(2S)-1-(2,4-difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone -Drug Synthesis Database

【结构式】

【分子编号】43511

【品名】(2S)-1-(2,4-difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone

【CA登记号】

【分子式】C₁₄H₁₆F₂O₃

【分子量】270.2760464

【元素组成】C 62.22% H 5.97% F 14.06% O 17.76%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XIX)

Alternatively, intermediate (XIII) can be obtained as follows: Heating of ethyl (S)-lactate (XIV) with morpholine affords amide (XVI), which then reacts with 3,4-dihydro-2H-pyran (A) in the presence of p-TsOH to give protected derivative (XVII). Grignard reaction between (XVII), bromo derivative (XVIII) and Mg turnings in THF yields protected ketone (XIX), which is treated with pyridinium p-toluenesulfonate (PPTS) (THP group removal) and reprotected by means of Tf2O and DIEA to give triflate derivative (XX). Conversion of (XX) into intermediate (XIII) is achieved by reaction with triazolone (VII) and NaH in THF.

参考文献中间体

合成目标

【1】 Tasaka, A.; Tamura, N.; Matsushita, Y.; Teranishi, K.; Hayashi, R.; Okonogi, K.; Itoh, K.; Optically active antifungal azoles. I. Synthesis and antifungal activity of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol and stereoisomers. Chem Pharm Bull 1993, 41, 6, 1035-42.
【2】 Kitazaki, T.; et al.; Optically active antifungal azoles. IX. An alternative synthetic route for 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone and its analogs. Chem Pharm Bull 1999, 47, 3, 360.

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)	13684	3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran	110-87-2	C₅H₈O	详情	详情
(VII)	43502	4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one		C₁₁H₉F₄N₃O₂	详情	详情
(XIII)	43507	2-[(1R)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one		C₂₀H₁₅F₆N₃O₃	详情	详情
(XIV)	43508	propyl (2S)-2-hydroxypropanoate	616-09-1	C₆H₁₂O₃	详情	详情
(XV)	10388	Morpholine	110-91-8	C₄H₉NO	详情	详情
(XVI)	41498	(2S)-2-hydroxy-1-(4-morpholinyl)-1-propanone		C₇H₁₃NO₃	详情	详情
(XVII)	43509	(2S)-1-(4-morpholinyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone		C₁₂H₂₁NO₄	详情	详情
(XVIII)	15488	1-bromo-2,4-difluorobenzene	348-57-2	C₆H₃BrF₂	详情	详情
(XIX)	43511	(2S)-1-(2,4-difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone		C₁₄H₁₆F₂O₃	详情	详情
(XX)	43510	(1S)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl trifluoromethanesulfonate		C₁₀H₇F₅O₄S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXV)

2) Propiophenone derivative (XXV) - prepared according to a procedure similar to that described for compound (XIX) - is subjected to a Grignard reaction with (chloromethyl)trimethylsilane (XXVI) and Mg in ether to give the silyl alcohol (XXVII), which by treatment with p-toluenesulfonic acid in MeOH undergoes b-elimination and deprotection to yield the allylic alcohol (XXVIII). Epoxidation of (XXVIII) with tert-butyl hydroperoxide and catalytic oxyvanadium acetylacetonate gives the epoxy-alcohol (XXIX), which is subjected to a Mitsunobu reaction with benzoic acid (XXX) by means of DEAD and PPh3 in THF to provide benzoate (XXXI). Solvolysis of compound (XXXI) in MeOH with catalytic NaOMe yields the epoxyalcohol (XXXII), which is mesylated with methanesulfonyl chloride and triethylamine in CH2Cl2 to afford the protected alcohol (XXXIII). Finally, treatment of compound (XXXIII) with 1H-1,2,4-triazole (XXIV) and NaH in DMF affords the desired intermediate (IX).

参考文献中间体

合成目标

【1】 Sorbera, L.A.; del Fresno, M.; Rabasseda, X.; CS-758. Drugs Fut 2003, 28, 3, 217.
【2】 Konos, T.; Miyaoka, T.; Tajima, Y.; Oida, S.; Triazole antifungals. III. Stereocontrolled synthesis of an optically active triazolylmethyloxirane precursor to antifungal oxazolodine derivatives. Chem Pharm Bull 1991, 39, 9, 2241.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	31738	1-[[(2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole		C₁₂H₁₁F₂N₃O	详情	详情
(XIV)	13135	1H-1,2,4-Triazole; 1,2,4-Triazole	288-88-0	C₂H₃N₃	详情	详情
(XXV)	43511	(2S)-1-(2,4-difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone		C₁₄H₁₆F₂O₃	详情	详情
(XXVI)	59954	(chloromethyl)(trimethyl)silane		C₄H₁₁ClSi	详情	详情
(XXVII)	59955	(3S)-2-(2,4-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(trimethylsilyl)-2-butanol		C₁₈H₂₈F₂O₃Si	详情	详情
(XXVIII)	59956	(2S)-3-(2,4-difluorophenyl)-3-buten-2-ol		C₁₀H₁₀F₂O	详情	详情
(XXIX)	27877	(1S)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]-1-ethanol		C₁₀H₁₀F₂O₂	详情	详情
(XXX)	10202	Benzoic acid	65-85-0	C₇H₆O₂	详情	详情
(XXXI)	43518	(1S)-1-[(2S)-2-(2,4-difluorophenyl)oxiranyl]ethyl benzoate		C₁₇H₁₄F₂O₃	详情	详情
(XXXII)	27875	(1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]-1-ethanol		C₁₀H₁₀F₂O₂	详情	详情
(XXXIII)	59957	(1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]ethyl methanesulfonate		C₁₁H₁₂F₂O₄S	详情	详情

Extended Information