Potassium Phosphate, Tribasic → HCID 24746279, compound

HRID 1173161Notes

Reaction equation

HRID 1173161 reaction equation
Br[C:2]1[CH:15]=[CH:14][C:5]2[CH:6]=[C:7]([C:9]([O:11]CC)=O)[S:8][C:4]=2[CH:3]=1.[CH2:16]1[C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:19][CH2:18][N:17]1C(OC(C)(C)C)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[NH2:41][C:42]1[CH:43]=[C:44]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:45]=[CH:46][C:47]=1[NH:48]C(=O)OC(C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.C(O)(C(F)(F)F)=O.C(Cl)Cl.CCOC(C)=O.O.C1COCC1>[NH2:48][C:47]1[CH:46]=[CH:45][C:44]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:43][C:42]=1[NH:41][C:9]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([N:23]3[CH2:22][CH2:21][C:20]4([CH2:16][NH:17][CH2:18][CH2:19]4)[CH2:25][CH2:24]3)[CH:15]=[CH:14][C:5]=2[CH:6]=1)=[O:11]

Participants

12

Reactant 6

HCID 62657Potassium Phosphate, TribasicHCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 13567982Ethyl 6-bromo-1-benzothiophene-2-carboxylateHCID 34178604tert-Butyl 2,8-diazaspiro[4.5]decane-2-carboxylateHCID 57717454N-(3-Amino[1,1'-biphenyl]-4-yl)-carbamic Acid tert-Butyl Ester

Product 1

HCID 24746279HCID 24746279, compound

Reagents, catalysts & solvents 5

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolventHCID 31374DimethylacetamideSolventHCID 21863450Trifluoroacetic acid methylene chlorideSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of ethyl 6-bromo-1-benzothiophene-2-carboxylate (250 mg, 0.88 mmol), tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (200 mg, 0.83 mmol), and K3PO4 (1.00 g, 4.72 mmol) in 2 mL of DMAc was deoxygenated by the freeze-pump-thaw method. The mixture was treated with Pd[P(tert-Bu)3]2 (130 mg, 0.250 mmol) and stirred at 90° C. overnight. The reaction mixture was partitioned between EtOAc and sat'd NaHCO3, the organic layer dried (Na2SO4), filtered and concentrated. The residue was dissolved in 1 mL of MeOH, 1 mL of THF and 1 mL of H2O, treated with LiOH monohydrate (100 mg, 2.40 mmol) and stirred for 12 h. The mixture was poured into EtOAc and washed with 2 N HCl, water, dried (Na2SO4), filtered and concentrated. The oily residue was dissolved in 2 mL of DM, treated with intermediate C (200 mg, 0.980 mmol), BOP (300 mg, 0.679 mmol), i-Pr2NEt (0.250 mL, 1.41 mmol) and stirred for 1 day at ambient temperature followed by 5 days at 60° C. The mixture was partitioned between EtOAc and sat'd NaHCO3, the organic layer was dried (Na2SO4) and concentrated. Chromatography on SiO2 (0 to 100% EtOAc/CH2Cl2) gave pure intermediate. The oil was stirred in 2 mL of 1:1 TFA/CH2Cl2 for 1 h and concentrated. The oil was dissolved in EtOAc, washed with sat'd NaHCO3, dried (Na2SO4) and concentrated, providing the title compound: MS (ESI+): cal'd [M+H]+ 483.2, obs'd 483.3.

Workup

  1. customwas deoxygenated by the freeze-pump-thaw method
  2. customThe reaction mixture was partitioned between EtOAc
  3. dry with materialthe organic layer dried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. dissolutionThe residue was dissolved in 1 mL of MeOH
  7. stirringstirred for 12 h
  8. washwashed with 2 N HCl, water
  9. dry with materialdried (Na2SO4)
  10. filtrationfiltered
  11. concentrationconcentrated
  12. dissolutionThe oily residue was dissolved in 2 mL of DM
  13. stirringstirred for 1 day at ambient temperature
  14. waitfollowed by 5 days at 60° C
  15. customThe mixture was partitioned between EtOAc
  16. dry with materialthe organic layer was dried (Na2SO4)
  17. concentrationconcentrated
  18. customChromatography on SiO2 (0 to 100% EtOAc/CH2Cl2) gave pure intermediate
  19. concentrationconcentrated
  20. dissolutionThe oil was dissolved in EtOAc
  21. washwashed with sat'd NaHCO3
  22. dry with materialdried (Na2SO4)
  23. concentrationconcentrated

Sources & evidence

ORD record
ord-ad2bfb6e1ced4c488b88f7705658b6d8
Source dataset
uspto-grants-2010_11
Patent number
US07834026B2

Reaction notes

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