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

HRID 634504Notes

Reaction equation

HRID 634504 reaction equation
[CH:1]([OH:3])=[O:2].[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:22]([C:24]3[O:25][C:26](=[O:46])[C:27]4[C:32]([C:33]=3[C:34]3[CH2:35][CH2:36][N:37]([C:40]([CH:42]5[CH2:45][NH:44][CH2:43]5)=[O:41])[CH2:38][CH:39]=3)=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH3:23])[N:12]=[C:13]([C:14]3[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([F:21])[CH:15]=3)[C:6]=12.[CH3:47]CN(C(C)C)C(C)C.C=O.[O-]S([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C.[Na].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C(O)=O.O.CC#N>[CH:1]([OH:3])=[O:2].[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:22]([C:24]3[O:25][C:26](=[O:46])[C:27]4[C:32]([C:33]=3[C:34]3[CH2:35][CH2:36][N:37]([C:40]([CH:42]5[CH2:43][N:44]([CH3:47])[CH2:45]5)=[O:41])[CH2:38][CH:39]=3)=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH3:23])[N:12]=[C:13]([C:14]3[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([F:21])[CH:15]=3)[C:6]=12

Participants

11

Reactant 7

HCID 176Acetic Acid2×HCID 712Formaldehyde2×HCID 24436Sodium SulfateHCID 81531DiisopropylethylamineHCID 5049666Sodium triacetoxyborohydrideHCID 5360545SodiumHCID 1181313363-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(1-(azetidine-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one formate

Product 1

HCID 1181311043-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(1-(1-methylazetidine-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one formateYield 82.3%

Reagents, catalysts & solvents 3

HCID 284Formic AcidSolvent2×HCID 6344DichloromethaneSolventHCID 18373917Acetonitrile--water (1/1)Solvent2×

Procedure

A mixture of 3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(1-(azetidine-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one formate (Example 150, 71.0 mg, 0.113 mmol), DIPEA (0.020 ml, 0.113 mmol), paraformaldehyde (69.3 mg, 2.30 mmol) and a spatula of Na2SO4 in DCM (2 ml) was stirred for 10 min at rt. Acetic acid (0.033 ml, 0.589 mmol) was then added followed by sodium triacetoxyhydroborate (82.2 mg, 0.387 mmol). After 6 hrs stirring at rt, volatiles were removed under reduced pressure. The residue was dissolved in DCM/EtOH 95:5 (10 ml) and washed with saturated sodium bicarbonate, then filtered on a phase separator and concentrated under reduced pressure. The residue was dissolved in DCM/MeOH 10:1 (1 ml), then formaldehyde (0.016 ml, 0.170 mmol) and AcOH (0.014 ml, 0.250 mmol) were added. After 5 min stirring, NaBH(OAc)3 (25 mg, 0.118 mmol) was added. The resulting mixture was stirred for 30 min at rt, then it was concentrated under reduced pressure. Purification by RP flash chromatography (Biotage Isolera, 12 g C18 column, gradient elution from 100:0 to 60:40 A/B in 15 CV; A: water/MeCN 95/5+0.01% HCOOH, B: water/MeCN 5/95+0.01% HCOOH) yielded title compound (59.8 mg, 0.093 mmol, 82% yield) as a white solid.

Workup

  1. customvolatiles were removed under reduced pressure
  2. dissolutionThe residue was dissolved in DCM/EtOH 95:5 (10 ml)
  3. washwashed with saturated sodium bicarbonate
  4. filtrationfiltered on a phase separator
  5. concentrationconcentrated under reduced pressure
  6. dissolutionThe residue was dissolved in DCM/MeOH 10:1 (1 ml)
  7. stirringAfter 5 min stirring
  8. stirringThe resulting mixture was stirred for 30 min at rt
  9. concentrationit was concentrated under reduced pressure
  10. customPurification by RP flash chromatography (Biotage Isolera, 12 g
  11. washC18 column, gradient elution from 100:0 to 60:40 A/B in 15 CV

Sources & evidence

ORD record
ord-a07ccd1e5ee84eefb3a82ba90cf34c1e
Source dataset
uspto-grants-2016_04
Patent number
US09321776B2

Reaction notes

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