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【结 构 式】 
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【分子编号】15785 【品名】1-(tert-butyl) 2-methyl (2S,4R)-4-azidotetrahydro-1H-pyrrole-1,2-dicarboxylate 【CA登记号】 |
【 分 子 式 】C11H18N4O4 【 分 子 量 】270.28848 【元素组成】C 48.88% H 6.71% N 20.73% O 23.68% |
合成路线1
该中间体在本合成路线中的序号：(VI)1) The mesylation of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester (I) with mesyl chloride and triethylamine in dichloromethane gives the corresponding mesylate (II), which is treated with sodium benzoate in DMSO yielding the (2S,4S)-benzoate (III). The hydrolysis of (III) with K2CO3 in methanol affords (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester (IV), which is mesylated with mesyl chloride and triethylamine as before giving the mesylate (V). The reaction of (V) with sodium azide in DMSO yields the corresponding (2S,4R)-azide (VI), which is reduced with H2 over Pd/C in methanol affording (2S,4R)-4-amino-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid methyl ester (VII). The acylation of (VII) with 4-chlorobenzenesulfonyl chloride (VIII) and triethylamine in dichloromethane gives the corresponding amide (IX), which is reduced with diisobutylaluminum hydride (DIBAL) in toluene/THF yielding the aldehyde (X). The Wittig condensation of aldehyde (X) with (4-carboxybutyl)triphenylphosphonium bromide (XI) by means of lithium bis(trimethylsilyl)amide (LBSA) in HMPT affords 6-[1-(tert-butoxycarbonyl)-4(R)-(4-chlorophenylsulfonamido)pyrrolidin-2(S)-yl]-5(Z)-hexenoic acid (XII), which is esterified and deprotected with methanol/HCl to give 6-[4(R)-(4-chlorophenylsulfonamido)pyrrolidin-2(S)-yl]-5(Z)-hexenoic acid methyl ester (XIII). The condensation of (XIII) with 3-(chloromethyl)pyridine (XIV) and triethylamine in refluxing THF yields 6-[4(R)-(4-chlorophenylsulfonamido)-1-(3-pyridylmethyl)pyrrolidin-2(S)-yl]-5(Z)-hexenoic acid methyl ester (XV), which is finally hydrolyzed with NaOH in methanol/water.
| 【1】 Graul, A.; Castaner, J.; KDI-792. Drugs Fut 1996, 21, 12, 1224. |
| 【2】 Setoi, H.; Sawada, A.; Tanaka, H.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); Pyrrolidine derivs. AU 8943753; EP 0367130; JP 1990152960; US 5130323; US 5264453; US 5514701 . |
| 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) | 15780 | 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate;(2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate | C11H19NO5 | 详情 | 详情 | |
| (II) | 15781 | 1-(tert-butyl) 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1,2-dicarboxylate | C12H21NO7S | 详情 | 详情 | |
| (III) | 15782 | 1-(tert-butyl) 2-methyl (2S,4S)-4-(benzoyloxy)tetrahydro-1H-pyrrole-1,2-dicarboxylate | C18H23NO6 | 详情 | 详情 | |
| (IV) | 15783 | 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate | C11H19NO5 | 详情 | 详情 | |
| (V) | 15784 | 1-(tert-butyl) 2-methyl (2S,4S)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1,2-dicarboxylate | C12H21NO7S | 详情 | 详情 | |
| (VI) | 15785 | 1-(tert-butyl) 2-methyl (2S,4R)-4-azidotetrahydro-1H-pyrrole-1,2-dicarboxylate | C11H18N4O4 | 详情 | 详情 | |
| (VII) | 15786 | 1-(tert-butyl) 2-methyl (2S,4R)-4-aminotetrahydro-1H-pyrrole-1,2-dicarboxylate | C11H20N2O4 | 详情 | 详情 | |
| (VIII) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (IX) | 15788 | 1-(tert-butyl) 2-methyl (2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]tetrahydro-1H-pyrrole-1,2-dicarboxylate | C17H23ClN2O6S | 详情 | 详情 | |
| (X) | 15789 | tert-butyl (2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]-2-formyltetrahydro-1H-pyrrole-1-carboxylate | C16H21ClN2O5S | 详情 | 详情 | |
| (XI) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
| (XII) | 15791 | (Z)-6-((2S,4R)-1-(tert-butoxycarbonyl)-4-[[(4-chlorophenyl)sulfonyl]amino]tetrahydro-1H-pyrrol-2-yl)-5-hexenoic acid | C21H29ClN2O6S | 详情 | 详情 | |
| (XIII) | 15792 | methyl (Z)-6-((2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]tetrahydro-1H-pyrrol-2-yl)-5-hexenoate | C17H23ClN2O4S | 详情 | 详情 | |
| (XIV) | 15793 | 3-(Chloromethyl)pyridine | 3099-31-8 | C6H6ClN | 详情 | 详情 |
| (XV) | 15794 | methyl (Z)-6-[(2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrol-2-yl]-5-hexenoate | C23H28ClN3O4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Treatment of the alcohol (I) with MsCl in the presence of TEA, followed by treatment with NaN3 in presence of HMPA yields the azide derivative (II). This species reacts with isobutyraldehide under reductive conditions (H2, Pd/C) leading to the substituted amine (III) which will be further substituted by reaction with the bromine derivative (IV) in basic conditions to yield derivative (V). Derivative (V) can also be obtained by following this pathway: Reduction of azide (II) with PPh3 in THF followed by reaction with refluxing water yields amine derivative (VI). This derivative is reductocondensed with the aldehyde (VII) and NaBH4 providing the substituted amine (VIII). This amine is further substituted by reductocondensation with isobutyraldehyde and NaCNBH3. Reduction of the substituted amine (V) with LiBH4 or LiAlH4 affords the alcohol (IX), which is converted into the corresponding azide (X) as already reported for (II). Reduction of azide (X) by means of SnCl2·2H2O/NaOH in water yields amine (XI), which is condensed with acid (XII) in presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrocloride (WSC) and HOBt. Elimination of the protecting group Boc with HCl provides derivative (XIII), which is finally condensed with the aromatic acid (XIV) in the same conditions described for the coupling of (XI) with (XII).
| 【1】 Nishi, K.; Seno, K.; Okuno, T.; et al.; Pyrrolidine inhibitors of human cytosolic phospholipase A2. J Med Chem 2000, 43, 6, 1041. |
| 【2】 Seno, K.; Ohtani, M.; Watanabe, F. (Shionogi & Co. Ltd.); Pyrrolidine derivs. having phospholipase A2 inhibitory activity. EP 0976748; WO 9833797 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 13226 | 2-Methylpropanal; Isobutyraldehyde | 78-84-2 | C4H8O | 详情 | 详情 |
| (I) | 15783 | 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate | C11H19NO5 | 详情 | 详情 | |
| (II) | 15785 | 1-(tert-butyl) 2-methyl (2S,4R)-4-azidotetrahydro-1H-pyrrole-1,2-dicarboxylate | C11H18N4O4 | 详情 | 详情 | |
| (III) | 40992 | 1-(tert-butyl) 2-methyl (2S,4R)-4-(isobutylamino)-1,2-pyrrolidinedicarboxylate | C15H28N2O4 | 详情 | 详情 | |
| (IV) | 40993 | 2-(bromomethyl)-1,1'-biphenyl | C13H11Br | 详情 | 详情 | |
| (V) | 40994 | 1-(tert-butyl) 2-methyl (2S,4R)-4-[([1,1'-biphenyl]-2-ylmethyl)(isobutyl)amino]-1,2-pyrrolidinedicarboxylate | C28H38N2O4 | 详情 | 详情 | |
| (VI) | 15786 | 1-(tert-butyl) 2-methyl (2S,4R)-4-aminotetrahydro-1H-pyrrole-1,2-dicarboxylate | C11H20N2O4 | 详情 | 详情 | |
| (VII) | 40996 | [1,1'-biphenyl]-2-carbaldehyde | C13H10O | 详情 | 详情 | |
| (VIII) | 40995 | 1-(tert-butyl) 2-methyl (2S,4R)-4-[([1,1'-biphenyl]-2-ylmethyl)amino]-1,2-pyrrolidinedicarboxylate | C24H30N2O4 | 详情 | 详情 | |
| (IX) | 40997 | tert-butyl (2R,4R)-4-[([1,1'-biphenyl]-2-ylmethyl)(isobutyl)amino]-2-hydroxy-1-pyrrolidinecarboxylate | C26H36N2O3 | 详情 | 详情 | |
| (X) | 40998 | tert-butyl (2S,4R)-2-(azidomethyl)-4-[([1,1'-biphenyl]-2-ylmethyl)(isobutyl)amino]-1-pyrrolidinecarboxylate | C27H37N5O2 | 详情 | 详情 | |
| (XI) | 40999 | tert-butyl (2S,4R)-2-(aminomethyl)-4-[([1,1'-biphenyl]-2-ylmethyl)(isobutyl)amino]-1-pyrrolidinecarboxylate | C27H39N3O2 | 详情 | 详情 | |
| (XII) | 41000 | (E)-3-[4-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl]-2-propenoic acid | C13H9NO4S | 详情 | 详情 | |
| (XIII) | 41001 | tert-butyl (2S,4R)-4-[([1,1'-biphenyl]-2-ylmethyl)(isobutyl)amino]-2-[[((E)-3-[4-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl]-2-propenoyl)amino]methyl]-1-pyrrolidinecarboxylate | C40H46N4O5S | 详情 | 详情 | |
| (XIV) | 41002 | 2-(2,4-difluorobenzoyl)benzoic acid | C14H8F2O3 | 详情 | 详情 |