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【结 构 式】 
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【分子编号】50004 【品名】cis-1,4-Dichloro-2-butene;(Z)-1,4-Dichlorobutene;(Z)-1,4-Dichloro-2-butene;(2Z)-1,4-Dichloro-2-butene;cis-1,2-Bis(chloromethyl)ethene 【CA登记号】1476-11-5 |
【 分 子 式 】C4H6Cl2 【 分 子 量 】124.99704 【元素组成】C 38.44% H 4.84% Cl 56.73% |
合成路线1
该中间体在本合成路线中的序号：(II)The cyclization of diethyl malonate (I) with cis-1,4-dichloro-2-butene (II) by means of LiH in DMF gives 3-cyclopentene-1,1-dicarboxylic acid diethyl ester (III), which is monodecarboxylated by hydrolysis with NaOH in ethanol, followed by heating at 170-180 C to yield 3-cyclopentene-1-carboxylic acid (IV). The reaction of (IV) with SOCl2 affords the acyl chloride (V), which by reaction with ethanol provides the ethyl ester (VI). The oxidation of (VI) with OsO4 and N-methylmorpholine N-oxide (NMMO) in acetone/water gives the dihydroxy compound (VII), which is further oxidized with NaIO4 in THF to yield the dialdehyde (VIII). The cyclization of (VIII) by means of glycine ethyl ester and acetonedicarboxylic acid affords the 9-azabicyclo[3,3,1]nonan-3-one derivative (IX), which is reduced with NaBH4 in ethanol to provide the corresponding alcohol (X). The protection of the OH group of (X) with dihydropyran and methanesulfonic acid gives the tetrahydropyranyl ether (XI), which is cyclized by means of tBuO-K in hot toluene, yielding the tricyclic ketone (XII). The deprotection of (XII) with 5N HCl affords the alcohol (XIII), which is finally esterified with 1H-indole-3-carbonyl chloride (XIV) by means of tetrafluoroboric acid and silver tetrafluoroborate in nitroethane. Alternatively, 1H-indole (XV) is condensed with oxalyl chloride (XVI) to give 3-indolylglyoxylyl chloride (XVII), which is used to acylate the alcohol (XIII) by means of tetrafluoroboric acid and silver tetrafluoroborate as before. Simultaneous decarbonylation takes place in this acylation reaction.
| 【1】 Gittos, M.W. (Merrell Pharmaceuticals, Inc.); Esters of hexahydro-8-hydroxy-2, 6-methano-2H-quinolizin-3(4H)-one and related compds.. AU 8780596; EP 0266730; JP 1988258476 . |
| 【2】 Gittos, M.W.; Fatmi, M.; Potent 5-HT3 antagonists incorporating a novel bridged pseudopelletierine ring system. Actual Chim Ther 1989, 16, 187. |
| 【3】 Gittos, M.W.; Fatmi, M.; Galvan, M.; Dolasetron Mesylate. Drugs Fut 1993, 18, 6, 506. |
| 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) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (II) | 50004 | cis-1,4-Dichloro-2-butene;(Z)-1,4-Dichlorobutene;(Z)-1,4-Dichloro-2-butene;(2Z)-1,4-Dichloro-2-butene;cis-1,2-Bis(chloromethyl)ethene | 1476-11-5 | C4H6Cl2 | 详情 | 详情 |
| (III) | 50000 | diethyl 3-cyclopentene-1,1-dicarboxylate | C11H16O4 | 详情 | 详情 | |
| (IV) | 50001 | 3-cyclopentene-1-carboxylic acid | C6H8O2 | 详情 | 详情 | |
| (V) | 50002 | 3-Cyclopentenecarboxylic acid | 7686-77-3 | C6H7ClO | 详情 | 详情 |
| (VI) | 13469 | ethyl 3-cyclopentene-1-carboxylate | C8H12O2 | 详情 | 详情 | |
| (VII) | 13470 | ethyl 3,4-dihydroxycyclopentanecarboxylate | C8H14O4 | 详情 | 详情 | |
| (VIII) | 13471 | ethyl 4-oxo-2-(2-oxoethyl)butanoate | C8H12O4 | 详情 | 详情 | |
| (IX) | 13472 | ethyl 9-(2-ethoxy-2-oxoethyl)-7-oxo-9-azabicyclo[3.3.1]nonane-3-carboxylate | C15H23NO5 | 详情 | 详情 | |
| (X) | 13473 | ethyl 9-(2-ethoxy-2-oxoethyl)-7-hydroxy-9-azabicyclo[3.3.1]nonane-3-carboxylate | C15H25NO5 | 详情 | 详情 | |
| (XI) | 13474 | ethyl 9-(2-ethoxy-2-oxoethyl)-7-(tetrahydro-2H-pyran-2-yloxy)-9-azabicyclo[3.3.1]nonane-3-carboxylate | C20H33NO6 | 详情 | 详情 | |
| (XII) | 50003 | 5-(tetrahydro-2H-pyran-2-yloxy)-8-azatricyclo[5.3.1.0(3,8)]undecan-10-one | C15H23NO3 | 详情 | 详情 | |
| (XIII) | 13475 | 5-Hydroxy-8-azatricyclo[5.3.1.0(3,8)]undecan-10-one | C10H15NO2 | 详情 | 详情 | |
| (XIV) | 17153 | 1H-indole-3-carbonyl chloride | C9H6ClNO | 详情 | 详情 | |
| (XV) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
| (XVI) | 29841 | Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride | 79-37-8 | C2Cl2O2 | 详情 | 详情 |
| (XVII) | 13476 | Indole-3-glyoxylyl chloride; 2-(1H-Indol-3-yl)-2-oxoacetyl chloride | 22980-09-2 | C10H6ClNO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVI)Protection of 3-pyrroline (XII) with Boc2O in MeOH followed by oxidation of the resulting N-Boc-pyrroline (XIII) with m-CPBA in CH2Cl2 provides epoxide (XIV), which is also alternatively prepared by reaction of 1-Boc-3-pyrroline (XIII) with NBS in aqueous DMSO and subsequent cyclization of the obtained bromohydrin (XV) in 1 N NaOH. A further method to prepare pyrroline (XIII) is by condensation of cis-1,4-dichloro-2-butene (XVI) with tert-butyl carbamate in the presence of NaH in dry DMF. Ring opening of epoxide (XIV) with NaN3 in dioxane/H2O leads to the trans-azidoalcohol (XVII), which is alkylated with iodomethane and NaH in THF to give the methyl ether (XVIII). After catalytic hydrogenation of azide (XVIII) over Pd/C, the N-Boc protecting group in the resulting amine (XIX) is replaced with a benzyl group by acidic hydrolysis followed by alkylation with benzyl chloride and Et3N to give the protected pyrrolidine (XX) . Optical resolution of racemic trans-3-amino-1-benzyl-4-methoxypyrrolidine (XX) using D-(+)-tartaric acid provides the target (S,S)-enantiomer, which is then protected as the tert-butyl carbamate (XXI) by treatment with Boc2O in MeOH. Subsequent reduction of carbamate (XXI) with LiAlH4 in THF followed by reprotection of the resulting Nmethylamine with Boc2O in CH2Cl2 provides compound (XXII), which is finally debenzylated by catalytic hydrogenation over Pd/C in EtOH to the desired pyrrolidine (VIII) .
Epoxide (XIV) is converted to the aminopyrrolidine (X) by two additional strategies. Ring opening of epoxide (XIV) with aqueous methylamine yields the racemic trans-aminoalcohol (XXIII), which is resolved by acylation with N-Boc-L-phenylalanine and EDC in CH2Cl2 followed by separation of the diastereomers by column chromatography. Hydrolysis of the desired diastereomer (XXIV) with 20% NaOH in EtOH affords the (S,S)-enantiomer of amino alcohol (XXIII), which is protected as the bis-carbamate (XXV) using Boc2O in MeOH. Finally, methylation of alcohol (XXV) with iodomethane and NaH in DMF, followed by removal of both Boc groups with p-TsOH in i-PrOH provides the target (S,S)-3-methoxy-4-(methylamino)pyrrolidine ditosylate (X) .
Alternatively, reaction of epoxide (XIV) with benzylamine provides the racemic amino alcohol (XXVI), which can be resolved by recrystallization of the diastereoisomeric salts with (+)-mandelic acid in acetonitrile/water. Subsequent debenzylation of the target enantiomer with H2 and Pd/C in BuOH provides the (S,S)-amino alcohol (XXVII). Protection of the primary amino group of compound (XXVII) with Boc2O in EtOH gives the bis-carbamate (XXVIII), which is finally submitted to N,O-dialkylation with iodomethane and NaH, followed by Boc group cleavage with p-TsOH in THF/MeOH to yield the key intermediate (X) .
| 【1】 Tomita, K., Chiba, K., Kashimoto, S., Shibamori, K., Tsuzuki, Y. (Dainippon Sumitomo Pharma Co., Ltd.). Novel compound, process for producing the same, and antitumor agent. EP 0787726, US 5817669, WO 1995034559. |
| 【2】 Tsuzuki, Y., Chiba, K., Mizuno, K., Tomita, K., Suzuki, K. Practical synthesis of (3S,4S)-3-methoxy-4-methylaminopyrrolidine. Tetrahedron Asymmetry 2001, 12(21): 2989-97. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| （LVIV） | 69218 | (S,S)-tert-butyl 3-hydroxy-4-(methylamino)pyrrolidine-1-carboxylate | C10H20N2O3 | 详情 | 详情 | |
| (VIII) | 26649 | tert-butyl (3S,4S)-4-methoxypyrrolidinyl(methyl)carbamate | C11H22N2O3 | 详情 | 详情 | |
| (X) | 69211 | (3S,4S)-4-methoxy-N-methylpyrrolidin-3-amine compound with 1-methyl-4-(methylsulfonyl)benzene (1:2) | C6H14N2O.2C8H10O2S | 详情 | 详情 | |
| (XII) | 22833 | 2,5-dihydro-1H-pyrrole;3-Pyrroline | 109-96-6 | C4H7N | 详情 | 详情 |
| (XIII) | 22834 | 2,5-Dihydro-1H-pyrrole-1-carboxylic acid 1,1-d;2,5-Dihydropyrrole-1-carboxylic acid tert-butyl ester;tert-Butyl 2H-pyrrole-1(5H)-carboxylate;1-tert-Butoxycarbonylpyrroline;tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate | 73286-70-1 | C9H15NO2 | 详情 | 详情 |
| (XIV) | 22835 | tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate | C9H15NO3 | 详情 | 详情 | |
| (XV) | 69212 | (3S,4R)-tert-butyl 3-bromo-4-hydroxypyrrolidine-1-carboxylate | C9H16BrNO3 | 详情 | 详情 | |
| (XVI) | 50004 | cis-1,4-Dichloro-2-butene;(Z)-1,4-Dichlorobutene;(Z)-1,4-Dichloro-2-butene;(2Z)-1,4-Dichloro-2-butene;cis-1,2-Bis(chloromethyl)ethene | 1476-11-5 | C4H6Cl2 | 详情 | 详情 |
| (XVII) | 69213 | (3S,4S)-tert-butyl 3-azido-4-hydroxypyrrolidine-1-carboxylate | C9H16N4O3 | 详情 | 详情 | |
| (XVIII) | 69214 | (3S,4S)-tert-butyl 3-azido-4-methoxypyrrolidine-1-carboxylate | 429673-78-9 | C10H18N4O3 | 详情 | 详情 |
| (XIX) | 69215 | (3S,4S)-tert-butyl 3-amino-4-methoxypyrrolidine-1-carboxylate | 429673-79-0 | C10H20N2O3 | 详情 | 详情 |
| (XX) | 26651 | (3S,4S)-1-benzyl-4-methoxy-3-pyrrolidinamine | C12H18N2O | 详情 | 详情 | |
| (XXI) | 26652 | tert-butyl (3S,4S)-1-benzyl-4-methoxypyrrolidinylcarbamate | C17H26N2O3 | 详情 | 详情 | |
| (XXII) | 26653 | tert-butyl (3S,4S)-1-benzyl-4-methoxypyrrolidinyl(methyl)carbamate | C18H28N2O3 | 详情 | 详情 | |
| (XXIII) | 69216 | rac-tert-butyl 3-hydroxy-4-(methylamino)pyrrolidine-1-carboxylate | C10H20N2O3 | 详情 | 详情 | |
| (XXIV) | 69217 | (3S,4S)-tert-butyl 3-((S)-2-((tert-butoxycarbonyl)amino)-N-methyl-3-phenylpropanamido)-4-hydroxypyrrolidine-1-carboxylate | C24H37N3O6 | 详情 | 详情 | |
| (XXV) | 69219 | (3S,4S)-tert-butyl 3-((tert-butoxycarbonyl)(methyl)amino)-4-hydroxypyrrolidine-1-carboxylate | C15H28N2O5 | 详情 | 详情 | |
| (XXVI) | 69220 | (3S,4S)-tert-butyl 3-(benzylamino)-4-hydroxypyrrolidine-1-carboxylate | 252574-03-1 | C16H24N2O3 | 详情 | 详情 |
| (XXVII) | 22837 | tert-butyl (3S,4S)-3-amino-4-hydroxy-1-pyrrolidinecarboxylate | 190792-74-6 | C9H18N2O3 | 详情 | 详情 |
| (XXVIII) | 69221 | (3S,4S)-tert-butyl 3-((tert-butoxycarbonyl)amino)-4-hydroxypyrrolidine-1-carboxylate | C14H26N2O5 | 详情 | 详情 |