Tosylmethyl isocyanide → 1,4-Dioxaspiro[4.5]decane-8-carbonitrile
Reaction equation
Cl.[N:2]12C[CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[OH:12])C1)[CH2:9]2.[O:13]1C2(CCC(=O)CC2)O[CH2:15][CH2:14]1.CC1C=CC(S(C[N+]#[C-])(=O)=O)=CC=1>>[O:12]1[C:5]2([CH2:4][CH2:10][CH:8]([C:9]#[N:2])[CH2:7][CH2:6]2)[O:13][CH2:14][CH2:15]1Participants
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 crystalized 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.
Sources & evidence
- ORD record
- ord-7af09fc8b97a4d80815b627902052b61
- Source dataset
- uspto-grants-2016_06
- Patent number
- US09359356B2
Reaction notes
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