Hydrochloric Acid → tert-butyl (1S,2R)-2-(5-bromo-6-cyanopyridin-3-ylamino)cyclohexylcarbamate

HRID 1504752Notes

Reaction equation

HRID 1504752 reaction equation
[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C.[Br:25][C:26]1[C:27]([C:33]#[N:34])=[N:28][CH:29]=[C:30](F)[CH:31]=1.Cl>CN1C(=O)CCC1.ClCCl>[Br:25][C:26]1[CH:31]=[C:30]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:29]=[N:28][C:27]=1[C:33]#[N:34]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 1514389(1S,2R)-Cyclohexane-1,2-diamine, N1-BOC protected2×HCID 469414773-Bromo-5-fluoropicolinonitrile

Product 1

HCID 86716545tert-butyl (1S,2R)-2-(5-bromo-6-cyanopyridin-3-ylamino)cyclohexylcarbamate

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
120 °C

Procedure

This example describes the procedure for conversion of (A1) to (A3) as shown in Scheme 1. Tert-butyl [(1S,2R)-2-aminocyclohexyl]carbamate was purchased from Small Molecules, Inc. (CAS: 365996-30-1, Hoboken, N.J.). DIPEA (18.5 mL, 106 mmol) and tert-butyl [(1S,2R)-2-aminocyclohexyl]carbamate (17.7 g, 82.7 mmol) were added to 3-bromo-5-fluoropyridine-2-carbonitrile (Frontier Scientific; CAS: 950670-18-5, Logan, Utah) (16.4 g, 81.6 mmol) dissolved in NMP (16.3 mL) in a 150 mL sealed tube. The reaction was heated to 120° C. for 24 hours before cooling to ambient temperature. Hydrochloric acid (1.0 M in water, 100 mL, 100 mmol) was added. Dichloromethane was then added dropwise until a freely stirring suspension was formed. The precipitate was collected by filtration, washed with cold diethyl ether (30 mL), and dried under reduced pressure to afford a portion of tert-butyl {(1S,2R)-2-[(5-bromo-6-cyanopyridin-3-yl)-amino]cyclohexyl}carbamate. The mother liquors were separated and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether and water to yield an additional portion of tert-butyl {(1S,2R)-2-[(5-bromo-6-cyanopyridin-3-yl)amino]cyclohexyl}carbamate. MS ESI calc'd. for C17H24BrN4O2 [M+H]+ 395 and 397. found 395 and 397. 1H NMR (500 MHz, CD3OD) δ 8.02 (d, J=2.3 Hz, 1H), 7.23 (br s, 1H), 6.59-6.46 (m, 1H), 3.83 (s, 1H), 1.65 (s, 6H), 1.56-1.17 (m, 11H).

Workup

  1. customsealed tube
  2. temperaturebefore cooling to ambient temperature
  3. customwas formed
  4. filtrationThe precipitate was collected by filtration
  5. washwashed with cold diethyl ether (30 mL)
  6. customdried under reduced pressure

Sources & evidence

ORD record
ord-a4633489cf72461e8f6e62eb3b9274e7
Source dataset
uspto-grants-2015_12
Patent number
US09216173B2

Reaction notes

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