Ammonia → 1-amino-3-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentanecarbonitrile

A mixture of 3-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentanone (I-8E, 5.96 g, 19.97 mmol), ammonium chloride (5.34 g, 100 mmol), sodium cyanide (4.89 g, 100 mmol), 7 M methanol solution of ammonia (28.5 ml, 200 mmol), and dichloromethane (15 mL) was stirred at room temperature for 1 day. Additional 7 M methanol solution of ammonia (15 mL) was added. The mixture was stirred at room temperature for 1 day and then concentrated. The residue was partitioned between ethyl acetate (70 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was separated and extracted with ethyl acetate (3×50 mL). The combined ethyl acetate solutions were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-amino-3-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentanecarbonitrile as a semi-solid. The semi-solid material was mixed with a mixture of concentrated hydrochloric acid (56 ml, 1843 mmol), water (28 ml, 1554 mmol), acetic acid (35 ml), and dioxane (35 ml). The mixture was stirred at 100° C. under nitrogen for 10 h and then concentrated to give a solid. The solid was dissolved in methanol (20 mL) and mixed with toluene (20 mL). The mixture was concentrated to dryness. This drying procedure was repeated one more time to give a dry solid. The solid was dissolved in anhydrous methanol (300 mL). Thionyl chloride (11.66 mL, 160 mmol) was added dropwise at 0° C. under nitrogen. The reaction mixture was stirred at 70° C. for 7 h before being concentrated. The residue was made basic with saturated aqueous sodium bicarbonate solution (100 mL) and some potassium carbonate solid and extracted with ethyl acetate (100 mL, 3×30 mL). The combined ethyl acetate extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Flash chromatography purification (80 g silica gel column, gradient elution from 20 to 100% ethyl acetate in hexanes) afforded methyl 1-amino-3-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentanecarboxylate (5.7 g, 15.94 mmol) as a liquid. LC/MS M+1=358.

1. stirringThe mixture was stirred at room temperature for 1 day
2. concentrationconcentrated
3. customThe residue was partitioned between ethyl acetate (70 mL) and saturated aqueous sodium bicarbonate solution (100 mL)
4. customThe aqueous layer was separated
5. extractionextracted with ethyl acetate (3×50 mL)
6. dry with materialThe combined ethyl acetate solutions were dried over anhydrous sodium sulfate
7. concentrationconcentrated under reduced pressure

ORD record

ord-012fab5f18db4c16b8511cd498cd0dc2

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09115054B2