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【结 构 式】 
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【分子编号】12709 【品名】[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methanol 【CA登记号】22323-82-6 |
【 分 子 式 】C6H12O3 【 分 子 量 】132.15948 【元素组成】C 54.53% H 9.15% O 36.32% |
合成路线1
该中间体在本合成路线中的序号：(IV)This compound can be prepared by two related ways: 1) The diazotation of L-serine methyl ester (I) with NaNO2 - HCl gives methyl (S)-glycerate (II), which by reaction with 2,2-dimethoxypropane and p-toluenesulfonic acid (or acetone and ZnCl2) is converted to methyl (S)-O-isopropylideneglycerate (III). The reduction of (III) with LiAlH4 in refluxing ether affords (S)-2,3-O-isopropylideneglycerol (IV), which by reaction with tosyl chloride in pyridine is converted to the corresponding tosylate (V). The partial hydrolysis of (V) with HCl in acetone affords (S)-glycerol-1-tosylate (VI), which is finally condensed with 1-phenylpiperazine (VII) in refluxing benzene. 2) The partial hydrolysis of (S)-2,3-epoxypropyl tosylate (VIII) with HCl as before gives the glycerol tosylate (VI), already obtained.
| 【1】 Borsa, M.; Tonon, G.; Malandrino, S. (Dompé Farm. SpA); Optically active compounds with antitussive and central sedative activity, a process for the preparation thereof and compositions containing the same. EP 0147847; US 4699911; US 4764515 . |
| 【2】 Giani, R.; Marione, E.; Melillo, G.; Borsa, M.; Tonon, G.C.; Synthesis and pharmacological screening of new phenylpiperazinepropane derivatives and their enantiomers. Arzneim-Forsch Drug Res 1988, 38, 8, 1139-41. |
| 【3】 Prous, J.; Castaner, J.; LEVDROPROPIZINE < Rec INN >. Drugs Fut 1989, 14, 6, 522. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10272 | [[Amino(imino)methyl]sulfanyl]methane | 2986-19-8 | C2H6N2S | 详情 | 详情 | |
| (I) | 20915 | methyl (2S)-2-amino-3-hydroxypropanoate | 5680-80-8 | C4H9NO3 | 详情 | 详情 |
| (II) | 20916 | methyl (2R)-2,3-dihydroxypropanoate | C4H8O4 | 详情 | 详情 | |
| (III) | 20917 | methyl (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxylate | 52373-72-5 | C7H12O4 | 详情 | 详情 |
| (IV) | 12709 | [(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methanol | 22323-82-6 | C6H12O3 | 详情 | 详情 |
| (V) | 20919 | [(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate | 23788-74-1 | C13H18O5S | 详情 | 详情 |
| (VI) | 20920 | (2R)-2,3-dihydroxypropyl 4-methylbenzenesulfonate | C10H14O5S | 详情 | 详情 | |
| (VII) | 10756 | N-Phenylpiperazine; 1-Phenylpiperazine; Phenyl piperazine | 92-54-6 | C10H14N2 | 详情 | 详情 |
| (VIII) | 16242 | (2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate | 113826-06-5 | C10H12O4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)3) The reaction of 2(S),3-O-isopropylideneglycerol (XV) with methanesulfonyl chloride and triethylamine in dichloromethane gives the corresponding mesylate (XVI), which is condensed with cytosine (XII) by means of cesium carbonate as before yielding 1-[2(S),3-(isopropylidenedioxy)propyl]cytosine (XVII). The deprotection of (XVII) with aqueous acetic acid at 100 C affords the corresponding diol (XVIII), which is treated with trityl chloride, DMAP and triethylamine in DMF to give the monotrityl compound (XIX). The condensation of (XIX) with diethyl tosyloxymethylphosphonate (VIII) [obtained by reaction of diethylphosphite (XX) with paraformaldehyde, followed by tosylation with tosyl chloride] by a previous treatment of (XX) with DMF dimethylacetal, then condensation by means of NaH in DMF, and a final hydrolysis with hot aqueous acetic acid yields the 1-[2(S)-(diethoxyphosphorylmethoxy)-3-hydroxypropyl]cytosine (XIV) (already obtained), which is finally treated with bromotrimethylsilane as before. 4) The reaction of the acetonide (XVI) with N4-benzoylcytosine (XXI) by means of potassium tert-butoxide or cesium carbonate gives the condensation product (XXII), which is deprotected with HCl in acetic acid yielding the diol (XXIII). The reaction of (XXIII) with trityl chloride and DMAP in refluxing pyridine affords the monotritylated compound (XXIV), which is condensed with the phosphonate (VIII) by means of NaH in DMF to give the fully protected HPMPC compound (XXV). The successive deprotections of (XXV), first with HCl in dichloromethane to eliminate the trityl group yielding (XXVI), then with bromotrimethylsilane to obtain the free phosphono group giving (XXVII), and finally with concentrated aqueous NH4OH to eliminate the benzoyl group affords cidofovir. 5) The benzoylation of acetonide derivative (XVII) with benzoyl anhydride in refluxing pyridine gives the benzoyl citosine derivative (XXII) already obtained.
| 【1】 Fromtling, R.A.; Castaner, J.; Cidofovir. Drugs Fut 1996, 21, 10, 1003. |
| 【2】 Bronson, J.J.; Ferrara, L.M.; Howell, H.G.; Brodfuehrer, P.R.; Martin, J.C.; A new synthesis of the potent and selective anti-herpesvirus agent (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine. Nucleosides Nucleotides 1990, 9, 6, 745-69. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 12702 | (diethoxyphosphoryl)methyl 4-methylbenzenesulfonate | 31618-90-3 | C12H19O6PS | 详情 | 详情 |
| (XII) | 12706 | Cytosine; 4-Amino-2(1H)-pyrimidinone | 71-30-7 | C4H5N3O | 详情 | 详情 |
| (XIV) | 12708 | diethyl [[(1S)-2-[4-amino-2-oxo-1(2H)-pyrimidinyl]-1-(hydroxymethyl)ethyl]oxy]methylphosphonate | C12H22N3O6P | 详情 | 详情 | |
| (XV) | 12709 | [(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methanol | 22323-82-6 | C6H12O3 | 详情 | 详情 |
| (XVI) | 12710 | [(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl methanesulfonate | C7H14O5S | 详情 | 详情 | |
| (XVII) | 12711 | 4-Amino-1-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]-2(1H)-pyrimidinone | C10H15N3O3 | 详情 | 详情 | |
| (XVIII) | 12695 | 4-Amino-1-[(2S)-2,3-dihydroxypropyl]-2(1H)-pyrimidinone | C7H11N3O3 | 详情 | 详情 | |
| (XIX) | 12713 | 4-Amino-1-[(2S)-2-hydroxy-3-(trityloxy)propyl]-2(1H)-pyrimidinone | C26H25N3O3 | 详情 | 详情 | |
| (XX) | 12714 | diethyl phosphonate; diethyl phosphite | 762-04-9 | C4H11O3P | 详情 | 详情 |
| (XXI) | 12715 | N-(2-Oxo-1,2-dihydro-4-pyrimidinyl)benzamide; N-Benzoylcytosine | 26661-13-2 | C11H9N3O2 | 详情 | 详情 |
| (XXII) | 12716 | N-(1-[[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methyl]-2-oxo-1,2-dihydro-4-pyrimidinyl)benzamide | C17H19N3O4 | 详情 | 详情 | |
| (XXIII) | 12717 | N-[1-[(2S)-2,3-Dihydroxypropyl]-2-oxo-1,2-dihydro-4-pyrimidinyl]benzamide | C14H15N3O4 | 详情 | 详情 | |
| (XXIV) | 12718 | N-[1-[(2S)-2-Hydroxy-3-(trityloxy)propyl]-2-oxo-1,2-dihydro-4-pyrimidinyl]benzamide | C33H29N3O4 | 详情 | 详情 | |
| (XXV) | 12719 | diethyl ([(1S)-2-[4-(benzoylamino)-2-oxo-1(2H)-pyrimidinyl]-1-[(trityloxy)methyl]ethyl]oxy)methylphosphonate | C38H40N3O7P | 详情 | 详情 | |
| (XXVI) | 12720 | diethyl [[(1S)-2-[4-(benzoylamino)-2-oxo-1(2H)-pyrimidinyl]-1-(hydroxymethyl)ethyl]oxy]methylphosphonate | C19H26N3O7P | 详情 | 详情 | |
| (XXVII) | 12721 | [[(1S)-2-[4-(Benzoylamino)-2-oxo-1(2H)-pyrimidinyl]-1-(hydroxymethyl)ethyl]oxy]methylphosphonic acid | C15H18N3O7P | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIV)2) Synthesis of Oxazolidinone (II): 2a) The reaction of 4-benzyloxyaniline (IX) with 1,4-dioxaspiro[4.5]decan-2(S)-ylmethyl methanesulfonate (X) by means of TEA at 140 C gives 3-(4-benzyloxyphenylamino)propane-1,2(R)-diol (XI), which is cyclized with diethyl carbonate and sodium methoxide in refluxing toluene, yielding 3-(4-benzyloxyphenyl)-5(R)-(hydroxymethyl)oxazolidin-2-one (XII). The methylation of (XII) with dimethyl sulfate, NaOH and tetrabutylammonium bisulfate in hot toluene/water affords the corresponding methoxymethyl derivative (XIII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol/dichloromethane to give oxazolidinone (II). 2b) The methylation of 4(S)-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane (XIV) with dimethyl sulfate and NaOH gives 4(S)-(methoxymethyl)-2,2-dimethyl-1,3-dioxolane (XV), which is hydrolyzed with hot aqueous HCl to 3-methoxypropane-1,2(R)-diol (XVI). The cyclization of (XVI) with diethyl carbonate by means of NaH affords 4(S)-(methoxymethyl)-1,3-dioxolan-2-one (XVII) (2, 5). The condensation of (XVII) with N-(4-benzyloxyphenyl)carbamic acid methyl ester (XVIII) (obtained by reaction of 4-benzyloxyaniline (IX) with methyl chloroformate) by means of K2CO3 at 160 C provides the protected oxazolidinone (XIII), which is finally debenzylated as before to give oxazolidinone (II).
| 【1】 Castaner, J.; Sorbera, L.A.; Rabasseda, X.; Befloxatone. Drugs Fut 1999, 24, 10, 1057. |
| 【2】 Koenig, J.-J.; Schoofs, A.; Jarreau, F.-X.; Rovei, V. (Laboratoires Delalande); 3-Aryl oxazolidinones, process for their preparation and their therapeutical use. EP 0424243; EP 0424244; EP 0428421; JP 1992502333; JP 1992502334; JP 1992502335; US 5036090; US 5036091; US 5171747; US 5196543; WO 9105775 . |
| 【3】 Jarreau, F.-X.; Koenig, J.-J.; Rovei, V. (Laboratoires Delalande); 3-Aryl-oxazolidinone derivs., process for their preparation and their use in therapeutics. EP 0511031; FR 2675504; JP 1993112542; US 5264443 . |
| 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) | 28682 | (5R)-3-(4-hydroxyphenyl)-5-(methoxymethyl)-1,3-oxazolidin-2-one | C11H13NO4 | 详情 | 详情 | |
| (IX) | 22460 | 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine | C13H13NO | 详情 | 详情 | |
| (X) | 28688 | (2R)-1,4-dioxaspiro[4.5]dec-2-ylmethyl methanesulfonate | C10H18O5S | 详情 | 详情 | |
| (XI) | 28689 | (2R)-3-[4-(benzyloxy)anilino]-1,2-propanediol | C16H19NO3 | 详情 | 详情 | |
| (XII) | 28695 | (5R)-3-[4-(benzyloxy)phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one | C17H17NO4 | 详情 | 详情 | |
| (XIII) | 28690 | (5R)-3-[4-(benzyloxy)phenyl]-5-(methoxymethyl)-1,3-oxazolidin-2-one | C18H19NO4 | 详情 | 详情 | |
| (XIV) | 12709 | [(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methanol | 22323-82-6 | C6H12O3 | 详情 | 详情 |
| (XV) | 28691 | (4S)-4-(methoxymethyl)-2,2-dimethyl-1,3-dioxolane | C7H14O3 | 详情 | 详情 | |
| (XVI) | 28692 | (2R)-3-methoxy-1,2-propanediol | C4H10O3 | 详情 | 详情 | |
| (XVII) | 28693 | (4S)-4-(methoxymethyl)-1,3-dioxolan-2-one | C5H8O4 | 详情 | 详情 | |
| (XVIII) | 28694 | methyl 4-(benzyloxy)phenylcarbamate | C15H15NO3 | 详情 | 详情 |