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【结 构 式】 
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【分子编号】12350 【品名】Benzyl (2R)oxiranylmethyl ether; (2R)-2-[(Benzyloxy)methyl]oxirane 【CA登记号】14618-80-5 |
【 分 子 式 】C10H12O2 【 分 子 量 】164.20408 【元素组成】C 73.15% H 7.37% O 19.49% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of (R)-O-benzylglycidol (I) with octadecanol (II) by means of NaH in hot DMF gives (R)-1-(benzyloxy)-3-(octadecyloxy)-2-propanol (III), which is methylated with methyl iodide and NaH in DMF yielding the corresponding methyl ether (IV). The debenzylation of (IV) with H2 over Pd/C in THF affords the primary alcohol (V), which is finally treated with POCl3/pyridine in CHCl3 and condensed with choline tosylate (VI) to furnish the target phosphorylcholine derivative.
| 【1】 Bittman, R.; Lohmeyer, M.; Antitumor ether lipids and alkylphosphocholines. Drugs Fut 1994, 19, 11, 1021. |
| 【2】 Barner, R.; Hirth, G.; Synthese von Glyceryätherphosphatiden. Herstellung von 1-O-octadecyl-2-O-acetyl-sn-glyceryl-3-phosphorylchloline (`Platelet Activating Factor'), des Enantiomeren sowie einiger analoger Verbindungen. Helv Chim Acta 1982, 65, 1059-84. |
| 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) | 21494 | 1-octadecanol | 112-92-5 | C18H38O | 详情 | 详情 |
| (III) | 41263 | (2R)-1-(benzyloxy)-3-(octadecyloxy)-2-propanol | C28H50O3 | 详情 | 详情 | |
| (IV) | 41264 | 1-([[(2R)-2-methoxy-3-(octadecyloxy)propyl]oxy]methyl)benzene; benzyl (2R)-2-methoxy-3-(octadecyloxy)propyl ether | C29H52O3 | 详情 | 详情 | |
| (V) | 40717 | (2S)-2-methoxy-3-(octadecyloxy)-1-propanol | C22H46O3 | 详情 | 详情 | |
| (VI) | 41265 | 2-hydroxy-N,N,N-trimethyl-1-ethanaminium 4-methylbenzenesulfonate | C12H21NO4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)The chiral sulfonate [(R)-IX] has been obtained in a different way: The cyclization of 2(S)-(benzyloxymethyl)oxirane (XII) with 2-aminoethyl hydrogen sulfate sodium salt (XIII) by means of NaOH in methanol gives 2(R)-(benzyloxymethyl)morpholine (XIV), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol to the chiral alcohol (XV). The condensation of (XV) with 4-fluorobenzyl chloride (XVI) by means of K2CO3 and NaI in refluxing butanone affords 4-(4-fluorobenzyl)-2(R)-(hydroxymethyl)morpholine (XVII), which is finally tosylated with tosyl chloride as before to afford [(R)-IX], already obtained.
| 【1】 Morie, T.; Kato, S.; Harada, H.; Yoshida, N.; Matsumoto, J.; Synthesis and biological activities of the optical isomers of (±)-4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide (mosapride). Chem Pharm Bull 1994, 42, 4, 877. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 12346 | [(2R)-4-(4-fluorobenzyl)-1,4-oxazinan-2-yl]methyl phenylmethanesulfonate | C19H22FNO4S | 详情 | 详情 | |
| (XII) | 12350 | Benzyl (2R)oxiranylmethyl ether; (2R)-2-[(Benzyloxy)methyl]oxirane | 14618-80-5 | C10H12O2 | 详情 | 详情 |
| (XIII) | 12351 | Sodium 1-amino-2-(sulfonatooxy)ethane | C2H6NNaO4S | 详情 | 详情 | |
| (XIV) | 12352 | Benzyl (2R)-1,4-oxazinan-2-ylmethyl ether; (2R)-2-[(Benzyloxy)methyl]-1,4-oxazinane | C12H17NO2 | 详情 | 详情 | |
| (XV) | 12353 | (2R)-1,4-Oxazinan-2-ylmethanol | C5H11NO2 | 详情 | 详情 | |
| (XVI) | 12354 | 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene | 352-11-4 | C7H6ClF | 详情 | 详情 |
| (XVII) | 12344 | [4-(4-fluorobenzyl)-2-morpholinyl]methyl 4-methylbenzenesulfonate | C19H22FNO4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)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4
该中间体在本合成路线中的序号：(I)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5
该中间体在本合成路线中的序号：(V)Suzuki coupling between 4-methoxyphenylboronic acid (I) and 1-bromo-4-(trifluoromethoxy)benzene (II) gave the biphenyl derivative (III). Methyl ether cleavage in (III) by means of BBr3 provided the biphenyl alcohol (IV), which was condensed with (S)-benzyl glycidyl ether (V) under basic conditions, yielding the chiral glycerol diether (VI). Mitsunobu coupling of alcohol (VI) with the di-Boc-protected hydroxylamine (VII) using DEAD/PPh3 afforded carbamate (VIII). Subsequent catalytic hydrogenolysis of the benzyl ether of (VIII) gave alcohol (IX). Condensation of this alcohol (IX) with 5,5-dimethylhydantoin (X) under Mitsunobu conditions, followed by acidic cleavage of the Boc protecting groups, furnished the hydroxylamine derivative (XI). This was finally N-formylated by treatment with formic acetic anhydride.
| 【1】 Curtin, M.L.; et al.; Discovery and characterization of the potent, selective and orally bioavailable MMP inhibitor ABT-770. Bioorg Med Chem Lett 2001, 11, 12, 1557. |
| 【2】 Dellaria, J.F. Jr.; Gong, J.; Steinman, D.H.; Michaelides, M.R.; Giesler, J.; Davidsen, S.K.; Curtin, M.L.; Florjancic, A.S.; Xu, L.; Guo, Y.; Holms, J.H.; Wada, C.K.; Heyman, H.R. (Abbott Laboratories Inc.); Reverse hydroxamate inhibitors of matrix metalloproteinases. JP 2001523272; WO 9906361 . |
| 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) | 39246 | 4-methoxyphenylboronic acid | 5720-07-0 | C7H9BO3 | 详情 | 详情 |
| (II) | 52466 | 4-Bromophenyl trifluoromethyl ether; 4-(Trifluoromethoxy)bromobenzene; 4-Bromo-(trifluoromethoxy)-benzene; 4-Bromo-alpha,alpha,alpha-trifluoroanisole; 4-Bromotrifluoromethoxybenzene; 1-Bromo-4-(trifluoromethoxy)benzene | 407-14-7 | C7H4BrF3O | 详情 | 详情 |
| (III) | 52467 | 4-(methyloxy)-4'-[(trifluoromethyl)oxy]-1,1'-biphenyl; methyl 4'-[(trifluoromethyl)oxy][1,1'-biphenyl]-4-yl ether | C14H11F3O2 | 详情 | 详情 | |
| (IV) | 52468 | 4'-[(trifluoromethyl)oxy][1,1'-biphenyl]-4-ol | C13H9F3O2 | 详情 | 详情 | |
| (V) | 12350 | Benzyl (2R)oxiranylmethyl ether; (2R)-2-[(Benzyloxy)methyl]oxirane | 14618-80-5 | C10H12O2 | 详情 | 详情 |
| (VI) | 52469 | 1-[(phenylmethyl)oxy]-3-({4'-[(trifluoromethyl)oxy][1,1'-biphenyl]-4-yl}oxy)-2-propanol | C23H21F3O4 | 详情 | 详情 | |
| (VII) | 34722 | 2-[([[(tert-butoxycarbonyl)amino]oxy]carbonyl)oxy]-2-methylpropane | C10H19NO5 | 详情 | 详情 | |
| (VIII) | 52470 | 4-({2-[{[(1,1-dimethylethyl)oxy]carbonyl}({[(1,1-dimethylethyl)oxy]carbonyl}oxy)amino]-3-[(phenylmethyl)oxy]propyl}oxy)-4'-[(trifluoromethyl)oxy]-1,1'-biphenyl | C33H38F3NO8 | 详情 | 详情 | |
| (IX) | 52471 | 4-({2-[{[(1,1-dimethylethyl)oxy]carbonyl}({[(1,1-dimethylethyl)oxy]carbonyl}oxy)amino]-3-hydroxypropyl}oxy)-4'-[(trifluoromethyl)oxy]-1,1'-biphenyl | C26H32F3NO8 | 详情 | 详情 | |
| (X) | 32473 | 5,5-dimethyl-2,4-imidazolidinedione | 77-71-4 | C5H8N2O2 | 详情 | 详情 |
| (XI) | 52472 | 3-[2-(hydroxyamino)-3-({4'-[(trifluoromethyl)oxy][1,1'-biphenyl]-4-yl}oxy)propyl]-5,5-dimethyl-2,4-imidazolidinedione | C21H22F3N3O5 | 详情 | 详情 |