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【结 构 式】 
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【分子编号】12698 【品名】[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]methanol 【CA登记号】14347-78-5 |
【 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)The reaction of D-mannitol (I) with acetone and ZnCl2 gives the diacetonide (II), which is oxidized with Pb(OAc)4 to yield the acetonide of (R)-glyceraldehyde (III). The reduction of (III) with H2 over Pd/C affords the (S)-glycerin acetonide (IV), which is treated with TsCl in pyridine to provide the corresponding tosylate (V). The condensation of (V) with the urea derivative (VI) by means of KOH in DMSO gives the adduct (VII), which is deprotected with HCl in acetone to yield the diol (VIII). Monotosylation of (VIII) with TsCl in pyridine affords the primary tosylate (IX), which is treated with Na in methanol to provide the epoxide (X). Finally this compound is treated with tert-butylamine to furnish the target (R)-enantiomer.
| 【1】 Hofer, O.; Schlogl, K.; Absolute configuration and enantiomeric purity of celiprolol. Arzneim-Forsch Drug Res 1986, 36, 8, 1157. |
| 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) | 45943 | (2R,3R,4R,5R)-1,2,3,4,5-heptanepentol | C7H16O5 | 详情 | 详情 | |
| (II) | 45944 | (1S,2S)-1,2-bis[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1,2-ethanediol | 1707-77-3 | C12H22O6 | 详情 | 详情 |
| (III) | 36759 | (4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde | 15186-48-8 | C6H10O3 | 详情 | 详情 |
| (IV) | 12698 | [(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]methanol | 14347-78-5 | C6H12O3 | 详情 | 详情 |
| (V) | 15208 | (S)-(+)-2,2-Dimethyl-4-(hydroxymethyl)-1,3-dioxolane-p-toluenesulfonate; [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate | 23735-43-5 | C13H18O5S | 详情 | 详情 |
| (VI) | 33817 | N'-(3-acetyl-4-hydroxyphenyl)-N,N-diethylurea | C13H18N2O3 | 详情 | 详情 | |
| (VII) | 45945 | N'-(3-acetyl-4-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]phenyl)-N,N-diethylurea | C19H28N2O5 | 详情 | 详情 | |
| (VIII) | 45946 | N'-(3-acetyl-4-[[(2R)-2,3-dihydroxypropyl]oxy]phenyl)-N,N-diethylurea | C16H24N2O5 | 详情 | 详情 | |
| (IX) | 45947 | (2S)-3-(2-acetyl-4-[[(diethylamino)carbonyl]amino]phenoxy)-2-hydroxypropyl 4-methylbenzenesulfonate | C23H30N2O7S | 详情 | 详情 | |
| (X) | 45948 | N'-[3-acetyl-4-[(2R)oxiranylmethoxy]phenyl]-N,N-diethylurea | C16H22N2O4 | 详情 | 详情 | |
| (XI) | 17895 | 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine | 75-64-9 | C4H11N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)2) The reaction of 2(R),3-O-isopropylideneglycerol (IV) with benzyl bromide by means of benzyltriethylammonium bromide (BTA) in refluxing aqueous NaOH gives (S)-3-O-benzylglycerol (V), which is monotritylated with 4-methoxytriphenylmethyl chloride (VI) and dimethylaminopyridine (DMAP) yielding the secondary alcohol (VII). The condensation of (VII) with diethyl tosyloxymethylphosphonate (VIII) by means of NaH in THF affords the fully protected phosphorylmethoxy derivative (IX), which is detritylated by treatment with aqueous acetic acid at 100 C to give 3-benzyloxy-2(S)-(diethoxyphosphorylmethoxy)-1-propanol (X). The reaction of (X) with methanesulfonyl chloride and triethylamine in dichloromethane yields the corresponding mesylate (XI), which is condensed with cytosine (XII) by means of cesium carbonate in hot DMF affording 1-[3-benzyloxy-2(S)-(diethoxyphosphorylmethoxy)propyl]cytosine (XIII). The debenzylation of (XIII) by treatment with Pd(OH)2 on carbon in refluxing ethanol/cyclohexene gives the corresponding alcohol (XIV), which is finally treated with bromotrimethylsilane in acetonitrile to eliminate the ethyl groups of the phosphonate.
| 【1】 Martin, J.C.; Webb, R.R. II, Wos, J.A.; Bronson, J.J.; Synthesis of (S)-N1-(3-hydroxy-2-phosphonylmethoxy)propylcytosine, (S)-HPMPC. Tetrahedron Lett 1988, 29, 5475-8. |
| 【2】 Fromtling, R.A.; Castaner, J.; Cidofovir. Drugs Fut 1996, 21, 10, 1003. |
| 【3】 Bronson, J.J.; Ghazzouli, I.; Hitchcock, M.J.M.; Webb, R.R. II, Martin, J.C.; Synthesis and antiviral activity of the nucleotide analogue (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine. J Med Chem 1989, 32, 7, 1457-63. |
| 【4】 Martin, J.C.; Bronson, J.J.; Webb, R.R. II, Hitchcock, M.J.M.; Ghazzouli, I.; Synthesis and antiherpesvirus activity of (S)-1-((3-hydroxy-2-phosphonylmethoxy)propyl)cytosine (HPMPC) and related nucleotide analogues. Nucleosides Nucleotides 1989, 8, 5-6, 923-6. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 12698 | [(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]methanol | 14347-78-5 | C6H12O3 | 详情 | 详情 |
| (V) | 12699 | (2S)-3-(Benzyloxy)-1,2-propanediol; (S)-(-)-1-Benzylglycerol | 17325-85-8 | C10H14O3 | 详情 | 详情 |
| (VI) | 12700 | 4-[Chloro(diphenyl)methyl]phenyl methyl ether; 1-[Chloro(diphenyl)methyl]-4-methoxybenzene; p-Anisylchlorodiphenylmethane | 14470-28-1 | C20H17ClO | 详情 | 详情 |
| (VII) | 12701 | (2R)-1-(Benzyloxy)-3-[(4-methoxyphenyl)(diphenyl)methoxy]-2-propanol | C30H30O4 | 详情 | 详情 | |
| (VIII) | 12702 | (diethoxyphosphoryl)methyl 4-methylbenzenesulfonate | 31618-90-3 | C12H19O6PS | 详情 | 详情 |
| (IX) | 12703 | diethyl [((1R)-2-(benzyloxy)-1-[[(4-methoxyphenyl)(diphenyl)methoxy]methyl]ethyl)oxy]methylphosphonate | C35H41O7P | 详情 | 详情 | |
| (X) | 12704 | diethyl [[(1S)-2-(benzyloxy)-1-(hydroxymethyl)ethyl]oxy]methylphosphonate | C15H25O6P | 详情 | 详情 | |
| (XI) | 12705 | (2R)-3-(benzyloxy)-2-[(diethoxyphosphoryl)methoxy]propyl methanesulfonate | C16H27O8PS | 详情 | 详情 | |
| (XII) | 12706 | Cytosine; 4-Amino-2(1H)-pyrimidinone | 71-30-7 | C4H5N3O | 详情 | 详情 |
| (XIII) | 12707 | diethyl ([(1S)-2-[4-amino-2-oxo-1(2H)-pyrimidinyl]-1-[(benzyloxy)methyl]ethyl]oxy)methylphosphonate | C19H28N3O6P | 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 |
合成路线3
该中间体在本合成路线中的序号：(I)A new synthesis of MKC-242 has been described: The tosylation of 2,2-dimethyl-1,3-dioxolane-4(R)-methanol (I) with tosyl chloride in pyridine gives the expected tosylate (II), which is condensed with pyrocatechol monobenzyl ether (III) by means of NaH in N-methylpyrrolidone (NMP) yielding 4(S)-(2-benzyloxyphenoxymethyl)-2,2-dimethyl-1,3-dioxolane (IV). The hydrolysis of the dioxolane ring with hot acetic acid affords the diol (V), which is tosylated with tosyl chloride, triethylamine and dimethylaminopyridine (DMAP) in dichloromethane to give the ditosylate (VI). The debenzylation of (VI) with H2 over Pd/C in methanol/ethyl acetate yields the phenol (VII), which is cyclized by means of K2CO3 in NMP affording 2(R)-(tosyloxymethyl)-1,4-benzodioxane (VIII). Finally, this compound is condensed with 3-(1,3-benzodioxol-5-yloxy)propylamine (IX) by means of ethyl diisopropylamine in NMP. The amine (IX) used as second starting compound has been obtained as follows: The condensation of N-(3-bromopropyl)phthalimide (X) with 5-hydroxy-1,3-benzodioxole (XI) by means of NaH in hot NMP gives N-[3-(1,3-benzodioxol-5-yloxy)propyl]phthalimide (XII), which is then treated with hydrazine in refluxing methanol to obtain amine (IX).
| 【1】 Sugano, M.; Saito, K.; Yamabe, H.; Chaki, H.; Abe, M.; Tabata, R.; Synthesis and 5-HT1A affinity of an optically active benzodioxane derivative MKC-242; a novel anxiolytic and antidepressant agent. 214th ACS Natl Meet (Sept. 7-11, Las Vegas) 1997, Abst MEDI 019. |
| 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) | 12698 | [(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]methanol | 14347-78-5 | C6H12O3 | 详情 | 详情 |
| (II) | 15208 | (S)-(+)-2,2-Dimethyl-4-(hydroxymethyl)-1,3-dioxolane-p-toluenesulfonate; [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate | 23735-43-5 | C13H18O5S | 详情 | 详情 |
| (III) | 15209 | Phenol, 2-(phenylmethoxy)-; 2-(benzyloxy)phenol | 6272-38-4 | C13H12O2 | 详情 | 详情 |
| (IV) | 15210 | benzyl 2-[[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]phenyl ether; (4R)-4-[[2-(benzyloxy)phenoxy]methyl]-2,2-dimethyl-1,3-dioxolane | C19H22O4 | 详情 | 详情 | |
| (V) | 15211 | (2S)-3-[2-(benzyloxy)phenoxy]-1,2-propanediol | C16H18O4 | 详情 | 详情 | |
| (VI) | 15212 | (1S)-2-[2-(benzyloxy)phenoxy]-1-[(4-methylphenoxy)methyl]ethyl 4-methylbenzenesulfonate | C30H30O6S | 详情 | 详情 | |
| (VII) | 15213 | (1S)-2-(2-hydroxyphenoxy)-1-[(4-methylphenoxy)methyl]ethyl 4-methylbenzenesulfonate | C23H24O6S | 详情 | 详情 | |
| (VIII) | 15214 | (2S)-2-[(4-methylphenoxy)methyl]-2,3-dihydro-1,4-benzodioxine; (2S)-2,3-dihydro-1,4-benzodioxin-2-ylmethyl 4-methylphenyl ether | C16H16O3 | 详情 | 详情 | |
| (IX) | 15206 | 3-(1,3-benzodioxol-5-yloxy)-1-propanamine; 3-(1,3-benzodioxol-5-yloxy)propylamine | C10H13NO3 | 详情 | 详情 | |
| (X) | 15216 | N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione | 5460-29-7 | C11H10BrNO2 | 详情 | 详情 |
| (XI) | 10985 | 1,3-Benzodioxol-5-ol; Sesamol | 533-31-3 | C7H6O3 | 详情 | 详情 |
| (XII) | 15218 | 2-[3-(1,3-benzodioxol-5-yloxy)propyl]-1H-isoindole-1,3(2H)-dione | C18H15NO5 | 详情 | 详情 |