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【结 构 式】 
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【分子编号】15783 【品名】1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate 【CA登记号】 |
【 分 子 式 】C11H19NO5 【 分 子 量 】245.2756 【元素组成】C 53.87% H 7.81% N 5.71% O 32.62% |
合成路线1
该中间体在本合成路线中的序号：(IV)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：(I)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 |
合成路线3
该中间体在本合成路线中的序号：(II)Conversion of 4-hydroxy-L-proline (I) into the corresponding cis-N-Boc-4-hydroxy-L-proline methyl ester (II) is performed as follows: Treatment of (I) with SOCl2 in MeOH followed by reaction with Boc2O and Et3N in EtOAc affords the corresponding protected acid chloride; then the methyl ester moiety is formed under Mitsunobu conditions with formic acid, DIAD and PPh3 in THF followed by treatment with NaOH in MeOH. The OH group of (II) is converted into thioether (IV) by first mesylation with MsCl and Et3N in toluene followed by reaction with triphenylmethanethiol (III) in THF in the presence of NaH. Reduction of the methyl ester of (IV) with LiBH4 in THF provides alcohol (V), which is mesylated with MsCl and Et3N in THF and then treated with NaN3 and HMPA to furnish azide (VI). Boc removal in (VI) is performed by treatment with HCl in EtOAc to give derivative (VII), which is then converted into compound (VIII) by condensation with 2-(2,4-difluorobenzoyl)benzoic acid (XI) by means of water-soluble carbodiimide (WSC) and HOBt in DMF (compound (XI) can be obtained by Friedel-Crafts reaction between phthalic anhydride (IX) and 1,3-difluorobenzene (X) in the presence of AlCl3). Reduction of the azido moiety of (VIII) by means of SnCl2 and NaOH in EtOH furnishes amine (XII), which is finally converted into the desired product by condensation with carboxylic acid (XIII) by means of WSC and HOBt (derivative (XIII) can be obtained by Knoevenagel reaction between 4-formyl-benzoic acid (XIV) and 2,4-thiazolidinedione (XV) in refluxing 2-methoxyethanol in the presence of piperidine).
| 【1】 Nishi, K.; Seno, K.; Ono, T.; Yamada, K.; Murakami, Y.; Nakamoto, S.; Okuno, T.; Pyrrolidine inhibitors of human cytosolic phospholipase A2. Part 2: Synthesis of potent and crystallized 4-triphenylmethylthio derivative "pyrrophenone". Bioorg Med Chem Lett 2001, 11, 4, 587. |
| 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) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (II) | 15783 | 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate | C11H19NO5 | 详情 | 详情 | |
| (III) | 18831 | tritylhydrosulfide; triphenylmethanethiol | 3695-77-0 | C19H16S | 详情 | 详情 |
| (IV) | 50070 | 1-(tert-butyl) 2-methyl (2S,4R)-4-(tritylsulfanyl)-1,2-pyrrolidinedicarboxylate | C30H33NO4S | 详情 | 详情 | |
| (V) | 50071 | tert-butyl (2S,4R)-2-(hydroxymethyl)-4-(tritylsulfanyl)-1-pyrrolidinecarboxylate | C29H33NO3S | 详情 | 详情 | |
| (VI) | 50072 | tert-butyl (2S,4R)-2-(azidomethyl)-4-(tritylsulfanyl)-1-pyrrolidinecarboxylate | C29H32N4O2S | 详情 | 详情 | |
| (VII) | 50073 | (2S,4R)-2-(azidomethyl)-4-(tritylsulfanyl)pyrrolidine; (3R,5S)-5-(azidomethyl)pyrrolidinyl trityl sulfide | C24H24N4S | 详情 | 详情 | |
| (VIII) | 50074 | [(2S,4R)-2-(azidomethyl)-4-(tritylsulfanyl)pyrrolidinyl][2-(2,4-difluorobenzoyl)phenyl]methanone | C38H30F2N4O2S | 详情 | 详情 | |
| (IX) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (X) | 13095 | m-Difluorobenzene; 1,3-Difluorobenzene | 372-18-9 | C6H4F2 | 详情 | 详情 |
| (XI) | 41002 | 2-(2,4-difluorobenzoyl)benzoic acid | C14H8F2O3 | 详情 | 详情 | |
| (XII) | 50075 | [(2S,4R)-2-(aminomethyl)-4-(tritylsulfanyl)pyrrolidinyl][2-(2,4-difluorobenzoyl)phenyl]methanone | C38H32F2N2O2S | 详情 | 详情 | |
| (XIII) | 50076 | 4-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzoic acid | C11H7NO4S | 详情 | 详情 | |
| (XIV) | 18922 | 4-formylbenzoic acid | 619-66-9 | C8H6O3 | 详情 | 详情 |
| (XV) | 10883 | 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione | 2295-31-0 | C3H3NO2S | 详情 | 详情 |