | 详情 | 详情 |
| (IX) | 14101 | Chlorosulfonyl isocyanate | 1189-71-5 | CClNO3S | 详情 | 详情 |
| (X) | 20251 | 2-[(isocyanatosulfonyl)oxy]-1,3-diisopropylbenzene | C13H17NO4S | 详情 | 详情 | |
| (XIII) | 20243 | bromo(2,4,6-triisopropylbenzyl)magnesium | C16H25BrMg | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(A)The reduction of azide (I) with trimethylphosphine in THF gives the amine (II), which is treated with chlorosulfonyl isocyanate (A) in acetonitrile yielding the urea derivative (III). Finally, this compound is acetylated with acetic anhydride in pyridine to afford a mixture of alpha and beta acetylureas which is separated by centrifugal circular thin layer chromatography.
| 【1】 Velázquez, S.; Chamorro, C.; Perez-Perez, M.J.; Alvarez, R.; Jimeno, M.L.; Martin-Domenech, A.; Perez, C.; Gago, F.; De Clercq, E.; Balzarini, J.; San-Felix, A.; Camarasa, M.J.; Abasic analogues of TSAO-T as the first sugar derivatives that specifically inhibit HIV-1 reverse transcriptase. J Med Chem 1998, 41, 23, 4636. |
| 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) | 14101 | Chlorosulfonyl isocyanate | 1189-71-5 | CClNO3S | 详情 | 详情 |
| (I) | 26923 | (6R,8R,9R)-4-amino-8-azido-9-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1,7-dioxa-2lambda(6)-thiaspiro[4.4]non-3-ene-2,2-dione | C19H38N4O6SSi2 | 详情 | 详情 | |
| (II) | 26924 | (6R,8R,9R)-4,8-diamino-9-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1,7-dioxa-2lambda(6)-thiaspiro[4.4]non-3-ene-2,2-dione | C19H40N2O6SSi2 | 详情 | 详情 | |
| (III) | 26926 | N-[(6R,8R,9R)-4-amino-9-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2,2-dioxo-1,7-dioxa-2lambda(6)-thiaspiro[4.4]non-3-en-8-yl]urea | C20H41N3O7SSi2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(IV)Friedel-Crafts acylation of phenol (I) with nonanoyl chloride (II) in the presence of AlCl3 afforded ketone (III). Aminosulfonyl chloride (V) was prepared by decarboxylation of chlorosulfonyl isocyanate (IV) upon treatment with formic acid. Finally, condensation of the sodium phenolate of (III) with aminosulfonyl chloride (V) furnished the title sulfamate.
| 【1】 Ahmed, S.; et al.; Novel inhibitors of the enzyme estrone sulfatase (ES). Bioorg Med Chem Lett 2001, 11, 6, 841. |
| 【2】 Ahmed, S.; James, K.; Owen, C.P.; Patel, C.K.; Synthesis and biochemical evaluation of novel and potent inhibitors of the enzyme oestrone sulphatase (ES). J Steroid Biochem Mol Biol 2002, 80, 4-5, 419. |
| 【3】 Ahmed, S. (Kingston University); Sulphamate cpds.. WO 0104086 . |
| 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) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (II) | 30296 | nonanoyl chloride | 764-85-2 | C9H17ClO | 详情 | 详情 |
| (III) | 50915 | 4-n-Nonanoylphenol; 4-Hydroxynonanophenone | 14392-69-9 | C15H22O2 | 详情 | 详情 |
| (IV) | 14101 | Chlorosulfonyl isocyanate | 1189-71-5 | CClNO3S | 详情 | 详情 |
| (V) | 40598 | amidosulfonoyl chloride | 7778-42-9 | H2ClNO2S | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(II)Cycloaddition of norbornene (I) with chlorosulfonyl isocyanate (II) in EtOAc or Et2O followed by treatment with aqueous Na2SO3 affords (±)-exo-3-azatricyclo[4.2.1.O2,5]nonan-4-one (III), which by hydrolysis with HCl gives 3-aminonorbornane-2-carboxylic acid hydrochloride (IV). Treatment of amino acid (IV) with EtOH or MeOH by means of SOCl2 at reflux provides the hydrochloride salts of the corresponding ethyl (Va) or methyl (Vb) esters, respectively, which are neutralized with NaHCO3 to yield the free amines (VIa) and (VIb). Resolution of the racemic amino esters (VIa) or (VIb) with (S)-(+)-CSA in EtOAc/EtOH followed by neutralization of the obtained CSA salts (VIIa) or (VIIb) with Na2CO3 or K2CO3 in EtOAc leads to ethyl (VIIIa) or methyl (VIIIb) (1S,2R,3S,4R)-3-aminonorbornane-2-carboxylate, respectively. Alternatively, amino ester (VIIa) can be obtained by ring opening of racemic lactam (III) with EtOH in the presence of (S)-(+)-CSA in EtOAc at 50-75 °C. Reductive alkylation of amines (VIIIa) and (VIIIb) with 4-fluorobenzaldehyde (IX) by means of NaBH3CN and AcOH or NaOAc in EtOH gives the secondary amines (XIa) or (XIb) , which can also be prepared by alkylation of amines (VIII) with 4-fluorobenzyl bromide (Xa) or iodide (XIb) in the presence of Et3N in DMF at 70 °C . N-Acylation of amino esters (XIa) or (XIb) with the carboxylic acid (XII) using as coupling reagents EDC in the presence of DMAP , or NMM in DMF, or DCC in CH2Cl2/DMF, or HATU and NMM in DMF , yields amides (XIIIa) and (XIIIb) . Finally, amide esters (XIII) are submitted to intramolecular Claisen condensation by means of NaOEt in EtOH at 60 °C or Et3N at 60 °C . Alternatively, methyl ester (XIb) can be condensed with the carboxylic acid (XII) in the presence of DCC, NMM and Et3N in DMF at 50 °C , or in acetonitrile .
| 【1】 Tran, C.V., Ruebsam, F., Murphy, D.E. et al. (Anadys Pharmaceuticals, Inc.). 5,6-Dihydro-1H-pyridin-2-one compounds. CA 2682584, EP 2129224, JP 2010523586, US 2010034773, US 7939524, US 8101800, US 2012130068, US 8236948, WO 2008124450. |
| 【2】 Ruebsam, F., Dragovich, P., Webber, S.E., Murphy, D.E., Tran, C.V. (Anadys Pharmaceuticals, Inc.). [1,2,4]Thiadiazine 1,1-dioxide compounds. CN 10236871, US 2009306057, US 80976131, WO 2009152166. |
| 【3】 Dragovich, P.S., Thompson, P.A., Ruebsam, F. (Anadys Pharmaceuticals, Inc.). A method of inhibiting hepatitis C virus by combination of a 5,6-dihydro-1H-pyridin-2-one and one or more additional antiviral compounds. EP 2346329, US 2011229438, WO 2010042834. |
| 【4】 Ruebsam, F., Murphy, D.E., Tran, C.V. et al. Discovery of tricyclic 5,6-dihydro-1H-pyridin-2-ones as novel, potent, and orally bioavailable inhibitors of HCV NS5B polymerase. Bioorg Med Chem Lett 2009, 19(22): 6404-12. |
| 【5】 Ruebsam, F., Dragovich, P., Webber, S.E., Murphy, D.E., Tran, C.V. (Anadys Pharmaceuticals, Inc.). [1,2,4]Thiadiazin-3-yl acetic acid compound[[s]] and methods of making the acetic acid compound. US 2012116077, US 8222404. |
| 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) | 68649 | bicyclo[2.2.1]hept-2-ene | C7H10 | 详情 | 详情 | |
| (Va) | 68657 | (±)-(1S,2R,3S,4R)-ethyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate hydrochloride | C10H17NO2.HCl | 详情 | 详情 | |
| (Vb) | 68658 | (±)-(1S,2R,3S,4R)-methyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate hydrochloride | C9H15NO2.HCl | 详情 | 详情 | |
| (VIa) | 68655 | (±)-(1S,2R,3S,4R)-ethyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate | C10H17NO2 | 详情 | 详情 | |
| (VIb) | 68656 | (±)-(1S,2R,3S,4R)-methyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate | C9H15NO2 | 详情 | 详情 | |
| (VIIa) | 68652 | (1S,2R,3S,4R)-ethyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate (7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate | C10H17NO2.C10H16O4S | 详情 | 详情 | |
| (VIIb) | 68651 | (1S,2R,3S,4R)-methyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate (7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate | C9H15NO2S.C10H16O4S | 详情 | 详情 | |
| (VIIIa) | 68654 | (1S,2R,3S,4R)-methyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate | C10H17NO2 | 详情 | 详情 | |
| (VIIIb) | 68653 | (1S,2R,3S,4R)ethyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate | C9H15NO2 | 详情 | 详情 | |
| (Xa) | 24611 | 1-(bromomethyl)-4-fluorobenzene | 459-46-1 | C7H6BrF | 详情 | 详情 |
| (Xb) | 23601 | 1-fluoro-4-(iodomethyl)benzene | C7H6FI | 详情 | 详情 | |
| (XIa) | 68660 | (1S,2R,3S,4R)-ethyl 3-((4-fluorobenzyl)amino)bicyclo[2.2.1]heptane-2-carboxylate | C17H22FNO2 | 详情 | 详情 | |
| (XIb) | 68661 | (1S,2R,3S,4R)-methyl 3-((4-fluorobenzyl)amino)bicyclo[2.2.1]heptane-2-carboxylate | C16H20FNO2 | 详情 | 详情 | |
| (XIIIa) | 68663 | (1S,2R,3S,4R)-ethyl 3-(N-(4-fluorobenzyl)-2-(7-(methylsulfonamido)-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-3-yl)acetamido)bicyclo[2.2.1]heptane-2-carboxylate | C27H31FN4O7S2 | 详情 | 详情 | |
| (XIIIb) | 68664 | (1S,2R,3S,4R)-methyl 3-(N-(4-fluorobenzyl)-2-(7-(methylsulfonamido)-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-3-yl)acetamido)bicyclo[2.2.1]heptane-2-carboxylate | C26H29FN4O7S2 | 详情 | 详情 | |
| (II) | 14101 | Chlorosulfonyl isocyanate | 1189-71-5 | CClNO3S | 详情 | 详情 |
| (III) | 68650 | (±)-exo-3-azatricyclo[4.2.1.O2.5 nonan-4-one;(1S,2R,5S,6R)-3-azatricyclo[4.2.1.02.5]nonan-4-one | C8H11NO | 详情 | 详情 | |
| (IV) | 68659 | (±)-(1S,2R,3S,4R)-3-aminobicyclo[2.2.1]heptane-2-carboxylic acid hydrochloride | C8H13NO2.HCl | 详情 | 详情 | |
| (IX) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (XII) | 68662 | 2-(7-(methylsulfonamido)-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-3-yl)acetic acid | C10H11N3O6S2 | 详情 | 详情 |