Diisopropylethylamine → HCID 86761772, compound

HRID 1941862Notes

Reaction equation

HRID 1941862 reaction equation
[F:1][C:2]([F:10])([F:9])[C@@:3]([OH:8])([CH3:7])[C:4](O)=[O:5].N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:44]([O:48][C:49](=[O:68])[NH:50][C:51]1[O:52][CH2:53][C:54]([F:67])([F:66])[C@:55]([C:58]2[CH:63]=[C:62]([NH2:64])[CH:61]=[CH:60][C:59]=2[F:65])([CH3:57])[N:56]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C)C=O.C(#N)C.O.C(O)=O>[C:44]([O:48][C:49](=[O:68])[NH:50][C:51]1[O:52][CH2:53][C:54]([F:67])([F:66])[C@:55]([C:58]2[CH:63]=[C:62]([NH:64][C:4](=[O:5])[C@:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])[CH:61]=[CH:60][C:59]=2[F:65])([CH3:57])[N:56]=1)([CH3:45])([CH3:46])[CH3:47]

Participants

9

Reactant 4

HCID 81531DiisopropylethylamineHCID 2760712(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 58304160HCID 58304160, compound

Product 1

HCID 86761772HCID 86761772, compound

Reagents, catalysts & solvents 4

HCID 284Formic AcidSolventHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolvent

Procedure

A solution of (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid (CAS44864-47-3) (20 mg, 0.125 mmol) in N,N-dimethylformamide (1 ml), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (HATU) (66 mg, 0.167 mmol) and diisopropylethylamine (35 mg, 0.267 mmol) was stirred at room temperature for 45 minutes. Thereafter, [(R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester (30 mg, 0.063 mmol) (intermediate XXV-1) was added and stirring continued at room temperature overnight. For the workup, formic acid was added to the incomplete reaction, the mixture was divided in two portions and directly injected on a preparative HPLC column using a gradient of water (+0.1% of formic acid)/acetonitrile=90:10 to 5:95 as the eluent. The {(R)-5,5-difluoro-4-[2-fluoro-5-((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionylamino)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl}-carbamic acid tert-butyl ester was obtained as a colorless, amorphous solid (8 mg, 25% of theory). MS (ISP): m/z=500.2 [M+H]+. b) (R)—N-[3-((R)-2-Amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propionamide 2,2,2-trifluoroacetate A solution of the {(R)-5,5-difluoro-4-[2-fluoro-5-((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionyl-amino)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl}-carbamic acid tert-butyl ester (8 mg, 0.016 mmol) in 2,2,2-trifluoroacetic acid was stirred at room temperature during 1 hour. Thereafter, the reaction mixture was evaporated at reduced pressure and kept under high vacuum overnight to yield the title compound as yellow oil in quantitative yield. MS (ISP): m/z=400.1 [M+H]+.

Sources & evidence

ORD record
ord-02bd650728934a1093c475dab5cd1c5f
Source dataset
uspto-grants-2013_03
Patent number
US08389513B2

Reaction notes

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