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【结 构 式】 
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【分子编号】51236 【品名】2,4-Dimethylpyrrole 【CA登记号】625-82-1 |
【 分 子 式 】C6H9N 【 分 子 量 】95.1442 【元素组成】C 75.74% H 9.53% N 14.72% |
合成路线1
该中间体在本合成路线中的序号：(VI)Vilsmeier reaction of 4-methoxy-3-pyrrolin-2-one (I) with phosphoryl bromide and N,N-dimethylformamide, followed by basic hydrolysis, provides 5-bromo-3-methoxypyrrole-2-carbaldehyde (II), which is then subjected to Suzuki coupling with 1-Boc-2-indoleboronic acid (III) to afford the indolyl pyrrolealdehyde (IV). In a related method, intermediate (IV) is prepared by reaction of pyrrolinone (I) with phosphoryl bromide and diethylformamide, followed by Suzuki coupling of the resulting bromopyrrole (V) with the indoleboronic acid (III) and basic enamine hydrolysis. The title compound is then obtained by simultaneous condensation and deprotection of pyrrole aldehyde (IV) with 2,4-dimethylpyrrole (VI) in methanolic hydrogen chloride (1). Scheme 1.
| 【1】 Attardo, G., Dairi, K., Lavallee, J.-F., Rioux, E., Tripathy, S. (Gemin X Biotechnologies, Inc.). Triheterocyclic compounds, compositions, and methods for treating cancer or viral diseases. EP 1644363, JP 2007502845, US 2005014802, WO 2004106328. |
| 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) | 65258 | 4-methoxy-3-pyrrolin-2-one | C5H7NO2 | 详情 | 详情 | |
| (II) | 65259 | 5-bromo-3-methoxypyrrole-2-carbaldehyde | C6H6BrNO2 | 详情 | 详情 | |
| (III) | 65260 | 1-Boc-2-indoleboronic acid; N-Boc-indole-2-boronic acid; 1-(tert-Butoxycarbonyl)-1H-indol-2-ylboronic acid | 213318-44-6 | C13H16BNO4 | 详情 | 详情 |
| (IV) | 65261 | C19H20NO4 | 详情 | 详情 | ||
| (V) | 65262 | C10H15BrN2O | 详情 | 详情 | ||
| (VI) | 51236 | 2,4-Dimethylpyrrole | 625-82-1 | C6H9N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)The pyrrolidine building blocks are in turn synthesized as shown in Scheme 5. 3(R)-Hydroxypyrrolidine (IV) is protected as the N-Boc derivative (LIV), followed by O-alkylation with benzyl bromide and acidic deprotection of the resulting benzyl ether (LV) to furnish 3(R)-benzyloxypyrrolidine (II). Condensation of pyrrolidine (II) with cyclohexene oxide (XXXI) gives the trans-pyrrolidinocyclohexanol (LVI) as a diastereomeric mixture, which is separated either by crystallization with di-p-toluoyl-L-tartaric acid (DTTA) or by diastereoselective N-oxidation of the undesired diastereoisomer to furnish the target isomer (IX). Alternatively, intermediate (IX) can be obtained by ring opening of epoxide (XXXI) with pyrrolidine (II) in the presence of chiral catalysts. In a different strategy, enantioselective ring opening of cyclohexene oxide (XXXI) with B-bromodiisopinocamphenylborane provides the optically enriched trans-bromohydrin (LVII), which is then condensed with benzyloxypyrrolidine (II) to yield the (1S,2R)-pyrrolidinocyclohexanol (LVIII). Inversion of the configuration of alcohol (LVIII) to produce (IX) is then accomplished by Mitsunobu coupling with formic acid, followed by acidic hydrolysis of the resulting (1R,2R)-formate ester (LIX). Further synthetic strategies leading to the pyrrolidinocyclohexanol (IX) involve cyclization of (R,R)-2-aminocyclohexanol (LX) with 2(R)-benzyloxy-1,4-butanediol ditosylate (LXI), and condensation of (LX) with cyclohexanone (XXVI), followed by asymmetric hydroboration and oxidative work-up of the resulting enamine (LXII) (2). Alternatively, (R,R)-2-aminocyclohexanol (LX) can be converted to the intermediate acetoxysuccinimide (XII) by condensation with 2(R)-acetoxysuccinic anhydride (VI) (prepared from L-malic acid [LXIII] and acetyl chloride) to produce a regioisomeric mixture of succinamic acids (LXIVa) and (LXIVb), which undergoes cyclization to imide (XII) upon heating with acetyl chloride (4). Similarly, racemic trans-2-benzyloxycyclohexylamine (LXV) is resolved by enantioselective N-acylation with isopropyl methoxyacetate in the presence of lipase, followed by hydrolysis of the resulting (R,R)-methoxyacetamide (LXVI) to provide (LXVII) (5). Acylation of (R,R)-2-benzyloxycyclohexylamine (LXVII) with O-acetylmalic anhydride (VI), followed by cyclization with acetyl chloride, yields the N-(2-benzyloxycyclohexyl)succinimide (LXVIII), which is then debenzylated to (XII) by catalytic hydrogenation over Pd/C (4). Scheme 5.
| 【2】 Plouvier, B.M.C., Chou, D.T.H., Jung, G. et al. (Cardiome Pharma Corp.). Synthetic process for aminocyclohexyl ether compounds. WO 2006088525. |
| 【4】 Roth, C.J., Jung, G., Plouvier, B.M.C., Chou, D.T.H., Yee, J.G.K. (Cardiome Pharma Corp.). Synthetic processes for the preparation of aminocyclohexyl ether compounds. WO 2006138673. |
| 【5】 Balkenhohl, F., Ditrich, K., Nübling, C. (BASF AG). Racemate separation of primary and secondary heteroatom-substituted amine by enzyme-catalysed acylation. WO 9623894. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (LXIVa) | 65319 | C12H19NO6 | 详情 | 详情 | ||
| (LXIVb) | 65320 | C12H19NO6 | 详情 | 详情 | ||
| (II) | 65264 | (3R)-benzyloxypyrrolidine | C11H15NO | 详情 | 详情 | |
| (IV) | 14490 | (3R)tetrahydro-1H-pyrrol-3-ol; R-3-hydroxypyrrolidine | 2799-21-5 | C4H9NO | 详情 | 详情 |
| (VI) | 65267 | (2R)-acetoxysuccinic anhydride | 79814-40-7 | C6H6O5 | 详情 | 详情 |
| (VI) | 51236 | 2,4-Dimethylpyrrole | 625-82-1 | C6H9N | 详情 | 详情 |
| (IX) | 65271 | (2R)-[(3R)-benzyloxy-1-pyrrolidinyl]cyclohexan-(1R)-ol | C16H25NO2 | 详情 | 详情 | |
| (XII) | 65273 | (2R)-acetoxy-N-[(2R)-hydroxy-(1R)-cyclohexyl]succinimide | C12H17O5 | 详情 | 详情 | |
| (XXVI) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (XXXI) | 17986 | 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide | 286-20-4 | C6H10O | 详情 | 详情 |
| (LIV) | 65310 | (R )-1-Boc-3-hydroxypyrrolidine; (R )-N-(tert-Butoxycarbonyl)-3-hydroxypyrrolidine; (R )-3-Hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester | 103057-44-9 | C9H17O3N | 详情 | 详情 |
| (LV) | 65311 | C16H23O3N | 详情 | 详情 | ||
| (LVI) | 65312 | C17H25NO2 | 详情 | 详情 | ||
| (LVII) | 65313 | trans-2-bromocyclohexanol | C6H11BrO | 详情 | 详情 | |
| (LVIII) | 65314 | C17H24NO2 | 详情 | 详情 | ||
| (LIX) | 65315 | C18H25NO3 | 详情 | 详情 | ||
| (LX) | 65316 | (1R,2R)-2-aminocyclohexanol | C6H13NO | 详情 | 详情 | |
| (LXI) | 65317 | C25H28O7S2 | 详情 | 详情 | ||
| (LXII) | 65318 | C17H23NO | 详情 | 详情 | ||
| (LXIII) | 11058 | (S)-(+)-Hydroxysuccinic acid; (S)-(+)-Malic acid; (S)-(+)-2-Hydroxybutanedioic acid; L-(-)-Apple acid | 97-67-6 | C4H6O5 | 详情 | 详情 |
| (LXV) | 65321 | racemic trans-2-benzyloxycyclohexylamine | C13H17NO | 详情 | 详情 | |
| (LXVI) | 65322 | C16H23NO3 | 详情 | 详情 | ||
| (LXVII) | 65323 | C13H19NO | 详情 | 详情 | ||
| (LXVIII) | 65324 | C19H23NO5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Vilsmeier reaction between 2,4-dimethylpyrrole (I) and dimethylformamide (II) by means of phosphorous oxychloride in dichloroethane provides carbaldehyde (III), which is then condensed with 2-indolinone (IV) in ethanol in the presence of piperidine.
| 【1】 Tang, P.C.; Sun, L.; McMahon, G.; Hirth, K.P.; Shawver, L.K. (Sugen, Inc.); Indolinone combinatorial libraries and related products and methods for the treatment of disease. EP 0929520; JP 2001503736; WO 9807695 . |
| 【2】 Tang, P.C.; Sun, L.; McMahon, G. (Sugen, Inc.); Indolinone cpds. for the treatment of disease. EP 0769947; JP 2000026412; US 5780496; US 5792783; US 5880141; US 5883113; US 5883116; WO 9640116 . |
合成路线4
该中间体在本合成路线中的序号：(I)Aldehyde (II) was prepared by Vilsmeier-Haack formylation of 2,4-dimethylpyrrole (I). Subsequent condensation of the pyrrole aldehyde (II) with 5-chlorooxindole (III) in the presence of piperidine furnished the title compound.
| 【1】 Tang, P.C.; Sun, L.; McMahon, G. (Sugen, Inc.); Indolinone cpds. for the treatment of disease. EP 0769947; JP 2000026412; US 5780496; US 5792783; US 5880141; US 5883113; US 5883116; WO 9640116 . |