Sodium Bicarbonate → HCID 178521182, compound

HRID 2270029Notes

Reaction equation

HRID 2270029 reaction equation
[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:18][C:19]([N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)=[O:20].C(=O)(O)[O-].[Na+]>CC#N>[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:29][CH2:30][N:21]1[C:19](=[O:20])[CH2:18][N:14]1[CH2:15][CH2:16][CH:11]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[NH:8][N:7]=2)[CH2:12][CH2:13]1

Participants

5

Reactant 3

HCID 516892Sodium BicarbonateHCID 184672392-Bromo-1-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethan-1-oneHCID 178505426HCID 178505426, compound

Product 1

HCID 178521182HCID 178521182, compoundYield 55.3%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a solution of 4-(6- fluoro- 1 H-indazol-3-yl)piperidine (4.8 g, 18.9 mmol) in CH3CN (200 ml) was added 2-bromo-1-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethanone (4.8 g, 18.9 mmol) and sodium bicarbonate (1.9 g, 22.7 mmol) at room temperature. The reaction mixture was warmed to reflux (4 hours), cooled to room temperature and filtered through a pad of celite. The solids were washed with DCM and the combined filtrates were concentrated. The remaining residue was purified via preparative HPLC (silica gel, 5-10% McOH/DCM) to give 4.1 g of 1-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethanone which was used without further purification. To a suspension of the latter (3.7 g, 9.4 mmol) in THF (100 ml) was added (dropwise) lithium aluminum hydride (11.3 ml of 1.0M solution in THF, 11.3 mmol) at room temperature, under nitrogen. The reaction mixture was warmed to reflux (5 hours), cooled to room temperature and carefully quenched with water (10 ml). The precipitated salts were removed via filtration and washed with 1:1 EtOAc/DCM. The combined filtrates were concentrated and the remaining oil was purified via flash column chromatography (silica gel 10% MeOH/DCM) to give 2.2 g of the product. The dimaleate salt was prepared in methanol (30 ml) with maleic acid (3.0 eq.), m.p. 185°-187° C.

Workup

  1. temperatureThe reaction mixture was warmed
  2. temperatureto reflux (4 hours)
  3. filtrationfiltered through a pad of celite
  4. washThe solids were washed with DCM
  5. concentrationthe combined filtrates were concentrated
  6. customThe remaining residue was purified via preparative HPLC (silica gel, 5-10% McOH/DCM)

Sources & evidence

ORD record
ord-a50300dab6a14119829d57b6375d51da
Source dataset
uspto-grants-2001_12
Patent number
USRE037478E1

Reaction notes

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