(1-aminocyclohexyl)methanol

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:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Amino-1-cyclohexanecarboxylic acid(51.5 g, Aldrich) was added to 150 ml of THF followed by boron trifluoride etherate(27 ml, Aldrich). The reaction mixture was heated to 40° C., stirred for 10 minutes and then a 1.0M solution of diborane(380 ml, Aldrich) was added. The mixture was refluxed for 2 hr, cooled and added THF/water (1:1,25 ml) followed by 6N NaOH(95 ml). The reaction mixture was refluxed for 2 hr, cooled to room temperature and the organic layer was separated, washed with brine, dried and concentrated to give a light yellow oil (34.0 g). 1H NMR consistent with the proposed structure. The mixture was refluxed for 2 hr cooled The reaction mixture was refluxed for 2 hr cooled to room temperature the organic layer was separated washed with brine dried concentrated

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

Procedure: 1-Amninocyclohexane-1-carboxylic acid was protected as the benzyloxycarbonylamine according to Method B1a, Step 1. 1-(Benzyloxycarbonylamino)cyclohexane-1-carboxylic acid was reduced to 1-(benzyloxycarbonylamino)-1-(hydroxymethyl)cyclohexane according to Method B1a, Step 2. The carbamate was deprotected according to Method B1a, Step 3 to give 1-amino-1-(hydroxymethyl)cyclohexane. The 2-hydroxyethylamine was sequentially treated with SOCl2 and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.5]decane. The thiazolidine was alkylated with isobutyl bromide according to Method D2b to afford 2-(2-methyl-4-nitrophenylimino)-1-isobutyl-3-thia-1-azaspiro[4.5]decane.

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

Procedure: 1-Amninocyclohexane-1-carboxylic acid was protected as the benzyloxycarbonylamine according to Method B1a, Step 1. 1-(Benzyloxycarbonylamino)cyclohexane-1-carboxylic acid was reduced to 1-(benzyloxycarbonylamino)-1-(hydroxymethyl)cyclohexane according to Method B1a, Step 2. The carbamate was deprotected according to Method B1a, Step 3 to give 1-amino-1-(hydroxymethyl)cyclohexane. The 2-hydroxyethylamine was sequentially treated with SOCl2 and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.5]decane. The thiazolidine was alkylated with isobutyl bromide according to Method D2b to afford 2-(2-methyl-4-nitrophenylimino)-1-isobutyl-3-thia-1-azaspiro[4.5]decane.

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

Procedure: 1-Amninocyclohexane-1-carboxylic acid was protected as the benzyloxycarbonylamine according to Method B1a, Step 1. 1-(Benzyloxycarbonylamino)cyclohexane-1-carboxylic acid was reduced to 1-(benzyloxycarbonylamino)-1-(hydroxymethyl)cyclohexane according to Method B1a, Step 2. The carbamate was deprotected according to Method B1a, Step 3 to give 1-amino-1-(hydroxymethyl)cyclohexane. The 2-hydroxyethylamine was sequentially treated with SOCl2 and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.5]decane. The thiazolidine was alkylated with isobutyl bromide according to Method D2b to afford 2-(2-methyl-4-nitrophenylimino)-1-isobutyl-3-thia-1-azaspiro[4.5]decane.

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

Procedure: 1-Amino-1-(hydroxymethyl)cyclohexane (Method B1a) was dissolved in p-dioxane (80 mL) then treated with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.5]decane (20%), which was reacted with isobutyl bromide in a manner analogous to Method D2a to yield 1-isobutyl-2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.5]decane (0.026 g, 2%): TLC (20% EtOAc/hex) Rf0.69.

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

Procedure: 1-Amino-1-(hydroxymethyl)cyclohexane (Method B1a) was dissolved in p-dioxane (80 mL) then treated with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.5]decane (20%), which was reacted with isobutyl bromide in a manner analogous to Method D2a to yield 1-isobutyl-2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.5]decane (0.026 g, 2%): TLC (20% EtOAc/hex) Rf0.69.

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

Procedure: A slurry of 1-(benzyloxycarbonylamino)-1-(hydroxymethyl)cyclohexane (4.0 g, 15 mmol) and 10% Pd/C (0.40 g) in MeOH (75 ml) was stirred under H2 (1 atm.) for 1 h, then treated with Celite®. The resulting mixture was filtered and concentrated under reduced pressure to give 1-amino-1-(hydroxymethyl)cyclohexane. treated with Celite® The resulting mixture was filtered concentrated under reduced pressure

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

Procedure: A slurry of 1-(benzyloxycarbonylamino)-1-(hydroxymethyl)cyclohexane (4.0 g, 15 mmol) and 10% Pd/C (0.40 g) in MeOH (75 ml) was stirred under H2 (1 atm.) for 1 h, then treated with Celite®. The resulting mixture was filtered and concentrated under reduced pressure to give 1-amino-1-(hydroxymethyl)cyclohexane. treated with Celite® The resulting mixture was filtered concentrated under reduced pressure

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

Procedure: Triethylamine (2.2 ml, 16.12 mmol, 2 eq), hydroxybenzotriazole hydrate (0.217 g, 1.61 mmol, 0.2 eq), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.7 g, 8.87 mmol, 1.1 eq) are added to a cold (ice bath) solution of 6-chloronicotinic acid (1.27 g, 8.06 mmol, 1 eq) and (1-aminocyclohexyl)methanol (1.04 g, 8.06 mmol, 1 eq) in dichloromethane (80 ml), stirred 30 min at 0° C. and then at room temperature for 1 h. The organic layer is then washed with water, with a saturated solution of aqueous sodium hydrogenocarbonate and dried over magnesium sulfate. The solvent is finally removed to give 2.46 g of a yellow oil. at room temperature for 1 h The organic layer is then washed with water, with a saturated solution of aqueous sodium hydrogenocarbonate dried over magnesium sulfate The solvent is finally removed