With the rapid development and complex challenges of chemical substances, the synthesis of new drugs is usually one of the most effective ways to increase yield.100058-61-5, name is 3-(Benzyloxy)cyclobutanol, molecular formula is C11H14O2, molecular weight is 178.23, as common compound, the synthetic route is as follows.Safety of 3-(Benzyloxy)cyclobutanol
Example lbb – Preparation of R Synthesis of 2-bromo-l-(bromomethyl)-l-(phenylmethoxy)ethane [0299] The mixture of 1 (60.1 g, 0.47 mol), benzyl bromide (80 g, 0.47 mol) and Hg2Cl2 (100 mg, 0.2 mmol) was heated to 150 C over night. TLC showed the reaction was completed. The product 2 (98 g, 70% yield) was obtained by distillation (180 C) in vacuum as a colorless oil. [0300] 1H NMR (400 MHz, CDCl3):7.37-7.28 (m, 5H), 4.65 (s, 2H), 3.82-3.77 (m, 1H), 3.56 (d, 4H, J=5.2 Hz). Synthesis of l-(methylsulfinyl)-l-methylthio-3-(phenylmethoxy)cyclobutane [0301] To the mixture of 3 (45.1 g, 0.36 mol) in THF (400 mL) was added n- BuLi (145 mL, 0.36 mol, 2.5 M) at -10 C under N2 drop wise. It was stirred further 2 h at this temperature. And then it was cooled to -78 C and the mixture of 2 (46.2 g, 0.15 mol) in THF (100 mL) was added drop wise over 0.5 h. The result mixture was stirred further 2 h at – 78 C and over night at r.t. It was quenched by the addition of H20 (100 mL) and the mixture was extracted with EtOAc (300 mL*3). The combined extracts were dried over Na2SC>4 and concentrated in vacuo to give the crude product. It was purified by column chromatography (Eluan: EtO Ac/Pet. ether= 1/2, v/v) to give the product 4 (30 g, 73% yield) as a yellow oil. [0302] 1H NMR (400 MHz, CDCl3):7.36-7.26 (m, 5H), 4.47 (d, 2H), 4.38-4.31 (m, 0.6H), 4.21-4.18 (m, 0.4H), 3.10-2.98 (m, 0.8H), 2.78-2.64 (m, 1.2 H), 2.55 (s, 1.2 H), 2.44 (s, 1.8 H), 2.42-2.15 (m, 2H), 2.12 (d, 3H). Synthesis of 3-(phenylmethoxy)cyclobutan-l-one [0303] To a solution of compound 4 (30 g, 0.1 1 mol) in dry ether (500 mL) was HC104 (22.5 mL, 35%) at 0 C drop wise, while keep the temperature bellow 10 C . It was stirred further 2 h at 0 C and over night at r.t. Solid NaHC03 and MgSC>4 were added and the resulting mixture was stirred further 0.5 h at r.t. It was filtered and the cake was washed with ether. The filtrate was concentrate in vacuo to give the crude product. It was purified by column chromatography (Eluant: EtOAc/Pet.ether=l/4, v/v) to give the product 5 (14.0 g, 72% yield) as a yellow oil. [0304] 1H NMR (400 MHz, CDC13): 7.39-7.25 (m, 5H), 4.52 (s, 2H), 4.40-4.34 (m, 1H), 3.26-3.10 (m, 4H). Synthesis of 3-(phenylmethoxy)cyclobutan-l-ol [0305] To the mixture of 5 (14.0 g, 79.46 mmol) in EtOH (150 mL) was added aBH4 (3.32 g, 87.40 mmol) at 0 C over 0.5 h. The resulting mixture was stirred further 2 h at 0 C and TLC showed the reaction was completed. The solvent was removed in vacuo and the residue was diluted with MeOH (100 mL) and quenched by HC1 (1M). The organic solvent was removed in vacuo and the residue was extracted with EtOAc (200 mL*3). The combined extracts were dried over Na2SC>4 and concentrated in vacuo to give the crude product. It was purified by column chromatography (Eluant: EtOAc/Pet.ether=l/4, v/v) to give the product 6 (14 g, 99% yield) as a yellow oil. [0306] 1H NMR (400 MHz, CDC13): 7.39-7.27 (m, 5H), 4.43 (s, 2H) 1H), 3.68-3.59 (m, 1H), 2.76-2.67 (m, 2H), 2.37 (br, 1H), 2.05-1.89 (m, 2H). Synthesis of 5-(phenylmethoxy)-2-[3-(phenylmethoxy)cyclobutoxy]pyrimidine [0307] To the mixture of 6 (10.5 g, 58.93 mmol) in DMSO (100 mL) was added NaH (3.06 g, 60%, 76.61 mmol) at r.t. The resulting mixture was stirred for 0.5 h at r.t, and then the mixture of 7 (13.0 g, 58.93 mmol) in DMSO (50 mL) was added drop wise over 10 min. The whole mixture was stirred further 0.5 h, TLC showed the reaction was completed. It was quenched by the addition of H20 (200 mL) and the mixture was extracted with EtOAc (200 mL*3). The combined extracts were dried over a2S04 and concentrated in vacuo to give the crude product. It was purified by column chromatography (Eluant: EtOAc/Pet.ether=l/5, v/v) to give the product 8 (10.0 g, 47% yield) as a white solid. [0308] 1H NMR (400 MHz, CDC13): 8.19 (s, 2H), 7.38-7.25 (m, 10H), 5.05 (s, 2H), 4.76-4.68 (m, 1H), 4.43 (s, 2H), 3.82-3.75 (m, 1H), 2.87-2.81 (m, 2H), 2.24-2.17 (m, Synthesis of 2-(3-hydroxycyclobutoxy)pyrimidin-5-ol [0309] To the mixture of 8 (8.84 g, 24.42 mmol) in dry DCM (250 mL) was added BC13 (100 mL, 1M in DCM, 0.1 mol) at -20 C under N2. The resulting mixture was stirred further 0.5 h at -20 C . TLC showed the reaction was completed, and then it was quenched by the addition of MeOH (20 mL). The solvent was removed in vacuo to give the crude product. It was diluted with DCM (50 ml) and the solid was filtered out by filtration. The cake was suspended in H20 (20 mL) and filtered, dried in vacuo to give the product (2.2 g, 50% yield) as a white solid. [0310] 1H NMR (400 MHz, DMSO-d6): 9.76 (s, 1H), 8.12 (s, 2H), 5.07 (br, 1H), 4.59-4.52 (m, 1H), 3.85-3.78 (m, 1H), 2.76-2.72 (m, 2H), 1.91-1.85 (m, 2H). LCMS [mobile phase: from 50% water (0.1% TFA) and 50% CH3CN to 5% water (0.1% TFA) and 95% CH3CN in 6.0 min, finally under these conditions for 0.5 min.] purity is >95%, Rt = 1.84 min; MS Calcd.: 182.2; MS Found: 183.1
At the same time, in my other blogs, there are other synthetic methods of this type of compound,100058-61-5, 3-(Benzyloxy)cyclobutanol, and friends who are interested can also refer to it.
Reference:
Patent; TRIUS THERAPEUTICS INC.; LAWRENCE LIVERMORE NATIONAL SECURITY, LLC; BENSEN, Daniel; BORCHARDT, Allen; CHEN, Zhiyong; FINN, John, M.; LAM, Thanh, To; LEE, Suk, Joong; LI, Xiaoming; TARI, Leslie, William; TENG, Min; TRZOSS, Michael; ZHANG, Junhu; JUNG, Michael, E.; LIGHTSTONE, Felice, C.; WONG, Sergio, E.; NGUYEN, Toan, B.; WO2014/43272; (2014); A1;,
Alcohol – Wikipedia,
Alcohols – Chemistry LibreTexts