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 928258Notes

Reaction equation

HRID 928258 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 (4.0 g) in acetonitrile (20.0 mL) at 0° C. was added phosphoric acid (20.0 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 (20 mL) and water (20 mL). After this addition was complete saturated Na2CO3 (80.0 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 (20 mL). The organic layers were combined and 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 anhydrous Form 1. (2.85 g, 84%). XRPD data is shown in FIG. 1; DSC data is shown in FIG. 2; TGA is shown in FIG. 3; Raman data is shown in FIGS. 4, 5A, 6A and 7A.

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 (20 mL)
  8. dry with materialdried with Na2SO4
  9. concentrationThe organic layer was then concentrated to 4 vol of ethyl acetate
  10. customto precipitate within 5 minutes
  11. stirringThis mixture was stirred for 16 hours
  12. customThe resulting white solids were collected
  13. filtrationa filter over 5 minutes
  14. customThe solid was dried in a vacuum oven under full vacuum overnight (35° C., 16 hours)

Sources & evidence

ORD record
ord-c3f548a4b93849bbba4787911f253479
Source dataset
uspto-grants-2016_03
Patent number
US09290500B2

Reaction notes

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