Hydrochloric Acid → 3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one formate

HRID 634505Notes

Reaction equation

HRID 634505 reaction equation
N#N.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:14]([C:16]3[O:17][C:18](=[O:39])[C:19]4[C:24]([C:25]=3[C:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH:27]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:15])[N:11]=[C:12](I)[C:5]=12.[F:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[C:45]([OH:47])[CH:46]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>C1COCC1.O.C(O)=O.O.CC#N>[CH:18]([OH:39])=[O:17].[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:14]([C:16]3[O:17][C:18](=[O:39])[C:19]4[C:24]([C:25]=3[C:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH:27]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:15])[N:11]=[C:12]([C:43]3[CH:44]=[C:45]([OH:47])[CH:46]=[C:41]([F:40])[CH:42]=3)[C:5]=12

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 947NitrogenHCID 62657Potassium Phosphate, TribasicHCID 447173083-Fluoro-5-hydroxybenzeneboronic acidHCID 118131159Tert-butyl 4-(3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate

Product 1

HCID 1181311263-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one formateYield 303.8%

Reagents, catalysts & solvents 3

HCID 284Formic AcidSolvent2×HCID 18373917Acetonitrile--water (1/1)Solvent2×HCID 21881883Oxolane--water (1/1)Solvent

Conditions

Temperature
85 °C

Procedure

N2 was bubbled for 5 min through a suspension of tert-butyl 4-(3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)-5,6-dihydropyridine-1(2 H)-carboxylate (Intermediate D14, 735 mg, 1.197 mmol), 3-fluoro-5-hydroxyphenylboronic acid (0.28 g, 1.795 mmol), S-Phos-Pd-G2 (0.130 g, 0.179 mmol) and potassium phosphate (572 mg, 2.695 mmol) in THF/water 3:1 (8 ml). The mixture was heated at 85° C. for 1 hr by MW irradiation. A second run was performed in the same conditions on a mixture of reagents in the exact same amounts. The two reaction mixtures were combined and cone HCl (20 ml) was slowly added while stirring. Stirring went on at rt for 3 h, then volatiles were removed under reduced pressure. Purification by RP flash chromatography (Biotage Isolera, 60 g C18 column, gradient elution from 100:0 to 70:30 A/B in 15 CV; A: water/MeCN 95/5+0.01% HCOOH, B: water/MeCN 5/95+0.01% HCOOH) yielded 3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one formate (0.990 g, 1.818 mmol, 76% yield) as a pale yellow powder.

Workup

  1. additionA second run was performed in the same conditions on a mixture of reagents in the exact same amounts
  2. customThe two reaction mixtures
  3. stirringStirring
  4. customvolatiles were removed under reduced pressure
  5. customPurification by RP flash chromatography (Biotage Isolera, 60 g
  6. washC18 column, gradient elution from 100:0 to 70:30 A/B in 15 CV

Sources & evidence

ORD record
ord-c5b88c0c481143d4ae278c0008105569
Source dataset
uspto-grants-2016_04
Patent number
US09321776B2

Reaction notes

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