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【结 构 式】 
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【分子编号】43223 【品名】S-ethyl 2,2,2-trifluoroethanethioate 【CA登记号】383-64-2 |
【 分 子 式 】C4H5F3OS 【 分 子 量 】158.1443096 【元素组成】C 30.38% H 3.19% F 36.04% O 10.12% S 20.28% |
合成路线1
该中间体在本合成路线中的序号：(III)The reaction of N-(tert-butoxycarbonyl)-L-serine methyl ester (I) with hydrazine gives the corresponding hydrazide (II), which is acylated with trifluorothioacetic acid S-ethyl ester (III), yielding the diacylated hydrazine (IV). The cyclization of (IV) by means of DEAD and PPh3 affords the pyrazolidinone (V), which is deacylated with NaOH to furnish 4(S)-(tert-butoxycarbonyl)pyrazolidin-3-one (VI). The condensation of (VI) with vinylphosphonate (VII) gives the adduct (VIII), which is cyclized with the oxalyl monoester chloride (IX) by means of DIEA, yielding the pyrazolopyrazole (X). Finally, this compound is deprotected in acid medium and acylated with thiazole derivative (XI) by means of a Pd(0) catalyst to furnish the target compound.
| 【1】 Ternansky, R.J.; Draheim, S.E.; The synthesis of bicyclic pyrazolidinone antibacterial agents. 30th Nat Org Symp (Vancouver) 1987. |
| 【2】 Jungheim, L.N.; Holmes, R.E. (Eli Lilly and Company); Substd. diazolidinones. US 4826993 . |
| 【3】 Jungheim, L.N.; Ternansky, R.J.; Holmes, R.E.; BICYCLIC PYRAZOLIDINONE ANTIBACTERIAL AGENTS. Drugs Fut 1990, 15, 2, 149. |
| 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) | 43221 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoate | 2766-43-0 | C9H17NO5 | 详情 | 详情 |
| (II) | 43222 | tert-butyl (1S)-2-hydrazino-1-(hydroxymethyl)-2-oxoethylcarbamate | C8H17N3O4 | 详情 | 详情 | |
| (III) | 43223 | S-ethyl 2,2,2-trifluoroethanethioate | 383-64-2 | C4H5F3OS | 详情 | 详情 |
| (IV) | 43224 | tert-butyl (1S)-1-(hydroxymethyl)-2-oxo-2-[2-(2,2,2-trifluoroacetyl)hydrazino]ethylcarbamate | C10H16F3N3O5 | 详情 | 详情 | |
| (V) | 43225 | tert-butyl (4S)-3-oxo-1-(2,2,2-trifluoroacetyl)pyrazolidinylcarbamate | C10H14F3N3O4 | 详情 | 详情 | |
| (VI) | 43226 | tert-butyl (4S)-3-oxopyrazolidinylcarbamate | C8H15N3O3 | 详情 | 详情 | |
| (VII) | 43227 | diethyl 1-cyanovinylphosphonate | C7H12NO3P | 详情 | 详情 | |
| (VIII) | 43228 | diethyl 2-[(4S)-4-[(tert-butoxycarbonyl)amino]-3-oxopyrazolidinyl]-1-cyanoethylphosphonate | C15H27N4O6P | 详情 | 详情 | |
| (IX) | 15585 | allyl 2-chloro-2-oxoacetate | C5H5ClO3 | 详情 | 详情 | |
| (X) | 43229 | allyl (6S)-6-[(tert-butoxycarbonyl)amino]-2-cyano-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-3-carboxylate | C16H20N4O5 | 详情 | 详情 | |
| (XI) | 24316 | 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl chloride | C6H6ClN3O2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The reaction of N-(tert-butoxycarbonyl)-L-serine methyl ester (I) with hydrazine gives the corresponding hydrazide (II), which is acylated with trifluorothioacetic acid S-ethyl ester (III), yielding the diacylated hydrazine (IV). The cyclization of (IV) by means of DEAD and PPh3 affords the pyrazolidinone (V), which is deacylated with NaOH to furnish 4(S)-(tert-butoxycarbonyl)pyrazolidin-3-one (VI). The condensation of (VI) with vinylphosphonate (VII) gives the adduct (VIII), which is cyclized with the oxalyl monoester chloride (IX) by means of DIEA, yielding the pyrazolopyrazole (X). Finally, this compound is deprotected in acid medium and acylated with thiazole derivative (XI) by means of a Pd(0) catalyst to furnish the target compound.
| 【1】 Ternansky, R.J.; Draheim, S.E.; The synthesis of bicyclic pyrazolidinone antibacterial agents. 30th Nat Org Symp (Vancouver) 1987. |
| 【2】 Jungheim, L.N.; Holmes, R.E. (Eli Lilly and Company); Substd. diazolidinones. US 4826993 . |
| 【3】 Jungheim, L.N.; Ternansky, R.J.; Holmes, R.E.; BICYCLIC PYRAZOLIDINONE ANTIBACTERIAL AGENTS. Drugs Fut 1990, 15, 2, 149. |
| 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) | 43221 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoate | 2766-43-0 | C9H17NO5 | 详情 | 详情 |
| (II) | 43222 | tert-butyl (1S)-2-hydrazino-1-(hydroxymethyl)-2-oxoethylcarbamate | C8H17N3O4 | 详情 | 详情 | |
| (III) | 43223 | S-ethyl 2,2,2-trifluoroethanethioate | 383-64-2 | C4H5F3OS | 详情 | 详情 |
| (IV) | 43224 | tert-butyl (1S)-1-(hydroxymethyl)-2-oxo-2-[2-(2,2,2-trifluoroacetyl)hydrazino]ethylcarbamate | C10H16F3N3O5 | 详情 | 详情 | |
| (V) | 43225 | tert-butyl (4S)-3-oxo-1-(2,2,2-trifluoroacetyl)pyrazolidinylcarbamate | C10H14F3N3O4 | 详情 | 详情 | |
| (VI) | 43226 | tert-butyl (4S)-3-oxopyrazolidinylcarbamate | C8H15N3O3 | 详情 | 详情 | |
| (VII) | 43230 | diethyl 1-(methylsulfonyl)vinylphosphonate | C7H15O5PS | 详情 | 详情 | |
| (VIII) | 43231 | diethyl 2-[(4S)-4-[(tert-butoxycarbonyl)amino]-3-oxopyrazolidinyl]-1-(methylsulfonyl)ethylphosphonate | C15H30N3O8PS | 详情 | 详情 | |
| (IX) | 15585 | allyl 2-chloro-2-oxoacetate | C5H5ClO3 | 详情 | 详情 | |
| (X) | 43232 | allyl (6S)-6-[(tert-butoxycarbonyl)amino]-2-(methylsulfonyl)-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-3-carboxylate | C16H23N3O7S | 详情 | 详情 | |
| (XI) | 24316 | 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl chloride | C6H6ClN3O2S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)N-Acylation of sisomicin (I) with ethyl trifluorothioacetate (XII) in MeOH gives 6-trifluoroacetyl-sisomicin (XIII) (2-4), which by selective N-protection with CbzOSu in the presence of zn(OAc)2 and Et3N in MeOH/THF yields 2’,3-diCbz-sisomicin (XIV). N-Acylation of compound (XIV) with the activated carboxylic acid (XV) provides 6'-(trifluoroacetamido)-2’,3-diCbz-1-[4-amino-2(S)-hydroxybutryl]sisomicin (XVI). Hydrolysis of the trifluoroacetamide group in compound (XVI) with NH4OH in acetonitrile, followed by reductive alkylation with Obenzoylglycoaldehyde (XVII) in the presence of NaBH3CN in MeOH affords the secondary amino alcohol (XVIII). Finally, compound (XVIII) is deprotected by removal the O-benzoyl group by means of NaOH in MeOH/H2O, followed by catalytic hydrogenolysis with H2 over Pd/C in AcOH .
| 【1】 Nagabhushan, T.l. (Schering Corp.). Process for the manufacture of 6’-Nalkyl derivatives of sisomicin and verdamicin; novel intermediates useful therein, and novel 6’-N-alkylverdamicins prepared thereby. US 3997524. |
| 【2】 Aggen, J.B., Armstrong, E.S., Goldblum, A.A. et al. Synthesis, structure and in vivo activity of the neoglycoside ACHN-490. 49th Intersci Conf Antimicrob Agents Chemother (ICAAC) (Sept 12-15, San Francisco) 2009, Abst F1-840. |
| 【3】 Aggen, J.B., Armstrong, E.S., Goldblum, A.A. et al. Synthesis and spectrum of the neoglycoside ACHN-490. Antimicrob Agents Chemother 2010, 54(11): 4636-42. |
| 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) | 44199 | (2R,3R,4R,5R)-2-[((1S,2R,3R,4S,6R)-4,6-diamino-3-[[(2S,3R)-3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl]oxy]-2-hydroxycyclohexyl)oxy]-5-methyl-4-(methylamino)tetrahydro-2H-pyran-3,5-diol; Sisomicin | 32385-11-8 | C19H37N5O7 | 详情 | 详情 |
| (XII) | 43223 | S-ethyl 2,2,2-trifluoroethanethioate | 383-64-2 | C4H5F3OS | 详情 | 详情 |
| (XIII) | 67697 | N-(((2R,3S)-3-amino-2-(((1S,2R,3R,4S,6R)-4,6- diamino-3-(((2S,3S,4S,5S)-3,5-dihydroxy-5-methyl-4- (methylamino)tetrahydro-2H-pyran-2-yl)oxy)-2- hydroxycyclohexyl)oxy)-3,4-dihydro-2H-pyran-6-yl) methyl)-2,2,2-trifluoroacetamide | C21H36F3N5O8 | 详情 | 详情 | |
| (XIV) | 67698 | 2’,3-diCbz-sisomicin | C37H48F3N5O12 | 详情 | 详情 | |
| (XV) | 67699 | (2S)-2,5-dioxotetrahydrofuran-3-yl 4 -(((benzyloxy)carbonyl)amino)-2-hydroxybutanoate (XVI) C49H61F3N6O16 6’-(trifluoroacetamido)-2',3- diCbz-1-[4-amino-2(S)-hydroxybutryl]sisomicin | C16H17NO8 | 详情 | 详情 | |
| (XVI) | 67701 | C49H61F3N6O16 | 详情 | 详情 | ||
| (XVII) | 15605 | 2-oxoethyl benzoate | C9H8O3 | 详情 | 详情 | |
| (XVIII) | 67700 | C56H70N6O17 | 详情 | 详情 |