Sodium hydride → 4-[6-((1R,4S)-4-Amino-1,2,3,4-tetrahydro-naphthalen-1-yloxy)-[1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl]-piperidine-1-carboxylic acid tert-butyl ester

HRID 630718Notes

Reaction equation

HRID 630718 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+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][C:29]2[N:33]3[CH:34]=[C:35](F)[CH:36]=[CH:37][C:32]3=[N:31][N:30]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][CH:25]([CH2:28][C:29]2[N:33]3[CH:34]=[C:35]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:36]=[CH:37][C:32]3=[N:31][N:30]=2)[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 86686674(1R,4S)-4-Amino-1,2,3,4-tetrahydronaphthalen-1-olHCID 866869824-(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 866869834-[6-((1R,4S)-4-Amino-1,2,3,4-tetrahydro-naphthalen-1-yloxy)-[1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl]-piperidine-1-carboxylic acid tert-butyl esterYield 44.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of Intermediate A (392 mg, 2.40 mmol) in dry DMF (5 mL) was added NaH (60% dispersion in mineral oil, 240 mg, 6.00 mmol) and the resulting brown suspension was stirred at RT for 45 min (CARE: gas evolution). Intermediate 22a (669 mg, 2.00 mmol) was added and the dark brown solution stirred at 60° C. for 2 h. The cooled solution was concentrated in vacuo, redissolved in MeOH (5 mL), applied to an SCX-2 cartridge (20 g) and washed with MeOH (100 mL). The product was eluted with 2M NH3 in MeOH (75 mL); concentration in vacuo left a dark brown residue. FCC, using 4-9% [2M NH3 in MeOH] in DCM, gave the title compound as a brown oil (421 mg, 44%). LCMS (Method 3): Rt 2.45 min, m/z 478 [MH+].

Workup

  1. stirringthe dark brown solution stirred at 60° C. for 2 h
  2. concentrationThe cooled solution was concentrated in vacuo
  3. dissolutionredissolved in MeOH (5 mL)
  4. washwashed with MeOH (100 mL)
  5. washThe product was eluted with 2M NH3 in MeOH (75 mL)
  6. concentrationconcentration in vacuo
  7. waitleft a dark brown residue

Sources & evidence

ORD record
ord-bbf9cea876b24d4cac58c2e9611df8a7
Source dataset
uspto-grants-2016_04
Patent number
US09315503B2

Reaction notes

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