Dichloromethane → BI-135585 monohydrate

HRID 241247Notes

Reaction equation

HRID 241247 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]1=[O:38].ClCCl.C(=O)([O-])[O-].[K+].[K+].C(N[C@H](C(O)=O)CS)(=O)C>CC(O)C>[OH2:12].[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:33]=[CH:34][N:29]([CH3:28])[C:30](=[O:38])[CH:31]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1

Participants

7

Reactant 5

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 12035N-Acetyl-L-CysteineHCID 44599033(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-oneHCID 678142991-Methyl-2-oxo-1,2-dihydropyridine-4-boronic acid

Product 1

HCID 49803362BI-135585 monohydrateYield 88.2%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent2×

Conditions

Temperature
80 °C

Procedure

A reaction flask is charged with (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (19.66 g, 45.47 mmol) (see Ex. 588 of WO/2009/017664), compound 1 (7.65 g, 50.02 mmol), [1,1′-bis(diphenylphosphino)ferroncene]dichloropalladium(II), complex with dichloromethane (37.40 mg, 0.046 mmol), potassium carbonate (18.85 g, 136.42 mmol) and 2-propanol (100 mL). The flask is evacuated and refilled with argon three times. The contents of the reactor are heated to 80° C. and held for about 6 hours at which time compound 1 is completely consumed. The contents of the reactor are then treated with a solution of N-acetyl-L-cysteine (0.75 g, 4.58 mmol) in 2-propanol (100 mL) and stirred at 80° C. for 2 hours. The resultant suspension is then filtered. (The suspension is maintained at 50° C. to 70° C. during the filtration step.) The resultant solids are then rinsed with 2-propanol (50 mL pre-heated to 70° C.). The combined filtrate and washes is heated to 70° C., maintained at reduced pressure until about 150 ml of volatiles are removed, cooled to 65° C., and seeded with compound 2. The resultant suspension is stirred at 60-65° C. for 0.5 hours, cooled to 0° C. over about 2 hours, and maintained at 0° C. for 1 hour. The resultant solids are collected by filtration and washed with cold 2-propanol (50 mL). The solids are then recrystallized from a mixture of 2-propanol (40 mL) and water (200 mL) to provide compound 2 (monohydrate) as a white solid. Yield: 19.38 g, 88.2% yield based on BI135541. Purity: 98.96 wt %. Analysis of the product agrees with the data reported in Example 48, Method 2 of WO/2009/134400 which describes the synthesis of the monohydrate of compound 1 by reacting 4-iodo-1-methylpyridin-2(1H)-one with (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one.

Workup

  1. customThe flask is evacuated
  2. additionrefilled with argon three times
  3. customis completely consumed
  4. filtrationThe resultant suspension is then filtered
  5. temperature(The suspension is maintained at 50° C. to 70° C. during the filtration step
  6. wash) The resultant solids are then rinsed with 2-propanol (50 mL pre-heated to 70° C.)
  7. temperatureThe combined filtrate and washes is heated to 70° C.
  8. temperaturemaintained at reduced pressure until about 150 ml of volatiles
  9. customare removed
  10. temperaturecooled to 65° C.
  11. stirringThe resultant suspension is stirred at 60-65° C. for 0.5 hours
  12. temperaturecooled to 0° C. over about 2 hours
  13. temperaturemaintained at 0° C. for 1 hour
  14. filtrationThe resultant solids are collected by filtration
  15. washwashed with cold 2-propanol (50 mL)
  16. customThe solids are then recrystallized from a mixture of 2-propanol (40 mL) and water (200 mL)

Sources & evidence

ORD record
ord-54570a488e1847ca95223a8f701cc7dd
Source dataset
uspto-grants-2014_02
Patent number
US08648192B2

Reaction notes

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