Triethylamine → HCID 66634944, compound

HRID 2280387Notes

Reaction equation

HRID 2280387 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.OC1C2N=NNC=2C=CC=1.[NH2:37][C@@H:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][C@H:39]1[F:51]>CN(C=O)C.[Cl-].[Na+].O>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:37][C@@H:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])[CH2:40][C@H:39]2[F:51])=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 10928Ethyl chloroformateHCID 816264-Amino-5-chloro-2-methoxybenzoic acidHCID 45489895rac-tert-butyl (3R,4R)-4-amino-3-fluoropiperidine-1-carboxylateHCID 178418300HCID 178418300, compound

Product 1

HCID 66634944HCID 66634944, compoundYield 93%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent3×HCID 57417360Sodium chloride; waterSolvent

Procedure

To a solution of 0.41 g (2.02 mmol) of 4-amino-5-chloro-2-methoxybenzoic acid in 10 mL of dry DMF was added 0.29 g (2.89 mmol) of triethylamine at room temperature under N2-atmosphere. After stirring for 10 min at rt, a solution of 0.22 g (2.02 mmol) of ethyl chloroformate in 2 mL of DMF was added dropwise at rt and stirring was continued for 30 min, while the temperature was maintained at rt (cooling with waterbath at rt). Then 0.27 g (2.02 mmol) of hydroxybenzotriazole was added as a solid in one portion at rt and the solution was stirred for 30 min. Subsequently, a solution of 0.42 g (1.93 mmol) of amine 5 in 3 mL of DMF was added dropwise at rt and the reaction mixture was stirred overnight at rt. Afterwards, the mixture was poured in 20 mL of brine and extracted with EtOAc (3×25 mL). The combined organic fraction was washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The crude mixture was subjected to flash silicagel chromatography (hex/EtOAc/Et3N 1:1:0.1) to yield 0.72 g (93%) of pure trans-tert-butyl 4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-fluoropiperidine-1-carboxylate 6 as a solid. 1H NMR (CDCl3): δ 1.47 (9H, s); 2.17-2.28 (1H, m); 2.96-3.19 (2H, m); 3.74 (1H, dm, J=13.7 Hz); 3.90 (3H, s); 3.92-4.40 (3H, m); 4.45 (1H, ddt, J=4.4 Hz, 8.3 Hz, J=48.4 Hz); 6.30 (1H, s); 7.82 (1H, d, J=7.2 Hz); 8.08 (1H, s). 19F NMR (CDCl3): δ −189.0 (d, J=44.7 Hz). 13C NMR (CDCl3): δ 28.4 (3×), 29.1 (br), 41.5 (br), 45.6 (br), 50.1 (br), 56.4, 80.4, 88.2 (d, J=182.3 Hz), 97.9, 111.8, 112.1, 133.2, 147.1, 154.7, 157.6; 164.5. IR (ATR, cm−1): ν=3478, 3378, 1683, 1619, 1593, 1420, 1247, 1146. MS (ES+) m/z (%): 346/48 (M+H+, 100); 402/404 (M+H+, 60).

Workup

  1. stirringstirring
  2. waitwas continued for 30 min, while the temperature
  3. temperaturewas maintained at rt
  4. temperature(cooling with waterbath at rt)
  5. stirringthe solution was stirred for 30 min
  6. stirringthe reaction mixture was stirred overnight at rt
  7. extractionextracted with EtOAc (3×25 mL)
  8. washThe combined organic fraction was washed with brine
  9. dry with materialdried over MgSO4
  10. filtrationfiltered
  11. customevaporated under reduced pressure

Sources & evidence

ORD record
ord-e52d4f27c3db43fd9c1b5a9976ce3998
Source dataset
uspto-grants-2015_09
Patent number
US09139523B2

Reaction notes

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