Sodium Carbonate → HCID 58465932, compound

HRID 455685Notes

Reaction equation

HRID 455685 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:15]3([N:20]=[C:19]([NH2:21])[CH:18]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[O:17][CH2:16]3)[C:14]3[CH:13]=[C:12]([Cl:28])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.[F:41][C:42]1[C:47](B(O)O)=[CH:46][CH:45]=[CH:44][N:43]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:28][C:12]1[N:11]=[CH:10][C:9]2[O:8][C:5]3[C:4]([C@@:15]4([N:20]=[C:19]([NH2:21])[C@H:18]([CH:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)[O:17][CH2:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([C:47]1[C:42]([F:41])=[N:43][CH:44]=[CH:45][CH:46]=1)=[CH:7][CH:6]=3.[Cl:28][C:12]1[N:11]=[CH:10][C:9]2[O:8][C:5]3[C:4]([C@:15]4([N:20]=[C:19]([NH2:21])[C@H:18]([CH:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)[O:17][CH2:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([C:47]1[C:42]([F:41])=[N:43][CH:44]=[CH:45][CH:46]=1)=[CH:7][CH:6]=3

Participants

8

Reactant 4

HCID 10340Sodium CarbonateHCID 312751,4-DioxaneHCID 27832702-Fluoropyridine-3-boronic acidHCID 58465961HCID 58465961, compound

Product 2

HCID 58465932HCID 58465932, compoundHCID 58465976HCID 58465976, compound

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
120 °C

Procedure

A glass microwave reaction vessel was charged with 7-bromo-3-chloro-6′-cyclohexyl-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.075 g, 0.162 mmol), 2 M aqueous sodium carbonate (0.8 mL, 1.600 mmol), and dioxane (1.6 mL). The vessel was capped and the solution was degassed by bubbling nitrogen gas through the solution for 10 minutes. Next, Pd(PPh3)4 (7.49 mg, 6.48 μmol) and (2-fluoropyridin-3-yl)boronic acid (0.027 g, 0.194 mmol) were added and the vessel was sealed. The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 20 minutes. The reaction was poured into water and the mixture was extracted with EtOAc. The combined organic extracts were washed with water, saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel chromatography by eluting with 1:20 MeOH in DCM, to provide the product as a racemic mixture of diastereomers. The diastereomers were seperated by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 70% over 20 min to provide racemic (3′R, 6′S)-3-chloro-6′-cyclohexyl-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine and racemic (3′S, 6′S)-3-chloro-6′-cyclohexyl-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine each as a white solid after isolating the free base by partitoning between DCM and 1 N NaOH. [M+H]+=479.1 for each racemic diastereomer pair.

Workup

  1. customA glass microwave reaction vessel
  2. customThe vessel was capped
  3. customthe solution was degassed
  4. customby bubbling nitrogen gas through the solution for 10 minutes
  5. customthe vessel was sealed
  6. extractionthe mixture was extracted with EtOAc
  7. washThe combined organic extracts were washed with water, saturated aqueous sodium chloride
  8. dry with materialdried over sodium sulfate
  9. filtrationThe solution was filtered
  10. concentrationconcentrated in vacuo
  11. customto give the crude material
  12. customThe crude material was purified by silica gel chromatography
  13. washby eluting with 1:20 MeOH in DCM
  14. customto provide the product
  15. additionas a racemic mixture of diastereomers
  16. customThe diastereomers were seperated by reverse-phase preparative HPLC
  17. customover 20 min

Sources & evidence

ORD record
ord-6080d82a722a470b875b59c8b4c09b01
Source dataset
uspto-grants-2013_07
Patent number
US08497264B2

Reaction notes

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