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【结 构 式】 
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【分子编号】41265 【品名】2-hydroxy-N,N,N-trimethyl-1-ethanaminium 4-methylbenzenesulfonate 【CA登记号】 |
【 分 子 式 】C12H21NO4S 【 分 子 量 】275.36908 【元素组成】C 52.34% H 7.69% N 5.09% O 23.24% S 11.64% |
合成路线1
该中间体在本合成路线中的序号：(VI)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：(VII)The reaction of 2-(hydroxymethyl)propenoic acid ethyl ester (I) with PBr3 and then with hexadecyl mercaptane (II) and TEA gives 2-(hexadecylsulfanylmethyl)propenoic acid methyl ester (III), which is reduced with DIBAL in THF to the corresponding carbinol (IV). The methylation of (IV) with methyl iodide and NaH in THF affords the methyl ether (V), which is hydroxylated at the double bond with BH3/Me2S and NaBO3 providing 3-(hexadecylsulfanyl)-2-(methoxymethyl)-1-propanol (VI). Finally this compound is treated with POCl3 and TEA in chloroform and condensed with choline tosylate (VII) to furnish the target phosphorylcholine derivative.
| 【1】 Bittman, R.; Lohmeyer, M.; Antitumor ether lipids and alkylphosphocholines. Drugs Fut 1994, 19, 11, 1021. |
| 【2】 Reddy, K.C.; Byun, H.S.; Bittman, R.; Antitumor ether lipids: An improved synthesis of ilmofosine and an enantioselective synthesis of an ilmofosine analog. Tetrahedron Lett 1994, 35, 17, 2679. |
| 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) | 11327 | ethyl 2-(hydroxymethyl)acrylate | 10029-04-6 | C6H10O3 | 详情 | 详情 |
| (II) | 41266 | 1-hexadecanethiol; hexadecylhydrosulfide | 2917-26-2 | C16H34S | 详情 | 详情 |
| (III) | 11329 | ethyl 2-[(hexadecylsulfanyl)methyl]acrylate | C22H42O2S | 详情 | 详情 | |
| (IV) | 11330 | 2-[(Hexadecylsulfanyl)methyl]-2-propen-1-ol | C20H40OS | 详情 | 详情 | |
| (V) | 11331 | 2-[(Hexadecylsulfanyl)methyl]-2-propenyl methyl ether; 3-(Hexadecylsulfanyl)-2-(methoxymethyl)-1-propene | C21H42OS | 详情 | 详情 | |
| (VI) | 11332 | 3-(Hexadecylsulfanyl)-2-(methoxymethyl)-1-propanol | C21H44O2S | 详情 | 详情 | |
| (VII) | 41265 | 2-hydroxy-N,N,N-trimethyl-1-ethanaminium 4-methylbenzenesulfonate | C12H21NO4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)The reaction of tetrahydrofuran-2,2-dimethanol (I) with butyryl chloride (II) and Na2CO3 in dichloromethane gives the dibutyrate (III), which is asymmetrized by means of pancreas lipase type II (PPL) or microbial lipase Mucor javanicus (LMJ), yielding the (R)-monobutyrate (IV). The protection of the OH group of (IV) with Tr-Cl and pyridine in dichloromethane affords the trityl ether (V), which is treated with K2CO3 in methanol to provide the chiral carbinol (VI). The reaction of (VI) with octadecyl bromide (VII) by means of NaH and tetrabutylammonium iodide (TBAI) in refluxing THF gives the corresponding ether (VIII), which is deprotected with TFA in dichloromethane/water to yield the chiral carbinol (IX). Finally this carbinol is condensed with POCl3, choline tosylate (X), TEA and pyridine in THF to afford the target compound.
| 【1】 Prasad, K.; et al.; Asymmetrization of tetrahydrofuran-2,2-dimethanol: Synthesis of the enantiomers of SRI 62-834. J Org Chem 1995, 60, 23, 7693. |
| 【2】 Estermann, H.; Houlihan, W.J.; Kapa, P.K.; Underwood, R.L. (Novartis AG; Novartis Deutschland GmbH); Enantiomers of 2-tetrahydrofuran derivs., intermediates therefor and their preparation. EP 0462935; JP 1992270276 . |
| 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) | 47573 | [2-(hydroxymethyl)tetrahydro-2-furanyl]methanol | C6H12O3 | 详情 | 详情 | |
| (II) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (III) | 47575 | [2-[(butyryloxy)methyl]tetrahydro-2-furanyl]methyl butyrate | C14H24O5 | 详情 | 详情 | |
| (IV) | 47576 | [(2S)-2-(hydroxymethyl)tetrahydro-2-furanyl]methyl butyrate | C10H18O4 | 详情 | 详情 | |
| (V) | 47577 | [(2S)-2-[(trityloxy)methyl]tetrahydro-2-furanyl]methyl butyrate | C29H32O4 | 详情 | 详情 | |
| (VI) | 47578 | [(2R)-2-[(trityloxy)methyl]tetrahydro-2-furanyl]methanol | C25H26O3 | 详情 | 详情 | |
| (VII) | 28797 | 1-bromooctadecane | 112-89-0 | C18H37Br | 详情 | 详情 |
| (VIII) | 47582 | (2R)-2-[(octadecyloxy)methyl]-2-[(trityloxy)methyl]tetrahydrofuran; octadecyl [(2R)-2-[(trityloxy)methyl]tetrahydro-2-furanyl]methyl ether | C43H62O3 | 详情 | 详情 | |
| (IX) | 41307 | [(2S)-2-[(octadecyloxy)methyl]tetrahydro-2-furanyl]methanol | C24H48O3 | 详情 | 详情 | |
| (X) | 41265 | 2-hydroxy-N,N,N-trimethyl-1-ethanaminium 4-methylbenzenesulfonate | C12H21NO4S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XII)The reaction of tetrahydrofuran-2,2-dimethanol (I) with butyryl chloride (II) and Na2CO3 in dichloromethane gives the dibutyrate (III), which is asymmetrized by means of pancreas lipase type II (PPL) or microbial lipase Mucor javanicus (LMJ) yielding the (R)-monobutyrate (IV). The protection of the OH group of (IV) with Tr-Cl and pyridine in dichloromethane affords the trityl ether (V), which is treated with K2CO3 in methanol to provide the chiral carbinol (VI). The reaction of (VI) with benzyl bromide by means of NaH and tetrabutylammonium iodide (TBAI) in refluxing THF gives the corresponding benzyl ether (VII), which is deprotected with TFA in dichloromethane/water to yield the chiral carbinol (VIII). The reaction of (VIII) with octadecyl bromide (IX) by means of NaH and tetrabutylammonium iodide (TBAI) in refluxing THF gives the corresponding octadecyl ether (X), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol to yield the chiral carbinol (XI). Finally, this carbinol is condensed with POCl3, choline tosylate (XII), TEA and pyridine in THF to afford the target compound.
| 【1】 Prasad, K.; et al.; Asymmetrization of tetrahydrofuran-2,2-dimethanol: Synthesis of the enantiomers of SRI 62-834. J Org Chem 1995, 60, 23, 7693. |
| 【2】 Estermann, H.; Houlihan, W.J.; Kapa, P.K.; Underwood, R.L. (Novartis AG; Novartis Deutschland GmbH); Enantiomers of 2-tetrahydrofuran derivs., intermediates therefor and their preparation. EP 0462935; JP 1992270276 . |
| 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) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (II) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (III) | 47575 | [2-[(butyryloxy)methyl]tetrahydro-2-furanyl]methyl butyrate | C14H24O5 | 详情 | 详情 | |
| (IV) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (V) | 47577 | [(2S)-2-[(trityloxy)methyl]tetrahydro-2-furanyl]methyl butyrate | C29H32O4 | 详情 | 详情 | |
| (VI) | 47578 | [(2R)-2-[(trityloxy)methyl]tetrahydro-2-furanyl]methanol | C25H26O3 | 详情 | 详情 | |
| (VII) | 47579 | benzyl [(2R)-2-[(trityloxy)methyl]tetrahydro-2-furanyl]methyl ether; (2R)-2-[(benzyloxy)methyl]-2-[(trityloxy)methyl]tetrahydrofuran | C32H32O3 | 详情 | 详情 | |
| (VIII) | 47580 | [(2S)-2-[(benzyloxy)methyl]tetrahydro-2-furanyl]methanol | C13H18O3 | 详情 | 详情 | |
| (IX) | 28797 | 1-bromooctadecane | 112-89-0 | C18H37Br | 详情 | 详情 |
| (X) | 47581 | (2R)-2-[(benzyloxy)methyl]-2-[(octadecyloxy)methyl]tetrahydrofuran; benzyl [(2R)-2-[(octadecyloxy)methyl]tetrahydro-2-furanyl]methyl ether | C31H54O3 | 详情 | 详情 | |
| (XI) | 41307 | [(2S)-2-[(octadecyloxy)methyl]tetrahydro-2-furanyl]methanol | C24H48O3 | 详情 | 详情 | |
| (XII) | 41265 | 2-hydroxy-N,N,N-trimethyl-1-ethanaminium 4-methylbenzenesulfonate | C12H21NO4S | 详情 | 详情 |