Background and overview[1]
(R)-2-(9-(pyridin-2-yl)-6-dioxaspiro[4.5]decan-9-yl)acetonitrile is a pharmaceutical intermediate that can be synthesized from but-3-ene -l-alcohol and cyclopentanone are used as starting materials and are prepared through a six-step reaction.
Preparation[1]
Preparation of 1,6-oxaspiro[4.5]dec-9-ol (C)
To a solution of but-3-en-l-ol (100 g, 1.38 mol) was added cyclopentanone (232 g, 2.77 mol) in dichloromethane (DCM) (1,200 mL). The well-stirred suspension was cooled to 0°C and a solution of trifluoroacetic acid (TFA) (1,000 mL) was added over 60 min. The solution was stirred at room temperature for 12 hours. The reactant solution was concentrated. The residue was dissolved in MeOH (2,000 mL), Na2CO3 (300 g) was added thereto, and stirred at room temperature for 2 hours, filtered and concentrated. The crude product was extracted with CH2Cl2 (2 x 500 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give compound 6-oxaspiro[4.5]dec-9-ol (20 g, crude).
Preparation of 2, 6-oxaspiro[4.5]dec-9-one (2)
To a solution of 6-oxaspiro[4.5]dec-9-ol (20 g, crude) was added PCC (20 g) and silica gel (20 g) in THF (200 mL). The solution was stirred at room temperature for 12 hours. The reactant solution was concentrated. The crude product was purified via flash chromatography (SiO2; 20:1 hexane:EtOAc) to afford 6-oxaspiro[4.5]dec-9-one (10 g, 4.7%) as a colorless clear liquid Yield, 2 steps, confirmed by 1HNMR).
3. Preparation of methyl 2-cyano-2-(6-oxaspiro[4.51dec-9-ylidene]acetate (3)
To a solution of 6-oxaspiro[4.5]dec-9-one (10 g, 64.8 mmol) was added methyl 2-cyanoacetate (9.6 g, 97.2 mmol) in toluene (100 mL), AcOH ( 0.8g, 14mmol) and NH4OAc (1.2g, 16.2mmol). The solution was stirred at reflux for 4 hours until no more water was collected in the Dean-stark. The reaction mixture was slowly quenched with water (100 mL) and the mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified via flash chromatography (SiO2; 20:1 hexanes:EtOAc) to afford 2-cyano-2-(6-oxaspiro[4.5]dec-9-ylidene as a colorless clear liquid ) Methyl acetate (8g, 55% yield, confirmed by 1H NMR).
4. Preparation of methyl 2-cyano-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)acetate (4)
A solution of 2-bromopyridine (5.3 g, 34.1 mmol) was added to anhydrous THF (50 mL). The well-stirred suspension was cooled to 0°C and a solution of (1-methylethyl)magnesium chloride (17 mL, 34.1 mmol) was added over 0.5 h. The solution was stirred at room temperature for 4 hours. CuI (2g, 3.41mmol) was added thereto, and stirred at room temperature for 0.5 hours. To this was added methyl 2-cyano-2-(6-oxaspiro[4.5]dec-9-ylidene)acetate (8 g, 34.1 mmol) in anhydrous THF (50 mL). The resulting mixture was stirred at room temperature for 16 hours and poured into 100 g of ice and 2N HCl (50 mL). The aqueous layer was then extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified via flash chromatography (SiO2; 5:1 Hexanes:EtOAc) to afford 2-cyano-2-(9-(pyridin-2-yl)-6-oxa as a colorless clear liquid Spiro[4.5]dec-9-yl)acetic acid methyl ester (4 g, 38% yield, confirmed by 1H NMR).
Preparation of 5.2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)acetonitrile (5)
To a solution of methyl 2-cyano-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)acetate (4 g, 12.7 mmol) in ethanol was added KOH (1.4 g, 25.4 mmol) in glycol (50 mL). The solution was stirred at 120°C for 4 hours. The reaction mixture was slowly quenched with water (100 mL) and the mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified via flash chromatography (SiO2; 4:1 Hexane:EtOAc) to afford 2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9 as a white solid -base) acetonitrile (3g, 90% yield, confirmed by 1H NMR).
6. Preparation of (R)-2-(9-(pyridin-2-yl)-6-dioxaspiro[4.5]decan-9-yl)acetonitrile (6)
The solution of 2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)acetonitrile (6.5g) was purified by chiral separation to obtain a white solid (R)-2-(9-(pyridin-2-yl)-6-dioxaspiro[4.5]decan-9-yl)acetonitrile (3 g, 45% yield, confirmed by 1H NMR).
References
[1] [Invented in China] CN201780041032.8 Deuterated compounds for the treatment of pain
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