Trifluoroacetic acid → 1-(6-azaspiro[3.4]oct-2-yl)-N-(1-methylcyclobutyl)piperidine-4-carboxamide trifluoroacetate

HRID 1777306Notes

Reaction equation

HRID 1777306 reaction equation
[CH3:1][C:2]1([NH:6][C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:18][C:17]4([CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)[CH2:16]3)[CH2:11][CH2:10]2)=[O:8])[CH2:5][CH2:4][CH2:3]1.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[CH2:18]1[C:17]2([CH2:22][CH2:21][NH:20][CH2:19]2)[CH2:16][CH:15]1[N:12]1[CH2:11][CH2:10][CH:9]([C:7]([NH:6][C:2]2([CH3:1])[CH2:5][CH2:4][CH2:3]2)=[O:8])[CH2:14][CH2:13]1

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 90089500Tert-butyl 2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

Product 1

HCID 900826771-(6-azaspiro[3.4]oct-2-yl)-N-(1-methylcyclobutyl)piperidine-4-carboxamide trifluoroacetate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

tert-Butyl 2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.747 g, 1.84 mmol) was dissolved in DCM (8 mL) and TFA (2 mL) was added. The reaction mixture was stirred at rt overnight under nitrogen, then the solvents were removed in vacuo, to give 1-(6-azaspiro[3.4]oct-2-yl)-N-(1-methylcyclobutyl)piperidine-4-carboxamide trifluoroacetate as a dark yellow oil which was used directly without further purification. The residue was dissolved in DCM (10 mL) and NEt3 (0.56 g, 0.77 mL, 5.52 mmol) and 4-nitrophenyl chloroformate (0.555 g, 2.76 mmol) were added and the reaction mixture was stirred at rt overnight under nitrogen. The solvents were removed in vacuo, and the residue was partitioned between DCM (15 mL) and 1 N NaOH sol. (15 mL). The aqueous layer was extracted with DCM (4×20 mL), dried over MgSO4 and the solvent evaporated. The residue was semi-purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 A, 25 mL per min, gradient 0% to 10% MeOH in DCM]) to give 4-nitrophenyl 2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.60 g, 69%) as a yellow gum as a mixture of diastereomers.

Workup

  1. customthe solvents were removed in vacuo

Sources & evidence

ORD record
ord-66e639b4cbe6454e978bc62ce8dac0e2
Source dataset
uspto-grants-2016_02
Patent number
US09266857B2

Reaction notes

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