Preparation method of spiro[2.5]oct-6-yl-methanol_Industrial additives

Background and overview^[1]

Spiro[2.5]oct-6-yl-methanol can be used as a pharmaceutical synthesis intermediate. If spiro[2.5]oct-6-yl-methanol is inhaled, move the patient to fresh air; if skin contact occurs, take off contaminated clothing, rinse the skin thoroughly with soap and water, and seek medical attention if you feel unwell; If eye contact occurs, separate eyelids, rinse with running water or saline, and seek medical attention immediately; if ingested, rinse mouth immediately, do not induce vomiting, and seek medical attention immediately.

Preparation^[1]

Spiro[2.5]oct-6-yl-methanol is prepared as follows:

1) Spiro[2.5]octane-6-carboxylic acid ethyl ester (I-7A). To a solution of diethylzinc (35 mL, 1 M in hexanes) in DCM (30 mL) cooled to 0° C., a solution of TFA (2.7 mL, 35.0 mmol) in DCM (12 mL) was added dropwise. After the reaction mixture was stirred at 0°C for 1 h, a solution of CH2I2 (2.8 mL, 35.0 mmol) in DCM (12 mL) was slowly added, and the mixture was stirred for another 40 min. Then, a solution of ethyl 4-methylenecyclohexanecarboxylate (2.36 g, 14.0 mmol) in DCM (5 mL) was added dropwise to the flask, and the reaction mixture was stirred for another 2 h. The reaction mixture was then diluted with DCM and washed with saturated aqueous NH4Cl solution. The organic layer was collected, washed with brine, dried over sodium sulfate, filtered, and concentrated to give an oily residue, which was passed through a short silica gel column to obtain ethyl spiro[2.5]octane-6-carboxylate. 1HNMR (MHz, CDCl3) δ4.13 (q, J=7.2Hz, 2H), 2.31 (m, 1H), 1.90-1.86 (m, 2H), 1.67-1.61 (m, 4H), 1.24 (t, H =7.2Hz, 3H), 0.95-0.95(m, 2H), 0.29-0.18(m, 4H). MSm/z183(M+1).

2) Spiro[2.5]oct-6-ylmethanol (I-7B). To a solution of ethyl spiro[2.5]oct-6-ylcarboxylate (18.5 mmol) in anhydrous THF (27 mL) cooled to 0° C., lithium aluminum hydride (24 mL, 1 M in THF) was added dropwise. After stirring at room temperature for 14 h, the reaction mixture was cooled to 0°C, then quenched by dropwise addition of H2O (1.6 mL), 15% NaOH (1.6 mL), H2O (2.4 mL) and Na2SO4, and vacuum filtered to obtain spiro[2.5 ] Oct-6-ylmethanol, which can be used directly without purification. 1HNMR (MHz, DMSO) δ4.38 (t, J=5.2Hz, 1H), 3.23 (dd, J=6.4 and 5.2Hz, 2H), 1.69-1.59 (m, 4H), 1.35-1.32 (m, 1H ), 1.06-1.05(m, 2H), 0.87-0.84(m, 2H), 0.25-0.22(m, 2H), 0.13-0.11(m, 2H). MSm/z141(M+1).

Main reference materials

[1] CN201180067346.8 Compositions and methods for modulating FXR