Cyclopropylamine → HCID 178516968, compound

HRID 707320Notes

Reaction equation

HRID 707320 reaction equation
[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([NH:15][C:16]2[C:21](Br)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:12]1.C[C:24](C)([O-:26])C.[Na+].[CH:29]1([NH2:32])[CH2:31][CH2:30]1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(OCC)(=O)C.O1CCCC1.ClCCl.[Pd+2].O.C(N(CC)CC)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([N:15]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:21]3[N:32]([CH:29]3[CH2:31][CH2:30]3)[C:24]2=[O:26])[CH2:12]1

Participants

11

Reactant 4

HCID 69828CyclopropylamineHCID 94429TriphosgeneHCID 23676156Sodium t-butoxideHCID 178419395HCID 178419395, compound2×

Product 1

HCID 178516968HCID 178516968, compoundYield 13.4%

Reagents, catalysts & solvents 6

HCID 105144Allyl(1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)chloropalladium(II)CatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×HCID 8471TriethylamineSolventHCID 8857Ethyl AcetateSolvent

Procedure

Trans-N1-(benzo[d]thiazol-2-yl)-N3-(3-bromopyridin-2-yl)cyclobutane-1,3-diamine (intermediate 33, 0.362 g, 0.965 mmol), sodium tert-butoxide (0.232 g, 2.411 mmol), and chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2′-4′-6′-tri-1-1,1′-biphenyl)]2-(2-aminoethyl)phenyl)palladium(ii) (0.058 g, 0.072 mmol) were placed in a microwave vessel under argon. Dry, sparged dioxane (1.5 mL) was added followed by cyclopropylamine (0.170 ml, 2.424 mmol). The mixture was sealed under argon and stirred at room temperature for 15 minutes then heated in a 90° C. oil bath for 30 minutes. The reaction was cooled and opened. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with water (10 mL). The organic phase was dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude was further dried under high vacuum to give a solid foam. It was dissolved in dry tetrahydrofuran (10 mL) and added to an ice cooled solution of triphosgene (0.112 g) in dry tetrahydrofuran (10 mL) and dichloromethane (10 mL). Triethylamine (6 mL) was added and the reaction stirred for 20 minutes. Water (50 mL) was added and the reaction stirred for 10 minutes. The phases were separated and the organic dried with magnesium sulfate before evaporating to dryness under reduced pressure. The crude product was purified using silica chromatography (20-100% ethyl acetate in hexane gradient) followed by reverse phase HPLC to give 3-(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-1-cyclopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (48.8 mg, 0.129 mmol, 13.40% yield). M+1: 378. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95-1.07 (m, 2 H) 1.07-1.20 (m, 2 H) 2.43-2.63 (m, 2 H) 2.83-3.02 (m, 1 H) 3.45-3.66 (m, 2 H) 4.50-4.72 (m, 1 H) 5.37 (quin, J=8.36 Hz, 1 H) 6.08 (br. s., 1 H) 7.01 (dd, J=7.43, 5.48 Hz, 1 H) 7.08 (t, J=7.53 Hz, 1 H) 7.23-7.32 (m, 1 H) 7.36 (d, J=7.63 Hz, 1 H) 7.59 (dd, J=10.86, 8.31 Hz, 2 H) 8.05 (d, J=4.89 Hz, 1 H).

Workup

  1. customDry
  2. customsparged dioxane (1.5 mL)
  3. additionwas added
  4. customThe mixture was sealed under argon
  5. temperaturethen heated in a 90° C. oil bath for 30 minutes
  6. temperatureThe reaction was cooled
  7. washwashed with water (10 mL)
  8. dry with materialThe organic phase was dried with magnesium sulfate
  9. customevaporated to dryness under reduced pressure
  10. customThe crude was further dried under high vacuum
  11. customto give a solid foam
  12. stirringthe reaction stirred for 20 minutes
  13. stirringthe reaction stirred for 10 minutes
  14. customThe phases were separated
  15. dry with materialthe organic dried with magnesium sulfate
  16. custombefore evaporating to dryness under reduced pressure
  17. customThe crude product was purified

Sources & evidence

ORD record
ord-a0f7fbcd5f984781b22173a87183c1d5
Source dataset
uspto-grants-2015_11
Patent number
US09174992B2

Reaction notes

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