* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With triethylamine In tetrahydrofuran at 0℃; for 0.5 h; Stage #2: With sodium tetrahydroborate In tetrahydrofuran; water at 0 - 20℃; for 1 h;
Intermediate A51I: Methyl 4-(hydroxymethyl)bicyclo[2.2.2]octane-1-carboxylate To a solution of Intermediate A51A (1.0531 g, 4.96 mmol) in THF (40 mL) at 0° C. were added TEA (1.729 mL, 12.40 mmol) and ethyl carbonochloridate (1.131 g, 10.42 mmol) in THF (2 mL) dropwise. The reaction mixture became a suspension (Et3N HCl salt). The reaction mixture was stirred at 0° C. for 30 min. The suspension was filtered and washed with THF. The filtrate was added to a suspension of sodium borohydride (0.751 g, 19.85 mmol) in water (2 mL) at 0° C. The reaction mixture was stirred at RT for 1 h. The reaction mixture partitioned with EtOAc and water. The organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography (40 g REDISEP® column, eluting with 10-50percent EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate A51I (0.9 g, 91percent). (ES): m/z=199 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ ppm 3.66 (s, 3H), 3.30 (s, 2H), 1.91-1.73 (m, 6H), 1.52-1.41 (m, 6H).
With borane-THF In tetrahydrofuran for 1 h; Inert atmosphere; Cooling with ice
Under a nitrogen atmosphere, 5.6 g of the compound represented by the formula (I-70-2) and 50 mL of tetrahydrofuran were added to the reaction vessel. 32 mL of a 0.9 mol / L borane-tetrahydrofuran complex was added dropwise while cooling with ice, and the mixture was stirred for 1 hour. After 5percent hydrochloric acid was added dropwise, it was extracted with ethyl acetate and washed with brine. Dried over sodium sulfate, and the solvent was distilled off to obtain 4.7 g of a compound represented by the formula (I-70-3).
Reference：
[1] Tetrahedron Letters, 1999, vol. 40, # 4, p. 781 - 784
[2] Journal of Labelled Compounds and Radiopharmaceuticals, 2007, vol. 50, # 4, p. 219 - 223
[3] Journal of Organic Chemistry, 1985, vol. 50, # 7, p. 1079 - 1087
[4] Patent: US6649600, 2003, B1, . Location in patent: Page/Page column 58-59
[5] Patent: WO2013/68328, 2013, A1, . Location in patent: Page/Page column 27
[6] Patent: JP2017/210409, 2017, A, . Location in patent: Paragraph 0202-0203; 0205
With Dess-Martin periodane In dichloromethane at 20℃;
Intermediate A51L: Methyl 4-formylbicyclo[2.2.2]octane-1-carboxylate To a solution of Intermediate A511 (540 mg, 2.72 mmol) in CH2Cl2 (20 mL) was added Dess-Martin periodinane (1502 mg, 3.54 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was cooled to 0° C. and carefully quenched with a solution of NaHCO3. The layers were separated. The aqueous layer was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography (40 g REDISEP® column, eluting with 10-50percent EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate A51L (400 mg, 74.8percent). (ES): m/z=199 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ ppm 9.48 (s, 1H), 3.68 (s, 3H), 1.94-1.78 (m, 6H), 1.78-1.61 (m, 6H).
Reference：
[1] Tetrahedron Letters, 1999, vol. 40, # 4, p. 781 - 784
[2] Patent: US9273058, 2016, B2, . Location in patent: Page/Page column 534
[3] Journal of Labelled Compounds and Radiopharmaceuticals, 2007, vol. 50, # 4, p. 219 - 223
[4] Journal of Organic Chemistry, 1985, vol. 50, # 7, p. 1079 - 1087
With dimethylsulfide borane complex; In tetrahydrofuran; at 0 - 20℃; for 4h;
To a stirred solution of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (1.5 g, 7.1 mmol) in THF (17 mL), was added borane dimethyl sulfide complex (2.0 mL, 21 mmol) at 0 C. The reaction was warmed to rt and stirred. After 4 h, the reaction mixture was quenched with MeOH (dropwise addition over 15 mins with cooling) and stirred at rt for 2 h. The solvent was concentrated and the crude product was purified by flash column chromatography (80 g silica gel cartridge; A=PE, B=EtOAc; 25 min grad.; 0% to 50% B; flow rate=60 mL/min; TLC visualized with KMnO4). The pure fractions were combined, concentrated and dried in vacuo to afford the title compound (1.3 g, 6.6 mmol, 93% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) delta 3.56 (s, 3H), 3.36 (s, 2H), 3.05 (s, 1H), 1.78-1.64 (m, 6H), 1.37-1.27 (m, 6H).
Example 91 4-Hydroxymethylbicyclo[2.2.2]octano-1-carboxylic acid methyl ester (XVI, Step M) 4-methyl morpholine (15 ml, 136 mmol) and iso-butyl chloroformate (15.0 ml, 123 mmol) are successively added to bicyclo[2.2.2]octane-1,4-dicarboxylic acid monomethyl ester (IV) in DME (165 ml), cooled to -7 C. After about 2 minutes, the reaction mixture is filtered and the solid is rinsed with DME. The combined filtrates are transferred to a two liter round-bottomed flask and cooled to -5 C. An aqueous solution of sodium borohydride (7.02 g, 185 mmol), in 75 ml water is added over about 1 minute (CAUTION: massive evolution of gas). After 10 minutes, the reaction mixture is diluted with water (100 ml) and extracted with ethyl acetate (3*250 ml). The combined organic layers are washed with saline (150 ml*3), dried over anhydrous sodium sulfate and concentrated to give the title compound.
With dimethylsulfide borane complex; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; Reflux;
4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (25 g, 118 mmol, 1 equiv) was dissolved in THF (200 mL) in a 1 liter 3-neck round bottom flask fitted with a rubber septum, a mechanical stirrer and a Claisen adaptor fitted with a nitrogen inlet and an internal temperature probe and cooled to 0 C in an ice bath. A gas bubbler outlet fitted with a needle was attached through the septum and the reaction was performed under a gentle stream of nitrogen. A 2.0 M solution of borane dimethylsulfide complex in THF (70.7 mL, 141 mmol, 1.2 equiv) was added drop wise through the septum ensuring the internal temperature did not rise above 4 C. The reaction vessel was allowed to warm slowly to room temperature and stirred overnight. Methanol (150 mL) was carefully added through the septum and the septum was quickly replaced with a reflux condenser fitted with a gas bubbler outlet. The solution was heated at reflux for 6 hours then cooled to room temperature, transferred to a 2 liter round bottom flask and concentrated by rotary evaporation to a clear colorless oil which was carried forward without further purification.
4.7 g
With borane-THF; In tetrahydrofuran; for 1h;Inert atmosphere; Cooling with ice;
Under a nitrogen atmosphere, 5.6 g of the compound represented by the formula (I-70-2) and 50 mL of tetrahydrofuran were added to the reaction vessel. 32 mL of a 0.9 mol / L borane-tetrahydrofuran complex was added dropwise while cooling with ice, and the mixture was stirred for 1 hour. After 5% hydrochloric acid was added dropwise, it was extracted with ethyl acetate and washed with brine. Dried over sodium sulfate, and the solvent was distilled off to obtain 4.7 g of a compound represented by the formula (I-70-3).
With Dess-Martin periodane; In dichloromethane; at 20℃;
Intermediate A51L: Methyl 4-formylbicyclo[2.2.2]octane-1-carboxylate To a solution of Intermediate A511 (540 mg, 2.72 mmol) in CH2Cl2 (20 mL) was added Dess-Martin periodinane (1502 mg, 3.54 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was cooled to 0 C. and carefully quenched with a solution of NaHCO3. The layers were separated. The aqueous layer was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography (40 g REDISEP column, eluting with 10-50% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate A51L (400 mg, 74.8%). (ES): m/z=199 [M+H]+; 1H NMR (400 MHz, chloroform-d) delta ppm 9.48 (s, 1H), 3.68 (s, 3H), 1.94-1.78 (m, 6H), 1.78-1.61 (m, 6H).
67%
With Dess-Martin periodane; In dichloromethane; at 20℃; for 3h;
To a solution of Intermediate 159A (0.10 g, 0.50 mmol) in DCM (5 mL) was added DMP (0.28 g, 0.66 mmol) and the reaction was stirred at rt. After 3 h, the reaction was cooled to 0 C. and carefully quenched with a solution of sat. NaHCO3 (aq.) (30 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2*15 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography (12 g silica gel cartridge, A=PE, B=EtOAc; 15 min grad.; 20% to 100% B; flow rate=12 mL/min; TLC visualized with KMnO4). The pure fractions were combined, concentrated and dried in vacuo to afford the title compound (0.070 g, 0.34 mmol, 67% yield) as colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) delta 9.4 (s, 1H), 3.66 (s, 3H), 1.86-1.82 (m, 7H), 1.69-1.66 (m, 5H).
With ruthenium 1,1,1-tris(diphenylphosphinomethyl)ethane; hydrogen; toluene-4-sulfonic acid; In para-xylene; at 200℃; under 104192 Torr; for 24h;Autoclave;
At atmospheric conditions, 0.25g of the Ru-TRIPHOS catalyst ruthenium 1 ,1 ,1 -tris(diphenylphosphinomethyl)ethane, 25 mg of p-toluenesulfonic acid, 2.5g of dimethyl bicyclo[2.2.2]octane-1 ,4-dicarboxylate and 50 imL of p-xylene were added to a 100 imL autoclave reactor. The reactor was then purged three times by pressurizing with nitrogen to 200 psig, then venting the pressure to atmospheric each time. The reactor was then purged three times by pressurizing with hydrogen to approximately 300 psig, then venting the pressure to atmospheric each time. Agitation at 800 rpm was then commenced, and hydrogen was then added to bring the pressure to 1600 psig. The temperature was then increased to 200 C while allowing pressure to rise. After the temperature reaches 200 C, the hydrogen pressure was increased to 2000 psig. These conditions (200 C and 2000 psig) were held for 24 hours of reaction. After 24 hours of reaction, the agitation was stopped, and the heat turned off to let the autoclave start cooling. After cooling to room temperature, pressure was released, and the contents were purged with nitrogen gas and vented. The solution was finally discharged from the autoclave and analyzed by GC-MS and 1H NMR. The conversion of dimethyl bicyclo[2.2.2]octane-1 ,4-dicarboxylate is 30% and the only product methyl 4-(hydroxymethyl)bicyclo[2.2.2]octane-1 -carboxylate (100% selectivity).
Example 92 4-Hydroxymethylbicyclo[2.2.2]octane-1-carboxylic acid (XVII, Step N) Lithium hydroxide (2 N, 250 ml) is added to a mixture of 4-hydroxymethyl-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester (XVI, Example 91) in a mixture of THF (50 ml) and methanol (75 ml). The resulting reaction mixture is stirred at 20-25 for 16 hr, and then concentrated. The residue is diluted with water (30 ml) and washed with methylene chloride (100 ml) and ethyl acetate (100 ml). The aqueous layer is acidified with concentrated hydrochloric acid pH about 0 and extracted with ethyl acetate (3*250 ml). The ethyl acetate layers are combined and washed with saline (3*50 ml), dried over anhydrous sodium sulfate and concentrated to give the title compound, NMR (400 MHz, CDCl3) delta 3.09, 1.72 and 1.29.
With triethylamine; In tetrahydrofuran; at 0 - 20℃;
Step 1. Methyl-4-(hydroxymethyl)bicyclo[2.2.2]octane-1-carboxylate (10 g, 50.4 mmol, 1 equiv) from the previous step was dissolved in THF (100 mL) and triethylamine (7.73 mL, 55.5 mmol, 1.1 equiv) and chilled to 0 C in an ice bath. Trimethylchlorosilane (6.77 mL, 53.0 mmol, 1.05 equiv) was then added dropwise during which time copious white solid formed. The reaction was stirred at this temperature for 2 hours at which point 1H NMR analysis of an aliquot indicated incomplete conversion to product so additional triethylamine (7.73 mL, 55.5 mmol, 1.1 equiv) and trimethylchlorosilane (6.77 mL, 53.0 mmol, 1.05 equiv) were added and the reaction warmed to room temperature and stirred for 16 hours. Hexanes (200 mL) were added and solids removed by filtration through a pad of Celite. Removal of volatiles in vacuo gave a clear yellow oil which was carried to the next step without further purification. Step 2. The yellow oil from the first step was transferred to a 500 mL 3 -neck round bottom flask charged with N-Cbz-4-piperidone (11.29 g, 48.4 mmol, 0.96 equiv) andtriethylsilane (8.06 mL, 50.4 mmol, 1 equiv) and fitted with a pressure equalized dropping funnel, a mechanical stirrer and a Claisen adaptor fitted with a nitrogen inlet and an internal temperature probe and cooled to -78 C in an ice bath. Trimethylsilyl trifluoromethanesulfonate (4.56 mL, 25.2 mmol, 0.5 equiv) was added dropwise from the dropping funnel over ~3 minutes ensuring that the internal temperature did not rise above -60 C. After 5 minutes, the reaction was warmed to 0 C and held there with stirring for 1 hour then warmed to room temperature. The reaction mixture was partitioned between ethyl acetate and water and the organic layer was washed with brine, then dried on anhydrous sodium sulfate, filtered and concentrated in vacuo and left on a high- vacuum pump overnight. The resulting orange oil contained -30% triethylsilyl-containing impurities as indicated by 1H NMR which were removed by trituration with hexanes (3 x 10 mL) to give an orange oil which was carried forward without further purification.Step 3. A 500 mL thick- walled glass Parr Shaker flask was charged with 30 % (w/w) palladium on carbon (2.1 g, 5.92 mmol, 16 mol%) and a solution of the orange oil from Step 2 (17.4 g, 37.7 mmol, 1 equiv) in methanol (100 mL) and pressurized to 48 psi with hydrogen. Agitation on a Parr shaker for 90 minutes at room temperature led to complete removal of the carbamate as indicated by LCMS analysis of an aliquot. Solids were removed by filtration through a pad of Celite and the filtrate was concentrated in vacuo. The residue was reconstituted in 0.5 M hydrochloric acid (100 mL) and water (100 mL) to give a cloudy suspension of pH < 1 that was washed with toluene (50 mL). The aqueous layer was brought to pH 10.5 with 1 M sodium hydroxide to give a milky white suspension. The amine was then extracted into dichloromethane (3 x 100 mL) and the combined organic layers washed with brine (50 mL), dried on anhydrous sodium sulfate, filtered and concentrated in vacuo to give the amine as a white powder: [MH]+ calc'd m/z 282.2; found m/z 282.0.
With 2,6-dimethylpyridine; trifluoromethylsulfonic anhydride; In dichloromethane; for 1.5h;Cooling with ice;
Intermediate PMethyl 4-((Trifluoromethylsulfonyloxy)methyl)bicyclo[2.2.2]octane- 1 - carboxylateTo a solution of methyl 4-(hydroxymethyl)bicyclo[2.2.2]octane-l -carboxylate(2.70 g, prepared according to International Patent Application Publication No. WO2001034610) and 2,6-lutidine (2.54 mL) in dichloromethane (55 mL) was added triflic anhydride (2.97 mL) under cooling with ice, the mixture was stirred at the same temperature for 1.5 hours.After dilution of the mixture with water, the mixture was extracted with dichloromethane. The organic extracts were washed with aqueous sodium hydro gencarbonate solution, 10%hydrochloric acid and brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane : ethyl acetate = 6: 1) of the residue gave P (4.38 g).1H NMR (CDC13): delta 1.51-1.58 (m, 6H), 1.82-1.85 (m, 6H), 3.66 (s, 3H), 4.17 (s,
methyl 4-(((5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)oxy)methyl)bicyclo[2.2.2]octane-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41.5%
With di-tert-butyl (E)-azodicarboxylate; triphenylphosphine; In toluene; at 0 - 90℃; for 18.0833h;
To a solution of 5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-ol (108 mg, 0.545 mmol), methyl 4-(hydroxymethyl)bicyclo[2.2.2]octane-l-carboxylate (90 mg, 0.454 mmol) and triphenylphosphine (179 mg, 0.681 mmol) in toluene (2 mL) at 0 C was added (£)-di-tert-butyl diazene-l,2-dicarboxylate (157 mg, 0.681 mmol) in toluene (0.5 mL) slowly. The reaction mixture was stirred at room temperature for 5 min and the reaction mixture was heated to 90 C for 18 hours. After cooled to room temperature, dichloromethane (5 mL) and water (5 mL) were added to the reaction mixture. The layers were separated. The organic layer was washed with brine, dried over MgS04, filtered and concentrated in vacuo to afford the crude. This crude was purified by preparative HPLC (PHENOMENEX Axia 5 muiotaeta C18 30 x 100 mm column; detection at 220 nm; flow rate = 40 mL/min; continuous gradient from 30% B to 100% B over 10 min + 5 min hold time at 100% B, where A = 90: 10:0.1 H20:MeOH:TFA and B = 90: 10:0.1 MeOH:H20:TFA) to give the title compound (75 mg, 41.5% Yield; 95% pure by LC/MS) as a light yellow oil. [M+Na]+ = 401, pi MR (400 MHz, CDC13) delta 6.70 (dd, J= 14.3, 1.6 Hz, 2H), 3.65 (s, 3H), 3.63 (s, 2H), 2.96 (s, 2H), 1.86 - 1.77 (m, 6H), 1.59 - 1.55 (m, 6H), 1.48 (s, 6H).
General procedure: [1269] ^ Borane-tetrahydrofuran complex (1 M THF solution, 22.7 mL) was added dropwise to a solution of 4-(methoxycarbonyl)bicyclo[2.2.1]heptane-l-carboxylic acid (3.00 g) in THF (60 mL) at -40C, the resultant was stirred for 1 hour at the same temperature, and was further stirred for 2 hours at 0C. An aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture at 0C, and extraction thereof was performed using ethyl acetate. The obtained organic layer was sequentially washed with water and a saturated saline solution, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure, thereby obtaining the title compound (2.50 g). 1H NMR (400 MHz, DMSO-d^ 1.21-1.24 (2H, m), 1.42 (2H, s), 1.55-1.61 (4H, m), 1.82-1.89 (2H, m), 3.42 (2H, d, J = 5.36 Hz), 3.58 (3H, s), 4.47 (1H, t, J = 5.36 Hz).
36
[ 18720-35-9 ]
[ 541-41-3 ]
[ 94994-15-7 ]
Yield
Reaction Conditions
Operation in experiment
91%
Intermediate A51I: Methyl 4-(hydroxymethyl)bicyclo[2.2.2]octane-1-carboxylate To a solution of Intermediate A51A (1.0531 g, 4.96 mmol) in THF (40 mL) at 0 C. were added TEA (1.729 mL, 12.40 mmol) and ethyl carbonochloridate (1.131 g, 10.42 mmol) in THF (2 mL) dropwise. The reaction mixture became a suspension (Et3N HCl salt). The reaction mixture was stirred at 0 C. for 30 min. The suspension was filtered and washed with THF. The filtrate was added to a suspension of sodium borohydride (0.751 g, 19.85 mmol) in water (2 mL) at 0 C. The reaction mixture was stirred at RT for 1 h. The reaction mixture partitioned with EtOAc and water. The organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography (40 g REDISEP column, eluting with 10-50% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate A51I (0.9 g, 91%). (ES): m/z=199 [M+H]+; 1H NMR (400 MHz, chloroform-d) delta ppm 3.66 (s, 3H), 3.30 (s, 2H), 1.91-1.73 (m, 6H), 1.52-1.41 (m, 6H).
With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 3h;
Intermediate A51J: Methyl 4-(fluoromethyl)bicyclo[2.2.2]octane-1-carboxylate To a solution of Intermediate A511 (306 mg, 1.543 mmol) in CH2Cl2 (5 mL) at -78 C. under nitrogen was added DAST (0.245 mL, 1.852 mmol). The reaction mixture was stirred at RT for 3 h. The reaction mixture was cooled to 0 C. and carefully quenched with a saturated solution of NaHCO3. The layers were separated. The aqueous layer was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography (40 g REDISEP column, eluting with 10-50% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate A51J (130 mg, 42%). 1H NMR (400 MHz, chloroform-d) delta ppm 3.66 (s, 3H), 2.15-1.95 (m, 4H), 1.94-1.22 (m, 1H).
With pyridine; In dichloromethane; at 20℃; for 3h;Inert atmosphere;
Under a nitrogen atmosphere, 4.7 g of the compound represented by the formula (I-70-3), 2.5 g of pyridine and 50 mL of dichloromethane were added to the reaction vessel. 3.0 g of methanesulfonyl chloride was added dropwise while cooling with ice, and the mixture was stirred at room temperature for 3 hours. It was poured into water and washed sequentially with 5% hydrochloric acid and brine. Purification by column chromatography (silica gel, hexane / ethyl acetate) gave 5.9 g of a compound represented by the formula (I-70-4).
With [2-(di-tert-butylphosphinomethyl)-6-(diethylaminomethyl)pyridine]carbonylchlorohydridoruthenium (ll); hydrogen; potassium hydroxide; In para-xylene; at 140℃; under 39547.2 - 52476.2 Torr; for 8.0h;Autoclave;
At atmospheric conditions, 0.1 g of the Milstein catalyst precursor [2-(Di-tert- butylphosphinomethyl)-6- (0259) (diethylaminomethyl)pyridine]carbonylchlorohydridoruthenium(ll), 30 mg of potassium hydroxide, 2.5g of dimethyl bicyclo[2.2.2]octane-1 ,4-dicarboxylate and 50 imL of p- xylene were added to a 100 imL autoclave reactor. The reactor was then purged three times by pressurizing with nitrogen to 200 psig, then venting the pressure to atmospheric each time. The reactor was then purged three times by pressurizing with hydrogen to approximately 300 psig, then venting the pressure to atmospheric each time. Agitation at 800 rpm was then commenced, and hydrogen was then added to bring the pressure to 750 psig. The temperature was then increased to 140 °C while allowing pressure to rise. After the temperature reaches 140 °C, the hydrogen pressure was increased to 1000 psig. These conditions (140 °C and 1000 psig) were held for 8 hours of reaction. After 8 hours of reaction, the agitation was stopped and the heat turned off to let the autoclave start cooling. After cooling to room temperature, pressure was released, and the contents were purged with nitrogen gas and vented. The solution was finally discharged from the autoclave and analyzed by GC-MS and 1H NMR. The conversion of dimethyl bicyclo[2.2.2]octane-1 ,4-dicarboxylate is 94percent; the selectivity of bicyclo[2.2.2]octane-1 ,4-diyldimethanol is 93percent; and the selectivity of methyl 4-(hydroxymethyl)bicyclo[2.2.2]octane-1 -carboxylate is 7percent.
methyl 4-(((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)methyl)bicyclo[2.2.2]octane-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With 2,6-di-tert-butyl-pyridine; silver trifluoromethanesulfonate; In dichloromethane; at 0 - 20℃; for 12h;
To a 20 mL scintillation vial were added methyl 4-(hydroxymethyl) bicyclo[2.2.2]octane-1-carboxylate (200 mg, 1.0 mmol) (Al Hussainy, R. et al. Nucl. Med. Biol. 2012, 39, 1068-1076), 2,6-di-tert-butylpyridine (0.91 mL, 4.0 mmol), dry DCM (2 mL) followed by silver trifluoromethanesulfonate (780 mg, 3.0 mmol) at 0 C. A solution of 4-(bromomethyl)-5-yclopropyl-3-(2,6-dichlorophenyl)isoxazole (1.1 g, 3.0 mmol) in DCM (2 mL) was added dropwise at 0 C. The reaction was stirred at rt for 12 h and diluted with DCM:MeOH (1:1; 10 mL). The solids were filtered and the filtrate was concentrated. The crude product was purified by flash column chromatography (24 g silica gel cartridge; A=Hex, B=EtOAc; 15 min grad.; 0% B to 25% B; flow rate=24 mL/min). The pure fractions were combined, concentrated and dried in vacuo to afford the title compound (0.18 g, 35% yield) as a pale yellow solid. MS (ESI) 464 (M+H).
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