|
【结 构 式】 
|
【分子编号】38496 【品名】diethyl methylphosphonate 【CA登记号】683-08-9 |
【 分 子 式 】C5H13O3P 【 分 子 量 】152.130182 【元素组成】C 39.48% H 8.61% O 31.55% P 20.36% |
合成路线1
该中间体在本合成路线中的序号：(II)Regiospecific opening of the chiral 2-(benzyloxymethyl)oxirane (I) with lithiated diethyl methylphosphonate in the presence of boron trifluoride etherate afforded phosphonate (III). After conversion of (III) to the chloromethyl ether (IV), upon treatment with paraformaldehyde and HCl, condensation with the sodium salt of 2-amino-6-chloropurine (V) gave the nucleoside phosphonate (VI). Simultaneous hydrogenolysis of the chlorine atom and benzyl ether of (VI) by transfer hydrogenation in the presence of ammonium formate and Pd/C yielded (VII). Finally, the phosphonate ester groups of (VII) were cleaved by means of bromotrimethylsilane.
| 【1】 Zaveri, N.; et al.; Enantiomerically pure 2-aminopurine cyclic and acyclic nucleotide phosphonate analogs as antiviral agents aganist human cytomegalovirus. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, 19, Abst MEDI 129. |
| 【2】 Reist, E.J.; Bradford, W.W.; Zaveri, N.T. (SRI International); Enantiomerically pure 2-aminopurine phosphonate nucleotide analogs as antiviral agents. US 5877166; WO 9741133 . |
| 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) | 12350 | Benzyl (2R)oxiranylmethyl ether; (2R)-2-[(Benzyloxy)methyl]oxirane | 14618-80-5 | C10H12O2 | 详情 | 详情 |
| (II) | 38496 | diethyl methylphosphonate | 683-08-9 | C5H13O3P | 详情 | 详情 |
| (III) | 38497 | diethyl (3R)-4-(benzyloxy)-3-hydroxybutylphosphonate | C15H25O5P | 详情 | 详情 | |
| (IV) | 38498 | diethyl (3R)-4-(benzyloxy)-3-(chloromethoxy)butylphosphonate | C16H26ClO5P | 详情 | 详情 | |
| (V) | 11644 | 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine | 10310-21-1 | C5H4ClN5 | 详情 | 详情 |
| (VI) | 38499 | diethyl (3R)-3-[(2-amino-6-chloro-9H-purin-9-yl)methoxy]-4-(benzyloxy)butylphosphonate | C21H29ClN5O5P | 详情 | 详情 | |
| (VII) | 38500 | diethyl (3R)-3-[(2-amino-9H-purin-9-yl)methoxy]-4-hydroxybutylphosphonate | C14H24N5O5P | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Regiospecific opening of the chiral 2-(benzyloxymethyl)oxirane (I) with lithiated diethyl methylphosphonate in the presence of boron trifluoride etherate afforded phosphonate (III). After conversion of (III) to the chloromethyl ether (IV), upon treatment with paraformaldehyde and HCl, condensation with the sodium salt of 2-amino-6-chloropurine (V) gave the nucleoside phosphonate (VI). Simultaneous hydrogenolysis of the chlorine atom and benzyl ether of (VI) by transfer hydrogenation in the presence of ammonium formate and Pd/C yielded (VII). The phosphonate ester groups of (VII) were then cleaved by means of bromotrimethylsilane to give phosphonic acid (VIII). Finally, intramolecular cyclization of (VIII) by treatment with DCC furnished the title compound.
| 【1】 Zaveri, N.; et al.; Enantiomerically pure 2-aminopurine cyclic and acyclic nucleotide phosphonate analogs as antiviral agents aganist human cytomegalovirus. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, 19, Abst MEDI 129. |
| 【2】 Reist, E.J.; Bradford, W.W.; Zaveri, N.T. (SRI International); Enantiomerically pure 2-aminopurine phosphonate nucleotide analogs as antiviral agents. US 5877166; WO 9741133 . |
| 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) | 12350 | Benzyl (2R)oxiranylmethyl ether; (2R)-2-[(Benzyloxy)methyl]oxirane | 14618-80-5 | C10H12O2 | 详情 | 详情 |
| (II) | 38496 | diethyl methylphosphonate | 683-08-9 | C5H13O3P | 详情 | 详情 |
| (III) | 38497 | diethyl (3R)-4-(benzyloxy)-3-hydroxybutylphosphonate | C15H25O5P | 详情 | 详情 | |
| (IV) | 38498 | diethyl (3R)-4-(benzyloxy)-3-(chloromethoxy)butylphosphonate | C16H26ClO5P | 详情 | 详情 | |
| (V) | 11644 | 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine | 10310-21-1 | C5H4ClN5 | 详情 | 详情 |
| (VI) | 38499 | diethyl (3R)-3-[(2-amino-6-chloro-9H-purin-9-yl)methoxy]-4-(benzyloxy)butylphosphonate | C21H29ClN5O5P | 详情 | 详情 | |
| (VII) | 38500 | diethyl (3R)-3-[(2-amino-9H-purin-9-yl)methoxy]-4-hydroxybutylphosphonate | C14H24N5O5P | 详情 | 详情 | |
| (VIII) | 38501 | (3R)-3-[(2-amino-9H-purin-9-yl)methoxy]-4-hydroxybutylphosphonic acid | C10H16N5O5P | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The condensation between 4-hydroxy-3-methoxy-5-methylbenzaldehyde (I) and 3-aminopyridine (II) yields the corresponding benzalimine (III). The phenolic hydroxyl group of (III) is then protected as the silyl ether (IV) by using t-butyldimethylsilyl chloride and imidazole. Condensation of imine (IV) with the lithium derivative of diethyl methylphosphonate (V) affords the beta-amino phosphonate (VI). Finally, desilylation of (VI) with tetrabutylammonium fluoride and acetic acid provides the target phenol.
| 【1】 Phan, H.T.; et al.; Synthesis of a new series of compounds with lipoprotein(a)-lowering activity, Part 3: beta-Substituted-beta-amino-ethylphosphonates. Drugs Fut 2002, 27, Suppl. A. |
| 【2】 Ife, R.J.; Nguyen, L.M.; Bentzen, C.L.; Diep, V.V.; Azoulay, R.; Phan, H.T.; Niesor, E.J. (Ilex Oncology Research-Europe SA); beta-Substd. beta-aminoethyl phosphonates. US 2002111488; WO 0234756 . |
| 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) | 43812 | 1-(6-methoxy-2-naphthyl)-1-ethanone | 3900-45-6 | C13H12O2 | 详情 | 详情 |
| (II) | 33327 | 3-Pyridinylamine; 3-Aminopyridine; 3-Pyridinamine | 462-08-8 | C5H6N2 | 详情 | 详情 |
| (III) | 58411 | 2-methoxy-6-methyl-4-[(3-pyridinylimino)methyl]phenol | C14H14N2O2 | 详情 | 详情 | |
| (IV) | 58412 | N-[(E)-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-methoxy-5-methylphenyl)methylidene]-N-(3-pyridinyl)amine; N-[(E)-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-methoxy-5-methylphenyl)methylidene]-3-pyridinamine | C20H28N2O2Si | 详情 | 详情 | |
| (V) | 38496 | diethyl methylphosphonate | 683-08-9 | C5H13O3P | 详情 | 详情 |
| (VI) | 58413 | diethyl 2-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-methoxy-5-methylphenyl)-2-(3-pyridinylamino)ethylphosphonate | C25H41N2O5PSi | 详情 | 详情 |