Phosphoric Acid → methyl ((1S,2R,3S,4R)-2,3-dihydroxy-4-((2-(3-((trifluoromethyl)thio)phenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclopentyl)sulfamate

HRID 928259Notes

Reaction equation

HRID 928259 reaction equation
C(OC(=O)[NH:7][S:8]([O:11][CH2:12][C@@H:13]1[C@@H:20]2[C@@H:16]([O:17]C(C)(C)[O:19]2)[CH:15]([NH:23][C:24]2[N:29]3[N:30]=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([S:39][C:40]([F:43])([F:42])[F:41])[CH:34]=4)[CH:32]=[C:28]3[N:27]=[CH:26][CH:25]=2)[CH2:14]1)(=[O:10])=[O:9])(C)(C)C.P(=O)(O)(O)O.C(OCC)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O>[S:8](=[O:10])(=[O:9])([O:11][CH2:12][C@H:13]1[CH2:14][C@@H:15]([NH:23][C:24]2[N:29]3[N:30]=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([S:39][C:40]([F:43])([F:42])[F:41])[CH:34]=4)[CH:32]=[C:28]3[N:27]=[CH:26][CH:25]=2)[C@H:16]([OH:17])[C@@H:20]1[OH:19])[NH2:7]

Participants

7

Reactant 4

HCID 1004Phosphoric AcidHCID 8857Ethyl AcetateHCID 10340Sodium CarbonateHCID 86692840HCID 86692840, compound

Product 1

HCID 71715374methyl ((1S,2R,3S,4R)-2,3-dihydroxy-4-((2-(3-((trifluoromethyl)thio)phenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclopentyl)sulfamate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6342AcetonitrileSolvent

Procedure

To a solution of tert-butyl-[({(3aR,4R,6aS)-2,2-dimethyl-6-[(2-{3-(trifluoromethylthio)phenyl}pyrazolo[1,5-a]pyrimidin-7-yl)amino]tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methoxy)sulfonyl]carbamate (5.0 g) in acetonitrile (25.0 mL) at 0° C. was added phosphoric acid (25.0 mL) while maintaining the temperature below 10° C. This mixture was warmed to ambient temperature and stirred for 4 hours. At this time HPLC analysis showed that <1% starting material or reaction intermediates remained. To the reaction was added ethyl acetate (25 mL) and water (25 mL). After this addition was complete saturated Na2CO3 (100.0 mL) was added until the pH was between 6-7. After stirring for 10 minutes the phases were separated and the aqueous layer was back extracted with ethyl acetate (25 mL). The combine organics were then washed with 10% brine (50 mL). The organic layers were dried with Na2SO4. The organic layer was then concentrated to 4 vol of ethyl acetate. The solution started to precipitate within 5 minutes. This mixture was stirred for 16 hours. The resulting white solids were collected using a filter over 5 minutes. The solid was dried in a vacuum oven under full vacuum overnight (35° C., 16 hours). This yielded (s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamate Form 2 monohydrated (3.04 g, 77%). XRPD data is shown in FIG. 8; DSC data is shown in FIG. 9; TGA is shown in FIG. 10; Raman data is shown in FIGS. 11, 5B, 6B and 7B.

Workup

  1. temperaturewhile maintaining the temperature below 10° C
  2. custommaterial or reaction intermediates
  3. additionAfter this addition
  4. additionwas added until the pH
  5. stirringAfter stirring for 10 minutes the phases
  6. customwere separated
  7. extractionthe aqueous layer was back extracted with ethyl acetate (25 mL)
  8. washThe combine organics were then washed with 10% brine (50 mL)
  9. dry with materialThe organic layers were dried with Na2SO4
  10. concentrationThe organic layer was then concentrated to 4 vol of ethyl acetate
  11. customto precipitate within 5 minutes
  12. stirringThis mixture was stirred for 16 hours
  13. customThe resulting white solids were collected
  14. filtrationa filter over 5 minutes
  15. customThe solid was dried in a vacuum oven under full vacuum overnight (35° C., 16 hours)

Sources & evidence

ORD record
ord-73de144e455341358f67e59b8e166eda
Source dataset
uspto-grants-2016_03
Patent number
US09290500B2

Reaction notes

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