Sodium triacetoxyborohydride → 5-(1-(3-(Methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)ethyl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

HRID 1045360Notes

Reaction equation

HRID 1045360 reaction equation
[CH3:1][O:2][CH2:3][C:4]1([C:9]([N:11]2[CH2:20][CH2:19][C:18]3[N:17]=[CH:16][C:15]([C:21]([F:24])([F:23])[F:22])=[CH:14][C:13]=3[CH2:12]2)=[O:10])[CH2:8][CH2:7][NH:6][CH2:5]1.[C:25]([C:28]1[CH:39]=[CH:38][C:31]2[N:32]([CH3:37])[C:33](=[O:36])[N:34]([CH3:35])[C:30]=2[CH:29]=1)(=O)[CH3:26].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH3:1][O:2][CH2:3][C:4]1([C:9]([N:11]2[CH2:20][CH2:19][C:18]3[N:17]=[CH:16][C:15]([C:21]([F:22])([F:24])[F:23])=[CH:14][C:13]=3[CH2:12]2)=[O:10])[CH2:8][CH2:7][N:6]([CH:25]([C:28]2[CH:39]=[CH:38][C:31]3[N:32]([CH3:37])[C:33](=[O:36])[N:34]([CH3:35])[C:30]=3[CH:29]=2)[CH3:26])[CH2:5]1

Participants

6

Reactant 3

HCID 5049666Sodium triacetoxyborohydrideHCID 171392895-Acetyl-1,3-Dimethyl-1H-Benzo[D]Imidazol-2(3H)-OneHCID 59569566HCID 59569566, compound

Product 1

HCID 441245565-(1-(3-(Methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)ethyl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

Reagents, catalysts & solvents 2

HCID 178460666HCID 178460666, compoundCatalystHCID 8028TetrahydrofuranSolvent

Procedure

The title compound was prepared according to general procedures described in Scheme 6: A mixture of (3-(methoxymethyl)pyrrolidin-3-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone VIc (50 mg, 0.146 mmol), 5-acetyl-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one (30 mg, 0.146 mmol) and Ti(OiPr)4 (51 mg, 0.182 mmol) in THF (2.5 mL) was irradiated in a Microwave instrument at 100° C. for 30 min (Personal Chemistry Emrys™ Optimizer microwave reactor). The reaction mixture was cooled and NaBH(OAc)3 (93 mg, 0.438 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was dissolved in 30 mL of ethyl acetate and washed with sat. NaHCO3. The organic layer was washed with brine (×3), then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to yield the desired final product as trifluoroacetic salt with purity greater than 95% (18.0 mg, 23.2% yield): 1H NMR (300 MHz, CD3Cl3): δ 8.71 (s, 1H), 7.72 (s, 1H), 7.29 (bs, 1H), 7.01 (bs, 1H), 6.92 (s, 1H), 5.23 (m, 2H), 4.87 (m, 1H), 4.73 (m, 1H), 4.10-3.86 (m, 4H), 3.71 (m, 1H), 3.40 (m, 3H), 3.32-3.24 (m, 6H), 3.12 (m, 3H), 2.91 (bs, 1H), 2.66 (d, 1H), 2.42 (s, 1H), 2.30 (s, 1H), 1.81 (m, 2H); MS (ESI) m/z: Calculated for C27H32F3N5O3: 531.3. found: 532.0 (M+H)+.

Workup

  1. customThe title compound was prepared
  2. customwas irradiated in a Microwave instrument at 100° C. for 30 min (Personal Chemistry Emrys™ Optimizer microwave reactor)
  3. temperatureThe reaction mixture was cooled
  4. customThe solvent was removed in vacuo
  5. dissolutionThe residue was dissolved in 30 mL of ethyl acetate
  6. washwashed with sat. NaHCO3
  7. washThe organic layer was washed with brine (×3)
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe crude product was purified by reverse phase preparative HPLC

Sources & evidence

ORD record
ord-d8cbbe7a29d74211a963d8e3e56bcd55
Source dataset
uspto-grants-2013_10
Patent number
US08569282B2

Reaction notes

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