Hydrochloric Acid → HCID 89908081, compound

HRID 525774Notes

Reaction equation

HRID 525774 reaction equation
Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.C([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34])C.CCN(C(C)C)C(C)C.[NH4+].[Cl-].O[Li].O.Cl>C1COCC1.CC(O)C>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]([C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([NH:34][CH2:33][CH2:32][C:31]([OH:35])=[O:30])=[N:3][CH:4]=2)=[O:7])=[CH:10][CH:11]=1

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 25517Ammonium ChlorideHCID 81531DiisopropylethylamineHCID 168937Lithium hydroxide, monohydrateHCID 458475beta-Alanine, ethyl ester, hydrochlorideHCID 722015896-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide

Product 1

HCID 89908081HCID 89908081, compound

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1, 100 mg, 0.248 mmol), β-Alanine ethyl ester hydrochloride (267 mg, 1.736 mmol), DIPEA (0.433 mL, 2.480 mmol) and iPrOH (3 mL) were added to a vial, which was sealed and the RM was stirred at 110° C. for 44 h. The RM was treated with saturated aq. NH4Cl and extracted with EtOAc. The combined extracts were washed with sat. aq. Na2CO3 (20 mL) and brine (10 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 10). Fractions containing product were combined, treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure to give an aq. residue which was extracted with DCM and EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The resulting ester was dissolved in MeOH (0.5 mL) and THF (1 mL), treated with LiOH.H2O (0.548 mL, 0.548 mmol) and stirred for at RT for 90 min. The RM was acidified with aq. 1 M HCl (4 eq.) and the organic solvents were evaporated off under reduced pressure. The product was filtered off, washed with water and n-hexane and dried to give the title product as a white crystalline solid. HPLC (Condition 7) tR=6.08 min, UPLC-MS (Condition 8) tR=0.98 min, m/z=452 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.62 (t, J=6.45 Hz, 2H) 3.79 (q, J=6.26 Hz, 2H) 6.95 (s, 1H) 7.35 (d, J=8.99 Hz, 2H) 7.85-7.95 (m, J=9.38 Hz, 3H) 8.41 (d, J=1.95 Hz, 1H) 8.67 (d, J=2.35 Hz, 1H) 8.86-9.06 (m, 1H) 10.22 (s, 1H) 12.23 (br. s, 1H) 13.18 (br. s, 1H).

Workup

  1. additionwere added to a vial, which
  2. customwas sealed
  3. extractionextracted with EtOAc
  4. washThe combined extracts were washed with sat. aq. Na2CO3 (20 mL) and brine (10 mL)
  5. dry with materialdried over Na2SO4
  6. customthe solvent was evaporated off under reduced pressure
  7. customto give a residue which
  8. customwas purified by preparative HPLC (Condition 10)
  9. additionFractions containing product
  10. additiontreated with sat. aq. Na2CO3
  11. customthe MeCN was evaporated off under reduced pressure
  12. customto give an aq. residue which
  13. extractionwas extracted with DCM and EtOAc
  14. dry with materialThe combined extracts were dried over Na2SO4
  15. customthe solvent was evaporated off under reduced pressure
  16. dissolutionThe resulting ester was dissolved in MeOH (0.5 mL)
  17. stirringstirred for at RT for 90 min
  18. customthe organic solvents were evaporated off under reduced pressure
  19. filtrationThe product was filtered off
  20. washwashed with water and n-hexane
  21. customdried

Sources & evidence

ORD record
ord-5530bbe259f94489978cd0c2e38488f8
Source dataset
uspto-grants-2016_05
Patent number
US09340537B2

Reaction notes

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