Trimethyl orthoformate → Methyl (3-amino-4-fluoro-5-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate

HRID 921749Notes

Reaction equation

HRID 921749 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([N:15]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:16](=[O:19])[O:17][CH3:18])[CH:5]=[C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:7]=1[F:8].[O:29]1[CH2:32][C:31](=O)[CH2:30]1.C(OC)(OC)OC.C([O-])(=O)C.[K+].C([BH3-])#N.[Na+]>CO.O1CCCC1>[NH2:1][C:2]1[CH:3]=[C:4]([N:15]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:16](=[O:19])[O:17][CH3:18])[CH:5]=[C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH:31]3[CH2:32][O:29][CH2:30]3)[CH2:13][CH2:14]2)[C:7]=1[F:8]

Participants

8

Reactant 5

HCID 9005Trimethyl orthoformateHCID 517044Potassium AcetateHCID 5003444Sodium cyanoborohydrideHCID 150242543-OxetanoneHCID 86708631Methyl (3-amino-4-fluoro-5-(piperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate

Product 1

HCID 86708633Methyl (3-amino-4-fluoro-5-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)(4-methoxybenzyl)carbamateYield 92.4%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

methyl (3-amino-4-fluoro-5-(piperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate (470 mg, 0.605 mmol) (crude product from above, contains DCE and TFA) was dissolved in methanol (5 ml)+Tetrahydrofuran (5 ml). oxetan-3-one (0.15 ml, 2.56 mmol), Trimethyl orthoformate (1 ml, 9.05 mmol) and potassium acetate (119 mg, 1.210 mmol) were added and the mixture stirred at room temperature for 15 minutes. pH was checked to be ˜4.5. Sodium cyanoborohydride (160 mg, 2.55 mmol) was added and stirring at room temperature continued for 20 hours. The reaction mixture was partitioned between EtOAc and dilutes aq. NaHCO3 solution. The organic layer was washed with brine, then dried over MgSO4 and evaporated to dryness to give crude methyl (3-amino-4-fluoro-5-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate (248.4 mg) which was used without further purification.

Workup

  1. stirringstirring at room temperature
  2. waitcontinued for 20 hours
  3. customThe reaction mixture was partitioned between EtOAc
  4. washThe organic layer was washed with brine
  5. dry with materialdried over MgSO4
  6. customevaporated to dryness

Sources & evidence

ORD record
ord-7e975669969240d7be4c99969357e044
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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