Dichloromethane → Oxetan-3-yl{4,6-diamino-2-[6-fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidin-5-yl}carbamate

HRID 626618Notes

Reaction equation

HRID 626618 reaction equation
ClC(O[C:6](=[O:12])[O:7][C:8](Cl)(Cl)Cl)(Cl)Cl.[F:13][C:14]1[CH:15]=[C:16]2[N:22]([C:23]3[N:28]=[C:27]([NH2:29])[C:26]([NH2:30])=[C:25]([NH2:31])[N:24]=3)[N:21]=[C:20]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[F:39])[C:17]2=[N:18][CH:19]=1.[C:40](=[O:43])(O)[O-].[Na+].Cl[CH2:46]Cl>N1C=CC=CC=1>[O:43]1[CH2:40][CH:8]([O:7][C:6](=[O:12])[NH:30][C:26]2[C:25]([NH2:31])=[N:24][C:23]([N:22]3[C:16]4[C:17](=[N:18][CH:19]=[C:14]([F:13])[CH:15]=4)[C:20]([CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[F:39])=[N:21]3)=[N:28][C:27]=2[NH2:29])[CH2:46]1

Participants

6

Reactant 4

HCID 6344DichloromethaneHCID 94429TriphosgeneHCID 516892Sodium BicarbonateHCID 675168882-[6-Fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidine-4,5,6-triamine

Product 1

HCID 57335164Oxetan-3-yl{4,6-diamino-2-[6-fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidin-5-yl}carbamate

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent2×

Conditions

Temperature
0 °C

Procedure

Under argon, 60.4 μl (0.98 mmol) of 3-hydroxyethane were initially charged in dichloromethane (6.2 ml), 0.5 eq of bis(trichloromethyl)carbonate was then added and the mixture was cooled to 0° C. 79 μl (0.98 mmol) of pyridine were then added dropwise, and the reaction mixture was brought to RT and stirred for another 1 h. The mixture was then once more cooled to 0° C., and finally a solution of 334 mg (0.815 mmol) of the compound from example 6A in pyridine (2 ml) was added. The reaction mixture was stirred at RT overnight, saturated aqueous sodium bicarbonate solution was then added and the mixture was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was separated by means of preparative RP-HPLC (acetonitrile:water (+0.1% formic acid)-gradient) and the product fractions were concentrated. The crude product obtained in this manner was chromatographed on silica gel (dichloromethane:methanol 100:1, 30:1) and then re-purified by preparative RP-HPLC (acetonitrile:water (+0.1% formic acid)−gradient).

Workup

  1. customwas brought to RT
  2. temperatureThe mixture was then once more cooled to 0° C.
  3. stirringThe reaction mixture was stirred at RT overnight
  4. extractionthe mixture was extracted twice with ethyl acetate
  5. dry with materialThe combined organic phases were dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was separated by means of preparative RP-HPLC (acetonitrile:water (+0.1% formic acid)-gradient)
  9. concentrationthe product fractions were concentrated

Sources & evidence

ORD record
ord-4546e1fedf0e4fae94de520602bc3c6c
Source dataset
uspto-grants-2016_04
Patent number
US09309239B2

Reaction notes

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