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【结 构 式】 
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【分子编号】15605 【品名】2-oxoethyl benzoate 【CA登记号】 |
【 分 子 式 】C9H8O3 【 分 子 量 】164.16072 【元素组成】C 65.85% H 4.91% O 29.24% |
合成路线1
该中间体在本合成路线中的序号：(I)There are two options for the synthesis of lamivudine: In the first approach the intact nucleoside analogue is prepared in racemic form by resolution to afford the required chiral product. This can be effected by an enzyme-mediated enantiospecific reaction. In the second approach synthesis of a chiral sugar component precedes coupling with the cytosine base under conditions where the chirality of the sugar precursor is maintained. The first approach is outlined in Scheme 18435601a. The oxathiolane (III) is obtained as a 1:1 mixture of anomers from reaction of benzoyloxyacetaldehyde (I) with mercaptoacetaldehyde dimethylacetal (II) in the presence of a Lewis acid. Treatment of (III) with silylated cytosine (IV) in the presence of TMS-triflate affords a 1:1 mixture of beta- and alpha-anomers (V) from which the required beta-anomer may be obtained by crystallization. Various alternative coupling conditions have been reported which yield almost exclusively the beta-anomer, notably as a result of the use of SnCl4. Subsequent deprotection affords the racemic nucleoside (VI) (BCH189). The resolution may be effected by a variety of enzymatic processes. Treatment of the nucleoside with phosphorus oxychloride and trimethylphosphate affords the 5'-monophosphate (VII). The natural enantiomer is selectively recognized by the 5'-nucleotidase from Crotalus atrox venom to afford the (+)-beta-D-nucleoside (VIII) and leave the unatural (-)-beta-L-enantiomer as the monophosphate (IX). Facile separation of these two products and subsequent dephosphorylation of (IX) using bacterial alkaline phosphatase affords lamivudine. Selective enzymatic recognition of the natural enantiomer may also be used to advantage in the resolution using cytidine deaminase derived from E. coli. In this case the enzyme is responsible for enantiospecific hydrolysis of the natural form to afford a readily separable mixture of lamivudine and the uridine derivative (X). Other enzymes including esterases and phosphodiesterases have application in the resolution of derivatives of the racemic nucleoside.
| 【1】 Choi, W.-B.; Yeola, S.; Liotta, D.C.; Wilson, L.S.; Schinazi, R.F.; In situ complexation directs the stereochemistry of N-glycosylation in the synthesis of oxathiolanyl and dioxolanyl nucleoside analogues. J Am Chem Soc 1991, 113, 9377-9. |
| 【2】 Coates, J.A.V.; Mutton, I.M.; Penn, C.R.; Storer, R.; Williamson, C. (BioChem Pharma Inc.); 1,3-Oxathiolane nucleoside analogues. EP 0625150; JP 1993501117; JP 1999080153; JP 2000128787; WO 9117159 . |
| 【3】 Belleau, B.; Nguyen-Ba, N. (BioChem Pharma Inc.); Substd.-1,3-oxathiolanes with antiviral properties. EP 0382526; EP 0711771; JP 1996119967; JP 2000143662; US 5047407 . |
| 【4】 Storer, R.; Belleau, B.; Noble, S.A.; Lamont, B.; Clemens, I.R.; Williamson, C.; The resolution and absolute stereochemistry of the enantiomers of cis-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine (BCH189): Equipotent anti-HIV agents. Nucleosides Nucleotides 1993, 12, 2, 225. |
| 【5】 Storer, R.; Wilcox, P.; Daniel, M.; Collis, P.; Cameron, J.M.; Lamivudine. Drugs Fut 1993, 18, 4, 319. |
| 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) | 15605 | 2-oxoethyl benzoate | C9H8O3 | 详情 | 详情 | |
| (II) | 15606 | 2,2-dimethoxy-1-ethanethiol; 2,2-dimethoxyethylhydrosulfide | C4H10O2S | 详情 | 详情 | |
| (III) | 15607 | (5-methoxy-1,3-oxathiolan-2-yl)methyl benzoate | C12H14O4S | 详情 | 详情 | |
| (IV) | 12706 | Cytosine; 4-Amino-2(1H)-pyrimidinone | 71-30-7 | C4H5N3O | 详情 | 详情 |
| (V) | 15609 | [5-[4-amino-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolan-2-yl]methyl benzoate | C15H15N3O4S | 详情 | 详情 | |
| (VI) | 15610 | 4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone | C8H11N3O3S | 详情 | 详情 | |
| (VII) | 15611 | [5-[4-amino-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolan-2-yl]methyl dihydrogen phosphate | C8H12N3O6PS | 详情 | 详情 | |
| (VIII) | 15612 | 4-amino-1-[(2S,5R)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone | C8H11N3O3S | 详情 | 详情 | |
| (IX) | 15613 | [(2R,5S)-5-[4-amino-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolan-2-yl]methyl dihydrogen phosphate | C8H12N3O6PS | 详情 | 详情 | |
| (X) | 15614 | 1-[(2S,5R)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2,4(1H,3H)-pyrimidinedione | C8H10N2O4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)The reaction of 1,4-dithiane-2,5-diol (XII) with 2-(benzoyloxy)acetaldehyde (XIII) in hot pyridine gives 5-acetoxy-2-(benzoyloxymethyl)-1,3-oxathiolane (XIV), which is condensed with fully silylated cytosine (XV) (obtained by silylation of cytosine (XVI) with HMDS) by means of TBDMS-OTf, yielding, after acetylation with Ac2O, a mixture of the desired racemic-cis substituted fluorocytosine (XVII) along with its racemic trans isomer, which are separated by flash chromatography. The deacylation of (XVII) with ammonia in methanol gives the racemic cis-2-(hydroxymethyl)-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (XVIII), which is phosphorylated with POCl3 and water in trimethyl phosphate yielding the racemic phosphate (XIX). The enantioselective dephosphorylation of (XIX) with 5'-nucleotidase (Sigma), affords a mixture of the (+)-(cis)-dephosphorylated compound (XXI) and unreacted (-)-(cis)-compound (XX) that are separated by column chromatography. Finally, (XX) is dephosphorylated by means of alkaline phosphatase (Sigma) to afford the target compound.
| 【1】 Dionne, G. (BioChem Pharma Inc.); 1,3-Oxathiolane nucleoside analogues. EP 0526253; JP 1995500317; US 5538975; WO 9303027 . |
| 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) | 36958 | 1,4-dithiane-2,5-diol | 40018-26-6 | C4H8O2S2 | 详情 | 详情 |
| (XIII) | 15605 | 2-oxoethyl benzoate | C9H8O3 | 详情 | 详情 | |
| (XIV) | 36964 | [5-(acetoxy)-1,3-oxathiolan-2-yl]methyl benzoate | C13H14O5S | 详情 | 详情 | |
| (XV) | 36959 | 5-fluoro-N-(trimethylsilyl)-2-[(trimethylsilyl)oxy]-4-pyrimidinamine; N-[5-fluoro-2-[(trimethylsilyl)oxy]-4-pyrimidinyl]-N-(trimethylsilyl)amine | C10H20FN3OSi2 | 详情 | 详情 | |
| (XVI) | 16747 | 4-amino-5-fluoro-2(1H)-pyrimidinone; 5-fluorocytosine | 2022-85-7 | C4H4FN3O | 详情 | 详情 |
| (XVII) | 36960 | [(2R,5S)-5-[4-(acetamido)-5-fluoro-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolan-2-yl]methyl benzoate | C17H16FN3O5S | 详情 | 详情 | |
| (XVIII) | 36961 | 4-amino-5-fluoro-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone | C8H10FN3O3S | 详情 | 详情 | |
| (XIX) | 64685 | (rac)-({(2R*,5S*)-5-[4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolan-2-yl}methyl dihydrogen phosphate) | C8H11FN3O6PS | 详情 | 详情 | |
| (XX) | 36962 | [(2R,5S)-5-[4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolan-2-yl]methyl dihydrogen phosphate | C8H11FN3O6PS | 详情 | 详情 | |
| (XXI) | 36963 | 4-amino-5-fluoro-1-[(2S,5R)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone | C8H10FN3O3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)A new asymmetric synthesis has been reported. Oxidative cleavage of mono-benzoyl glycerol (IX) by means of NaIO4 provided aldehyde (X). Condensation of (X) with mercaptoethanol (XI) in the presence of ploystyryl diphenylphosphane-iodine complex gave rise to the oxathiolane (XII). Sharpless asymmetric oxidation of (XII) using tert-butyl hydroperoxide and L-diethyl tartrate led to an 82:18 mixture of (E)- and (Z)-sulfoxides (XIII) and (XIV). The desired (E)-isomer (XIII) was then isolated by column chromatography, displaying an enantiomeric excess of 60%. Coupling of (XIII) with N-acetylcytosine (VII) under Pummerer rearrangement conditions led to an equimolecular mixture of (Z)- and (E)-adducts (XV) and (XVI). After chromatographic separation of the desired (Z)-isomer (XV), the acetyl and benzoyl protecting groups were removed by treatment with sodium methoxide.
| 【1】 Caputo, R.; et al.; A new strategy for the asymmetric synthesis of 1,3-oxathiolane-based nucleoside analogues. Eur J Org Chem 1999, 6, 1455. |
| 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) | 55073 | N(4)-Acetylcytosine | 14631-20-0 | C6H7N3O2 | 详情 | 详情 |
| (IX) | 55075 | 2,3-dihydroxypropyl benzoate | C10H12O4 | 详情 | 详情 | |
| (X) | 15605 | 2-oxoethyl benzoate | C9H8O3 | 详情 | 详情 | |
| (XII) | 55076 | 1,3-oxathiolan-2-ylmethyl benzoate | C11H12O3S | 详情 | 详情 | |
| (XIII) | 55077 | [(2R)-3-oxo-1,3lambda~4~-oxathiolan-2-yl]methyl benzoate | C11H12O4S | 详情 | 详情 | |
| (XIV) | 55080 | [(2S)-3-oxo-1,3lambda~4~-oxathiolan-2-yl]methyl benzoate | C11H12O4S | 详情 | 详情 | |
| (XV) | 55078 | {(2R,4R)-4-[4-(acetylamino)-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolan-2-yl}methyl benzoate | C17H17N3O5S | 详情 | 详情 | |
| (XVI) | 55079 | {(2R,4S)-4-[4-(acetylamino)-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolan-2-yl}methyl benzoate | C17H17N3O5S | 详情 | 详情 | |
| (XXI) | 36375 | 2-Sulfanyl-1-ethanol; 2-Mercaptoethanol | 60-24-2 | C2H6OS | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Ketal exchange between the chiral acetonide (I) and 2-(benzoyloxy)acetaldehyde (II) under acidic conditions affords the 2-(benzoyloxymethyl) dioxolane (III) as a diastereomeric mixture. Alternatively, diazotization of D-serine (IV) in the presence of NaNO2 and H2SO4 produces D-glyceric acid (V), which is further esterified with methanol to afford the methyl ester (VI). Condensation of dihydroxy ester (VI) with 2-(benzoyloxy)acetaldehyde dimethyl acetal (VII) then gives dioxolane (III).
| 【1】 Nguyen-Ba, N. (Shire BioChem Inc.); Antiviral nucleoside analogues. EP 1140937; JP 2002533470; US 6358963; WO 0039143 . |
| 【2】 Cimpoia, A.; Janes, L.; Kazlauskas, R. (Shire BioChem Inc.); Stereoselective synthesis of nucleoside analogues. WO 0047759 . |
| 【3】 Cimpoia, A.; Wang, Y.-F. (Shire BioChem Inc.); Stereoselective synthesis of nucleoside analogues. WO 0158894 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 57514 | methyl (2S,4R)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylate | C13H14O6 | 详情 | 详情 | |
| (IIIb) | 57515 | methyl (2R,4R)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylate | C13H14O6 | 详情 | 详情 | |
| (I) | 20917 | methyl (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxylate | 52373-72-5 | C7H12O4 | 详情 | 详情 |
| (II) | 15605 | 2-oxoethyl benzoate | C9H8O3 | 详情 | 详情 | |
| (IV) | 15728 | (+)-2-Amino-3-hydroxypropionic acid; D-(+)-Serine; D-serine | 312-84-5 | C3H7NO3 | 详情 | 详情 |
| (V) | 57516 | (2R)-2,3-dihydroxypropanoic acid | C3H6O4 | 详情 | 详情 | |
| (VI) | 20916 | methyl (2R)-2,3-dihydroxypropanoate | C4H8O4 | 详情 | 详情 | |
| (VII) | 57517 | 2,2-dimethoxyethyl benzoate | C11H14O4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XVII)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 |