1,4-dioxaspiro[4.5]decane-8-carbonitrile

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: U.S. Pat. No. 8,314,119 shows synthesis of (4s)-1-azaadamantan-4-ol HCl salt from a 7-step process of: (1) Reducing of 1,4-dioxaspiro[4.5]decan-8-one with TOSMIC giving 1,4-dioxaspiro[4.5]decane-8-carbonitrile; (2) Reducing resulting product with LAH giving 1,4-dioxaspiro[4.5]decan-8-ylmethanamine; (3) Cyclizing resulting product with a double-Mannich type condensation using paraformaldehyde and sulfuric acid to form azaadamantan-4-one; (4) Reducing ketone group of azaadamantan-4-one to an alcohol using NaBH4 in presence of borane-THF complex to form a diastereomeric mixture of 1-azaadamantan-4-ol N-borane complex; (5) Coupling resulting product with 4-chlorobenzoic acid; (6) Separating (4s) isomer by column chromatography (silica gel, using 3:1 hexanes-EtOAc), followed by removing 4-chlorobenzoic acid moiety with NaOH; and (7) Removing BH3 group with HCl giving (4s)-1-azaadamantan-4-ol HCl salt. U.S. Pat. No. 8,314,119 is incorporated herein by reference.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: U.S. Pat. No. 8,314,119, issued 20 Nov. 2012, shows synthesis of (4s)-1-azaadamantan-4-ol HCl salt from a 7-step process of: (1) Reducing 1,4-dioxaspiro[4.5]decan-8-one with TOSMIC to form 1,4-dioxaspiro[4.5]decane-8-carbonitrile; (2) Reducing resulting product with LAH to form 1,4-dioxaspiro[4.5]decan-8-ylmethanamine; (3) Cyclizing resulting product with a double-Mannich type condensation using paraformaldehyde and sulfuric acid to form azaadamantan-4-one; (4) Reducing the ketone group of azaadamantan-4-one to an alcohol using NaBH4 in presence of borane-THF complex to form a diastereomer mixture of 1-azaadamantan-4-ol N-borane complex; (5) Coupling resulting product with 4-chlorobenzoic acid; (6) Separating (4s) isomer by column chromatography (silica gel, using 3:1 hexanes-EtOAc), followed by removing 4-chlorobenzoic acid moiety with NaOH; and (7) Removing BH3 group with HCl giving (4s)-1-azaadamantan-4-ol HCl salt. Alternatively, the (4s)-isomer from Step (6) can be coupled with 2-chloro-5-phenyl-1,3,4-thiadiazole, giving (4s)-4-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[3.3.1.13,7]-decane N-borane complex. Removal of borane group affords the free base, which was crystallized as a dihydrogen citrate salt. Resulting ether-linked azaadamantane derivative is useful for treating diminished CNS function associated with traumatic brain injury or treating conditions such as arthritis or osteoarthritic pain.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1,4-Dioxa-spiro[4.5]decane-8-carbonitrile (2.0 grams, 12.8 mmole) and 2 N hydrochloric acid (21.0 grams, 42.0 mmole) in tetrahydrofuran (30 ml) at room temperature was stirred over night. The mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered, and concentrated to an oil which was purified via flash chromatography on silica using 10% ethyl acetate/hexane as eluent to give an oil (0.800 g). MW 123.15. washed with water and brine dried over MgSO4 filtered concentrated to an oil which was purified via flash chromatography on silica using 10% ethyl acetate/hexane as eluent

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1,4-Dioxa-spiro[4,5]decan-8-one (2.0 grams, 12.8 mmole) and tosyl-methyl isocyanate (5.0 grams, 25.6 mmole) in dimethylformamide (25 ml) at 0° C. was added 1.0 M tBuOK in tButanol (25.6 ml) and stirred at 0° C. for 1 hour and room temperature over night. The mixture was diluted with water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to a solid which was purified via flash chromatography on silica using 30% ethyl acetate/hexane as eluent to give a solid (1.45 g). MW 167.209; MS (m/e) 168 (M++1). extracted with diethyl ether The combined extracts were washed with water and brine dried over MgSO4 filtered concentrated to a solid which was purified via flash chromatography on silica using 30% ethyl acetate/hexane as eluent