Hexamethyldisilazane → Letrozole

HRID 646656

Reaction equation

HRID 646656 reaction equation
C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C[Si](C)(C)N[Si](C)(C)C.[NH2-:20].[Na+].[F:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.[NH:31]1[CH:35]=[N:34][C:33]([CH2:36][C:37]2[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=2)=[N:32]1>O1CCCC1.CC(N(C)C)=O.CN(C)C=O>[NH:31]1[CH:35]=[N:34][C:33]([CH2:36][C:37]2[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=2)=[N:32]1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.[CH:25]1[C:26]([C:27]#[N:28])=[CH:29][CH:30]=[C:23]([CH:41]([N:42]2[N:32]=[CH:33][N:34]=[CH:35]2)[C:40]2[CH:43]=[CH:44][C:37]([C:36]#[N:20])=[CH:38][CH:39]=2)[CH:24]=1

Participants

11

Reactant 5

HCID 13838HexamethyldisilazaneHCID 145174-Fluorobenzonitrile2×HCID 24533Sodium amideHCID 2724254Sodium bis(trimethylsilyl)amide2×HCID 178509721HCID 178509721, compound

Product 3

HCID 3902LetrozoleHCID 145174-FluorobenzonitrileHCID 178509721HCID 178509721, compound

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent2×HCID 31374DimethylacetamideSolvent

Procedure

Most preferably, the base is sodium bis(trimethylsilyl)amide, which may be prepared from hexamethyldisilazane and sodium amide, or purchased as a 40 percent solution in tetrahydrofuran. To avoid reaction between the 4-fluorobenzonitrile V and the sodium bis(trimethylsilyl)amide, the base is preferably added gradually to the mixture of synthons (all known procedures first generate the anion of intermediate III prior to bringing it into contact with 4-fluorobenzonitrile V). Approximately equimolar amounts of the intermediate III and 4-fluorobenzonitrile V in dimethylacetamide, dimethylformamide, or tetrahydrofuran provide a yield of about 85 percent by weight of pure letrozole after isolation and purification. As no stoichiometric excess of 4-fluorobenzonitrile V is required, any side-reactions with the base are believed to be negligible.

Sources & evidence

ORD record
ord-af800d977dea40cdaf93e3d2be94c129
Source dataset
uspto-grants-2010_04
Patent number
US07705159B2

Linked notes

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