Methanol → 2-Hydroxyethyl{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-(2,2,2-trifluoroethyl)-1h-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}carbamate

HRID 1093168Notes

Reaction equation

HRID 1093168 reaction equation
[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:22]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:23]=[CH:24][C:10]=13)[CH2:2]2.CCN(CC)CC.ClC(Cl)(O[C:41](=[O:47])[O:42][C:43](Cl)(Cl)Cl)Cl.[CH3:49][OH:50]>C(Cl)Cl>[OH:50][CH2:49][CH2:43][O:42][C:41](=[O:47])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[N:12]=[C:11]3[N:22]([CH2:25][C:26]([F:28])([F:27])[F:29])[N:23]=[CH:24][C:10]3=[C:9]([N:3]3[CH2:2][CH:1]4[O:8][CH:5]([CH2:6][CH2:7]4)[CH2:4]3)[N:14]=2)=[CH:16][CH:17]=1

Participants

6

Reactant 4

HCID 887MethanolHCID 8471TriethylamineHCID 94429TriphosgeneHCID 574246364-[4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenylamine

Product 1

HCID 576542742-Hydroxyethyl{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-(2,2,2-trifluoroethyl)-1h-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}carbamate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

4-[4-(8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenylamine (7.96 g) from the previous step was reacted in 0.5 g portions. Into a 50 mL round-bottomed flask with stopper and magnetic stir bar was added amine (0.5 g) and methylene chloride (7.5 mL). With good stirring Et3N (0.5 mL) was added, followed by a clear, colorless solution of triphosgene (0.22 g) in methylene chloride (2.5 mL). After 1 min at room temperature, an aliquot of the reaction mixture was diluted in MeOH to form the methyl carbamate. Analysis by HPLC indicated methyl carbamate peak with a retention time of 2.315 min (91%) and an amine starting material peak with a retention time of 1.650 (1.9%). After 8 min total reaction time ethylene glycol (1.38 mL) was added at once. The cloudy solution turned into a clear, yellow solution. Stirring at room temperature continued for 75 min, at which time HPLC analysis indicates a new peak with a retention time of 2.032 min (88%). The 32 0.5 g runs were combined and the combined product was divided into two portions. Each portion was diluted with methylene chloride (400 mL), and washed with water (4×100 mL), dried with brine (100 mL), and then dried over Na2SO4. Concentration under reduced pressure and combination of the two portions gave 8.77 g of 83.3% pure material. This was triturated with methylene chloride to give 1.2 g of {4-[4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenyl}-carbamic acid 2-hydroxy-ethyl ester. Repeated chromatography of mother liquors with gradient of 0-5% MeOH in methylene chloride gave an additional 5.6 g of desired product, for a total of 6.8 g (70%).

Workup

  1. additionwas added

Sources & evidence

ORD record
ord-51513c99a5e64b7d8e1e880bc14b12c5
Source dataset
uspto-grants-2012_03
Patent number
US08129371B2

Reaction notes

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