【结 构 式】 |
【分子编号】45574 【品名】(2R)-1-(4-morpholinyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone 【CA登记号】 |
【 分 子 式 】C12H21NO4 【 分 子 量 】243.30308 【元素组成】C 59.24% H 8.7% N 5.76% O 26.3% |
合成路线1
该中间体在本合成路线中的序号:(V)The condensation of (R)-lactic acid (I) with morpholine (II) gives the corresponding morpholide (III), which is protected at the hydroxyl position with dihydropyran (IV) to yield the tetrahydropyranyl ether (V). The Grignard reaction of (V) with 2,4-difluorophenylmagnesium bromide (VI) affords the chiral 1-propanone (VII), which by a Corey's diastereoselective epoxidation with trimethylsulfoxonium iodide is converted into the oxirane (VIII). The opening of the oxirane ring of (VIII) by means of 1,2,4-triazole (IX) and NaH provides the tertiary alcohol (X), which is treated with pyridine p-toluenesulfonate to give the deprotected diol (XI) as a (2R,3R) and (2R,3S) 4:1 diastereomeric mixture, from which the desired (2R,3R)-isomer (XII) was isolated by crystallization. The reaction of (XII) with Ms-Cl and TEA, followed by cyclization with NaOMe, yields the oxirane (XIII), which is finally condensed with 7-chloroquinazolin-4(3H)-one (XIV) by means of K2CO3 in hot NMP.
【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】 Bartroli Orpi, J.; Anguita Lopez, M. (J. Uriach & Cia., SA); Method for preparing pyrimidone derivs. with antifungal activity. ES 2159488; WO 0166519 . |
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) | 11591 | methyl (2R)-2-hydroxypropanoate | 17392-83-5 | C4H8O3 | 详情 | 详情 |
(II) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
(III) | 56718 | (2R)-2-hydroxy-1-(4-morpholinyl)-1-propanone | C7H13NO3 | 详情 | 详情 | |
(IV) | 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 |
(V) | 45574 | (2R)-1-(4-morpholinyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone | C12H21NO4 | 详情 | 详情 | |
(VI) | 20262 | bromo(2,4-difluorophenyl)magnesium | C6H3BrF2Mg | 详情 | 详情 | |
(VII) | 56717 | (2S)-1-(2,4-difluorophenyl)-2-methyl-3-tetrahydro-2H-pyran-2-yl-1-propanone | C15H18F2O2 | 详情 | 详情 | |
(VIII) | 56719 | 2-({(1R)-1-[2-(2,4-difluorophenyl)-2-oxiranyl]ethyl}oxy)tetrahydro-2H-pyran; (1R)-1-[2-(2,4-difluorophenyl)-2-oxiranyl]ethyl tetrahydro-2H-pyran-2-yl ether | C15H18F2O3 | 详情 | 详情 | |
(IX) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
(X) | 56720 | (3R)-2-(2,4-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C17H21F2N3O3 | 详情 | 详情 | |
(XI) | 56721 | (3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol | C12H13F2N3O2 | 详情 | 详情 | |
(XII) | 13106 | (2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol | C12H13F2N3O2 | 详情 | 详情 | |
(XIII) | 31738 | 1-[[(2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole | C12H11F2N3O | 详情 | 详情 | |
(XIV) | 50077 | 7-chloro-4(3H)-quinazolinone | C8H5ClN2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(XXV)In a related procedure, protection of methyl (R)-lactate (XXIV) as the corresponding tetrahydropyranyl ether, followed by treatment with morpholine, gave amide (XXV). Subsequent addition of 2,4-difluorophenylmagnesium bromide (XXVI) to (XXV) afforded propiophenone (XXVII), which was converted into epoxide (XXVIII) by reaction with the ylide resulting from trimethylsulfoxonium iodide. Epoxide ring opening with 1,2,4-triazole (XVI) produced the triazolyl alcohol (XXIX). After acid cleavage of the tetrahydropyranyl protecting group of (XXIX), recrystallization of the diastereomeric mixture provided diol (XXX). Mesylation of the secondary hydroxyl group of (XXX), followed by basic cyclization of the resulting hydroxy mesylate (XXXI), produced epoxide (XXXII). Epoxide (XXXII) was reacted with 2,2-diethoxyethylamine (X) in the presence of Ti(iPrO)4 to give the amino alcohol (XXXIII). Condensation of amine (XXXIII) with carbamate (IX) generated urea (XXXIV), which was then cyclized to imidazolone (XVII) in the presence of HCl. This was finally converted to the title imidazolidinone by catalytic hydrogenation as above.
【3】 Kitazaki, T.; Matsushita, Y.; Hosono, H.; Itoh, K.; Mitsudera, H. (Takeda Chemical Industries, Ltd.); Triazole derivs. and their production. EP 0884311 . |
【1】 Ichikawa, T.; Matsushita, Y.; Yamada, M.; Tasaka, A.; Yamaguchi, M.; Itoh, K.; Okonogi, K.; Kitazaki, T.; TAK-456 and the water-soluble prodrug TAK-457, new antifungal triazoles: Synthesis and in vitro antifungal activity. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1085. |
【2】 Ichikawa, T.; et al.; Optically active antifungal azoles. XI. An alternative synthetic route for 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (TAK-456) and its analog. Chem Pharm Bull 2000, 48, 12, 1947. |
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) | 45560 | phenyl 4-(1H-1,2,3,4-tetraazol-1-yl)phenylcarbamate | C14H11N5O2 | 详情 | 详情 | |
(X) | 10331 | 2,2-Diethoxy-1-ethanamine; 2,2-Diethoxyethylamine; Aminoacetaldehyde diethyl acetal | 645-36-3 | C6H15NO2 | 详情 | 详情 |
(XVI) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
(XVII) | 45566 | 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-1,3-dihydro-2H-imidazol-2-one | C22H19F2N9O2 | 详情 | 详情 | |
(XXIV) | 11591 | methyl (2R)-2-hydroxypropanoate | 17392-83-5 | C4H8O3 | 详情 | 详情 |
(XXV) | 45574 | (2R)-1-(4-morpholinyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone | C12H21NO4 | 详情 | 详情 | |
(XXVI) | 20262 | bromo(2,4-difluorophenyl)magnesium | C6H3BrF2Mg | 详情 | 详情 | |
(XXVII) | 13102 | (2R)-1-(2,4-Difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone | C14H16F2O3 | 详情 | 详情 | |
(XXVIII) | 13103 | (1R)-1-[(2R)-2-(2,4-Difluorophenyl)oxiranyl]ethyl tetrahydro-2H-pyran-2-yl ether; 2-([(1R)-1-[(2R)-2-(2,4-Difluorophenyl)oxiranyl]ethyl]oxy)tetrahydro-2H-pyran | C15H18F2O3 | 详情 | 详情 | |
(XXIX) | 13105 | (2R,3R)-2-(2,4-Difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C17H21F2N3O3 | 详情 | 详情 | |
(XXX) | 13106 | (2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol | C12H13F2N3O2 | 详情 | 详情 | |
(XXXI) | 13107 | (1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl methanesulfonate | C13H15F2N3O4S | 详情 | 详情 | |
(XXXII) | 13114 | 1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole | C12H11F2N3O | 详情 | 详情 | |
(XXXIII) | 45572 | (2R,3R)-3-[(2,2-diethoxyethyl)amino]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C18H26F2N4O3 | 详情 | 详情 | |
(XXXIV) | 45573 | N-(2,2-diethoxyethyl)-N-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-N'-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]urea | C26H31F2N9O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(II)Addition of 2,5-difluorophenylmagnesium bromide (I) to the O-tetrahydropyranyl lactic acid amide (II) afforded the propiophenone derivative (III). Oxirane (IV) was then obtained by reaction of ketone (III) with the sulfur ylide generated from trimethylsulfoxonium iodide and either NaH or BuLi. Epoxide ring opening with the sodium salt of 1,2,4-triazole (V) led to the triazolyl alcohol (VI) as a mixture of diastereoisomers. After acid hydrolysis of the tetrahydropyranyl protecting group of (VI), the resultant mixture of diols was separated by column chromatography. The desired (R,R) diastereoisomer (VII) was converted to epoxide (IX) via formation of mesylate (VIII), which was subsequently cyclized in the presence of NaOMe. Nitrile (X) was then obtained by reaction of oxirane (IX) with either trimethylsilyl cyanide, followed by desilylation with Bu4NF, or with acetone cyanohydrin and LiH. Conversion of nitrile (X) into thioamide (XI) was accomplished by treatment with diethyl dithiophosphate. Cyclization of thioamide (XI) with 4-cyanophenacyl bromide (XII) gave rise to the thiazole derivative (XIII).
【1】 Yamazaki, T.; Sakai, T.; Shimma, N.; Umeda, I.; Ichihara, S.; Ohwada, J.; Hayase, T.; Isshiki, Y.; Liu, P.; Tsukazaki, M. (F. Hoffmann-La Roche AG); 3-[4-(4-Cyanophenyl)thiazol-2-yl)]-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol derivs. having antifungal activity. US 6300353; WO 9945008 . |
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) | 55920 | bromo(2,5-difluorophenyl)magnesium | C6H3BrF2Mg | 详情 | 详情 | |
(II) | 45574 | (2R)-1-(4-morpholinyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone | C12H21NO4 | 详情 | 详情 | |
(III) | 55921 | (2R)-1-(2,5-difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone | C14H16F2O3 | 详情 | 详情 | |
(IV) | 55922 | (1R)-1-[2-(2,5-difluorophenyl)-2-oxiranyl]ethyl tetrahydro-2H-pyran-2-yl ether; 2-({(1R)-1-[2-(2,5-difluorophenyl)-2-oxiranyl]ethyl}oxy)tetrahydro-2H-pyran | C15H18F2O3 | 详情 | 详情 | |
(V) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
(VI) | 55923 | (3R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C17H21F2N3O3 | 详情 | 详情 | |
(VII) | 55924 | (2R,3R)-2-(2,5-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol | C12H13F2N3O2 | 详情 | 详情 | |
(VIII) | 55925 | (1R,2R)-2-(2,5-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl methanesulfonate | C13H15F2N3O4S | 详情 | 详情 | |
(IX) | 55926 | 1-{[(2S,3R)-2-(2,5-difluorophenyl)-3-methyloxiranyl]methyl}-1H-1,2,4-triazole | C12H11F2N3O | 详情 | 详情 | |
(X) | 55927 | (2S,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile | C13H12F2N4O | 详情 | 详情 | |
(XI) | 55928 | (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanethioamide | C13H14F2N4OS | 详情 | 详情 | |
(XII) | 17122 | 4-(2-bromoacetyl)benzonitrile; 4-Cyanophenacyl bromide | 20099-89-2 | C9H6BrNO | 详情 | 详情 |
(XIII) | 55929 | 4-{2-[(1R,2R)-2-(2,5-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1,3-thiazol-4-yl}benzonitrile | C22H17F2N5OS | 详情 | 详情 |