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【结 构 式】 
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【分子编号】17236 【品名】(6R)-3-[(1R)-1-(3-aminophenyl)propyl]-4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one 【CA登记号】 |
【 分 子 式 】C25H31NO3 【 分 子 量 】393.52608 【元素组成】C 76.3% H 7.94% N 3.56% O 12.2% |
合成路线1
该中间体在本合成路线中的序号：(XII)The condensation of 4(R)-phenyloxazolidin-2-one (I) with 2(E)-pentenoyl chloride (II) by means of BuLi in THF gives 3-[2(E)-pentenoyl]-3(R)-phenyloxazolidin-2-one (III), which is treated with 3-[bis(trimethylsilyl)amino]phenylmagnesium bromide (IV) and CuBr in DMSO/THF regioselectively yielding the addition product (V). Elimination of the silyl groups of (VII) in mild acidic conditions and treatment of the resulting amine with benzyl bromide affords the dibenzylated amine derivative (VI), which is regioselectively acylated with 2-methoxy-2-methyl-1,3-dioxolane (V) and TiCl4 in dichloromethane under basic conditions giving the dione (VIII). The condensation of (VIII) with 1-phenyl-3-hexanone (IX) by means of Ti(OBu)Cl3 in dichloromethane as before yields the hydroxy-dione (X), which is cyclized by means of potassium tert-butoxide in THF to afford the dihydropyrone (XI). The debenzylation of (XI) by hydrogenation with H2 over Pd/C in methanol/ethyl acetate gives the free amine (XII), which is finally sulfonated with 5-(trifluoromethyl)pyridine-2-sulfonyl chloride (XIII) in pyridine/dichloromethane
| 【1】 Graul, J.; Wroblewski, T.; Castañer, J.; PNU-140690. Drugs Fut 1998, 23, 2, 146. |
| 【2】 Romines, K.R.; Bundy, G.L.; Schwartz, T.M.; Tommasi, R.A.; Strohbach, J.W.; Turner, S.R.; Thaisrivongs, S.; Aristoff, P.A.; Johnson, P.D.; Skulnick, H.I.; Skaletzki, L.L.; Anderson, D.J.; Morris, J.; Gammill, R.B.; Luke, G.P. (Pharmacia Corp.); Pyranone cpds. useful to treat retroviral infections. EP 0758327; JP 1997512821; US 5852195; WO 9530670 . |
| 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) | 12173 | (4S)-4-Phenyl-1,3-oxazolan-2-one; (4S)-4-Phenyl-2-oxazolidinone; (S)-(+)-4-Phenyl-2-oxazolidinone | 99395-88-7 | C9H9NO2 | 详情 | 详情 |
| (II) | 17226 | (E)-2-pentenoyl chloride | C5H7ClO | 详情 | 详情 | |
| (III) | 17227 | (4R)-3-[(E)-2-pentenoyl]-4-phenyl-1,3-oxazolan-2-one | C14H15NO3 | 详情 | 详情 | |
| (IV) | 17228 | N-(3-methylphenyl)-N,N-bis(trimethylsilyl)amine; trimethyl-N-(3-methylphenyl)-N-(trimethylsilyl)silanamine | C13H25NSi2 | 详情 | 详情 | |
| (V) | 17229 | (4R)-3-((3S)-3-[3-[bis(trimethylsilyl)amino]phenyl]pentanoyl)-4-phenyl-1,3-oxazolan-2-one | C26H38N2O3Si2 | 详情 | 详情 | |
| (VI) | 17230 | (4R)-3-[(3S)-3-[3-(dibenzylamino)phenyl]pentanoyl]-4-phenyl-1,3-oxazolidin-2-one | C34H34N2O3 | 详情 | 详情 | |
| (VII) | 17231 | 2-methoxy-2-methyl-1,3-dioxolane; methyl 2-methyl-1,3-dioxolan-2-yl ether | C5H10O3 | 详情 | 详情 | |
| (VIII) | 17232 | (2S)-2-[(1S)-1-[3-(dibenzylamino)phenyl]propyl]-1-[(4R)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]-1,3-butanedione | C36H36N2O4 | 详情 | 详情 | |
| (IX) | 17233 | 1-phenyl-3-hexanone | C12H16O | 详情 | 详情 | |
| (X) | 17234 | (2S,5R)-2-[(1S)-1-[3-(dibenzylamino)phenyl]propyl]-5-hydroxy-1-[(4R)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]-5-phenethyl-1,3-octanedione | C48H52N2O5 | 详情 | 详情 | |
| (XI) | 17235 | (6R)-3-[(1R)-1-[3-(dibenzylamino)phenyl]propyl]-4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one | C39H43NO3 | 详情 | 详情 | |
| (XII) | 17236 | (6R)-3-[(1R)-1-(3-aminophenyl)propyl]-4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one | C25H31NO3 | 详情 | 详情 | |
| (XIII) | 17237 | 5-(trifluoromethyl)-2-pyridinesulfonyl chloride | C6H3ClF3NO2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)2) The previously obtained dione (VIII) can also be condensed with 1-phenyl-4-pentyn-1-one (XIV) by means of Ti(OBu)Cl3 in dichloromethane as before yielding the unsaturated hydroxy-dione (XV), which is cyclized by means of potassium tert-butoxide in THF to afford the dihydropyrone (XVI). The hydrogenation of the triple bond of (XVI) with simultaneous debenzylation by means of H2 over Pd/C in methanol/ethyl acetate gives the previously obtained free amine derivative (XII).
| 【1】 Graul, J.; Wroblewski, T.; Castañer, J.; PNU-140690. Drugs Fut 1998, 23, 2, 146. |
| 【2】 Morris, J.K.; Phillips, G.; Judge, T.M.; et al.; Asymmetric syntheses and absolute stereochemistry of 5,6-dihydro-alpha-pyrones, a new class of potent HIV protease inhibitors. J Am Chem Soc 1997, 119, 15, 3627-8. |
| 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) | 17232 | (2S)-2-[(1S)-1-[3-(dibenzylamino)phenyl]propyl]-1-[(4R)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]-1,3-butanedione | C36H36N2O4 | 详情 | 详情 | |
| (XII) | 17236 | (6R)-3-[(1R)-1-(3-aminophenyl)propyl]-4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one | C25H31NO3 | 详情 | 详情 | |
| (XIV) | 17238 | 1-phenyl-4-hexyn-3-one | C12H12O | 详情 | 详情 | |
| (XV) | 17239 | (2S,5R)-2-[(1S)-1-[3-(dibenzylamino)phenyl]propyl]-5-hydroxy-1-[(4R)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]-5-phenethyl-6-octyne-1,3-dione | C48H48N2O5 | 详情 | 详情 | |
| (XVI) | 17240 | (6R)-3-[(1R)-1-[3-(dibenzylamino)phenyl]propyl]-4-hydroxy-6-phenethyl-6-(1-propynyl)-5,6-dihydro-2H-pyran-2-one | C39H39NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XV)The hydroxy ketoester (XIII) (Scheme 24009402a), which is cyclized by means of NaOH in methanol/water affording the dihydropyranone (XIV). The reduction of the nitro group of (XIV) with hydrogen over Pd/C in THF gives the corresponding aniline (XV), which is finally amidated with 5-(trifluoromethyl)pyridine-2-sulfonyl chloride and pyridine in DMSO.
| 【1】 Fors, K.S.; et al.; A convergent, scalable synthesis of HIV protease inhibitor PNU-140690. J Org Chem 1998, 63, 21, 7348. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 21167 | methyl (5R)-5-hydroxy-2-[(1S)-1-(3-nitrophenyl)propyl]-3-oxo-5-phenethyloctanoate | C26H33NO6 | 详情 | 详情 | |
| (XIV) | 21168 | (6R)-4-hydroxy-3-[(1R)-1-(3-nitrophenyl)propyl]-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one | C25H29NO5 | 详情 | 详情 | |
| (XV) | 17236 | (6R)-3-[(1R)-1-(3-aminophenyl)propyl]-4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one | C25H31NO3 | 详情 | 详情 | |
| (XVI) | 17237 | 5-(trifluoromethyl)-2-pyridinesulfonyl chloride | C6H3ClF3NO2S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VIII)A new synthesis of PNU-140690 has been developed: The condensation of 1-phenyl-3-hexanone (I) with methyl acetoacetate (II) by means of NaH in THF, followed by cyclization gives the hydroxypyrone (III), which by condensation with 3-nitrobenzaldehyde (IV) by means of AlCl3 in THF yields the benzylidene-pyrone (V). The alkylation of (V) with Et3Al, CuBr-Me2S in THF affords intermediate (VI), which is reduced at the nitro group with H2 over Pd/C in methanol giving the racemic amine (VII). The optical resolution of the N-benzyloxycarbonyl derivative of (VII) with chiral HPLC yielded the desired (R,R)-enantiomer (VIII), which was finally sulfonated with 5-(trifluoromethyl)pyridine-2-sulfonyl chloride (IX) in pyridine/dichloromethane.
| 【1】 Turner, S.R.; Strohbach, J.W.; Tommasi, R.A.; Aristoff, P.A.; Johnson, P.D.; Skulnick, H.I.; Dolak, L.A.; Seest, E.P.; Tomich, P.K.; Bohanon, M.J.; Horng, M.M.; Lynn, J.C.; Chong, K.T.; Hinshaw, R.R.; Watenpaugh, K.D.; Janakiraman, M.N.; Thaisrivongs, S.; Tipranavir (PNU-140690): A potent, orally bioavailable nonpeptidic HIV protease inhibitor of the 5,6-dihydro-4-hydroxy-2-pyrone sulfonamide class. J Med Chem 1998, 41, 18, 3467. |
| 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) | 17233 | 1-phenyl-3-hexanone | C12H16O | 详情 | 详情 | |
| (II) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (III) | 32879 | 4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one | C16H20O3 | 详情 | 详情 | |
| (IV) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (V) | 32880 | 3-[(Z)-(3-nitrophenyl)methylidene]-6-phenethyl-6-propyldihydro-2H-pyran-2,4-dione | C23H23NO5 | 详情 | 详情 | |
| (VI) | 32881 | 4-hydroxy-3-[1-(3-nitrophenyl)propyl]-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one | C25H29NO5 | 详情 | 详情 | |
| (VII) | 32882 | 3-[1-(3-aminophenyl)propyl]-4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one | C25H31NO3 | 详情 | 详情 | |
| (VIII) | 17236 | (6R)-3-[(1R)-1-(3-aminophenyl)propyl]-4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one | C25H31NO3 | 详情 | 详情 | |
| (IX) | 17237 | 5-(trifluoromethyl)-2-pyridinesulfonyl chloride | C6H3ClF3NO2S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IX)
| 【1】 Wilken J. Nerenz F, Kanschik-Conndsen A. 2004. A process for the synthesis of 3-hydroxy3-(2-phenylethyl) hexanoic acid，useful as an intermediate for antiviral. US 2004110957(本专利属于Honey-well International, Inc.，USA) |
| 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) | 21159 | (3R)-3-hydroxy-3-phenethylhexanoic acid | C14H20O3 | 详情 | 详情 | |
| (VII) | 66860 | (S)-4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one | C16H20O3 | 详情 | 详情 | |
| (I) | 17233 | 1-phenyl-3-hexanone | C12H16O | 详情 | 详情 | |
| (II) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (III) | 21156 | ethyl 3-hydroxy-3-phenethylhexanoate | C16H24O3 | 详情 | 详情 | |
| (IV) | 13355 | 2-Amino-1-phenyl-1-propanol; (1S,2R)-(+)-Norephedrine | 37577-28-9 | C9H13NO | 详情 | 详情 |
| (VI) | 66856 | (S)-ethyl 5-hydroxy-3-oxo-5-phenethyloctanoate | C18H26O4 | 详情 | 详情 | |
| (IX) | 17236 | (6R)-3-[(1R)-1-(3-aminophenyl)propyl]-4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one | C25H31NO3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XIX)
| 【1】 Judge TM, Phillips G, Moms JK, et aL. 1997. A symmetric syntheses and absolute stereochemistry of 5,6-dihydro-α-pyrones, a new class of potent HIV proteese inhibitors. J Am Chem Soc, 119 (15): 3627～3628 |
| 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) | 12173 | (4S)-4-Phenyl-1,3-oxazolan-2-one; (4S)-4-Phenyl-2-oxazolidinone; (S)-(+)-4-Phenyl-2-oxazolidinone | 99395-88-7 | C9H9NO2 | 详情 | 详情 |
| (II) | 17227 | (4R)-3-[(E)-2-pentenoyl]-4-phenyl-1,3-oxazolan-2-one | C14H15NO3 | 详情 | 详情 | |
| (III) | 17228 | N-(3-methylphenyl)-N,N-bis(trimethylsilyl)amine; trimethyl-N-(3-methylphenyl)-N-(trimethylsilyl)silanamine | C13H25NSi2 | 详情 | 详情 | |
| (V) | 17231 | 2-methoxy-2-methyl-1,3-dioxolane; methyl 2-methyl-1,3-dioxolan-2-yl ether | C5H10O3 | 详情 | 详情 | |
| (VI) | 17232 | (2S)-2-[(1S)-1-[3-(dibenzylamino)phenyl]propyl]-1-[(4R)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]-1,3-butanedione | C36H36N2O4 | 详情 | 详情 | |
| (XI) | 66877 | 2-(1-(3-(dibenzylamino)phenyl)propyl)-5-hydroxy-1-(2-oxo-4-phenyloxazolidin-3-yl)-5-phenethyloctane-1,3-dione | C48H52N2O5 | 详情 | 详情 | |
| (IV) | 17229 | (4R)-3-((3S)-3-[3-[bis(trimethylsilyl)amino]phenyl]pentanoyl)-4-phenyl-1,3-oxazolan-2-one | C26H38N2O3Si2 | 详情 | 详情 | |
| (VII) | 10385 | 4-Heptanone; Dipropyl ketone | 123-19-3 | C7H14O | 详情 | 详情 |
| (VIII) | 17233 | 1-phenyl-3-hexanone | C12H16O | 详情 | 详情 | |
| (IX) | 66878 | 2-(1-(3-(dibenzylamino)phenyl)propyl)-5-hydroxy-1-(2-oxo-4-phenyloxazolidin-3-yl)-5-propyloctane-1,3-dione | C43H50N2O5 | 详情 | 详情 | |
| (X) | 17234 | (2S,5R)-2-[(1S)-1-[3-(dibenzylamino)phenyl]propyl]-5-hydroxy-1-[(4R)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]-5-phenethyl-1,3-octanedione | C48H52N2O5 | 详情 | 详情 | |
| (XII) | 66875 | 3-(1-(3-(dibenzylamino)phenyl)propyl)-4-hydroxy-6,6-dipropyl-5,6-dihydro-2H-pyran-2-one | C34H41NO3 | 详情 | 详情 | |
| (XIII) | 17235 | (6R)-3-[(1R)-1-[3-(dibenzylamino)phenyl]propyl]-4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one | C39H43NO3 | 详情 | 详情 | |
| (XIV) | 66876 | N-(3-(1-(4-hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-pyran-3-yl)propyl)phenyl)-5-(trifluoromethyl)pyridine-2-sulfonamide | C26H31F3N2O5S | 详情 | 详情 | |
| (XVI) | 17238 | 1-phenyl-4-hexyn-3-one | C12H12O | 详情 | 详情 | |
| (XVII) | 17239 | (2S,5R)-2-[(1S)-1-[3-(dibenzylamino)phenyl]propyl]-5-hydroxy-1-[(4R)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]-5-phenethyl-6-octyne-1,3-dione | C48H48N2O5 | 详情 | 详情 | |
| (XVIII) | 17240 | (6R)-3-[(1R)-1-[3-(dibenzylamino)phenyl]propyl]-4-hydroxy-6-phenethyl-6-(1-propynyl)-5,6-dihydro-2H-pyran-2-one | C39H39NO3 | 详情 | 详情 | |
| (XIX) | 17236 | (6R)-3-[(1R)-1-(3-aminophenyl)propyl]-4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one | C25H31NO3 | 详情 | 详情 |