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HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
Inaccessible (Haz class 6.1), International
USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic
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Structure of 18720-35-9 * Storage: {[proInfo.prStorage]}
* 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.
To a stirred mixture of XVIII-1 (10 g, 47.2 mmol) in CH2Br2 (100 mL) was added HgO (17.5 g, 80.3 mmol) at rt. The mixture was heated to 80° C. and Br2 (3.6 mL, 47.2 mmol) was added dropwise during 40 min. After addition, the mixture was stirred at 80° C. for 3 h. Then the mixture was cooled to rt, and filtered. The filtrate was treated with MgSO4, filtered and concentrated in vacuo. The residue XVIII-2 (11 g, yield 94.8percent) was used in next step directly.
71.2%
With bromine In dichloromethane for 3.5 h; Reflux
To a refluxing suspension of 4-(methoxycarbonyl)bicycle [2.2.2] octane- 1- carboxylic acid (3.5 g, 16.49 mmol) compound and mercuric oxide, red (6.07 g, 28.0 mmol) in DCM (60 mL) was added drop wise solution of bromine (1.274 mL, 24.74 mmol) in DCM (25 mL) and refluxing was continued for another 3.5 h. The reaction mixture was filtered through celite and the filtrate was washed with water (2 x 100 mL). The organic layer was dried over Na2S04and concentrated under reduced pressure. The crude was purified by Combiflash Isco (Redisep, 40 g Silica, 6 percent EtOAc in petroleum ether) to yield methyl 4-bromobicyclo [2.2.2] octane-1- carboxylate (2.9 g, 11.73 mmol, 71.2 percent yield) as off white solid.XH NMR (DMSO- d6, δ = 2.50 ppm, 400 MHz): δ 3.56 (s, 3 H), 2.24 - 2.16 (m, 6 H), 1.92 - 1.85 (m, 6 H).
70%
Stage #1: With sodium hydroxide; phenolphthalein; silver nitrate In water; acetone Stage #2: With bromine In hexane at 20 - 80℃; for 1 h;
To a suspension of the title compound from the Preparative Example 39, Step C (1.0 g) in acetone (7.5 mL) was added phenolphthaleine (1 crystal). To this mixture was added IM aqueous NaOH until the color of the solution changed to red (pH ~ 8.5). Then a solution Of AgNO3 (850 mg) in H2O (1.25 mL) was added. The formed precipitate (Ag-salt) was collected by filtration, washed with H2O, acetone and Et2O and dried in vacuo at room temperature for 6 h and at 100°C for 18 h. The obtained solid (1.28 g) was suspended in hexane (15 mL), bromine (643 mg) was added dropwise and the mixture was stirred at room temperature for 30 min. Then the mixture was placed in a preheated oil bath (80°C) and stirred at the temperature for another 30 min. The mixture was filtered and the filter cake was washed with Et2O (2 x 30 mL). The combined filtrates were washed with saturated aqueous NaHCO3 (2 x 25 mL), dried (MgSO4), filtered and concentrated to afford the title compound (817 mg, 70percent). [MH]+ = 247/249.
68.7%
With bromine; mercury(II) oxide In dichloromethane for 1.5 h; Reflux
Intermediate A51D: Methyl 4-bromobicyclo[2.2.2]octane-1-carboxylate To a solution of Intermediate A51A (1.5 g, 7.07 mmol) in CH2Cl2 was added mercury(II) oxide (2.60 g, 12.01 mmol). The suspension was heated at reflux condition. To the reaction mixture was added a solution of bromine (0.473 ml, 9.19 mmol) in CH2Cl2 (5 mL) dropwise under refluxing. The reaction mixture was heated at reflux for 1.5 h and cooled to RT. It was passed through a pad of CELITE?, washed with EtOAc. The filtrate was concentrated. The residue was purified by silica gel chromatography (40 g REDISEP? column, eluting with 0-30percent EtOAc in hexane. Fractions containing the product were combined and evaporated to afford Intermediate A51D (1.2 g, 68.7percent). 1H NMR (400 MHz, chloroform-d) δ ppm 3.65 (s, 3H), 2.35-2.19 (m, 6H), 2.04-1.90 (m, 6H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 24, p. 5731 - 5737
[2] Patent: US2014/200215, 2014, A1, . Location in patent: Paragraph 1092
[3] Journal of Medicinal Chemistry, 2009, vol. 52, # 6, p. 1558 - 1568
[4] Patent: WO2015/5901, 2015, A1, . Location in patent: Page/Page column 468
[5] Patent: WO2006/128184, 2006, A2, . Location in patent: Page/Page column 171
[6] Patent: US9273058, 2016, B2, . Location in patent: Page/Page column 529; 530
[7] Journal of Organic Chemistry, 1970, vol. 35, p. 917 - 923
[8] Patent: US2010/267738, 2010, A1, . Location in patent: Page/Page column 34
[9] Patent: WO2012/145569, 2012, A1,
[10] Patent: US2010/249190, 2010, A1, . Location in patent: Page/Page column 84
Sodium borohydride (5.8 g, 0.15 mol) was added portionwise to an aqueous solution (120 mL) of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (6.5 g, 0.03 mol).The reaction mixture was stirred at room temperature overnight.Ice water bath cooling,Dilute aqueous hydrochloric acid (1.0M) to adjust the pH to 2-3,Solid filter,The cake was washed with cold water (20 mL) and dried under reduced pressure to give compound 9.1(5.66 g, yield: 100%) as a white solid.
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