Formaldehyde → N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

HRID 713308Notes

Reaction equation

HRID 713308 reaction equation
O[C:2](C(F)(F)F)=O.[F:8][CH:9]([F:37])[CH2:10][NH:11][C:12]1[N:17]=[C:16]2[CH2:18][NH:19][CH2:20][CH2:21][C:15]2=[N:14][C:13]=1[N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH2:24][CH2:23]1.CCN(C(C)C)C(C)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O.C(#N)C.O>CO>[F:37][CH:9]([F:8])[CH2:10][NH:11][C:12]1[N:17]=[C:16]2[CH2:18][N:19]([CH3:2])[CH2:20][CH2:21][C:15]2=[N:14][C:13]=1[N:22]1[CH2:23][CH2:24][CH:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH2:26][CH2:27]1

Participants

8

Reactant 6

HCID 712FormaldehydeHCID 962WaterHCID 81531DiisopropylethylamineHCID 5049666Sodium triacetoxyborohydrideHCID 18373917Acetonitrile--water (1/1)HCID 131734033N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt

Product 1

HCID 118159195N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amineYield 28.1%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

A solution of N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (155 mg, 0.287 mmol) in MeOH (2.87 mL) was treated with DIPEA (0.100 mL, 0.575 mmol), formaldehyde (0.021 mL, 0.29 mmol), and after stirring for 5 min, sodium triacetoxyborohydride (122 mg, 0.575 mmol). The reaction mixture was stirred for 30 min at room temperature. The reaction mixture was filtered and purified by HPLC (Pump: Waters 2525 or 2545; MS: ZQ; Software: MassLynx. A Xbridge™ C18, 5 μm, ID 30×75 mm column was used and eluted with 40% to 95% of 2080 (v/v) water/ACN (10 mmol NH4HCO3, pH 9.5-10) and water (10 mmol NH4HCO3, pH 9.5-10)) to give the title compound as an off-white semisolid (35.4 mg, 28.0%). 1H NMR (500 MHz, methanol-d4) δ ppm 1.95 (m, 2H), 2.12 (m, 2H), 2.47 (s, 3H), 2.79 (m, 4H), 2.96 (ddd, J=12.4, 8.8, 3.2 Hz, 2H), 3.35 (m, 2H), 3.49 (s, 2H), 3.75 (td, J=14.6, 4.4 Hz, 2H), 4.43 (tt, J=7.7, 3.5 Hz, 1H), 6.03 (m, 1H), 6.86 (m, 1H), 6.97 (ddd, J=11.2, 8.5, 3.2 Hz, 1H), 7.16 (td, J=9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 440.4.

Workup

  1. stirringThe reaction mixture was stirred for 30 min at room temperature
  2. filtrationThe reaction mixture was filtered
  3. custompurified by HPLC (Pump

Sources & evidence

ORD record
ord-1b0290e4f3584bf29d2b52dd95f0a770
Source dataset
uspto-grants-2015_11
Patent number
US09181249B2

Reaction notes

Loading…