Potassium Phosphate, Tribasic → methyl 3-((5-chloro-2-(5-fluoro-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

HRID 539922Notes

Reaction equation

HRID 539922 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH:14]3[CH2:15][CH2:16][CH:11]([CH2:12][CH2:13]3)[CH:10]2[C:17]([O:19][CH3:20])=[O:18])[C:5]([Cl:21])=[CH:4][N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:30][C:31]1[CH:32]=[C:33]2[C:39](B3OC(C)(C)C(C)(C)O3)=[N:38][N:37]([C:49]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:34]2=[N:35][CH:36]=1.B([O-])[O-]>O.C1COCC1.CCOC(C)=O.C(Cl)Cl.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>[Cl:21][C:5]1[C:6]([NH:8][CH:9]2[CH:14]3[CH2:15][CH2:16][CH:11]([CH2:12][CH2:13]3)[CH:10]2[C:17]([O:19][CH3:20])=[O:18])=[N:7][C:2]([C:39]2[C:33]3[C:34](=[N:35][CH:36]=[C:31]([F:30])[CH:32]=3)[N:37]([C:49]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)([C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[N:38]=2)=[N:3][CH:4]=1

Participants

10

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 679757175-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazolo[3,4-b]pyridineHCID 86707194Methyl 3-((2,5-dichloropyrimidin-4-yl)amino)-bicyclo-[2.2.2]octane-2-carboxylateHCID 178514824HCID 178514824, compound

Product 1

HCID 86707193methyl 3-((5-chloro-2-(5-fluoro-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylateYield 83%

Reagents, catalysts & solvents 5

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
90 °C

Procedure

A solution of (+/−)-trans-(2,3)-methyl 3-((2,5-dichloropyrimidin-4-yl)amino)-bicyclo-[2.2.2]octane-2-carboxylate, 37, (0.50 g, 1.51 mmol) and K3PO4 (0.96 g, 4.54 mmol) in water (2.5 mL) and THF (10.00 mL) was degassed for 15 min with a stream of nitrogen. Then, 5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-pyrazolo[3,4-b]pyridine, 6, (0.84 g, 1.67 mmol) was added and the mixture was degassed for an additional 15 min. Then, Pd(PPh3)4 (0.09 g, 0.08 mmol) was added to the mixture. The vessel was sealed and heated to 90° C. After 2.5 hr., an additional 0.1 equivalent of boronate, 6, was added and the mixture was heated for an additional 30 min. The cooled solution was diluted with EtOAc, washed with water, dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 0-35% EtOAc in DCM) gave the desired product (0.85 g, 83% yield) which was sufficiently pure for use in the next reaction: LC/MS Gradient 10-90%, 0.1% formic 5 min, C18/ACN, RT=3.85 min, (M+H) 673.27.

Workup

  1. customthe mixture was degassed for an additional 15 min
  2. customThe vessel was sealed
  3. temperaturethe mixture was heated for an additional 30 min
  4. washwashed with water
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-bd525aa0983d435a95cbcdd02603b08f
Source dataset
uspto-grants-2014_10
Patent number
US08871774B2

Reaction notes

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