tert-butyl 4-(benzyloxycarbonylamino)-4-carbamoylpiperidine-1-carboxylate synthesis

Yield:288154-17-6 70%

Reaction Conditions:

Stage #1: 4-(Benzyloxycarbonylamino)-1-(tert-butoxycarbonyl)-piperidine-4-carboxylic Acidwith 4-methyl-morpholine;isobutyl chloroformate in 1,2-dimethoxyethane at -15;
Stage #2: with ammonia in 1,2-dimethoxyethane at 20;

Steps:

1

A solution 4-(benzyloxycarbonylamino)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1A, 2.0 g, 1.0 equivalent) in DME (0.5 M) was treated with NMM (1.0 equivalent) and IBCF (1.0 equivalent) at -15° C. After 10 min, aqueous ammonia (1.5 equivalents) was added. The reaction mixture was stirred at room temperature for 1.5 hr. The reaction was complete as determined by LCMS analysis and then partitioned between ethyl acetate and water. The organics were subsequently washed with brine, then dried over Na₂SO₄, filter, and the volatiles removed under reduced pressure. The residue was purified by crystallization from diethyl ether to afford the tert-butyl 4-(benzyloxycarbonylamino)-4-carbamoylpiperidine-1-carboxylate (1B, 70%).1B (1.0 equivalent) and a catalytic amount of acetic acid in MeOH (0.05M) was passed through H-cube hydrogenator equipped with Pd/C cartridge at 50° C. The methanol in the reaction mixture was then removed under reduced pressure, and the product was washed with cold ether twice to afford the tert-butyl 4-amino-4-carbamoylpiperidine-1-carboxylate (1C, 90%).1C (0.3M) was added 2-chloro-1,1,1-trimethoxyethane (4.0 equivalents) and acetic acid (2.0 equivalents). The mixture was stirred for 12 hr at 118° C. Solvent was removed under reduced pressure and the residue was purified by crystallization from cold diethyl ether to afford tert-butyl 2-(chloromethyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (1D, 67%).1D in a seal tube was added 2.0 M ammonia in 2-propanol (0.04M). Excess ammonia gas was bubbled in and the mixture was heated at 60° C. for 12 hr. The reaction was complete as determined by LCMS analysis. After removal of solvent; the residue tert-butyl 2-(aminomethyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (1E) was used without further purification. ESI-MS: m/z 283.1 (M+H)⁺.For deprotection, 1E (1.0 equivalent) was dissolved in CH₂Cl₂ at 0° C., and slowly treated with a 1.6:1 solution of CH₂Cl₂/TFA (2:1 final ratio, 0.15 M). The reaction was completed in 30 minutes at 0° C. as determined by LCMS analysis. The volatiles were removed under reduced pressure to yield the respective 2-(aminomethyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (1G) as TFA salts which were used without further purification. ESI-MS: m/z 183.1 (M+H)⁺.

References:

US2009/253725,2009,A1 Location in patent:Page/Page column 51