Step A: Synthesis of 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)butanoic acid
1. tetraethyl-4-phosphonic acid crotonate (7.2 g, 28.8 mmol) was dissolved in 50 mL of anhydrous toluene and cooled to 0°C under nitrogen protection.
2. Potassium hexamethyldisilaminate (48 mL, 28.8 mmol, 0.5 M solution in toluene) was added slowly via syringe and stirred for 30 minutes.
3. Solid 1-tert-butoxycarbonyl-4-piperidone was added and the reaction mixture was gradually warmed to room temperature with continued stirring for 16 hours.
4. Upon completion of the reaction, the mixture was diluted with 300 mL of ethyl acetate, washed sequentially with saturated sodium chloride solution and dried over anhydrous sodium sulfate.
5. The solvent was removed by pressure-relief concentration and purified by fast column chromatography (150 g silica, 4/1 hexane/ethyl acetate) to give 327 mg (5% yield) of product as a mixture of isomers.
Step B: Synthesis of N-Boc-4-piperidine butyric acid
1. the isomeric mixture obtained above (327 mg, 1.1 mmol) was dissolved with 10% palladium carbon (200 mg, 0.22 mmol) in 10 mL of methanol.
2. The reaction mixture was stirred using a hydrogen balloon for 2 hours under a 1 atm hydrogen atmosphere.
3. Upon completion of the reaction, the catalyst was removed by diatomaceous earth filtration and the filtrate was concentrated.
4. The residue was dissolved in 8 mL of mixed 1/1 tetrahydrofuran/water solvent, lithium hydroxide (96 mg, 4.4 mmol) was added and stirred overnight.
5. 50 ml of ethyl acetate and 50 ml of 1 M hydrochloric acid were added to separate the organic and aqueous layers.
6. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 291 mg (98% yield) of N-Boc-4-piperidine butyric acid.
