5-(trifluoromethyl)-2-pyridinesulfonyl chloride -Drug Synthesis Database

【结构式】

【分子编号】17237

【品名】5-(trifluoromethyl)-2-pyridinesulfonyl chloride

【CA登记号】

【分子式】C₆H₃ClF₃NO₂S

【分子量】245.6092696

【元素组成】C 29.34% H 1.23% Cl 14.43% F 23.21% N 5.7% O 13.03% S 13.06%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(XIII)

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

参考文献中间体

合成目标

【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：(XVI)

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.

参考文献中间体

合成目标

【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	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3

该中间体在本合成路线中的序号：(IX)

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.

参考文献中间体

合成目标

【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

Extended Information