Triethylamine → HCID 56846742, compound

HRID 2369368Notes

Reaction equation

HRID 2369368 reaction equation
[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.ON1C2C=CC=CC=2N=N1.[F:37][C:38]1([F:56])[CH:43]([NH2:44])[CH2:42][CH2:41][N:40]([CH2:45][CH2:46][CH2:47][O:48][C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=2)[CH2:39]1>CN(C)C=O>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:44][CH:43]2[CH2:42][CH2:41][N:40]([CH2:45][CH2:46][CH2:47][O:48][C:49]3[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=3)[CH2:39][C:38]2([F:56])[F:37])=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 10928Ethyl chloroformateHCID 757711-HydroxybenzotriazoleHCID 816264-Amino-5-chloro-2-methoxybenzoic acidHCID 66611481HCID 66611481, compound

Product 1

HCID 56846742HCID 56846742, compoundYield 71%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

In a dry 50 mL flask, 0.44 g (2.2 mmol; 1.1 equiv) of 4-amino-5-chloro-2-methoxybenzoic acid and 0.30 g (3 mmol; 1.5 equiv) of triethylamine were dissolved in 25 mL of dimethylformamide and stirred during 10 minutes at room temperature. Then the mixture was cooled to 0° C. and 0.24 g (2.2 mmol; 1.1 equiv) of ethyl chloroformate was added and stirred during 30 minutes at room temperature. Then 0.29 g (2.2 mmol; 1.1 equiv) of 1-hydroxybenzotriazole was added and stirred during 30 minutes at room temperature. Then 0.57 g of 3,3-difluoro-1-[3-(4-fluorophenoxy)propyl]piperidin-4-amine 16 was added and the mixture was stirred at room temperature during 15 hours. After evaporation of the solvent in vacuo, the crude oil was redissolved in EtOAc and poured in 50 mL of brine and extracted with EtOAc (4×50 mL). The organic phases were washed with brine and dried over MgSO4. After filtration of the solids and evaporation of the solvent under vacuum, the crude oil was purified via flash chromatography (hexane/EtOAc 3:7, Rf=0.35) yielding 0.66 g (1.4 mmol; 71% yield) of pure 4-amino-5-chloro-N-{3,3-difluoro-1-[3-(4-fluorophenoxy)propyl]piperidin-4-yl}-2-methoxybenzamide 17 as white crystals. M.p.=125.8° C. (hexane/EtOH 1:1). 1H NMR (CDCl3): δ 1.70 (1H, ddd, J=24.8 Hz, 12.7 Hz, 3.9 Hz, CHaHb); 1.93 (2H, quintet, J=6.6 Hz, CH2); 2.01-2.12 (1H, m, CHaHb); 2.21 (1H, t, J=11.8 Hz, NCHaHb); 2.34 (1H, ddd, J=28.8 Hz, 11.3 Hz, 1.7 Hz, NCHaHbCF2); 2.50-2.69 (2H, m, NCH2); 2.92 (1H, d, J=11.8 Hz, NCHaHb); 3.19 (1H, td, J=11.3 Hz, 4.4 Hz, NCHaHbCF2); 3.86 (3H, s, OCH3); 3.96 (2H, t, J=6.6 Hz, OCH2); 4.43 (3H, s(broad), NCH and NH2); 6.26 (1H, s, CHar); 6.81 (2H, dd, J=8.8 Hz, 4.4 Hz, 2×CHar); 6.94 (2H, t, J=8.8 Hz, 2×CHar); 8.03 (1H, s(broad), NH); 8.06 (1H, s, CHar). 19F NMR (CDCl3): δ −107.6 (1F, d, J=240.7 Hz, CFaFb); −116.9 (1F, d(broad), J=240.7 Hz, CFaFb); −124.0 (1F, tt, J=7.9 Hz, 4.0 Hz, CarF). 13C NMR (CDCl3): δ 26.8 (CH2, alkyl); 29.6 (d, J=5.8 Hz, CH2); 50.2 (t, J=19.6 Hz, NCH); 51.5 (NCH2); 53.9 (NCH2, alkyl); 56.2 (OCH3); 58.0 (dd, J=29.4 Hz, 23.7 Hz, NCH2CF2); 66.3 (OCH2); 97.8 (CHar); 111.6 (CarCO); 111.9 (CarCl); 115.4 (d, J=8.1 Hz, 2×CHar); 115.7 (d, J=23.1 Hz, 2×CHar); 118.9 (t, J=245.8 Hz, CF2); 133.1 (CHar); 147.1 (CarNH2); 155.0 (d, J=2.3 Hz, OCar); 157.2 (d, J=237.7 Hz, CarF); 157.6 (CarOMe); 164.4 (C═O). IR (ATR, cm−1): ν=3480; 3398; 3329; 3194; 2964; 2886; 2818; 1641; 1614; 1584; 1538; 1506; 1462; 1318; 1247; 1208; 1146; 1124; 1074; 1037; 982; 910; 822; 753; 681. MS (ES+) m/z (%): 472/474 (M+H+, 100).

Workup

  1. temperatureThen the mixture was cooled to 0° C.
  2. stirringstirred during 30 minutes at room temperature
  3. stirringstirred during 30 minutes at room temperature
  4. stirringthe mixture was stirred at room temperature during 15 hours
  5. customAfter evaporation of the solvent in vacuo
  6. dissolutionthe crude oil was redissolved in EtOAc
  7. additionpoured in 50 mL of brine
  8. extractionextracted with EtOAc (4×50 mL)
  9. washThe organic phases were washed with brine
  10. dry with materialdried over MgSO4
  11. filtrationAfter filtration of the solids and evaporation of the solvent under vacuum
  12. customthe crude oil was purified via flash chromatography (hexane/EtOAc 3:7, Rf=0.35)

Sources & evidence

ORD record
ord-16b2d7f2776b4bfc91a0fed94c3ea454
Source dataset
uspto-grants-2014_04
Patent number
US08703958B2

Reaction notes

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