Dimethylformamide → 3-(4-(2-Chloro-5-fluorophenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile

HRID 58484Notes

Reaction equation

HRID 58484 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=4[Cl:26])[CH2:15][CH2:14]3)=[O:12])=[N:9][N:10]=2)[CH:7]=1.[CH3:27][N:28](C=O)C>C(=O)(O)[O-].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:26][C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[CH:16]1[CH2:17][CH2:18][N:13]([C:11]([C:8]2[N:6]3[CH:7]=[C:2]([C:27]#[N:28])[CH:3]=[CH:4][C:5]3=[N:10][N:9]=2)=[O:12])[CH2:14][CH2:15]1

Participants

5

Reactant 2

HCID 6228DimethylformamideHCID 118483329(6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-chloro-5-fluorophenyl) piperidin-1-yl)methanone

Product 1

HCID 1184834093-(4-(2-Chloro-5-fluorophenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrileYield 54%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
130 °C

Procedure

A solution of (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-chloro-5-fluorophenyl)piperidin-1-yl)methanone (50 mg, 0.21 mmol) in DMF (2.0 mL) zinc cyanide (48 mg, 0.41 mmol) was sparged with Ar for 20 min. To the solution was added Pd(PPh3)4 (13 mg, 0.011 mmol) and the vessel was sealed and heated to 130° C. with microwaves for 30 min. The mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with EtOAc (4×30 mL). The combined organic extracts were concentrated to dryness under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 50% EtOAc in hexanes) and freeze dried to give 3-(4-(2-chloro-5-fluorophenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile as a white solid (21 mg, 54%): mp 211-214° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.52-9.50 (m, 1H), 8.13 (dd, J=9.5, 1.0 Hz, 1H), 7.81 (dd, J=9.5, 1.5 Hz, 1H), 7.50 (dd, J=9.0, 5.5 Hz, 1H), 7.28 (dd, J=10.5, 3.5 Hz, 1H), 7.16-7.11 (m, 1H), 5.16-5.11 (m, 1H), 4.78-4.71 (m, 1H), 3.46-3.30 (m, 2H, overlaps with H2O), 3.11-3.01 (m, 1H), 1.99-1.70 (m, 4H); ESI MS m/z 384 [M+H]+.

Workup

  1. customthe vessel was sealed
  2. extractionextracted with EtOAc (4×30 mL)
  3. concentrationThe combined organic extracts were concentrated to dryness under reduced pressure
  4. customThe resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 50% EtOAc in hexanes)
  5. customfreeze dried

Sources & evidence

ORD record
ord-d8285b565e3a4af290ea5c08a1ef5df5
Source dataset
uspto-grants-2016_09
Patent number
US09434727B2

Reaction notes

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