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【结 构 式】

【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%

与该中间体有关的原料药合成路线共 5 条

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
Extended Information