Ammonia → (1S,4R)-4-[3-((S)-2-Methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine

HRID 1402256Notes

Reaction equation

HRID 1402256 reaction equation
[NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]3[CH3:31])=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH3:31][C@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][N:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:12][C@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:2]([NH2:1])[CH2:3][CH2:4]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1

Participants

8

Reactant 4

HCID 222AmmoniaHCID 24758Sodium hydrideHCID 86686674(1R,4S)-4-Amino-1,2,3,4-tetrahydronaphthalen-1-olHCID 866871056-Fluoro-3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridine

Product 1

HCID 86687106(1S,4R)-4-[3-((S)-2-Methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamineYield 58.4%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6228DimethylformamideSolvent2×HCID 6344DichloromethaneSolvent

Procedure

To a solution of Intermediate A (374 mg, 2.29 mmol) in dry DMF (3 mL) under N2 was added NaH (60% dispersion in oil, 183 mg, 4.58 mmol) and the resulting opaque brown solution was stirred at RT for 45 min (CARE: gas evolution). A solution of Intermediate 81c (537 mg, 2.29 mmol) in dry DMF (7 mL) was added and the dark brown solution stirred at 60° C. under N2 for 90 min. The cooled solution was concentrated in vacuo, redissolved in MeOH (3 mL) and AcOH (0.10 mL) and then applied to an SCX-2 cartridge (20 g), washing with MeOH (50 mL). The product was eluted with 2M NH3 in MeOH (50 mL); concentration in vacuo gave a dark brown solid. FCC, using 2-7% [2M NH3 in MeOH] in DCM, gave the title compound as a pale brown foam (505 mg, 58%). LCMS (Method 3): Rt 2.29 min, m/z 378 [MH+].

Workup

  1. stirringthe dark brown solution stirred at 60° C. under N2 for 90 min
  2. concentrationThe cooled solution was concentrated in vacuo
  3. dissolutionredissolved in MeOH (3 mL)
  4. washwashing with MeOH (50 mL)
  5. washThe product was eluted with 2M NH3 in MeOH (50 mL)
  6. concentrationconcentration in vacuo
  7. customgave a dark brown solid

Sources & evidence

ORD record
ord-4ca60b6aee9a4e97b536f97083b44e21
Source dataset
uspto-grants-2014_12
Patent number
US08907094B2

Reaction notes

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