Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate → (S)-3-Cyclohexyl-N-(2-methyl-pyrimidin-4-yl)-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide

HRID 1018866Notes

Reaction equation

HRID 1018866 reaction equation
F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(O)=O)CCCCC1.[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N+:51]=1[O-].[CH:57]1([CH2:63][C@@H:64]([N:73]2[CH2:81][C:80]3[C:75](=[CH:76][CH:77]=[CH:78][CH:79]=3)[C:74]2=[O:82])[C:65]([NH:67]C2SC=CN=2)=[O:66])[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1>>[CH:57]1([CH2:63][C@H:64]([N:73]2[CH2:81][C:80]3[C:75](=[CH:76][CH:77]=[CH:78][CH:79]=3)[C:74]2=[O:82])[C:65]([NH:67][C:52]2[CH:53]=[CH:54][N:49]=[C:50]([CH3:55])[N:51]=2)=[O:66])[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1

Participants

5

Reactant 4

HCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 1477119(S)-3-Cyclohexyl-2-(1-oxoisoindolin-2-yl)propanoic acidHCID 10133709(R)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamideHCID 178507601HCID 178507601, compound

Product 1

HCID 59898551(S)-3-Cyclohexyl-N-(2-methyl-pyrimidin-4-yl)-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide

Procedure

BOP coupling of (S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Example 1, Step A; 287 mg; 1.00 mmol) and 2-aminopyridine N-Oxide (110 mg; 1.00 mmol) in a manner similar to that used for the preparation of (R)-3-cyclohexyl-2-( 1-oxo-1, 3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 9, Step B) provided after flash chromatography (Merck Silica gel 60, 230-400 mesh, eluent: 2% methanol/ethyl acetate) 340 mg (55%)of (S)-N-(pyridin-N-oxide-2-yl)-3-cyclohexyl-2-( 1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide as an off white foam. The product did not appear to be pure by NMR and so it was further purified by reverse phase HPLC (Rainin Dynamax SD-1instrument) using a gradient of 10% acetonitrile/water/0.1% trifluoroacetic acid to 100% acetonitrile on a C18 column to provide 188 mg of pure (S-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-(1-oxy-pyridin-2-yl)-propionamide: ES-LRMS m/e calcd for C22H25N3O3 (M++H+) 380, found 380.

Sources & evidence

ORD record
ord-b2a95a72e62640f5891fe94610b37df3
Source dataset
uspto-grants-2002_11
Patent number
US06482951B2

Reaction notes

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