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【结 构 式】 
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【分子编号】41307 【品名】[(2S)-2-[(octadecyloxy)methyl]tetrahydro-2-furanyl]methanol 【CA登记号】 |
【 分 子 式 】C24H48O3 【 分 子 量 】384.64332 【元素组成】C 74.94% H 12.58% O 12.48% |
合成路线1
该中间体在本合成路线中的序号：(IX)The reaction of 3-chloropropanol (I) with 2-methoxypropene (II) by means of PPTS gives the mixed ketal (III), which is condensed with diethyl malonate (IV) by means of sodium ethoxide in hot ethanol, affording the adduct (V). The reduction of (V) with NaH and Red-Al in refluxing toluene provides the allyl alcohol derivative (VI), which is submitted to an asymmetric epoxidation to give the epoxide (VII). The reaction of (VII) with octadecyl bromide (VIII) by means of NaH and tetrabutylammonium iodide (TBAI) yields the corresponding ether (IX), which by reaction with PPTS in HOAc is converted to the tetrahydrofuran-2-methanol derivative (X). Finally, this compound is condensed with POCl3, TEA, choline mesylate (XI) and DMAP in dichloromethane/pyridine to afford the target compound.
| 【1】 Lohmeyer, M.; Bittman, R.; Antitumor ether lipids and alkylphosphocholines. Drugs Fut 1994, 19, 11, 1021. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 41308 | 2-hydroxy-N,N,N-trimethyl-1-ethanaminium methanesulfonate | C6H17NO4S | 详情 | 详情 | ||
| (I) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (II) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (III) | 41304 | 1-(3-chloropropoxy)-1-methylethyl methyl ether; 1-chloro-3-(1-methoxy-1-methylethoxy)propane | C7H15ClO2 | 详情 | 详情 | |
| (IV) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (V) | 41309 | diethyl 2-[3-(1-methoxy-1-methylethoxy)propyl]malonate | C14H26O6 | 详情 | 详情 | |
| (VI) | 41305 | 2-[3-(1-methoxy-1-methylethoxy)propyl]-2-propen-1-ol | C10H20O3 | 详情 | 详情 | |
| (VII) | 28797 | 1-bromooctadecane | 112-89-0 | C18H37Br | 详情 | 详情 |
| (VIII) | 41306 | [(2S)-2-[3-(1-methoxy-1-methylethoxy)propyl]oxiranyl]methyl octadecyl ether; (2S)-2-[3-(1-methoxy-1-methylethoxy)propyl]-2-[(octadecyloxy)methyl]oxirane | C28H56O4 | 详情 | 详情 | |
| (IX) | 41307 | [(2S)-2-[(octadecyloxy)methyl]tetrahydro-2-furanyl]methanol | C24H48O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)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3
该中间体在本合成路线中的序号：(XI)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 |