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【结 构 式】

【分子编号】13135

【品名】1H-1,2,4-Triazole; 1,2,4-Triazole

【CA登记号】288-88-0

【 分 子 式 】C2H3N3

【 分 子 量 】69.06604

【元素组成】C 34.78% H 4.38% N 60.84%
与该中间体有关的原料药合成路线共 40 条
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合成路线1

该中间体在本合成路线中的序号：(III)

The reaction of 1-(4-chlorophenoxy)-3,3-dimethyl-2-butanone (I) with dimethyl sulfide, dimethyl sulfate and sodium methoxide in acetonitrile gives 2,4-chlorophenoxymethyl)-2-(tertbutyl)oxirane (II), which is then condensed with 1,2,4-triazole (III) in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Holmwood, G.; Buechel, K.H.; Luerssen, K.; Frohberger, P.E.; Brandes, W.; Oxirane compounds. EP 0040345; EP 0072580; EP 0087148; ES 8203859; JP 2167270; JP 2167273; US 4532341; US 4626595; US 4723984; US 4789672; US 4871390; US 4897107; US 4904298; US 4911746 .
【2】 Holmwood, G.; Buechel, K.H.; Plempel, M.; Haller, T.; Antimicrobial azoles. DE 3018865; EP 0043419; JP 57009715; US 4652579 .
【3】 Fromtling, R.A.; Serradell, M.N.; Castaner, J.; BAY-N-7133. Drugs Fut 1984, 9, 6, 404.
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) 34149 1-(4-chlorophenoxy)-3,3-dimethyl-2-butanone C12H15ClO2 详情 详情
(II) 34150 2-(tert-butyl)-2-[(4-chlorophenoxy)methyl]oxirane; [2-(tert-butyl)-2-oxiranyl]methyl 4-chlorophenyl ether C13H17ClO2 详情 详情
(III) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情

合成路线2

该中间体在本合成路线中的序号：(IV)

The Friedel-Crafts' condensation of 1,3-difluorobenzene (I) with chloroacetyl chloride (II) by means of AlCl3 yields alpha-chloro-2,4-difluoroacetophenone (III), which is treated with 1,2,4-triazole (IV) and triethylamine in refluxing ethyl acetate giving alpha-(1H-12,4-triazol-1-yl)-2,4-diftuoroacetophenone (V). The reaction of (V) with trimethylsulfoxonium iodide (VI) by means of NaOH in toluene affords 1-[2-(2,4-di fluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-triazole (VII), which is finally treated again with 1,2,4-triazole (IV) and K2CO3 in hot DMF.

参考文献 中间体
合成目标
【1】 Narayanaswami, S.; Richardson, K. (Pfizer Inc.); Triazole antifungal agents. EP 0096569; ES 523038 .
【2】 Richardson, K. (Pfizer Inc.); Triazoles. GB 2099818; US 4404216 .
【3】 Fromtling, R.A.; Castaner, J.; Serradell, M.N.; Fluconazole. Drugs Fut 1985, 10, 12, 982.
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) 13095 m-Difluorobenzene; 1,3-Difluorobenzene 372-18-9 C6H4F2 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 16321 2-Chloro-2',4'-difluoroacetophenone; 2-Chloro-1-(2,4-difluorophenyl)-1-ethanone 51336-94-8 C8H5ClF2O 详情 详情
(IV) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(V) 15372 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)-1-ethanone; 2,4-Difluoro-alpha-(1H-1,2,4-triazolyl)acetophenone 863867-75-6 C10H7F2N3O 详情 详情
(VI) 29693 Trimethylsulfoxonium iodide 1774-47-6 C3H9IOS 详情 详情
(VII) 29839 1-[[2-(2,4-difluorophenyl)-2-oxiranyl]methyl]-1H-1,2,4-triazole 86386-76-7 C11H9F2N3O 详情 详情

合成路线3

该中间体在本合成路线中的序号：(II)

The condensation of 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-(benzoyloxymethyl)-1,3-dioxolane (I) with triazole (II) by means of NaH in DMSO, followed by hydrolysis with NaOH in dioxane water gives 2-(2,4-dichlorophenyl)-2-(1H)-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol (III), which is acylated with methanesulfonyl chloride in pyridine affording the corresponding 4-mesyloxymethyldioxolane (IV). Finally, this compound is condensed with 4-(4-isopropylpiperazin-1-yl)phenol (V) by means of NaH in hot DMSO. Compound (V) is obtained as follows: 4-(4-methoxyphenyl)piperazine (VI) is reductocondensed with acetone (A) by means of H2 over Pd/C giving 1-isopropyl-4-(4-methoxyphenyl)piperazine (VII), which is then demethylated with refluxing aqueous 48% HBr yielding (V)

参考文献 中间体
合成目标
【1】 Van Cutsem, J.; Heeres, J.; Hendrickx, R.; Antimycotic azoles. 6. Synthesis and antifungal properties of terconazole, a novel triazole ketal. J Med Chem 1983, 26, 4, 611-613.
【2】 Heeres, J.; Backx, L.J.J.; Mostmans, J.H. (Janssen Pharmaceutica NV); Novel 1-(1,3-dioxolan-2-ylmethyl)-1H-imidazoles. BE 0863382; FR 2378778; GB 1594859; JP 7895973; US 4144346; US 4223036 .
【3】 Serradell, M.N.; Castaner, J.; Fromtling, R.A.; Terconazole. Drugs Fut 1984, 9, 7, 529.
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) 30488 4-(4-isopropyl-1-piperazinyl)phenol; 1-Isopropyl-4-(4-hydroxyphenyl)piperazine C13H20N2O 详情 详情
(I) 30485 [(2S,4S)-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl benzoate; cis-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl benzoate C18H15BrCl2O4 详情 详情
(II) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(III) 30486 [(2S,4R)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methanol C13H13Cl2N3O3 详情 详情
(IV) 30487 1-[[(2S,4S)-2-(2,4-dichlorophenyl)-4-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole C16H19Cl2N3O3S 详情 详情
(V) 16312 1-(4-Methoxyphenyl)piperazine; Methyl 4-piperazinophenyl ether 38212-30-5 C11H16N2O 详情 详情
(VI) 23199 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether 67-64-1 C3H6O 详情 详情
(VII) 30489 1-isopropyl-4-(4-methoxyphenyl)piperazine; 4-(4-isopropyl-1-piperazinyl)phenyl methyl ether C14H22N2O 详情 详情

合成路线4

该中间体在本合成路线中的序号：(XI)

A new synthesis of the active (R,R)-isomer of SM-8668 has been reported: The Friedel-Crafts condensation of 1,3-difluorobenzene (I) with 2-bromopropionyl bromide (II) by means of AlCl3 gives the corresponding propiophenone (III), which is treated with sodium methylmercaptide to yield 2',4'-difluoro-2-(methylsulfanyl)propiophenone (IV). The reaction of (IV) with trimethylsulfoxonium chloride affords the epoxide (V) as a D,L-threo-mixture of isomers, which is treated with a chiral carboxylic acid (VI), giving the diastereomeric mixture of esters (VII). The separation of the isomers by column chromatography or fractional crystallization affords the (2R,3R)-isomer (VIII), which by hydrolysis with NaOH is converted to the diol (IX). The epoxidation of the diol (IX) with mesyl chloride, NaOH and benzyltriethylammonium chloride yields the (2R,3R)-epoxide (X), which is condensed with 1,2,4-triazole (XI) by means of NaOH to give the precursor (XII). Finally, this compound is oxidized with H2O2 and sodium tungstate.

参考文献 中间体
合成目标
【1】 Tanio, T.; Miyauchi, H.; Ohashi, N.; Synthesis and antifungal activities of optically active isomers of SM-8668. Bioorg Med Chem Lett 1995, 5, 9, 933.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(D,L-threo(V)) 13130 (1R)-1-[(2R)-2-(2,4-Difluorophenyl)oxiranyl]ethyl methyl sulfide; (2R)-2-(2,4-Difluorophenyl)-2-[(1R)-1-(methylsulfanyl)ethyl]oxirane C11H12F2OS 详情 详情
(D,L-threo(VII) 13132 (2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-(methylsulfanyl)butyl acetate C13H16F2O3S 详情 详情
(I) 13095 m-Difluorobenzene; 1,3-Difluorobenzene 372-18-9 C6H4F2 详情 详情
(II) 13127 2-Bromopropionyl bromide; 2-Bromopropanoyl bromide 563-76-8 C3H4Br2O 详情 详情
(III) 13128 2-Bromo-1-(2,4-difluorophenyl)-1-propanone C9H7BrF2O 详情 详情
(IV) 13129 1-(2,4-Difluorophenyl)-2-(methylsulfanyl)-1-propanone C10H10F2OS 详情 详情
(IX) 13133 (2R,3R)-2-(2,4-Difluorophenyl)-3-(methylsulfanyl)-1,2-butanediol C11H14F2O2S 详情 详情
(X) 13130 (1R)-1-[(2R)-2-(2,4-Difluorophenyl)oxiranyl]ethyl methyl sulfide; (2R)-2-(2,4-Difluorophenyl)-2-[(1R)-1-(methylsulfanyl)ethyl]oxirane C11H12F2OS 详情 详情
(XI) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(XII) 13108 (2R,3R)-2-(2,4-Difluorophenyl)-3-(methylsulfanyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol C13H15F2N3OS 详情 详情

合成路线5

该中间体在本合成路线中的序号：(II)

Reaction of 4-bromomethylbenzonitrile (I) with 1,2,4-triazole (II) in chloroform - acetonitrile gives 1-(4-cyanophenyl)methyl-1,2,4-triazole (III), which is treated with potassium tert-butoxide and 4-fluorobenzonitrile (IV) in DMF.

参考文献 中间体
合成目标
【1】 Bowman, R.M.; Steele, R.E.; Browne, L.J. (Novartis AG); Alpha-heterocycle substd. Tolunitriles. EP 0236940; JP 1987212369 .
【2】 Graul, A.; Castaner, J.; Prous, J.; Letrozole. Drugs Fut 1994, 19, 4, 335.
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) 14132 4-Chloro-1H-pyrazole 15878-00-9 C3H3ClN2 详情 详情
(I) 14200 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile 17201-43-3 C8H6BrN 详情 详情
(II) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(III) 14202 4-(1H-1,2,4-Triazol-1-ylmethyl)benzonitrile C10H8N4 详情 详情
(IV) 14144 4-Fluorobenzonitrile 1194-02-1 C7H4FN 详情 详情

合成路线6

该中间体在本合成路线中的序号：(X)

The reaction of 3-chloro-4-nitrobenzoic acid (I) with methylamine gives 3-(methylamino)-4-nitrobenzoic acid (II), which is hydrogenated in the presence of Raney Nickel to yield 4-amino-3-(methylamino)benzoic acid (III). Treatment of compound (III) with sodium nitrite affords 1-methyl-1H-benzotriazole-6-carboxylic acid (IV), which is reduced with lithium aluminum hydride in THF to give 6-(hydroxymethyl)-1-methyl-1H-benzotriazole (V). Oxidation of (V) with potassium permanganate in dichloroethane yields 1-methyl-1H-benzotriazole-6-carboxaldehyde (VI), which on treatment with the Grignard reagent derived from 1-bromo-4-chlorobenzene (VII) gives 6-(4-chloro-alpha-hydroxybenzyl)-1-methyl-1H-benzotriazole (VIII). Treatment of compound (VIII) with thionyl chloride in THF yields 6-(alpha,4-dichlorobenzyl)-1-methyl-1H-benzotriazole (IX), which is finally condensed with 1,2,4-triazole (X) and sodium hydride in DMF.

参考文献 中间体
合成目标
【1】 Raeymaekers, A.H.M.; Freyne, E.J.E.; Van Gelder, J.L.H.; Vener, M.G. (Janssen Pharmaceutica NV); (1H-Arol-1-ylmethyl)substd. Benzotriazole derivatives. AU 8816537; EP 0293978; JP 1988316775 .
【2】 Graul, A.; Prous, J.; Castaner, J.; Vorozole. Drugs Fut 1994, 19, 5, 457.
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) 14727 3-chloro-4-nitrobenzoic acid C7H4ClNO4 详情 详情
(II) 14728 3-(methylamino)-4-nitrobenzoic acid C8H8N2O4 详情 详情
(III) 14729 4-amino-3-(methylamino)benzoic acid C8H10N2O2 详情 详情
(IV) 14730 1-methyl-1H-1,2,3-benzotriazole-6-carboxylic acid C8H7N3O2 详情 详情
(V) 14731 (1-methyl-1H-1,2,3-benzotriazol-6-yl)methanol C8H9N3O 详情 详情
(VI) 14732 1-methyl-1H-1,2,3-benzotriazole-6-carbaldehyde C8H7N3O 详情 详情
(VII) 14733 4-Bromochlorobenzene; 1-bromo-4-chlorobenzene 106-39-8 C6H4BrCl 详情 详情
(VIII) 14734 (4-chlorophenyl)(1-methyl-1H-1,2,3-benzotriazol-6-yl)methanol C14H12ClN3O 详情 详情
(IX) 14735 6-[chloro(4-chlorophenyl)methyl]-1-methyl-1H-1,2,3-benzotriazole C14H11Cl2N3 详情 详情
(X) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情

合成路线7

该中间体在本合成路线中的序号：(XVIII)

By condensation of 3-[2(E)-(4-(2,2,3,3-tetrafluoropropoxy)phenyl)vinyl]-1H-1,2,4-triazole (I) with (+)-(R)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-epoxypropane (II) by means of anhydrous K2CO3 in hot DMF. The starting products (I) and (II) are obtained as follows: a) The condensation of 4-chlorobenzonitrile (III) with 2,2,3,3-tetrafluoropanol (IV) by means of NaH in DMF gives 4-(2,2,3,3-tetrafluoropropoxy)benzonitrile (V), which is reduced to the corresponding benzaldehyde (VI) with diisobutylaluminum hydride in toluene. The condensation of diethoxyphosphorylacetic acid ethyl ester (VII) with aldehyde (VI) by means of KOH in THF yields (E)-4-(2,2,3,3-tetrafluoropropoxy)cinnamic acid ethyl ester (VIII), which is saponified to the corresponding acid (IX) with NaOH in ethanol-water. The reaction of (IX) first with refluxing SOCl2 and then with aqueous ammonia in toluene affords the corresponding amide (X), which is finally condensed with formyl hydrazide (XI) by means of trimethyloxonium tetrafluoroborate in CH2Cl2 to give (I). b) The reaction of 1,3-dichloroacetone (XII) with 2,4-difluorobromobenzene (XIII) by means of butyllithium in ether gives 1,3-dichloro-2-(2,4-difluorophenyl)-2-propanol (XIV), which is converted into 3-chloro-2-(2,4-difluorophenyl)-1,2-epoxypropane (XV) by treatment with NaH in DMF. The reaction of (XV) with tellurium and sodium hydroxymethylsulfinate in water yields 2-(2,4-difluorophenyl)allyl alcohol (XVI), which by stereoselective epoxidation with titanium tetraisopropoxide and diethyl (+)-tartrate in methylene chloride is converted into (R)-(-)-2-(2,4-difluorophenyl)-2,3-epoxypropanol (XVII). The reaction of (XVII) with 1,2,4-triazole (XVIII) by means of K2CO3 in THF affords (S)-(-)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazole-1-yl)-propane-1,2-diol (XIX), which is finally treated with methanesulfonyl chloride and triethylamine in ether to give (II).

参考文献 中间体
合成目标
【1】 Murakami, K.; Mochizuki, H. (AstraZeneca plc; Mochida Pharmaceutical Co., Ltd.); Optically active triazole derivs. and compsns. EP 0472392; JP 1993009183 .
【2】 Fromtling, R.A.; Castaner, J.; ICI-D0870. Drugs Fut 1993, 18, 5, 424.
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) 15476 2,2,3,3-tetrafluoropropyl 4-[(E)-2-(1H-1,2,4-triazol-3-yl)ethenyl]phenyl ether; 3-[(E)-2-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]ethenyl]-1H-1,2,4-triazole C13H11F4N3O 详情 详情
(II) 15477 1-[[(2R)-2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole C11H9F2N3O 详情 详情
(III) 15478 4-methylcyclohexanecarbonitrile C8H13N 详情 详情
(IV) 15479 2,2,3,3-tetrafluoro-1-propanol 76-37-9 C3H4F4O 详情 详情
(V) 15480 4-(2,2,3,3-tetrafluoropropoxy)benzonitrile C10H7F4NO 详情 详情
(VI) 15481 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde C10H8F4O2 详情 详情
(VII) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(VIII) 15483 ethyl (E)-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-propenoate C14H14F4O3 详情 详情
(IX) 15484 (E)-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-propenoic acid C12H10F4O3 详情 详情
(X) 15485 (E)-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-propenamide C12H11F4NO2 详情 详情
(XI) 15486 formic hydrazide; Formylhydrazine 624-84-0 CH4N2O 详情 详情
(XII) 63907 1,3-dichloroacetone C3H4Cl2O 详情 详情
(XIII) 15488 1-bromo-2,4-difluorobenzene 348-57-2 C6H3BrF2 详情 详情
(XIV) 15489 1,3-dichloro-2-(2,4-difluorophenyl)-2-propanol C9H8Cl2F2O 详情 详情
(XV) 15490 2-(chloromethyl)-2-(2,4-difluorophenyl)oxirane C9H7ClF2O 详情 详情
(XVI) 15491 2-(2,4-difluorophenyl)-2-propen-1-ol C9H8F2O 详情 详情
(XVII) 64587 [(2R)-2-(2,4-difluorophenyl)oxiranyl]methanol C9H8F2O2 详情 详情
(XVIII) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(XIX) 15494 (2S)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol C11H11F2N3O2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(XVIII)

The intermediate (XIX) can be obtained by two related ways: 1. The condensation of 1,3-dichloroacetone (XIII) with 2,4-difluorobromobenzene (XII) by means of n-BuLi gives 1,3-dichloro-2-(2,4-difluorophenyl)-2-propanol (XIV), which is converted into the epoxide (XV) by reaction with KOH in toluene. The reaction of (XV) with isobutyric anhydride (XXII) yields the diester (XX), which is stereoselectively hydrolyzed with Lipase D in an acetate buffer to afford the (R)-monoester (XXIV). The reaction of (XXIV) with Ms-Cl and pyridine provides the monomesylate (XXV), which is treated with KOH in toluene to give the hydroxymethyl epoxide (XVII). Finally, this compound is treated with 1,2,4-triazole (XVIII) and K2CO3 in refluxing THF to afford the target intermediate. Alternatively, the mesylate (XXV) can be treated with 1,2,4-triazole (XVIII) and Na2CO3 in refluxing methanol to yield directly the target intermediate (XIX). 2. The acylation of 1,3-dihydroxypropanone (XXI) with butyric anhydride (XXII), pyridine and DMAP gives the diester (XXIII), which is submitted to a Grignard condensation with 2,4-difluorobromobenzene (XIII) by means of Mg to afford the already described intermediate, the diester (XIX).

参考文献 中间体
合成目标
【1】 Yasohara, Y.; et al.; A practical chemoenzymatic synthesis of a key intermediate of antifungal agents. Tetrahedron Lett 2001, 42, 19, 3331.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 63907 1,3-dichloroacetone C3H4Cl2O 详情 详情
(XIII) 15488 1-bromo-2,4-difluorobenzene 348-57-2 C6H3BrF2 详情 详情
(XIV) 15489 1,3-dichloro-2-(2,4-difluorophenyl)-2-propanol C9H8Cl2F2O 详情 详情
(XV) 15490 2-(chloromethyl)-2-(2,4-difluorophenyl)oxirane C9H7ClF2O 详情 详情
(XVII) 17058 [(2S)-2-(2,4-difluorophenyl)oxiranyl]methanol C9H8F2O2 详情 详情
(XVIII) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(XIX) 15494 (2S)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol C11H11F2N3O2 详情 详情
(XX) 50741 2-(2,4-difluorophenyl)-2-hydroxy-3-(isobutyryloxy)propyl 2-methylpropanoate C17H22F2O5 详情 详情
(XXI) 14575 Dihydroxyacetone; 1,3-dihydroxyacetone 96-26-4 C3H6O3 详情 详情
(XXII) 22334 1-methylpropionic anhydride 97-72-3 C8H14O3 详情 详情
(XXIII) 50742 3-(isobutyryloxy)-2-oxopropyl 2-methylpropanoate C11H18O5 详情 详情
(XXIV) 50743 (2R)-2-(2,4-difluorophenyl)-2,3-dihydroxypropyl 2-methylpropanoate C13H16F2O4 详情 详情
(XXV) 50744 (2S)-2-(2,4-difluorophenyl)-2-hydroxy-3-[(methylsulfonyl)oxy]propyl 2-methylpropanoate C14H18F2O6S 详情 详情

合成路线9

该中间体在本合成路线中的序号：(XVII)

The intermediate (II) can be obtained as follows: 2) The reaction of 2,4-difluorophenacyl chloride (XII) with sodium acetate and NaI in DMF gives the acetoxy derivative (XIII), which is treated with methyltriphenylphosphonium bromide and sodium bis(trimethylsilyl)amide in THF yielding 2-(2,4-difluorophenyl)-2-propen-1-ol acetate (XIV). The saponification of (XIV) with KOH in water affords the unsaturated alcohol (XV), which is regioselectively epoxidized with titanium tetraisopropoxide, tert-butyl hydroperoxide and L-(+)-tartaric acid diethyl ester giving (S)-(-)-[2-(2,4-difluorophenyl)oxiran-2-yl]methanol (XVI). The condensation of epoxide (XVI) with 1,2,4-triazole (XVII) by means of NaH in DMF yields (R)-(-)-2-(2,4-difluorophenyl)-3-(1,2,4-triazol-1-yl)propane-1,2-diol (XVIII), which is treated with methanesulfonyl chloride and triethylamine affording the corresponding mesyl ester (XIX). Cyclization of (XIX) with NaOH in DMF affords the corresponding epoxide (XX), which is condensed with diethyl malonate (XXI) by means of NaH in DMSO giving 5(R)-(2,4-difluorophenyl)-2-oxo-5-(1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-carboxylic acid ethyl ester (XXII). The reduction of (XXII) with NaBH4 in ethanol yields the 4(R)-(2,4-difluorophenyl)-2-(hydroxymethyl)-5-(1,2,4-triazol-1-yl)penta n-1,4-diol (XXIII), which is selectively esterified with p-toluenesulfonyl chloride and dimethylaminopyridine/triethylamine to primary monosulfonate (XXIV). Finally, this compound is cyclized to (II) by means of NaH in refluxing toluene.

参考文献 中间体
合成目标
【1】 Van Cutsem, J.; Backx, L.J.J.; Heeres, J.; J. Antimycotic azoles. 7. Synthesis and antifungal properties of a series of novel triazol-3-ones. J Med Chem 1984, 27, 7, 894-900.
【2】 Castañer, J.; Fromtling, R.A.; SCH 51048. Drugs Fut 1995, 20, 3, 241.
【3】 Saksena, A.K.; Girijavallabhan, V.M.; Ganguly, A.K.; Lovey, R.G. (Schering Corp.); Tri-substd. tetrahydrofuran antifungals. EP 0610377; JP 1995500605; WO 9309114 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 16311 [(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-methylbenzenesulfonate C21H21F2N3O4S 详情 详情
(XII) 16321 2-Chloro-2',4'-difluoroacetophenone; 2-Chloro-1-(2,4-difluorophenyl)-1-ethanone 51336-94-8 C8H5ClF2O 详情 详情
(XIII) 16322 2-(2,4-Difluorophenyl)-2-oxoethyl acetate C10H8F2O3 详情 详情
(XIV) 16323 2-(2,4-difluorophenyl)-2-propenyl acetate C11H10F2O2 详情 详情
(XV) 15491 2-(2,4-difluorophenyl)-2-propen-1-ol C9H8F2O 详情 详情
(XVI) 17058 [(2S)-2-(2,4-difluorophenyl)oxiranyl]methanol C9H8F2O2 详情 详情
(XVII) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(XVIII) 16327 (2R)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol C11H11F2N3O2 详情 详情
(XIX) 16328 (2R)-2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl methanesulfonate C12H13F2N3O4S 详情 详情
(XX) 15477 1-[[(2R)-2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole C11H9F2N3O 详情 详情
(XXII) 16331 ethyl (5R)-5-(2,4-difluorophenyl)-2-oxo-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furancarboxylate C16H15F2N3O4 详情 详情
(XXIII) 16332 (4R)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-5-(1H-1,2,4-triazol-1-yl)-1,4-pentanediol C14H17F2N3O3 详情 详情
(XXIV) 16333 (2S,4R)-4-(2,4-difluorophenyl)-4-hydroxy-2-(hydroxymethyl)-5-(1H-1,2,4-triazol-1-yl)pentyl 4-methylbenzenesulfonate C21H23F2N3O5S 详情 详情

合成路线10

该中间体在本合成路线中的序号：(XXVI)

Compound (XIII) can follow two different routes for its conversion into the intermediate product (XXIV): i) Reaction of (XIII) with vinylmagnesium bromide (XXI) in THF provides vinyl derivative (XXII), which is then converted into aldehyde (XXIII) by ozonolysis, followed by addition of dimethylsulfide (DMS). Reduction of aldehyde (XXIII) by means of NaBH4 in MeOH affords alcohol (XXIV). Conversion of (XXII) into (XXIV) can also be achieved by first treatment with NaIO4 and OsO4 in MeOH/H2O followed by reduction with NaBH4 in MeOH. ii) Treatment of (XIII) with (dimethylisopropoxysilyl)-methylmagnesium chloride (XXVII) in THF provides derivative (XXVIII), which is then converted into (XXIV) by treatment with H2O2/NaHCO3 in MeOH-THF. Final conversion of (XXIV) into the target product is achieved by first mesylation of (XXIV) by means of MsCl and Et3N in EtOAc to yield mesylated derivative (XXV), followed by its reaction with 1H-1,2,4-triazole in DMF in the presence of K2CO3.

参考文献 中间体
合成目标
【1】 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
(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
(XXI) 16524 bromo(vinyl)magnesium 1826-67-1 C2H3BrMg 详情 详情
(XXII) 43513 2-[(1R,2S)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-butenyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one C22H19F6N3O3 详情 详情
(XXIII) 43515 (2S,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[5-oxo-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl]butanal C21H17F6N3O4 详情 详情
(XXIV) 43516 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-dihydroxy-1-methylpropyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one C21H19F6N3O4 详情 详情
(XXV) 43517 2-((1R,2S)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]propyl)-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one C24H25F6N3O4S 详情 详情
(XXVI) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(XXVII) 43512 chloro[[isopropoxy(dimethyl)silyl]methyl]magnesium C6H15ClMgOSi 详情 详情
(XXVIII) 43514 2-[(1R,2S)-2-(2,4-difluorophenyl)-2-hydroxy-3-[isopropoxy(dimethyl)silyl]-1-methylpropyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one C26H31F6N3O4Si 详情 详情

合成路线11

该中间体在本合成路线中的序号：(XXVI)

Alternatively, derivative (XXIX) can be obtained in an analogous way as its enantiomer (XIX). Diastereoselective epoxidation of (XXIX) with trimethylsulfoxonium iodide and NaH in DMSO provides oxirane (XXX) (3). THP group removal by means of PPTS in EtOH, followed by reaction with 3,5-dinitrobenzoyl chloride (XXXI) and NaHCO3 in CH2Cl2, yields a diastereomeric mixture from which dinitrobenzoate derivative (2R,3R)-(XXXII) is obtained by recrystallization (1). Hydrolysis of (2R,3R)-(XXXII) in MeOH by treatment with aqueous NaOH gives compound (2R,3R)-(XXXIII), which is converted into ester (2R,3S)-(XXXIV) by Mitsunobu reaction with benzoic acid, Ph3P and DEAD in THF. Subsequent debenzoylation of (2R,3S)-(XXXIV) with NaOMe in MeOH affords oxiranyl ethanol derivative (2R,3R)-(XXXV), which is first converted into its triflate derivative by means of Tf2O and DIEA in CH2Cl2, and then into triazolone derivative (2S,3R)-(XXXVI) by reaction with intermediate (VII) and NaH in CH2Cl2/DMF. Finally, oxirane derivative (2S,3R)-(XXXVI) reacts with triazole (XXVI) and NaH in DMF to furnish the desired product.

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】 Tamura, N.; Okonogi, K.; Hayashi, R.; Matsushita, Y.; Kitazaki, T.; Tasaka, A.; Itoh, K.; Optically active antifungal azoles.VI. Synthesis and antifungal activity of N-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-N'-(4-substituted phenyl)-3(2H,4H)-1,2,4-triazolones and 5(1H,4H)-tetrazolones. Chem Pharm Bull 1996, 44, 2, 314.
【3】 Itoh, K.; Okonogi, K.; Tamura, N. (Takeda Chemical Industries, Ltd.); Azole cpds., their production and use. EP 0567982; US 5371101 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXXXIV) 43518 (1S)-1-[(2S)-2-(2,4-difluorophenyl)oxiranyl]ethyl benzoate C17H14F2O3 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
(XXVI) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(XXIX) 13102 (2R)-1-(2,4-Difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone C14H16F2O3 详情 详情
(XXX) 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
(XXXI) 12053 3,5-Dinitrobenzoyl chloride 99-33-2 C7H3ClN2O5 详情 详情
(XXXII) 27874 (1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]ethyl 3,5-dinitrobenzoate C17H12F2N2O7 详情 详情
(XXXIII) 27875 (1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]-1-ethanol C10H10F2O2 详情 详情
(XXXV) 27877 (1S)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]-1-ethanol C10H10F2O2 详情 详情
(XXXVI) 43519 2-[(1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]ethyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one C21H17F6N3O3 详情 详情

合成路线12

该中间体在本合成路线中的序号：(XXVI)

Alternatively, oxirane derivative (XXX) reacts with 1H-1,2,4-triazole (XXVI) and NaH in DMF to yield butanol derivative (XXXVII), which is treated with p-TsOH for THP removal followed by recrystallization to obtain diastereomer (2R,3R)-(XXXVIII). Conversion of (2R,3R)-(XXXVIII) into the corresponding mesylate derivative by means of MsCl and Et3N in AcOEt, followed by treatment with NaOMe in MeOH, gives oxirane (2R,3S)-(XXXIX), which is finally condensed with (VII) by means of K2CO3 or KHCO3 or LiOH in DMF. Alternatively, (2R,3R)-(XXXVIII) can be converted into p-toluenesulfonyloxy derivative (2R,3R)-(XL) (or, alternatively, its mesylate derivative), which is finally condensed with (VII) and K2CO3 in DMF.

参考文献 中间体
合成目标
【1】 Tasaka, A.; et al.; Optically active antifungal azoles. IV. Synthesis and antifungal activity of (2R,3R)-3-azolyl-2-(substituted phenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanols. Chem Pharm Bull 1995, 43, 3, 432.
【2】 Itoh, K.; Tasaka, A.; Matsushita, Y. (Takeda Chemical Industries, Ltd.); Optically active azole derivs., their production and use. CA 2134417; EP 0659751; JP 1995228574 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(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
(XXVI) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(XXX) 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
(XXXVII) 43520 (2S,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
(XXXVIII) 43521 (2S,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol C12H13F2N3O2 详情 详情
(XXXIX) 13114 1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole C12H11F2N3O 详情 详情
(XL) 43522 (1R,2S)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl 4-methylbenzenesulfonate C19H19F2N3O4S 详情 详情

合成路线13

该中间体在本合成路线中的序号：(IV)

The 2-(chloromethyl)quinoline (III) was synthesized by Friedländer reaction of aminobenzophenone (I) with ethyl 4-chloroacetoacetate (II) in the presence of H2SO4 in AcOH at 100 C. Then, displacement of the halogen atom of (III) with the sodium salt of 1,2,4-triazole (IV) in DMF at 80 C afforded the target compound.

参考文献 中间体
合成目标
【1】 Baba, A.; et al.; Studies on disease-modifying antirheumatic drugs. III. Bone resorption inhibitory effects of ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylate (TAK-603) and related compounds. Chem Pharm Bull 1999, 47, 3, 369.
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) 31794 (2-amino-4,5-dimethoxyphenyl)(3,4-dimethoxyphenyl)methanone C17H19NO5 详情 详情
(II) 23541 ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate 638-07-3 C6H9ClO3 详情 详情
(III) 31795 ethyl 2-(chloromethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-3-quinolinecarboxylate C23H24ClNO6 详情 详情
(IV) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情

合成路线14

该中间体在本合成路线中的序号：(XIV)

Condensation of isobutyrophenone (IV) with the lithium derivative of (S)-methyl p-tolyl sulfoxide (IX) produced alcohol (X) as a diastereomeric mixture. After chromatographic separation of the desired diastereoisomer, the methylsulfanyl group was selectively oxidized to sulfone (XI) with m-chloroperbenzoic acid. Reduction of the tolyl sulfoxide moiety of (XI) by means of NaI in the presence of acetyl chloride led to the corresponding sulfide (XII). Cyclization of the hydroxy sulfide (XII) to epoxide (XIII) was accomplished via S-alkylation with triethyloxonium tetrafluoroborate. Finally, opening of the chiral epoxide (XIII) with triazole (XIV) in the presence of K2CO3 furnished the title compound.

参考文献 中间体
合成目标
【1】 Tokizawa, M.; Kanamaru, Y.; Matsumoto, M.; Asaoka, T.; Matsuda, H.; Kuraishi, T.; Maebashi, K.; Taido, N.; Kawahara, R. (SSP Co., Ltd.); Triazole derivs.. EP 0435081; JP 1991223266; US 5147886 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(Xa) 56171 (2R)-3-methyl-1-[(4-methylphenyl)sulfinyl]-3-(methylsulfanyl)-2-[4-(trifluoromethyl)phenyl]-2-butanol C20H23F3O2S2 详情 详情
(Xb) 56172 (2S)-3-methyl-1-[(4-methylphenyl)sulfinyl]-3-(methylsulfanyl)-2-[4-(trifluoromethyl)phenyl]-2-butanol C20H23F3O2S2 详情 详情
(IV) 56166 2-methyl-2-(methylsulfanyl)-1-[4-(trifluoromethyl)phenyl]-1-propanone C12H13F3OS 详情 详情
(IX) 56170 methyl 4-methylphenyl sulfoxide; methyl(4-methylphenyl)oxo-lambda~4~-sulfane C8H10OS 详情 详情
(XI) 56173 (2R)-3-methyl-1-[(4-methylphenyl)sulfinyl]-3-(methylsulfonyl)-2-[4-(trifluoromethyl)phenyl]-2-butanol C20H23F3O4S2 详情 详情
(XII) 56174 (2R)-3-methyl-1-[(4-methylphenyl)sulfanyl]-3-(methylsulfonyl)-2-[4-(trifluoromethyl)phenyl]-2-butanol C20H23F3O3S2 详情 详情
(XIII) 56175 methyl 1-methyl-1-{(2R)-2-[4-(trifluoromethyl)phenyl]oxiranyl}ethyl sulfone; (2R)-2-[1-methyl-1-(methylsulfonyl)ethyl]-2-[4-(trifluoromethyl)phenyl]oxirane C13H15F3O3S 详情 详情
(XIV) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情

合成路线15

该中间体在本合成路线中的序号：(XV)

Treatment of epoxyalcohol (XI) with trifluoromethanesulfonic anhydride and diisopropyl ethylamine gave triflate (XII). Condensation of (XII) with imidazolone (IV) provided the required N-alkylated compound (XIII) along with some O-alkylated isomer, which were separated by column chromatography. Epoxide opening with triazole (XIV) afforded the imidazolone (XV), which was finally hydrogenated to produce the target imidazolidinone. Alternatively, condensation of triflate (XII) with imidazolidinone (V) furnished, after chromatographic separation of some O-alkylated isomer, imidazolidinone (XVI). Finally, the reaction of (XVI) with triazole (XIV) then provided an alternative route to the tiarget compound.

参考文献 中间体
合成目标
【1】 Itoh, K.; Tamura, N.; Matsushita, Y.; Hososno, H.; Hayashi, R.; Okonogi, K.; Kitazaki, T.; Tasaka, A.; Optically active antifungal azoles. VIII. Synthesis and antifungal activity of 1-[(1R,2R)-2-(2,4-difluoro- and 2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-(4-substituted phenyl)-2(1H,3H)-imidazolones and 2-imidazolidinones. Chem Pharm Bull 1999, 47, 3, 351.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 27860 1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-1,3-dihydro-2H-imidazol-2-one C11H8F4N2O2 详情 详情
(V) 27861 1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-imidazolidinone C11H10F4N2O2 详情 详情
(XI) 27877 (1S)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]-1-ethanol C10H10F2O2 详情 详情
(XII) 27878 (1S)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]ethyl trifluoromethanesulfonate C11H9F5O4S 详情 详情
(XIII) 27879 1-[(1R)-1-[(2S)-2-(2,4-difluorophenyl)oxiranyl]ethyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-1,3-dihydro-2H-imidazol-2-one C21H16F6N2O3 详情 详情
(XIV) 27880 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-1,3-dihydro-2H-imidazol-2-one C23H19F6N5O3 详情 详情
(XV) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(XVI) 27881 1-[(1R)-1-[(2S)-2-(2,4-difluorophenyl)oxiranyl]ethyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-imidazolidinone C21H18F6N2O3 详情 详情

合成路线16

该中间体在本合成路线中的序号：(VI)

Synthesis of intermediate (XX): The reaction of 2-chloro-2',4'-difluoroacetophenone (I) with sodium acetate and NaI in DMF gives 2-acetoxy-2',4'-difluoroacetophenone (II), which by methylenation with methyltriphenylphosphonium bromide and sodium bis(trimethylsilyl)amide in THF yields 2-(2,4-difluorophenyl)-2-propen-1-ol acetate ester (III). The hydrolysis of (III) with KOH in dioxane/water affords the corresponding alcohol (IV), which is regioselectively epoxidized with titanium tetraisopropoxide and L-(+)-diethyl tartrate in dichloromethane to (S)-(-)-2-(2,4-difluorophenyl)oxirane-2-methanol (V). The reaction of (V) with 1,2,4-triazole (VI) in DMF affords (R)-2-(2,4-difluorophenyl)-3-(1,2,4-triazol-1-yl)propane-1,2-diol (VII), which is selectively mesylated with methanesulfonyl chloride and triethylamine to the monomesylate (VIII). The cyclization of (VIII) with NaH in DMF gives the oxirane (IX), which is condensed with diethyl malonate (X) by means of NaH in DMSO to yield a mixture of (5R-cis)- and (5R-trans)-5-(2,4-difluorophenyl)-2-oxo-5-(1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-carboxylic acid ethyl ester (XI). The reduction of (XI) with NaBH4 and LiCl in ethanol affords (R)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-5-(1,2,4-triazol-1-yl) pentane-1,4-diol (XII), which is selectively tosylated with tosyl chloride and triethylamine in THF to the bistosylate (XIII). The cyclization of (XIII) by means of NaH in refluxing toluene gives (5R-cis)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-methanol tosylate ester (XIV). The reaction of (XIV) with 1-(4-hydroxyphenyl)-4-(4-nitrophenyl)piperazine (XV) to obtain compound (XVI), and the following reaction sequence (XVI) to (XVII) to (XVIII) to (XIX) to (5R-cis)-4-[4-[4-[4-[5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-ylmethoxy]phenyl]piperazin-1-yl]phenyl-3,4-dihydro-2H-1,2,4-triazol-3-one (XX) has been performed according to J Med Chem 1984, 27: 894-900.

参考文献 中间体
合成目标
【1】 Fromtling, R.A.; Castañer, J.; SCH-56592. Drugs Fut 1996, 21, 2, 160.
【2】 Saksena, A.K.; Girijavallabhan, V.M.; Lovey, R.G.; Pike, R.E.; Wang, H.; Liu, Y.-T.; Ganguly, A.K.; Bennett, F. (Schering Corp.); Tetrahydrofuran antifungals. EP 0736030; JP 1997500658; US 5661151; US 5703079; WO 9517407 .
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) 16321 2-Chloro-2',4'-difluoroacetophenone; 2-Chloro-1-(2,4-difluorophenyl)-1-ethanone 51336-94-8 C8H5ClF2O 详情 详情
(II) 16322 2-(2,4-Difluorophenyl)-2-oxoethyl acetate C10H8F2O3 详情 详情
(III) 16323 2-(2,4-difluorophenyl)-2-propenyl acetate C11H10F2O2 详情 详情
(IV) 15491 2-(2,4-difluorophenyl)-2-propen-1-ol C9H8F2O 详情 详情
(V) 17058 [(2S)-2-(2,4-difluorophenyl)oxiranyl]methanol C9H8F2O2 详情 详情
(VI) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(VII) 16327 (2R)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol C11H11F2N3O2 详情 详情
(VIII) 17061 (2R)-2-(2,4-difluorophenyl)-1-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-3-(1H-1,2,4-triazol-1-yl)-2-propanol C14H17F2N3O2S 详情 详情
(IX) 15477 1-[[(2R)-2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole C11H9F2N3O 详情 详情
(X) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(XI) 16331 ethyl (5R)-5-(2,4-difluorophenyl)-2-oxo-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furancarboxylate C16H15F2N3O4 详情 详情
(XII) 16332 (4R)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-5-(1H-1,2,4-triazol-1-yl)-1,4-pentanediol C14H17F2N3O3 详情 详情
(XIII) 17066 (4R)-4-(2,4-difluorophenyl)-4-hydroxy-2-([[(4-methylphenyl)sulfonyl]oxy]methyl)-5-(1H-1,2,4-triazol-1-yl)pentyl 4-methylbenzenesulfonate C28H29F2N3O7S2 详情 详情
(XIV) 16311 [(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-methylbenzenesulfonate C21H21F2N3O4S 详情 详情
(XV) 16345 4-[4-(4-nitrophenyl)piperazino]phenol C16H17N3O3 详情 详情
(XVI) 16347 [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-[4-(4-nitrophenyl)-1-piperazinyl]phenyl ether C30H30F2N6O4 详情 详情
(XVII) 17070 4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenylamine C30H32F2N6O2 详情 详情
(XVIII) 17071 N-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-N-(1-phenoxyvinyl)amine C38H38F2N6O3 详情 详情
(XIX) 16350 N-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-1-hydrazinecarboxamide C31H34F2N8O3 详情 详情
(XX) 16351 4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one C32H32F2N8O3 详情 详情

合成路线17

该中间体在本合成路线中的序号：(XI)

The synthesis of (2S,3S)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1,2,4-triazol-1-yl)butyronitrile (XV), a key intermediate the synthesis of ER-30346 has been described: The tritylation of 3-hydroxy-2(S)-methylpropionic acid methyl ester (I) with trityl chloride in hot pyridine gives the trityl ether (II), which is hydrolyzed with LiOH in H2O/THF/methanol yielding the free acid (III). The esterification of (III) with 2-mercaptopyridine (IV) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane gives the thioester (V), which is treated with 2,4-difluorophenylmagnesium bromide (VI) in THF yielding the propiophenone (VII), which by treatment with methyltriphenylphosphonium bromide/NaH in THF is converted into the methylene derivative (VIII). The oxidation of (VIII) with OsO4 and N-methylmorpholine oxide in acetone affords, after column chromatography, the chiral diol (IX), which is monomesylated with mesyl chloride/triethylamine in dichlormethane giving the monoester (X). The reaction of (X) with 1,2,4-triazol (XI) and NaH in DMF yields (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-1-(1,2,4-triazol-1-yl)-4-(triphenylmethoxy)-2-butanol (XII), which is detritylated with p-toluenesulfonic acid in methanol affording the diol (XIII). The oxidation of (XIII) with oxalyl chloride/DMSO in dichloromethane gives the aldehyde (XIV), which is finally treated with hydroxylamine-O-sulfonic acid in water yielding the desired bytyronitrile intermediate (XV) already referenced.

参考文献 中间体
合成目标
【1】 Kaku, Y.; et al.; A novel route for chiral synthesis of the triazole antifungal ER-30346. Chem Pharm Bull 1998, 46, 7, 1125.
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) 17128 Methyl (2S)-3-hydroxy-2-methylpropanoate 72657-23-9 C5H10O3 详情 详情
(II) 17129 Methyl (2S)-2-methyl-3-(trityloxy)propanoate C24H24O3 详情 详情
(III) 20259 (2S)-2-methyl-3-(trityloxy)propionic acid C23H22O3 详情 详情
(IV) 20260 2-Mercaptopyiridine; 2-pyridinethiol; 2-pyridinylhydrosulfide 2637-34-5 C5H5NS 详情 详情
(V) 20261 S-(2-pyridinyl) (2S)-2-methyl-3-(trityloxy)propanethioate C28H25NO2S 详情 详情
(VI) 20262 bromo(2,4-difluorophenyl)magnesium C6H3BrF2Mg 详情 详情
(VII) 17130 (2S)-1-(2,4-difluorophenyl)-2-methyl-3-(trityloxy)-1-propanone C29H24F2O2 详情 详情
(VIII) 17131 (2R)-3-(2,4-difluorophenyl)-2-methyl-3-butenyl trityl ether; 2,4-difluoro-1-[1-[(1R)-1-methyl-2-(trityloxy)ethyl]vinyl]benzene C30H26F2O 详情 详情
(IX) 17132 (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-4-(trityloxy)-1,2-butanediol C30H28F2O3 详情 详情
(X) 20266 (2R,3S)-2-(2,4-difluorophenyl)-2-hydroxy-3-methyl-4-(trityloxy)butyl methanesulfonate C31H30F2O5S 详情 详情
(XI) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(XII) 17135 (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-(trityloxy)-2-butanol C32H29F2N3O2 详情 详情
(XIII) 17136 (2S,3R)-3-(2,4-difluorophenyl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1,3-butanediol C13H15F2N3O2 详情 详情
(XIV) 17137 (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanal C13H13F2N3O2 详情 详情
(XV) 17123 (2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile C13H12F2N4O 详情 详情

合成路线18

该中间体在本合成路线中的序号：(XV)

Treatment of epoxyalcohol (IX) with trifluoromethanesulfonic anhydride and diisopropyl ethylamine gave triflate (XIII). Condensation of (XIII) with imidazolone (IV) provided the required N-alkylated compound (XIV) along with some O-alkylated isomer, which were separated by column chromatography. Epoxide opening with triazole (XV) afforded the imidazolone (XVI), which was finally hydrogenated to produce the target imidazolidinone. Alternatively, condensation of triflate (XIII) with imidazolidinone (V) furnished, after chromatographic separation of some O-alkylated isomer, imidazolidinone (XVII). Finally, the reaction of (XVII) with triazole (XV) then provided an alternative route to the target compound.

参考文献 中间体
合成目标
【1】 Itoh, K.; Tamura, N.; Matsushita, Y.; Hososno, H.; Hayashi, R.; Okonogi, K.; Kitazaki, T.; Tasaka, A.; Optically active antifungal azoles. VIII. Synthesis and antifungal activity of 1-[(1R,2R)-2-(2,4-difluoro- and 2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-(4-substituted phenyl)-2(1H,3H)-imidazolones and 2-imidazolidinones. Chem Pharm Bull 1999, 47, 3, 351.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 27860 1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-1,3-dihydro-2H-imidazol-2-one C11H8F4N2O2 详情 详情
(V) 27861 1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-imidazolidinone C11H10F4N2O2 详情 详情
(IX) 27865 (1S)-1-[(2R)-2-(2-fluorophenyl)oxiranyl]-1-ethanol C10H11FO2 详情 详情
(XIII) 27869 (1S)-1-[(2R)-2-(2-fluorophenyl)oxiranyl]ethyl trifluoromethanesulfonate C11H10F4O4S 详情 详情
(XIV) 27870 1-[(1R)-1-[(2S)-2-(2-fluorophenyl)oxiranyl]ethyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-1,3-dihydro-2H-imidazol-2-one C21H17F5N2O3 详情 详情
(XV) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(XVI) 27871 1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-1,3-dihydro-2H-imidazol-2-one C23H20F5N5O3 详情 详情
(XVII) 27872 1-[(1R)-1-[(2S)-2-(2-fluorophenyl)oxiranyl]ethyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-imidazolidinone C21H19F5N2O3 详情 详情

合成路线19

该中间体在本合成路线中的序号：(XVII)

The reaction of the 2'-deoxy uracil derivative (XIII) with Ms-Cl and pyridine gives the dimesylate (XIV), which is treated with NaOH in ethanol to yield the unstable intermediate (XV), which rearranges to the epoxide (XVI). The reaction of (XVI) with 1,2,4-triazole (XVII) by means of chlorophenyl dichlorophosphate (CPCP) and pyridine affords the triazolyl derivative (XVIII), which is hydrolyzed with NaOH in dioxane to provide the cytosine intermediate (XIX). Finally, the epoxide ring of (XIX) is cleaved by means of tBu-OK in DMSO to furnish the target cytosine derivative.

参考文献 中间体
合成目标
【1】 Lin, T.-S.; Cheng, Y.-C. (Yale University); L-2',3'-Dideoxy nucleoside analogs as anti-hepatitis B (HBV) and anti-HIV agents. EP 0707481; JP 1996510747; US 5627160; WO 9427616 .
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) 54714 5-fluoro-1-[(2S,4R,5S)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione C9H11FN2O5 详情 详情
(XIV) 54709 {(2S,3R,5S)-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-3-[(methylsulfonyl)oxy]tetrahydro-2-furanyl}methyl methanesulfonate C11H15FN2O9S2 详情 详情
(XV) 54710 [(1S,9S,10S)-4-fluoro-5-oxo-8,11-dioxa-2,6-diazatricyclo[7.2.1.0~2,7~]dodeca-3,6-dien-10-yl]methyl methanesulfonate C10H11FN2O6S 详情 详情
(XVI) 54711 1-[(1S,3S,5S)-2,6-dioxabicyclo[3.2.0]hept-3-yl]-5-fluoro-2,4(1H,3H)-pyrimidinedione C9H9FN2O4 详情 详情
(XVII) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(XVIII) 54712 1-[(1S,3S,5S)-2,6-dioxabicyclo[3.2.0]hept-3-yl]-5-fluoro-4-(1H-1,2,4-triazol-1-yl)-2(1H)-pyrimidinone C11H10FN5O3 详情 详情
(XIX) 54713 4-amino-1-[(1S,3S,5S)-2,6-dioxabicyclo[3.2.0]hept-3-yl]-5-fluoro-2(1H)-pyrimidinone C9H10FN3O3 详情 详情

合成路线20

该中间体在本合成路线中的序号：(XXIX)

Reaction of L-arabinose (XIII) with cyanamide (XIV) in aqueous methanolic ammonia gives the oxazolidine derivative (XV), which is cyclized with methyl propynoate (XVI) in refluxing ethanol to yield the anhydro uridine (XVII). Acylation of both OH groups of (XVII) by means of benzoyl cyanide (XVIII) in DMF affords the dibenzoate (XIX), which is treated with anhydrous HCl in DMF to provide the chloro uridine derivative (XX) or with HI in DMF or LiI and BH3/Et2O in DMF to provide the iodo uridine (XXI). Dehalogenation of (XX) or (XXI) by means of tri-butyltin hydride in refluxing benzene furnishes 3',5'-di-O-benzoyl-2'-deoxy-b-L-uridine (XXII). The trans-glycosylation of (XXII) with bis(trimethylsilyl)-5-fluorouracil (XXIII) by means of TMS-OTf in acetonitrile gives the corresponding 5-fluoro-L-uridine derivative (XXIV) as a mixture of the a- and b-anomers that is separated by chromatography. Debenzoylation of (XXIV) with ammonia in methanol yields 2'-deoxy-b-L-uridine (XXV), which is treated with MsCl and pyridine to afford the dimesylate (XXVI). Reaction of compound (XXVI) with NaOH in methanol/water provides the unstable intermediate (XXVII) that rearranges to the cyclic ether (XXVIII). Treatment of (XXVIII) with 1,2,4-triazole (XXIX) and p-chlorophenyl dichlorophosphate in pyridine provides the adduct (XXX), which by cleavage of the triazole ring by means of NH4OH in dioxane gives the corresponding cytidine derivative (XXXI). Finally, this compound is treated with potassium tert-butoxide in DMSO.

参考文献 中间体
合成目标
【3】 Gullen, E.; Zhu, Y.-L.; Liu, M.-C.; Dutschman, G.E.; Cheng, Y.-C.; Luo, M.-Z.; Lin, T.-S.; Design and synthesis of 2',3'-dideoxy-2',3'-didehydro-beta-L-cytidine (beta-L-d4C) and 2',3'-dideoxy-2',3'-didehydro-beta-L-5-fluorocytidine (beta-L-Fd4C), two exceptionally potent inhibitors of human hepatitis B virus (HBV) and potent inhibitors of human. J Med Chem 1996, 39, 9, 1757.
【1】 Holy, A.; Nucleic acid components and their analogues. CLIII. Preparation of 2'-deoxy-L-ribonucleosides of the pyrimidine series. Coll Czech Chem Commun 1972, 37, 12, 4072.
【2】 Bayes, M.; Sorbera, L.A.; Castaner, J.; ACH-126443. Drugs Fut 2002, 27, 12, 1131.
【4】 Lin, T.-S.; Cheng, Y.-C. (Yale University); L-2',3'-Dideoxy nucleoside analogs as anti-hepatitis B (HBV) and anti-HIV agents. EP 0707481; JP 1996510747; US 5627160; WO 9427616 .
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) 56917 alpha-L-arabinofuranose C5H10O5 详情 详情
(XIV) 19648 Cyanamide 420-04-2 CH2N2 详情 详情
(XV) 56918 (3aS,5S,6S,6aR)-5-(hydroxymethyl)-2-iminohexahydrofuro[2,3-d][1,3]oxazol-6-ol C6H10N2O4 详情 详情
(XVI) 19588 methyl propiolate 922-67-8 C4H4O2 详情 详情
(XVII) 39999 (2S,3S,3aR,9aS)-3-hydroxy-2-(hydroxymethyl)-2,3,3a,9a-tetrahydro-6H-furo[2',3':4,5][1,3]oxazolo[3,2-a]pyrimidin-6-one 3736-77-4 C9H10N2O5 详情 详情
(XVIII) 56919 2-oxo-2-phenylacetonitrile C8H5NO 详情 详情
(XIX) 40000 [(2S,3S,3aR,9aS)-3-(benzoyloxy)-6-oxo-2,3,3a,9a-tetrahydro-6H-furo[2',3':4,5][1,3]oxazolo[3,2-a]pyrimidin-2-yl]methyl benzoate C23H18N2O7 详情 详情
(XX) 40001 [(2S,3S,4S,5S)-3-(benzoyloxy)-4-chloro-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate C23H19ClN2O7 详情 详情
(XXI) 56920 {(2S,3S,4S,5S)-3-(benzoyloxy)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-4-iodotetrahydro-2-furanyl}methyl benzoate C23H19IN2O7 详情 详情
(XXII) 39996 [(2S,3R,5S)-3-(benzoyloxy)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate C23H20N2O7 详情 详情
(XXIII) 47859 5-fluoro-2-[(trimethylsilyl)oxy]-4-pyrimidinyl trimethylsilyl ether; 5-fluoro-2,4-bis[(trimethylsilyl)oxy]pyrimidine 17242-85-2 C10H19FN2O2Si2 详情 详情
(XXIV) 56921 {(2S,3R,5S)-3-(benzoyloxy)-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl}methyl benzoate C23H19FN2O7 详情 详情
(XXV) 54714 5-fluoro-1-[(2S,4R,5S)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione C9H11FN2O5 详情 详情
(XXVI) 54709 {(2S,3R,5S)-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-3-[(methylsulfonyl)oxy]tetrahydro-2-furanyl}methyl methanesulfonate C11H15FN2O9S2 详情 详情
(XXVII) 54710 [(1S,9S,10S)-4-fluoro-5-oxo-8,11-dioxa-2,6-diazatricyclo[7.2.1.0~2,7~]dodeca-3,6-dien-10-yl]methyl methanesulfonate C10H11FN2O6S 详情 详情
(XXVIII) 54711 1-[(1S,3S,5S)-2,6-dioxabicyclo[3.2.0]hept-3-yl]-5-fluoro-2,4(1H,3H)-pyrimidinedione C9H9FN2O4 详情 详情
(XXIX) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(XXX) 54712 1-[(1S,3S,5S)-2,6-dioxabicyclo[3.2.0]hept-3-yl]-5-fluoro-4-(1H-1,2,4-triazol-1-yl)-2(1H)-pyrimidinone C11H10FN5O3 详情 详情
(XXXI) 54713 4-amino-1-[(1S,3S,5S)-2,6-dioxabicyclo[3.2.0]hept-3-yl]-5-fluoro-2(1H)-pyrimidinone C9H10FN3O3 详情 详情

合成路线21

该中间体在本合成路线中的序号：(V)

The condensation of the chiral oxazolidinone (I) with 2,4-difluorophenacyl bromide (II) by means of NaHMDS in THF/Et2 O gives the chiral oxirane (III), which is treated with LiOH and H2O2 to eliminate the chiral auxiliary, yielding the carboxylic acid (IV). The cleavage of the oxirane ring of (IV) with 1,2,4-triazole (V) and NaH in hot DMF affords the chiral hydroxyacid (VI), which is submitted to Curtius rearrangement by means of DPPA in hot pyridine to provide the chiral oxazolidinone (VII). The cleavage of the oxazolidinone ring of (VII) by means of refluxing aq. HCl gives the chiral aminoalcohol (VIII), which is condensed with 2-amino-4-chlorobenzoic acid (IX) by means of DCC and HOBt to yield the corresponding amide (X). Finally, this compound is cyclized to the target quinazolinone by reaction with triethyl orthoformate in hot dioxane/NMP.

参考文献 中间体
合成目标
【1】 Bartroli, J.; et al.; Aldol condensation of Evans chiral enolates with acetophenones. Its application to the stereoselective synthesis of homochiral antifungal agents. J Org Chem 1995, 60, 10, 3000.
【2】 Bartroli, J.; et al.; New azole antigungals. 3. Synthesis and antifungal activity of 3-substituted-4(3H)-quinazolinones. J Med Chem 1998, 41, 11, 1869.
【3】 Bartrolí, J.; Turmo, E.; Anguita, M. (J. Uriach & Cía., SA); New pyrimidone derivs. with antifungal activity. EP 0783501; ES 2107376; ES 2120885; JP 1998508317; US 5807854; WO 9705130 .
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) 25713 (4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one C13H15NO3 详情 详情
(II) 47646 2-bromo-1-(2,4-difluorophenyl)-1-ethanone C8H5BrF2O 详情 详情
(III) 56711 (4S)-4-benzyl-3-{(2R)-2-[(2R)-2-(2,4-difluorophenyl)oxiranyl]propanoyl}-1,3-oxazolidin-2-one C21H19F2NO4 详情 详情
(IV) 56712 (2R)-2-[(2R)-2-(2,4-difluorophenyl)oxiranyl]propanoic acid C11H10F2O3 详情 详情
(V) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(VI) 56713 (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanoic acid C13H13F2N3O3 详情 详情
(VII) 56714 (4R,5R)-5-(2,4-difluorophenyl)-4-methyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-oxazolidin-2-one C13H12F2N4O2 详情 详情
(VIII) 56715 (2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol C12H14F2N4O 详情 详情
(IX) 52504 4-Chloro-2-aminobenzoic acid; 2-Amino-4-chlorobenzoic acid; 2-Carboxy-5-chloroaniline; 3-Amino-4-carboxy-1-chlorobenzene; 4-Chloroanthranilic acid 89-77-0 C7H6ClNO2 详情 详情
(X) 56716 2-amino-4-chloro-N-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]benzamide C19H18ClF2N5O2 详情 详情

合成路线22

该中间体在本合成路线中的序号：(IX)

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.

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】 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23

该中间体在本合成路线中的序号：(II)

Pyridopyrimidinone (I) was condensed with triazole (II) in the presence of 4-chlorophenyl dichlorophosphate and pyridine to afford (III). Further reaction of (III) with ammonia in dioxan gave amino compound (IV), which was submitted to a Heck reaction with 4-iodobenzoyl-L-glutamic acid diethyl ester (V) in the presence of palladium catalyst and CuI to provide the disubstituted acetylene (VI). Hydrogenation of both acetylene group and pyridine ring of (VI) over Pd/C gave intermediate (VII). The amide and ester groups of (VII) were finally hydrolyzed with 1 N NaOH to furnish the title compound.

参考文献 中间体
合成目标
【1】 Gossett, L.S.; Habeck, L.L.; Shackelford, K.A.; Mendelsohn, L.G.; Gates, S.B.; Worzalla, J.F.; Self, T.D.; Theobald, K.S.; Andis, S.L.; Schultz, R.M.; Shih, C.; The synthesis and biological activity of a series of 2,4-diaminopyrido[2,3-d]pyrimidine based antifolates as antineoplastic and antiarthritic agents. Bioorg Med Chem Lett 1999, 9, 1, 75.
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) 14282 N-(6-Ethynyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide C14H14N4O2 详情 详情
(II) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(III) 23132 N-[6-ethynyl-4-(1H-1,2,4-triazol-1-yl)pyrido[2,3-d]pyrimidin-2-yl]-2,2-dimethylpropanamide C16H15N7O 详情 详情
(IV) 23133 N-(4-amino-6-ethynylpyrido[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide C14H15N5O 详情 详情
(V) 14283 diethyl (2S)-2-[(4-iodobenzoyl)amino]pentanedioate C16H20INO5 详情 详情
(VI) 23135 diethyl (2S)-2-[[4-(2-[4-amino-2-[(2,2-dimethylpropanoyl)amino]pyrido[2,3-d]pyrimidin-6-yl]ethynyl)benzoyl]amino]pentanedioate C30H34N6O6 详情 详情
(VII) 23136 diethyl (2S)-2-[[4-(2-[4-amino-2-[(2,2-dimethylpropanoyl)amino]-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl]ethyl)benzoyl]amino]pentanedioate C30H42N6O6 详情 详情

合成路线24

该中间体在本合成路线中的序号：(II)

Pyridopyrimidinone (I) was condensed with triazole (II) in the presence of 4-chlorophenyl dichlorophosphate and pyridine to afford (III). Further reaction of (III) with ammonia in dioxan gave amino compound (IV), which was submitted to a Heck reaction with N-(2-bromothien-5-yl)-L-glutamic acid diethyl ester (V) in the presence of palladium catalyst and CuI to provide the disubstituted acetylene (VI). Hydrogenation of both acetylene group and pyridine ring of (VI) over Pd/C gave intermediate (VII). The amide and ester groups of (VII) were finally hydrolyzed with 1 N NaOH to furnish the title compound.

参考文献 中间体
合成目标
【1】 Gossett, L.S.; Habeck, L.L.; Shackelford, K.A.; Mendelsohn, L.G.; Gates, S.B.; Worzalla, J.F.; Self, T.D.; Theobald, K.S.; Andis, S.L.; Schultz, R.M.; Shih, C.; The synthesis and biological activity of a series of 2,4-diaminopyrido[2,3-d]pyrimidine based antifolates as antineoplastic and antiarthritic agents. Bioorg Med Chem Lett 1999, 9, 1, 75.
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) 14282 N-(6-Ethynyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide C14H14N4O2 详情 详情
(II) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(III) 23132 N-[6-ethynyl-4-(1H-1,2,4-triazol-1-yl)pyrido[2,3-d]pyrimidin-2-yl]-2,2-dimethylpropanamide C16H15N7O 详情 详情
(IV) 23133 N-(4-amino-6-ethynylpyrido[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide C14H15N5O 详情 详情
(V) 23137 diethyl (2S)-2-[[(5-bromo-2-thienyl)carbonyl]amino]pentanedioate C14H18BrNO5S 详情 详情
(VI) 23138 diethyl (2S)-2-([[5-(2-[4-amino-2-[(2,2-dimethylpropanoyl)amino]pyrido[2,3-d]pyrimidin-6-yl]ethynyl)-2-thienyl]carbonyl]amino)pentanedioate C28H32N6O6S 详情 详情
(VII) 23139 diethyl (2S)-2-([[5-(2-[4-amino-2-[(2,2-dimethylpropanoyl)amino]-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl]ethyl)-2-thienyl]carbonyl]amino)pentanedioate C28H40N6O6S 详情 详情

合成路线25

该中间体在本合成路线中的序号：(II)

Pyridopyrimidinone (I) was condensed with triazole (II) in the presence of 4-chlorophenyl dichlorophosphate and pyridine to afford (III). Further reaction of (III) with ammonia in dioxan gave amino compound (IV), which was submitted to a Heck reaction with N-(2-bromofuran-5-yl)-L-glutamic acid diethyl ester (V) in the presence of palladium catalyst and CuI to provide the disubstituted acetylene (VI). Hydrogenation of both acetylene group and pyridine ring of (VI) over Pd/C gave intermediate (VII). The amide and ester groups of (VII) were finally hydrolyzed with 1 N NaOH to furnish the title compound.

参考文献 中间体
合成目标
【1】 Gossett, L.S.; Habeck, L.L.; Shackelford, K.A.; Mendelsohn, L.G.; Gates, S.B.; Worzalla, J.F.; Self, T.D.; Theobald, K.S.; Andis, S.L.; Schultz, R.M.; Shih, C.; The synthesis and biological activity of a series of 2,4-diaminopyrido[2,3-d]pyrimidine based antifolates as antineoplastic and antiarthritic agents. Bioorg Med Chem Lett 1999, 9, 1, 75.
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) 14282 N-(6-Ethynyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide C14H14N4O2 详情 详情
(II) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(III) 23132 N-[6-ethynyl-4-(1H-1,2,4-triazol-1-yl)pyrido[2,3-d]pyrimidin-2-yl]-2,2-dimethylpropanamide C16H15N7O 详情 详情
(IV) 23133 N-(4-amino-6-ethynylpyrido[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide C14H15N5O 详情 详情
(V) 23140 diethyl (2S)-2-[(5-bromo-2-furoyl)amino]pentanedioate C14H18BrNO6 详情 详情
(VI) 23141 diethyl (2S)-2-[[5-(2-[4-amino-2-[(2,2-dimethylpropanoyl)amino]pyrido[2,3-d]pyrimidin-6-yl]ethynyl)-2-furoyl]amino]pentanedioate C28H32N6O7 详情 详情
(VII) 23142 diethyl (2S)-2-[[5-(2-[4-amino-2-[(2,2-dimethylpropanoyl)amino]-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl]ethyl)-2-furoyl]amino]pentanedioate C28H40N6O7 详情 详情

合成路线26

该中间体在本合成路线中的序号：(IX)

E-5842 was prepared by reacting (I) with citric acid monohydrate in ethanol. The base (I) can be obtained by two ways: 1) By condensation of 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (III) or 8-(4-fluorophenyl)-5-azoniaspiro[4.5]dec-7-ene chloride (IV) with 1-(4-chlorobutyl)-1H-1,2,4-triazole (V) or 1H-1,2,4-triazole, respectively, in dimethylformamide in the presence of potassium hydrogencarbonate. 2) By dehydration of 1-[4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidyl]butyl]-1H-1,2,4-triazole (VI) in refluxing hydrochloric acid/ethanol. The piperidinol (VI) can be obtained by two procedures: a) By condensation of 4-(4-fluorophenyl)-4-hydroxypiperidine (II) with 1-(4-chlorobutyl)-1H-1,2,4-triazole (V) in dimethylformamide in the presence of potassium hydrogencarbonate. b) By condensation of 1,4-dioxa-8-azaspiro[4.5]decane (VII) with 1-(4-chlorobutyl)-1H-1,2,4-triazole (V) and hydrolysis of the acetal to give 1-[4-(4-oxo-1-piperidyl)butyl]-1H-1,2,4-triazole (VIII), followed by addition of 4-fluorophenyllithium or 4-fluorophenyl magnesium bromide in ether or tetrahydrofuran to yield (VI).

参考文献 中间体
合成目标
【1】 Merce-Vidal, R.; Frigola-Constansa, J. (Laboratorios del Dr. Esteve, SA); Tetrahydropyridine-(or -4-hydroxypiperidine)alkyla. EP 0721455; FR 2723091; JP 1997503230; US 5731331; WO 9604287 .
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) 23463 4-(4-fluorophenyl)-1-[4-(1H-1,2,4-triazol-1-yl)butyl]-1,2,3,6-tetrahydropyridine C17H21FN4 详情 详情
(II) 15723 4-(4-fluorophenyl)-4-piperidinol; 4-(4-Fluorophenyl)-4-hydroxypiperidine 3888-65-1 C11H14FNO 详情 详情
(III) 23465 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine 1978-59-2 C11H12FN 详情 详情
(IV) 23466 8-(4-fluorophenyl)-5-azoniaspiro[4.5]dec-7-ene C15H19FN 详情 详情
(V) 23467 1-(4-chlorobutyl)-1H-1,2,4-triazole C6H10ClN3 详情 详情
(VI) 23468 4-(4-fluorophenyl)-1-[4-(1H-1,2,4-triazol-1-yl)butyl]-4-piperidinol C17H23FN4O 详情 详情
(VII) 11338 1,4-Dioxa-8-azaspiro[4.5]decane; 4-Piperidone ethylene ketal 177-11-7 C7H13NO2 详情 详情
(VIII) 23470 1-[4-(1H-1,2,4-triazol-1-yl)butyl]-4-piperidinone C11H18N4O 详情 详情
(IX) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情

合成路线27

该中间体在本合成路线中的序号：(IX)

The bromoacetylation of 5-fluorouridine (I) with 2-acetoxyisobutyryl bromide (II) in acetonitrile, ethyl acetate or dichloromethane gives a mixture of four bromoacylated compounds (III), (IV), (V) and (VI). This mixture, without separation, is treated with Zn/Ac-OH in DMF or methanol/ethyl acetate to yield two unsaturated uridine derivatives (VII) and (VIII), which are easily separated. The major isomer (VIII) is condensed with 1,2,4-triazole (IX) by means of POCl3 and TEA in acetonitrile to afford the triazolyl derivative (X), which is treated with ammonia in methanol to provide the cytidine derivative (XI). Finally, this compound is deacylated by means of NaOMe in methanol to afford the target fluorocytidine derivative.

参考文献 中间体
合成目标
【1】 Confalone, P.N.; Jin, F. (Pharmasset, Inc.); Method for the synthesis of 2',3'-dideoxy-2',3'-didehydronucleosides. WO 0270533 .
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) 32205 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-fluoro-2,4(1H,3H)-pyrimidinedione; 5-Fluorouridine 316-46-1 C9H11FN2O6 详情 详情
(II) 12806 2-bromo-1,1-dimethyl-2-oxoethyl acetate; alpha-Acetoxy-isobutyryl bromide 40635-67-4 C6H9BrO3 详情 详情
(III) 58289 {(2R,3R,5R)-3-(acetyloxy)-4-bromo-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl}methyl 2-(acetyloxy)-2-methylpropanoate C17H20BrFN2O9 详情 详情
(IV) 58290 {(2R,4S,5R)-4-(acetyloxy)-3-bromo-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl}methyl 2-(acetyloxy)-2-methylpropanoate C17H20BrFN2O9 详情 详情
(V) 58291 {(2R,3R,5R)-3-(acetyloxy)-4-bromo-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl}methyl acetate C13H14BrFN2O7 详情 详情
(VI) 58292 {(2R,5R)-4-(acetyloxy)-3-bromo-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl}methyl acetate C13H14BrFN2O7 详情 详情
(VII) 58293 {(2S,5R)-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2,5-dihydro-2-furanyl}methyl acetate C11H11FN2O5 详情 详情
(VIII) 58294 {(2S,5R)-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2,5-dihydro-2-furanyl}methyl 2-(acetyloxy)-2-methylpropanoate C15H17FN2O7 详情 详情
(IX) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(X) 58295 2-({(2S,5R)-5-[5-fluoro-2-oxo-4-(1H-1,2,4-triazol-1-yl)-1(2H)-pyrimidinyl]-2,5-dihydro-2-furanyl}methoxy)-1,1-dimethyl-2-propenyl acetate C18H20FN5O5 详情 详情
(XI) 58296 2-({(2S,5R)-5-[4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl]-2,5-dihydro-2-furanyl}methoxy)-1,1-dimethyl-2-propenyl acetate C16H20FN3O5 详情 详情

合成路线28

该中间体在本合成路线中的序号：(V)

Addition of Grignard reagent (II) to N-(4-formylphenyl)acetamide (I) produced carbinol (III). After conversion of (III) to mesylate (IV), displacement with 1,2,4-triazole (V) afforded triazolyl derivative (VI). Acid hydrolysis of the acetamido group of (VI) furnished aniline (VII). Treatment of aniline (VII) with carbon disulfide and NaOH, followed by methylation with iodomethane, gave the bis(methylthio)methylene derivative (VIII). Alternatively, aniline (VII) was converted to isothiocyanate (IX) by reaction with thiophosgene. The title benzothiazole was finally obtained by condensation of 2-aminobenzenethiol (X) with either (VIII) or (IX).

参考文献 中间体
合成目标
【1】 Venet, M.G.; Mabire, D.J.-P.; Lacrampe, J.F.A.; Sanz, G.C. (Janssen Pharmaceutica NV); N-[4-(heteroarylmethyl)phenyl]-heteroarylamines. EP 0907650; JP 2000503670; US 6124330; WO 9749704 .
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) 42212 N-(4-formylphenyl)acetamide 122-85-0 C9H9NO2 详情 详情
(II) 42213 bromo(1-ethylpropyl)magnesium C5H11BrMg 详情 详情
(III) 42214 N-[4-(2-ethyl-1-hydroxybutyl)phenyl]acetamide C14H21NO2 详情 详情
(IV) 42215 1-[4-(acetamido)phenyl]-2-ethylbutyl methanesulfonate C15H23NO4S 详情 详情
(V) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(VI) 42216 N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]acetamide C16H22N4O 详情 详情
(VII) 42217 4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]aniline; 4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenylamine C14H20N4 详情 详情
(VIII) 42218 1-[1-(4-[[bis(methylsulfanyl)methylene]amino]phenyl)-2-ethylbutyl]-1H-1,2,4-triazole C17H24N4S2 详情 详情
(IX) 42219 1-[2-ethyl-1-(4-isothiocyanatophenyl)butyl]-1H-1,2,4-triazole; 4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl isothiocyanate C15H18N4S 详情 详情
(X) 25182 2-aminobenzenethiol 137-07-5 C6H7NS 详情 详情

合成路线29

该中间体在本合成路线中的序号：(V)

In a different procedure, N-(4-bromophenyl)-2-benzothiazolamine (XI) was converted into the lithio derivative and subsequently condensed with 2-ethylbutanal (XII) to give carbinol (XIII). Treatment of (XIII) with methanesulfonyl chloride and triethylamine provided mesylate (XIV), which was finally displaced by 1,2,4-triazole (V), yielding the title compound.

参考文献 中间体
合成目标
【1】 Venet, M.G.; Mabire, D.J.-P.; Lacrampe, J.F.A.; Sanz, G.C. (Janssen Pharmaceutica NV); N-[4-(heteroarylmethyl)phenyl]-heteroarylamines. EP 0907650; JP 2000503670; US 6124330; WO 9749704 .
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) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(XI) 42220 N-(4-bromophenyl)-1,3-benzothiazol-2-amine; N-(1,3-benzothiazol-2-yl)-N-(4-bromophenyl)amine C13H9BrN2S 详情 详情
(XII) 42221 2-ethylbutanal 97-96-1 C6H12O 详情 详情
(XIII) 42222 1-[4-(1,3-benzothiazol-2-ylamino)phenyl]-2-ethyl-1-butanol C19H22N2OS 详情 详情
(XIV) 42223 1-[4-(1,3-benzothiazol-2-ylamino)phenyl]-2-ethylbutyl methanesulfonate C20H24N2O3S2 详情 详情

合成路线30

该中间体在本合成路线中的序号：(III)

Methanol derivative (I) is converted into the corresponding methyl chloride compound (II) by reaction with thionyl chloride in dichloromethane/cyclohexane. The desired product is then obtained by displacement of the chlorine by attack with 1H-1,2,4-triazole (III) in dioxane.

参考文献 中间体
合成目标
【1】 Pestellini, V.; Ghelardoni, M.; Giannotti, D.; Giolitti, A.; Barzanti, A.; Ciappi, R.; Ortolani, C. (Menarini Industrie Farma Riunite Srl); New (benzofuran-2-yl)imidazoles having pharmaceutically activity, their salts and relevant production processes. EP 0257171; JP 1988072687; US 4800208 .
【2】 Lombardi, P.; Di Pietro, G. (Menarini Industrie Farma Riunite Srl); Heterocyclic furan cpds., their preparation and use as aromatase inhibitors. WO 9818791 .
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) 47306 4-[1-benzofuran-2-yl(hydroxy)methyl]benzonitrile C16H11NO2 详情 详情
(II) 47307 4-[1-benzofuran-2-yl(chloro)methyl]benzonitrile C16H10ClNO 详情 详情
(III) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情

合成路线31

该中间体在本合成路线中的序号：(VIII)

The acylation of m-difluorobenzene (I) with 2-bromoacetyl bromide (II) by means of AlCl3 gives the phenacyl bromide (III), which is treated with ethylmercaptan (IV) and K2CO3 to yield the sulfanyl derivative (V). The fluorination of (V) with N-fluoro-4-methylpyridinium-2-sulfonate affords the difluoroacetyl derivative (VI). The methylenation of the carbonyl group of (VI) with trimethylsulfoxonium iodide provides the oxiranyl derivative (VII), which is opened with 1,2,4-triazole (VIII) and K2CO3, furnishing the propanol derivative (IX). The oxidation of the sulfanyl group of (IX) by means of H2O2 or MCPBA gives the corresponding sulfonyl derivative (X). Finally, the racemic mixture (X) is submitted to optical resolution by crystallization of the (+)-3-bromocamphorsulfonic acid. Alternatively, intermediate (VI) can be obtained as follows: The reaction of 2-chloro-2,2-difluoroacetic acid ethyl ester (XI) with ethylmercaptan (IV) by means of NaH gives the sulfanyl derivative (XII), which is finally condensed with 2,4-difluorobromobenzene (XIII) by means of BuLi to afford the desired intermediate (VI).

参考文献 中间体
合成目标
【1】 Kaneko, Y.; Takeda, S.; Eto, H.; et al.; New antifungal 1,2,4-triazoles with difluoro(substituted sulfonyl)methyl moiety. Chem Pharm Bull 2001, 49, 2, 173.
【2】 Sato, S.; Kaneko, Y.; Takeda, S.; Eto, H.; Tokizawa, M.; SS750, a new triazole agent: Structure-activity relationship of novel triazole-containing gem-difluoromethylsulfonyl moiety. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1080.
【3】 Matsumoto, M.; Kaneko, Y.; Maebashi, K.; Takeda, S.; Sato, S.; Tokizawa, M.; Ishida, K.; Eto, H.; Asaoka, T. (SSP Co., Ltd.); Triazole deriv. or salt thereof, preparation process thereof as well as pharmaceutical containing said cpd.. CA 2256060; EP 0927719; JP 1999240871; US 6083968 .
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) 13095 m-Difluorobenzene; 1,3-Difluorobenzene 372-18-9 C6H4F2 详情 详情
(II) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(III) 47646 2-bromo-1-(2,4-difluorophenyl)-1-ethanone C8H5BrF2O 详情 详情
(IV) 23712 1-ethanethiol; ethylhydrosulfide 75-08-1 C2H6S 详情 详情
(V) 47647 1-(2,4-difluorophenyl)-2-(ethylsulfanyl)-1-ethanone C10H10F2OS 详情 详情
(VI) 47648 1-(2,4-difluorophenyl)-2-(ethylsulfanyl)-2,2-difluoro-1-ethanone C10H8F4OS 详情 详情
(VII) 47649 2-(2,4-difluorophenyl)-2-[(ethylsulfanyl)(difluoro)methyl]oxirane; [2-(2,4-difluorophenyl)-2-oxiranyl](difluoro)methyl ethyl sulfide C11H10F4OS 详情 详情
(VIII) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(IX) 47650 2-(2,4-difluorophenyl)-1-(ethylsulfanyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol C13H13F4N3OS 详情 详情
(X) 47651 2-(2,4-difluorophenyl)-1-(ethylsulfonyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol C13H13F4N3O3S 详情 详情
(XI) 47652 Chlorodifluoroacetic acid ethyl ester; Difluorochloroacetic acid ethyl ester; Ethyl chlorodifluoroacetate; ethyl 2-chloro-2,2-difluoroacetate 383-62-0 C4H5ClF2O2 详情 详情
(XII) 47653 ethyl 2-(ethylsulfanyl)-2,2-difluoroacetate C6H10F2O2S 详情 详情
(XIII) 15488 1-bromo-2,4-difluorobenzene 348-57-2 C6H3BrF2 详情 详情

合成路线32

该中间体在本合成路线中的序号：(VI)

2-Chloro-2',4'-difluoroacetophenone (I) was converted to acetate ester (II) by displacement of the chlorine with sodium acetate in the presence of NaI. Subsequent Wittig reaction of (II) with methylenetriphenylphosphorane produced the allyl ester (III), which was hydrolyzed to alcohol (IV) with KOH in aqueous dioxan. Asymmeytric Sharpless epoxidation of (IV) with tert-butyl hydroperoxide in the presence of L-(+)-diethyl tartrate and titanium tetraisopropoxide furnished the (S)-epoxide (V). Ring opening of (V) with the sodium salt of 1,2,4-triazole (VI) gave the triazolyl diol (VII). After conversion of the primary hydroxyl group to tosylate (VIII), ring closure in the presence of NaH generated epoxide (IX). Condensation of (IX) with diethyl malonate afforded a mixture of diastereomeric butyrolactones (Xa, Xb), which was converted to triol (XI) by reduction with lithium borohydride. Treatment of (XI) with p-toluenesulfonyl chloride produced ditosylate (XII). Ring closure of (XII) employing NaH in boiling toluene gave rise to a diastereomeric mixture of tetrahydrofurans, from which the required cis isomer (XIII) was isolated by column chromatography.

参考文献 中间体
合成目标
【1】 Saksena, A.K.; Girijavallabhan, V.M.; Lovey, R.G.; Pike, R.E.; Wang, H.; Liu, Y.-T.; Ganguly, A.K.; Bennett, F. (Schering Corp.); Tetrahydrofuran antifungals. EP 0773941; WO 9638443 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(Xa) 34838 ethyl (3S,5R)-5-(2,4-difluorophenyl)-2-oxo-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furancarboxylate C16H15F2N3O4 详情 详情
(Xb) 34839 ethyl (3R,5R)-5-(2,4-difluorophenyl)-2-oxo-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furancarboxylate C16H15F2N3O4 详情 详情
(I) 16321 2-Chloro-2',4'-difluoroacetophenone; 2-Chloro-1-(2,4-difluorophenyl)-1-ethanone 51336-94-8 C8H5ClF2O 详情 详情
(II) 16322 2-(2,4-Difluorophenyl)-2-oxoethyl acetate C10H8F2O3 详情 详情
(III) 16323 2-(2,4-difluorophenyl)-2-propenyl acetate C11H10F2O2 详情 详情
(IV) 15491 2-(2,4-difluorophenyl)-2-propen-1-ol C9H8F2O 详情 详情
(V) 17058 [(2S)-2-(2,4-difluorophenyl)oxiranyl]methanol C9H8F2O2 详情 详情
(VI) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(VII) 16327 (2R)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol C11H11F2N3O2 详情 详情
(VIII) 16328 (2R)-2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl methanesulfonate C12H13F2N3O4S 详情 详情
(IX) 15477 1-[[(2R)-2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole C11H9F2N3O 详情 详情
(XI) 16332 (4R)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-5-(1H-1,2,4-triazol-1-yl)-1,4-pentanediol C14H17F2N3O3 详情 详情
(XII) 17066 (4R)-4-(2,4-difluorophenyl)-4-hydroxy-2-([[(4-methylphenyl)sulfonyl]oxy]methyl)-5-(1H-1,2,4-triazol-1-yl)pentyl 4-methylbenzenesulfonate C28H29F2N3O7S2 详情 详情
(XIII) 16311 [(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-methylbenzenesulfonate C21H21F2N3O4S 详情 详情

合成路线33

该中间体在本合成路线中的序号：(IX)

Friedel-Crafts hydroxymethylation of 3-methoxybenzoic acid (I) using aqueous formaldehyde and HCl gave rise to 6-methoxyisobenzofuran-1-one (II). After radical bromination of (II) with N-bromosuccinimide in the presence of benzoyl peroxide, the resulting 3-bromo derivative (III) was condensed with triphenyl phosphine to afford the phosphonium salt (IV). Wittig condensation of 3,5-dichloropyridine-4-carbaldehyde (V) with the phosphonium bromide (IV) provided the 3-(pyridylmethylene)isobenzofuranone (VI). Reaction of the enol lactone function of (VI) with hydrazine produced the phthalazinone derivative (VII), which was further converted to the 4-chlorophthalazine (VIII) upon treatment with POCl3. The 4-chloro group of (VIII) was finally displaced with the sodium salt of 1,2,4-triazole (IX) to give the title compound.

参考文献 中间体
合成目标
【2】 Norcini, G.; Morazzoni, G.; Leali, G.M.; Napoletano, M.; Grancini, G.; Pellacini, F. (Zambon Group SpA); Phthalazine derivs. phosphodiesterase 4 inhibitors. EP 1097142; US 6329370; WO 0005218 .
【1】 Norcini, G.; Pellacini, F.; Pradella, L.; Marchini, F.; Morazzoni, G.; Ferlenga, P.; Napoletano, M.; Phathalazine PDE4 inhibitors. Part 2: The synthesis and biological evaluation of 6-methoxy-1,4-disubstituted derivatives. Bioorg Med Chem Lett 2001, 11, 1, 33.
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) 28559 m-Anisic acid; 3-Methoxybenzoic acid 586-38-9 C8H8O3 详情 详情
(II) 50943 6-methoxyphthalide C9H8O3 详情 详情
(III) 50944 3-bromo-6-methoxy-2-benzofuran-1(3H)-one C9H7BrO3 详情 详情
(IV) 50945 (5-methoxy-3-oxo-1,3-dihydro-2-benzofuran-1-yl)(triphenyl)phosphonium bromide C27H22BrO3P 详情 详情
(V) 35536 3,5-dichloroisonicotinaldehyde; 3,5-Dichloropyridine-4-carbaldehyde 136590-83-5 C6H3Cl2NO 详情 详情
(VI) 50946 3-[(Z)-(3,5-dichloro-4-pyridinyl)methylidene]-6-methoxy-2-benzofuran-1-one C15H9Cl2NO3 详情 详情
(VII) 50947 4-[(3,5-dichloro-4-pyridinyl)methyl]-7-methoxy-1(2H)-phthalazinone C15H11Cl2N3O2 详情 详情
(VIII) 50948 4-chloro-1-[(3,5-dichloro-4-pyridinyl)methyl]-6-methoxyphthalazine; 4-chloro-1-[(3,5-dichloro-4-pyridinyl)methyl]-6-phthalazinyl methyl ether C15H10Cl3N3O 详情 详情
(IX) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情

合成路线34

该中间体在本合成路线中的序号：(VII)

The copper-promoted coupling between 2-iodothiophene (I) and ethyl bromodifluoroacetate (II) produced ethyl 2,2-difluoro-2-(2-thienyl)acetate (III). Addition of the organolithium reagent derived from 2,4-difluorobromobenzene (IV) to ester (III) yielded ketone (V). This was converted into the oxirane (VI) by reaction with dimethyloxosulfonium methylide in DMSO. Finally, oxirane ring opening with 1,2,4-triazole (VII) provided the title compound.

参考文献 中间体
合成目标
【1】 Sakamoto, T.; Eto, H.; Kaneko, Y.; New antifungal 1,2,4-triazoles with difluro(heteroaryl)methyl moiety. Chem Pharm Bull 2000, 48, 7, 982.
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) 43394 2-iodothiophene 3437-95-4 C4H3IS 详情 详情
(II) 43395 ethyl 2,2-difluoro-2-(2-thienyl)acetate C8H8F2O2S 详情 详情
(III) 43396 1-(2,4-difluorophenyl)-2,2-difluoro-2-(2-thienyl)-1-ethanone C12H6F4OS 详情 详情
(IV) 15488 1-bromo-2,4-difluorobenzene 348-57-2 C6H3BrF2 详情 详情
(V) 43397 2-(2,4-difluorophenyl)-2-[difluoro(2-thienyl)methyl]oxirane C13H8F4OS 详情 详情
(VI) 43398 2-(2,4-difluorophenyl)-1,1-difluoro-1-(2-thienyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanol C15H11F4N3OS 详情 详情
(VII) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情

合成路线35

该中间体在本合成路线中的序号：(XVI)

The chiral epoxy alcohol (XIII), prepared from methyl (R)-lactate, was converted to triflate (XIV) by treatment with trifluoromethanesulfonic anhydride in the presence of diisopropylethylamine. Condensation of triflate (XIV) with the sodium salt of imidazolone (XII) afforded (XV). Subsequent oxirane ring opening with 1,2,4-triazole (XVI) in the presence of NaH gave the triazolyl alcohol (XVII). The title imidazolidinone was then obtained by catalytic hydrogenation of imidazolone (XVII).

参考文献 中间体
合成目标
【2】 Itoh, K.; Okonogi, K.; Tasaka, A. (Takeda Chemical Industries, Ltd.); Azole cpds., their production and use. EP 0809640; JP 1997183769; WO 9625410 .
【1】 Hosono, H.; Itoh, K.; Kitazaki, T.; Ichikawa, T.; Okonogi, K.; Tasaka, A.; Matsushita, Y.; Hayashi, R.; Optically active antifungal azoles. X. Synthesis and antifungal activity of N-[4-(azolyl)phenyl] and N-[4-(azolylmethyl)phenyl]-N'[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H,1,2,4-triazol-1-yl)propyl]-azolones. Chem Pharm Bull 2000, 48, 12, 1935.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 45562 1-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-1,3-dihydro-2H-imidazol-2-one C10H8N6O 详情 详情
(XIII) 45563 (1S)-1-[(2S)-2-(2,4-difluorophenyl)oxiranyl]-1-ethanol C10H10F2O2 详情 详情
(XIV) 45564 (1S)-1-[(2S)-2-(2,4-difluorophenyl)oxiranyl]ethyl trifluoromethanesulfonate C11H9F5O4S 详情 详情
(XV) 45565 1-[(1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]ethyl]-3-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-1,3-dihydro-2H-imidazol-2-one C20H16F2N6O2 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

合成路线36

该中间体在本合成路线中的序号：(XVI)

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.

参考文献 中间体
合成目标
【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37

该中间体在本合成路线中的序号：(XXIV)

The known chiral epoxide (IX) can be synthesized by several different ways shown in the following: 1) 2(S)-Acetoxypropionic acid (XII) is treated first with oxalyl chloride in DMF/CH2Cl2, and then the resultant acyl chloride is submitted to a Friedel-Crafts reaction with 1,3-difluorobenzene (XIII) by means of AlCl3 to provide a 1:1 mixture of a(S)-acetoxypropiophenone (XIV) and a(S)-hydroxy-propiophenone (XV). This mixture is treated with H2SO4 in MeOH to give the pure alcohol (XV). Tosylation of alcohol (XV) with p-toluenesulfonyl chloride in pyridine furnishes tosylate (XVI), which is converted into a(R)-hydroxypropiophenone (XVII) by an SN2 displacement reaction with LiOH in DMF/H2O. Reaction of the hydroxy group of (XVII) with 2,3-dihydropyran (XVIII) and pyridi-nium p-toluenesulfonate (PPTS) in CH2Cl2 gives the protected compound (XIX), which is converted into the silyl alcohol (XXI) by a Grignard reaction with (chloro-methyl)dimethylisopropoxysilane (XX) in the presence of Mg and a small amount of MeI. Oxidative desilylation of (XXI) by means of NaHCO3 and H2O2 in THF/MeOH, followed by hydrolysis with TsOH in MeOH, affords the triol (XXII), which is then mesylated with methanesulfonyl chloride in pyridine to provide the dimesylate (XXIII). Finally, nucleofilic substitution of one mesylate group of (XXIII) with 1H-1,2,4-triazole (XXIV) by means of NaH in DMF with concomitant epoxide formation 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
(XII) 10142 (2R)-2-(Acetoxy)propionic acid 18668-00-3 C5H8O4 详情 详情
(XIII) 13095 m-Difluorobenzene; 1,3-Difluorobenzene 372-18-9 C6H4F2 详情 详情
(XIV) 59948 (1S)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl acetate C11H10F2O3 详情 详情
(XV) 45571 (2S)-1-(2,4-difluorophenyl)-2-hydroxy-1-propanone C9H8F2O2 详情 详情
(XVI) 59949 (1S)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl 4-methylbenzenesulfonate C16H14F2O4S 详情 详情
(XVII) 13100 (2R)-1-(2,4-Difluorophenyl)-2-hydroxy-1-propanone C9H8F2O2 详情 详情
(XVIII) 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
(XIX) 13102 (2R)-1-(2,4-Difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone C14H16F2O3 详情 详情
(XX) 59950 (chloromethyl)(dimethyl)silyl isopropyl ether; (chloromethyl)(isopropoxy)dimethylsilane C6H15ClOSi 详情 详情
(XXI) 59951 (2S,3R)-2-(2,4-difluorophenyl)-1-[isopropoxy(dimethyl)silyl]-3-(tetrahydro-2H-pyran-2-yloxy)-2-butanol C20H32F2O4Si 详情 详情
(XXII) 59952 (2R,3R)-2-(2,4-difluorophenyl)-1,2,3-butanetriol C10H12F2O3 详情 详情
(XXIII) 59953 (1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-[(methylsulfonyl)oxy]propyl methanesulfonate C12H16F2O7S2 详情 详情
(XXIV) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情

合成路线38

该中间体在本合成路线中的序号：(XIV)

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

合成路线39

该中间体在本合成路线中的序号：(XIV)

The oxidation of the hydroxymethyl group of 3,5-di-O-benzyl-4-C-(hydroxymethyl)-1,2-O-isopropylidene-alpha-D-ribo-pentofuranose (I) with oxalyl chloride and TEA in DMSO gives the aldehyde (II), which is treated with CBr4 and PPH3 in dichloromethane to yield the dibromovinyl compound (III). The reaction of (III) with BuLi in THF affords the ethynyl derivative (IV), which is silylated with Tes-Cl and BuLi in THF to provide the triethylsilylethynyl compound (V). Elimination of the acetonide group of (V) with HOAc and TFA gives the dihydroxycompound (VI), which is treated with Ac2O and pyridine, yielding the diacetate (VII). The condensation of the sugar(VII) with 5-fluorouracil (VIII) by means of Tms-OTf and N,O-bis(trimethylsilyl)acetamide in dichloroethane affords the adduct (IX), which is deacetylated with TEA in methanol to provide the hydroxy derivative (X). The debenzylation of (X) by means of BCl3 in dichloromethane furnishes the trihydroxy compound (XI), which is treated with acetyl bromide in acetonitrile to give the bromo diacetoxy derivative (XII). The debromination of (XII) is performed with Bu3SnH and AIBN in hot toluene, yielding the diacetate (XIII), which is condensed with 1,2,4-triazole (XIV) by means of 4-chlorophenyl dichlorophosphate in pyridine to afford the triazolopyrimidinone (XV). Finally, (XV) is converted into the target compound by cleavage of the triazole ring with NH4OH in dioxane and deacetylation with NaOH in methanol/water.

参考文献 中间体
合成目标
【1】 Kohgo, S.; Kitano, K.; Ohrui, H.; et al.; Synthesis of 4'-C-ethynyl-beta-D-arabino-and 4'-C-ethynyl-2'-deoxy-beta-D-ribo-pentofuranosylpyrimidines and -purines and evaluation of their anti-HIV activity. J Med Chem 2000, 43, 23, 4516.
【2】 Matsuoka, M.; Kodama, E.; Kitano, K.; Kohgo, S.; Mitsuya, H.; Ohrui, H. (Yamasa Shoyu Co., Ltd.); 4'-C-Ethynyl purine nucleosides. WO 0069876; WO 0069877 .
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) 30917 [(3aR,5S,6S,6aR)-6-(benzyloxy)-5-[(benzyloxy)methyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methanol C23H28O6 详情 详情
(II) 46262 (3aR,5R,6S,6aR)-6-(benzyloxy)-5-[(benzyloxy)methyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carbaldehyde C23H26O6 详情 详情
(III) 46263 (3aR,5R,6S,6aR)-6-(benzyloxy)-5-[(benzyloxy)methyl]-5-(2,2-dibromovinyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole; [(3aR,5R,6S,6aR)-6-(benzyloxy)-5-(2,2-dibromovinyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzyl ether C24H26Br2O5 详情 详情
(IV) 46264 [(3aR,5R,6S,6aR)-6-(benzyloxy)-5-ethynyl-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzyl ether; (3aR,5R,6S,6aR)-6-(benzyloxy)-5-[(benzyloxy)methyl]-5-ethynyl-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole C24H26O5 详情 详情
(V) 46265 [(3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyl-5-[2-(triethylsilyl)ethynyl]tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzyl ether; (2-[(3aR,5R,6S,6aR)-6-(benzyloxy)-5-[(benzyloxy)methyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]ethynyl)(triethyl)silane C30H40O5Si 详情 详情
(VI) 46266 (2S,3R,4S,5R)-4-(benzyloxy)-5-[(benzyloxy)methyl]-5-[2-(triethylsilyl)ethynyl]tetrahydro-2,3-furandiol C27H36O5Si 详情 详情
(VII) 46267 (2R,3R,4S,5R)-2-(acetoxy)-4-(benzyloxy)-5-[(benzyloxy)methyl]-5-[2-(triethylsilyl)ethynyl]tetrahydro-3-furanyl acetate C31H40O7Si 详情 详情
(VIII) 29341 (6R,9S,12S)-6-(cyclohexylmethyl)-12-[3-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]propyl]-9-(1H-indol-3-ylmethyl)-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oic acid C38H53N7O8S 详情 详情
(IX) 46268 (2R,3R,4S,5R)-4-(benzyloxy)-5-[(benzyloxy)methyl]-2-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-5-[2-(triethylsilyl)ethynyl]tetrahydro-3-furanyl acetate C33H39FN2O7Si 详情 详情
(X) 46269 1-[(2R,3R,4S,5R)-4-(benzyloxy)-5-[(benzyloxy)methyl]-3-hydroxy-5-[2-(triethylsilyl)ethynyl]tetrahydro-2-furanyl]-5-fluoro-2,4(1H,3H)-pyrimidinedione C31H37FN2O6Si 详情 详情
(XI) 46270 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-5-[2-(triethylsilyl)ethynyl]tetrahydro-2-furanyl]-5-fluoro-2,4(1H,3H)-pyrimidinedione C17H25FN2O6Si 详情 详情
(XII) 46271 [(2R,3R,4R,5R)-3-(acetoxy)-4-bromo-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2-[2-(triethylsilyl)ethynyl]tetrahydro-2-furanyl]methyl acetate C21H28BrFN2O7Si 详情 详情
(XIII) 46272 [(2R,3S,5R)-3-(acetoxy)-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2-[2-(triethylsilyl)ethynyl]tetrahydro-2-furanyl]methyl acetate C21H29FN2O7Si 详情 详情
(XIV) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(XV) 46273 [(2R,3S,5R)-3-(acetoxy)-5-[5-fluoro-2-oxo-4-(1H-1,2,4-triazol-1-yl)-1(2H)-pyrimidinyl]-2-[2-(triethylsilyl)ethynyl]tetrahydro-2-furanyl]methyl acetate C23H30FN5O6Si 详情 详情

合成路线40

该中间体在本合成路线中的序号：(V)

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).

参考文献 中间体
合成目标
【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
Extended Information