tert-Butyl methyl ether → Cyclohexanethiol
Reaction equation
[CH3:1][CH:2]([CH2:4][C@H:5]([CH2:10]N)[CH2:6][C:7]([OH:9])=[O:8])[CH3:3].[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[N:23]=[CH:22][CH:21]=[C:20]([C@H:24]([OH:35])[C@@H:25]3[N:30]4[CH2:31][C@H:32]([CH:33]=[CH2:34])[CH:27]([CH2:28][CH2:29]4)[CH2:26]3)[C:18]=2[CH:19]=1.[NH2:36][C:37]([NH2:39])=[S:38].C[O:41][C:42](C)(C)C>>[CH2:4]([CH:5]1[CH2:10][C:12](=[O:13])[O:9][C:7](=[O:8])[CH2:6]1)[CH:2]([CH3:3])[CH3:1].[CH:14]1([SH:38])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1.[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[N:23]=[CH:22][CH:21]=[C:20]([C@H:24]([OH:35])[C@@H:25]3[N:30]4[CH2:31][C@H:32]([CH:33]=[CH2:34])[CH:27]([CH2:28][CH2:29]4)[CH2:26]3)[C:18]=2[CH:19]=1.[NH2:36][C:37]([NH2:39])=[S:38].[CH:18]1([S:38][C:42]([CH2:10][C@@H:5]([CH2:4][CH:2]([CH3:3])[CH3:1])[CH2:6][C:7]([OH:9])=[O:8])=[O:41])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:19]1Participants
7
Procedure
FIG. 4 demonstrates a room temperature enantioselective synthesis of (S)-pregabalin in the presence of catalytic quantities of epimeric quinidine thiourea C2. Thiolysis of 3-isobutylglutaric anhydride with cyclohexane thiol in methyltertbutylether (MTBE), at room temperature (rt) in the presence of catalytic quantities of C2 affords (S)-3-cyclohexylsulfanylcarbonylmethyl-5-methyl-hexanoic acid in quantitative yield and in 92% ee (the ee increased to 94% when the reaction was carried out at 0° C.). Aminolysis of resulting thioester intermediate at 40° C. over 1.6 h afforded (S)-3-Carbamoylmethyl-5-methyl-hexanoic acid in 88% yield. This primary amide intermediate was subjected to a Hofmann rearrangement to afford (S)-pregabalin.
Workup
- customdemonstrates a room temperature
Sources & evidence
- ORD record
- ord-965583cabf5a4d74a493ae9a3b4eb8ab
- Source dataset
- uspto-grants-2013_07
- Patent number
- US08476441B2
Reaction notes
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