1-Propanol → Apitolisib

HRID 341321Notes

Reaction equation

HRID 341321 reaction equation
Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[C:8]([CH3:23])[C:6]=2[N:7]=1.C(O)CC.[NH2:34][C:35]1[N:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1.P([O-])([O-])(O)=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O>[CH3:23][C:8]1[C:6]2[N:7]=[C:2]([C:38]3[CH:37]=[N:36][C:35]([NH2:34])=[N:40][CH:39]=3)[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]=2[S:10][C:9]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([C@@H:19]([OH:21])[CH3:20])=[O:22])[CH2:14][CH2:13]1

Participants

7

Reactant 4

HCID 10311-PropanolHCID 24450Potassium Phosphate, DibasicHCID 17750211(2-Aminopyrimidin-5-yl)boronic acidHCID 86623526(S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one

Product 1

HCID 25254071Apitolisib

Reagents, catalysts & solvents 2

HCID 6102075Dichlorobis(triphenylphosphine)palladiumCatalystHCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

(S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one II (33.0 g, 75 mmol) was charged to a suitably sized reactor, followed by n-propanol (337 g), water (450 g), 2-aminopyrimidin-5-ylboronic acid III (12.5 g, 90 mmol) and dipotassium hydrogen phosphate (39.2 g, 225 mmol). The resulting mixture was degassed by vacuum/argon purge three times. Bis(triphenylphosphine)palladium (II) chloride (0.079 g, 0.112 mmol) was added and the slurry was again degassed by vacuum/argon purge three times. The mixture was heated within 2 h to 65° C. and stirred for 10 hours. The organic phase was separated and slowly filtered over a preheated pressure filter loaded with a ZETACARBON® R55SP pad (Cuno Inc., a 3M Company, Meriden Conn.). The filter unit was washed with a warm (80° C.) n-propanol (45 mL). Water (750 mL) were added to the filtrate and the resulting suspension was cooled to 10° C., aged for 1 h and filtered. The filter cake was washed with water (150 g) and dried under reduced pressure at 45° C. to afford (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one, GDC-0980, Formula I as a white solid (30.1 g, 79%).

Workup

  1. customThe resulting mixture was degassed by vacuum/argon
  2. custompurge three times
  3. customthe slurry was again degassed by vacuum/argon
  4. custompurge three times
  5. temperatureThe mixture was heated within 2 h to 65° C.
  6. customThe organic phase was separated
  7. filtrationslowly filtered over a preheated pressure
  8. filtrationfilter
  9. washThe filter unit was washed with
  10. additionWater (750 mL) were added to the filtrate
  11. temperaturethe resulting suspension was cooled to 10° C.
  12. waitaged for 1 h
  13. filtrationfiltered
  14. washThe filter cake was washed with water (150 g)
  15. customdried under reduced pressure at 45° C.

Sources & evidence

ORD record
ord-93c0c4fa7c9947069b5ac816aae47556
Source dataset
uspto-grants-2014_11
Patent number
US08895729B2

Reaction notes

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