2-Amino-5-chlorothiazole hydrochloride → (S)-N-(5-Chloro-thiazol-2-yl)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide

HRID 1018837Notes

Reaction equation

HRID 1018837 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.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][C:45]=3[F:48])[C:40]2=[O:49])[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.Cl.[NH2:51][C:52]1[S:53][C:54]([Cl:57])=[CH:55][N:56]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[Cl:57][C:54]1[S:53][C:52]([NH:51][C:36](=[O:38])[C@@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][C:45]=3[F:48])[C:40]2=[O:49])[CH2:34][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[N:56][CH:55]=1

Participants

5

Reactant 4

HCID 1487432-Amino-5-chlorothiazole hydrochlorideHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 9947513(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamideHCID 67484493(S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid

Product 1

HCID 10295765(S)-N-(5-Chloro-thiazol-2-yl)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionamideYield 28%

Procedure

BOP coupling of (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (ca. 1:1 mixture of regioisomers, prepared in Step C; 501 mg; 1.64 mmol) and 2-amino-5-chlorothiazole hydrochloride (643 mg; 3.64 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as outlined in Example 9, Step B) provided after normal phase HPLC (Waters Prep. 500, loaded on column with methylene chloride, eluent: 20% ethyl acetate/hexanes) 194 mg of (S)-N-(5-Chloro-thiazol-2-yl)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide: EI-HRMS m/e calcd for C20H21ClFN3O2S (M+) 421.1027, found 421.1024; and 173 mg of regioisomeric (S)-N-(5-Chloro-thiazol-2-yl)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide: EI-HRMS m/e calcd for C20H21ClFN3O2S (M+) 421.1027, found 421.1031.

Sources & evidence

ORD record
ord-6e10d02019ed4ec191c57a488cf0e5bf
Source dataset
uspto-grants-2002_11
Patent number
US06482951B2

Reaction notes

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