Trifluoroacetic acid → HCID 71164949, compound

HRID 2173089Notes

Reaction equation

HRID 2173089 reaction equation
C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24](C(OC(C)(C)C)=O)[CH2:25][C:18]=2[C:17]=1[F:34])=O)(C)(C)C.C([Sn](CCCC)(CCCC)[C:40]1[CH:41]=[C:42]2[N:47]([CH:48]=1)[CH2:46][CH2:45][O:44][CH2:43]2)CCC.[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58].[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:40]2[CH:41]=[C:42]3[N:47]([CH:48]=2)[CH2:46][CH2:45][O:44][CH2:43]3)[C:19]2[C:23](=[O:33])[NH:24][CH2:25][C:18]=2[C:17]=1[F:34]

Participants

7

Reactant 3

HCID 6422Trifluoroacetic acidHCID 71143891HCID 71143891, compoundHCID 86654740tert-Butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

Product 2

HCID 6422Trifluoroacetic acidHCID 71164949HCID 71164949, compoundYield 6.3%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 1140TolueneSolvent

Conditions

Temperature
90 °C

Procedure

In a 30 mL sealed cap glass tube, tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.301 mmol), 7-(tributylstannyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine (124 mg, 0.301 mmol) and tetrakis(triphenylphosphine)palladium(0) (174 mg, 0.150 mmol) were dissolved in toluene (5 mL). The cap was sealed and the reaction mixture was heated at 90° C. in an oil bath for 2 hours. Following work-up, the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, was purified by preparative HPLC eluting with a gradient of 55-95% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined and the solvent stripped by rotary evaporation to give a solid intermediate. The intermediate was subsequently dissolved in TFA (3 mL) and the reaction mixture was stirred for 1 hour. The mixture was concentrated, dissolved in DMSO (5 mL), and purified via preparatory HPLC eluting with a gradient of 20-50% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a pale yellow solid (7.3 mg, 6.3%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (d, J=7.33 Hz, 2H), 1.59 (br s, 1H), 1.63-1.92 (m, 4H), 3.98 (d, J=1.77 Hz, 3H), 4.26-4.46 (m, 3H), 4.74 (s, 2H), 6.54-6.71 (m, 2H), 7.74 (br s, 3H), 8.17-8.36 (m, 2H). ESI-MS m/z [M+H]+ calc'd for C20H24FN5O2, 386. found, 386.

Workup

  1. customIn a 30 mL sealed
  2. customcap glass tube
  3. customThe cap was sealed
  4. customthe intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, was purified by preparative HPLC
  5. washeluting with a gradient of 55-95% ACN (0.035% TFA) and H2O (0.05% TFA)
  6. customthe solvent stripped by rotary evaporation
  7. customto give a solid intermediate
  8. concentrationThe mixture was concentrated
  9. dissolutiondissolved in DMSO (5 mL)
  10. custompurified via preparatory HPLC
  11. washeluting with a gradient of 20-50% ACN (0.035% TFA) and H2O (0.05% TFA)
  12. customevaporated to a minimal volume

Sources & evidence

ORD record
ord-96c49172f8eb4db0afbe0521b8b1c109
Source dataset
uspto-grants-2015_06
Patent number
US09056873B2

Reaction notes

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