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【结 构 式】 
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【分子编号】16341 【品名】1H-1,2,4-triazol-1-ylsodium 【CA登记号】 |
【 分 子 式 】C2H2N3Na 【 分 子 量 】91.047868 【元素组成】C 26.38% H 2.21% N 46.15% Na 25.25% |
合成路线1
该中间体在本合成路线中的序号：(VIII)An alternative synthesis of the key intermediate (II) in the synthesis of Sch-51048 published in the original monograph has been reported:The reaction of 2-(2,4-difluorophenyl)allyl alcohol (I) with PBr3 in dichloromethane gives the corresponding allyl bromide (II), which is condensed with sodium diethyl malonate (III), yielding the diester (IV). The reduction of (VI) with NaBH4 in ethanol affords the diol (V), which is submitted to an asymmetric acetylation with vinyl acetate catalyzed by the enzyme Novo SP435, giving the chiral monoester (VI). The cyclization of (VI) with I2 and NaHCO3 in acetonitrile affords the tetrahydrofuran derivative (VII), which is allowed to react with the sodium salt of 1,2,4-triazole (VIII) in DMF, yielding the corresponding condensation product (IX). Hydrolysis of (IX) with NaOH in methanol gives the alcohol (X), which is tosylated with tosyl chloride in pyridine.
| 【1】 Puar, M.S.; Girijavallabhan, V.M.; Saksena, A.K.; Lovey, R.G.; Ganguly, A.K.; Pike, R.E.; Wang, H.Y.; Zaks, A.; Morgan, B.; Highly stereoselective access to novel 2,2,4-trisubstituted tetrahydrofurans by halocyclization: Practical chemoenzymatic synthesis of SCH 51048, a broad-spectrum orally active antifungal agent. Tetrahedron Lett 1995, 36, 11, 1787. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 | |
| (I) | 15491 | 2-(2,4-difluorophenyl)-2-propen-1-ol | C9H8F2O | 详情 | 详情 | |
| (II) | 16335 | 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene | C9H7BrF2 | 详情 | 详情 | |
| (III) | 16336 | [2-ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]sodium | C7H11NaO4 | 详情 | 详情 | |
| (IV) | 16337 | diethyl 2-[2-(2,4-difluorophenyl)-2-propenyl]malonate | C16H18F2O4 | 详情 | 详情 | |
| (V) | 16338 | 2-[2-(2,4-difluorophenyl)-2-propenyl]-1,3-propanediol | C12H14F2O2 | 详情 | 详情 | |
| (VI) | 16339 | (2S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-4-pentenyl acetate | C14H16F2O3 | 详情 | 详情 | |
| (VII) | 16340 | [(3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro-3-furanyl]methyl acetate | C14H15F2IO3 | 详情 | 详情 | |
| (VIII) | 16341 | 1H-1,2,4-triazol-1-ylsodium | C2H2N3Na | 详情 | 详情 | |
| (IX) | 16342 | [(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl acetate | C16H17F2N3O3 | 详情 | 详情 | |
| (X) | 16343 | [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methanol | C14H15F2N3O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)The reaction of allyl alcohol (I) with triethyl orthoacetate at 120 C gives the 4-pentenoic ester (II), which is hydrolyzed with KOH to the corresponding free acid (III). The reaction of (III) with (COCl)2 yields the acyl chloride (IV), which is condensed with 4(S)-isopropyloxazolidin-2-one (V) (a chiral auxiliary), by means of BuLi to afford the chiral imide (VI). The diastereoselective alkylation of (VI) with benzyloxymethyl chloride (VII) by means of TiCl4 and TEA in dichloromethane provides the alkylated compound (VIII) with a diastereoselectivity of 70/30% and combined yields of 84%. The reductive elimination of the chiral auxiliary in (VIII) by means of LiAlH4 gives the alcohol (IX), which is treated with Ac2O to yield the acetate (X). The cyclization of (X) by means of I2 and pyridine in acetonitrile affords the chiral tetrahydrofuran (XI)????XI)a, which is condensed with the sodium salt of 1,2,4-triazole (XII) in hot DMF to provide the adduct (XIII). The debenzylation of (XIII) with H2 over Pd/C gives the alcohol (XIV), which is finally treated with Ts-Cl and pyridine to give rise to the target intermediate tosylate (XV) (see scheme no. 20027601a, intermediate no. (II))
| 【1】 Saksena, A.K.; Girijavallabhan, V.M.; Wang, H.Y.; Liu, Y.T.; Pike, R.E.; Ganguly, A.K.; Concise asymmetric routes to 2,2,4-trisubstituted tetrahydrofurans via chiral titanium imide enolates: Key intermediates towards synthesis of highly active azole antifungals Sch 51048 and Sch 56592. Tetrahedron Lett 1996, 37, 32, 5657. |
| 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) | 15491 | 2-(2,4-difluorophenyl)-2-propen-1-ol | C9H8F2O | 详情 | 详情 | |
| (II) | 58303 | ethyl 4-(2,4-difluorophenyl)-4-pentenoate | C13H14F2O2 | 详情 | 详情 | |
| (III) | 17090 | 4-(2,4-difluorophenyl)-4-pentenoic acid | C11H10F2O2 | 详情 | 详情 | |
| (IV) | 17091 | 4-(2,4-difluorophenyl)-4-pentenoyl chloride | C11H9ClF2O | 详情 | 详情 | |
| (V) | 12867 | (4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone | 17016-83-0 | C6H11NO2 | 详情 | 详情 |
| (VI) | 58304 | (4S)-3-[4-(2,4-difluorophenyl)-4-pentenoyl]-4-isopropyl-1,3-oxazolidin-2-one | C17H19F2NO3 | 详情 | 详情 | |
| (VII) | 14560 | Benzyl chloromethyl ether; 1-[(chloromethoxy)methyl]benzene | 3587-60-8 | C8H9ClO | 详情 | 详情 |
| (VIII) | 58305 | (4S)-3-[(2R)-2-[(benzyloxy)methyl]-4-(2,4-difluorophenyl)-4-pentenoyl]-4-isopropyl-1,3-oxazolidin-2-one | C25H27F2NO4 | 详情 | 详情 | |
| (IX) | 58306 | (2S)-2-[(benzyloxy)methyl]-4-(2,4-difluorophenyl)-4-penten-1-ol | C19H20F2O2 | 详情 | 详情 | |
| (X) | 58307 | (2R)-2-[(benzyloxy)methyl]-4-(2,4-difluorophenyl)-4-pentenyl acetate | C21H22F2O3 | 详情 | 详情 | |
| (XI) | 58308 | (2R,4R)-4-[(benzyloxy)methyl]-2-(2,4-difluorophenyl)-2-(iodomethyl)tetrahydrofuran; benzyl [(3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro-3-furanyl]methyl ether | C19H19F2IO2 | 详情 | 详情 | |
| (XII) | 16341 | 1H-1,2,4-triazol-1-ylsodium | C2H2N3Na | 详情 | 详情 | |
| (XIII) | 58309 | 1-{[(2R,4R)-4-[(benzyloxy)methyl]-2-(2,4-difluorophenyl)tetrahydro-2-furanyl]methyl}-1H-1,2,4-triazole; benzyl [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl ether | C21H21F2N3O2 | 详情 | 详情 | |
| (XIV) | 16343 | [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methanol | C14H15F2N3O2 | 详情 | 详情 | |
| (XV) | 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3
该中间体在本合成路线中的序号：(XI)The Friedel Craft condensation of 1,3-difluorobenzene (I) with succinic anhydride (II) gives the 4-oxobutyric acid (III); which by a Wittig reaction with methylene triphenylphosphorane (IV) yields the 4-pentenoic acid (V). The condensation of (V) with the chiral auxiliary, 4(R)-benyzloxazolidin-2-one (VI) by means of pivaloyl chloride and BuLi affords the chiral imide (VII), which is submitted to a diastereoselective hydroxymethylation with trioxane and TiCl4 in THF to provide the hydroxymethyl adduct (VIII). The direct iodocyclization of (VIII) by means of I2 and pyridine in acetonitrile gives the chiral cis-tetrahydrofuran derivative (IX). The reductive cleavage of the chiral auxiliary of (IX) by means of LiBH4 in THF yields the iodoalcohol (X)???(X)a, which is condensed with 1,2,4-triazole sodium salt (XI) to afford the adduct (XII). Finally, this compound is treated with Ts-Cl and pyridine to afford the target intermediate tosylate (XIII) (see scheme no. 20027601a, intermediate no. (II)).
| 【1】 Saksena, A.K.; Girijavallabhan, V.M.; Wang, H.Y.; Liu, Y.T.; Pike, R.E.; Ganguly, A.K.; Concise asymmetric routes to 2,2,4-trisubstituted tetrahydrofurans via chiral titanium imide enolates: Key intermediates towards synthesis of highly active azole antifungals Sch 51048 and Sch 56592. Tetrahedron Lett 1996, 37, 32, 5657. |
| 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) | 11291 | Dihydro-2,5-furandione; Succinic anhydride | 108-30-5 | C4H4O3 | 详情 | 详情 |
| (III) | 17089 | 4-(2,4-difluorophenyl)-4-oxobutyric acid | 110931-77-6 | C10H8F2O3 | 详情 | 详情 |
| (IV) | 27301 | methylene(triphenyl)phosphorane | C19H17P | 详情 | 详情 | |
| (V) | 17090 | 4-(2,4-difluorophenyl)-4-pentenoic acid | C11H10F2O2 | 详情 | 详情 | |
| (VI) | 25351 | (4R)-4-benzyl-1,3-oxazolidin-2-one; (R)-(+)-4-benzyl-2-oxazolidinone | 102029-44-7 | C10H11NO2 | 详情 | 详情 |
| (VII) | 58310 | (4R)-4-benzyl-3-[4-(2,4-difluorophenyl)-4-pentenoyl]-1,3-oxazolidin-2-one | C21H19F2NO3 | 详情 | 详情 | |
| (VIII) | 58311 | (4R)-4-benzyl-3-[(2S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-4-pentenoyl]-1,3-oxazolidin-2-one | C22H21F2NO4 | 详情 | 详情 | |
| (IX) | 58312 | (4R)-4-benzyl-3-{[(3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro-3-furanyl]carbonyl}-1,3-oxazolidin-2-one | C22H20F2INO4 | 详情 | 详情 | |
| (X) | 17096 | [(3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro-3-furanyl]methanol | C12H13F2IO2 | 详情 | 详情 | |
| (XI) | 16341 | 1H-1,2,4-triazol-1-ylsodium | C2H2N3Na | 详情 | 详情 | |
| (XII) | 16343 | [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methanol | C14H15F2N3O2 | 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4
该中间体在本合成路线中的序号：(XVIII)Reaction of mesylate (XVII) with triazole sodium salt (XVIII) gave (XIX). Ozonization of olefinic double bond, followed by treatment with Me2S and K2CO3 provided ketone (XX). Then, haloform reaction with NaOBr gave acid (XXI), and reduction with LiAlH4 in cold Et2O afforded primary alcohol (XXII). Alcohol (XXII) was converted to mesylate (XXIII), and this was condensed with 4-(trifluoromethoxy)phenol (XXIV) to give ether (XXV). Deprotection of the trityl group with formic acid in EtOAc and subsequent reaction with methanesulfonyl chloride provided mesylate (XXVI), which was finally condensed with mercaptoimidazole (XXVII) to furnish the target compound.
| 【1】 Tsukuda, T.; Watanabe, M.; Ontsuka, H.; Hattori, K.; Shirai, M.; Shimma, N.; Synthesis of novel antifungal agents (2). Bioorg Med Chem Lett 1998, 8, 14, 1825. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 18762 | 1-Ethoxyethylene; Ethyl vinyl ether；Ethoxyethene | 109-92-2 | C4H8O | 详情 | 详情 |
| (XVIII) | 16341 | 1H-1,2,4-triazol-1-ylsodium | C2H2N3Na | 详情 | 详情 | |
| (XIX) | 18775 | 2-[(1S,2R,3R,4R)-4-isopropenyl-2-methoxy-1-methyl-3-(1H-1,2,4-triazol-1-ylmethyl)cyclohexyl]ethyl trityl ether; 1-([(1R,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexyl]methyl)-1H-1,2,4-triazole | C35H41N3O2 | 详情 | 详情 | |
| (XX) | 18776 | 1-[(1R,2R,3R,4S)-3-methoxy-4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-4-[2-(trityloxy)ethyl]cyclohexyl]-1-ethanone | C34H39N3O3 | 详情 | 详情 | |
| (XXI) | 18777 | (1R,2R,3R,4S)-3-methoxy-4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-4-[2-(trityloxy)ethyl]cyclohexanecarboxylic acid | C33H37N3O4 | 详情 | 详情 | |
| (XXII) | 18778 | [(1R,2R,3R,4S)-3-methoxy-4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-4-[2-(trityloxy)ethyl]cyclohexyl]methanol | C33H39N3O3 | 详情 | 详情 | |
| (XXIII) | 18779 | [(1R,2R,3R,4S)-3-methoxy-4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-4-[2-(trityloxy)ethyl]cyclohexyl]methyl methanesulfonate | C34H41N3O5S | 详情 | 详情 | |
| (XXIV) | 18780 | 4-(trifluoromethoxy)phenol | 828-27-3 | C7H5F3O2 | 详情 | 详情 |
| (XXV) | 18781 | 1-([(1R,2R,3S,6R)-2-methoxy-3-methyl-6-[[4-(trifluoromethoxy)phenoxy]methyl]-3-[2-(trityloxy)ethyl]cyclohexyl]methyl)-1H-1,2,4-triazole; 2-((1S,2R,3R,4R)-2-methoxy-1-methyl-3-(1H-1,2,4-triazol-1-ylmethyl)-4-[[4-(trifluoromethoxy)phenoxy]methyl]cyclohexyl)ethyl trityl ether | C40H42F3N3O4 | 详情 | 详情 | |
| (XXVI) | 18782 | 2-((1S,2R,3R,4R)-2-methoxy-1-methyl-3-(1H-1,2,4-triazol-1-ylmethyl)-4-[[4-(trifluoromethoxy)phenoxy]methyl]cyclohexyl)ethyl methanesulfonate | C22H30F3N3O6S | 详情 | 详情 | |
| (XXVII) | 18783 | 1-methyl-1H-imidazol-2-ylhydrosulfide; 1-methyl-1H-imidazole-2-thiol | 60-56-0 | C4H6N2S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XVIII)Reaction of mesylate (XVII) with triazole sodium salt (XVIII) gave (XIX). Ozonization of olefinic double bond, followed by treatment with Me2S and K2CO3 provided ketone (XX). Then, haloform reaction with NaOBr gave acid (XXI), and reduction with LiAlH4 in cold Et2O afforded primary alcohol (XXII). Alcohol (XXII) was converted to mesylate (XXIII), and this was condensed with 4-(trifluoromethoxy)phenol (XXIV) to give ether (XXV). Deprotection of the trityl group with formic acid in EtOAc and subsequent reaction with methanesulfonyl chloride provided mesylate (XXVI), which was finally condensed with morpholine (XXVII) to furnish the target compound.
| 【1】 Tsukuda, T.; Watanabe, M.; Ontsuka, H.; Hattori, K.; Shirai, M.; Shimma, N.; Synthesis of novel antifungal agents (2). Bioorg Med Chem Lett 1998, 8, 14, 1825. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 18762 | 1-Ethoxyethylene; Ethyl vinyl ether；Ethoxyethene | 109-92-2 | C4H8O | 详情 | 详情 |
| (XVIII) | 16341 | 1H-1,2,4-triazol-1-ylsodium | C2H2N3Na | 详情 | 详情 | |
| (XIX) | 18775 | 2-[(1S,2R,3R,4R)-4-isopropenyl-2-methoxy-1-methyl-3-(1H-1,2,4-triazol-1-ylmethyl)cyclohexyl]ethyl trityl ether; 1-([(1R,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexyl]methyl)-1H-1,2,4-triazole | C35H41N3O2 | 详情 | 详情 | |
| (XX) | 18776 | 1-[(1R,2R,3R,4S)-3-methoxy-4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-4-[2-(trityloxy)ethyl]cyclohexyl]-1-ethanone | C34H39N3O3 | 详情 | 详情 | |
| (XXI) | 18777 | (1R,2R,3R,4S)-3-methoxy-4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-4-[2-(trityloxy)ethyl]cyclohexanecarboxylic acid | C33H37N3O4 | 详情 | 详情 | |
| (XXII) | 18778 | [(1R,2R,3R,4S)-3-methoxy-4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-4-[2-(trityloxy)ethyl]cyclohexyl]methanol | C33H39N3O3 | 详情 | 详情 | |
| (XXIII) | 18779 | [(1R,2R,3R,4S)-3-methoxy-4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-4-[2-(trityloxy)ethyl]cyclohexyl]methyl methanesulfonate | C34H41N3O5S | 详情 | 详情 | |
| (XXIV) | 18780 | 4-(trifluoromethoxy)phenol | 828-27-3 | C7H5F3O2 | 详情 | 详情 |
| (XXV) | 18781 | 1-([(1R,2R,3S,6R)-2-methoxy-3-methyl-6-[[4-(trifluoromethoxy)phenoxy]methyl]-3-[2-(trityloxy)ethyl]cyclohexyl]methyl)-1H-1,2,4-triazole; 2-((1S,2R,3R,4R)-2-methoxy-1-methyl-3-(1H-1,2,4-triazol-1-ylmethyl)-4-[[4-(trifluoromethoxy)phenoxy]methyl]cyclohexyl)ethyl trityl ether | C40H42F3N3O4 | 详情 | 详情 | |
| (XXVI) | 18782 | 2-((1S,2R,3R,4R)-2-methoxy-1-methyl-3-(1H-1,2,4-triazol-1-ylmethyl)-4-[[4-(trifluoromethoxy)phenoxy]methyl]cyclohexyl)ethyl methanesulfonate | C22H30F3N3O6S | 详情 | 详情 | |
| (XXVII) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |