Pivalaldehyde → HCID 135505743, compound

HRID 2181780Notes

Reaction equation

HRID 2181780 reaction equation
[CH3:1][C@:2]([C:6]([OH:8])=[O:7])([CH2:4][SH:5])[NH2:3].CO[C:11](=O)[C@@H:12]([CH2:14]S)N.[CH3:17][C:18]([CH:21]=[O:22])(C)[CH3:19].C([N-]C(C)C)(C)C.[Li+]>>[OH:22][C:21]1[CH:14]=[CH:12][CH:11]=[CH:17][C:18]=1[C:19]1[S:5][CH2:4][C@:2]([CH3:1])([C:6]([OH:8])=[O:7])[N:3]=1

Participants

5

Reactant 4

HCID 12417PivalaldehydeHCID 443999HCID 443999, compoundHCID 2724682Lithium diisopropylamideHCID 9898840(S)-ALPHA-METHYLCYSTEINE

Product 1

HCID 135505743HCID 135505743, compound

Procedure

Substituted thiazolines, such as, for example, 4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methylthiazole-4-(S)-carboxylic acid, 4,5-dihydro-2-(2,3-di-hydroxyphenyl)-4-methylthiazole-4-(S)-carboxylic acid, 4,5-dihydro-2-(2-hydroxy-3-methoxyphenyl)-4-methylthiazole-4-(S)-carboxylic acid, 4,5-dihydro-2-(4-carboxy-2-hydroxyphenyl)-4-methylthiazole-4-(S)-carboxylic acid, 4,5-dihydro-2-(2-hydroxyphenyl)-4-methylthiazole-4-(S)-carboxylic acid, 4,5-dihydro-2-(3-hydroxyquinolin-2-yl)-4-methylthiazole-4-(S)-carboxylic acid, 4,5-dihydro-2-(2-hydroxynaphth-1-yl)-4-methylthiazole-4-(S)-carboxylic acid, 4,5-dihydro-2-(3-hydroxynaphth-2-yl)-4-methylthiazole-4-(S)-carboxylic acid, 4,5-dihydro-2-(2-hydroxyphenylmethyl)-4-methylthiazole-4-(S)-carboxylic acid, etc. are potential iron chelators. The preparation of these compounds is carried out via the coupling of (S)-α-methylcysteine or of a salt thereof with the appropriate nitrile or imidoester compound and has already been described in the literature. Thus, the coupling of (S)-α-methylcysteine hydrochloride with 2,4-dihydroxy-benzonitrile is carried out, for example, according to J. Med. Chem. 1999, 42, 2432-2440 in degassed methanol by heating at 71° C. for 3 days with addition of degassed phosphate buffer to achieve a pH of 6, whereby, after working up the reaction mixture, 4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methylthiazole-4-(S)-carboxylic acid is obtained in 57% yield. Analogously, 4,5-dihydro-2-(2-hydroxyphenyl)-4-methylthiazole-4-(S)-carboxylic acid is prepared in a yield of only 32%. An important intermediate compound for the synthesis of the abovementioned target compounds is in this case (S)-α-methylcysteine, which is obtained, for example, according to Tetrahedron 1993, 49 (24), 5359-5364 in a Seebach-analogous synthesis by acidic hydrolysis of 2S,4S-methyl 2-tert-butyl-1,3-thiazolidine-3-formyl-4-methyl-4-carboxylate. 2S,4S-Methyl 2-tert-butyl-1,3-thiazolidine-3-formyl-4-methyl-4-carboxylate is in this case prepared starting from (S)-cysteine methyl ester and pivaldehyde via 2S-methyl 2-tert-butyl-1,3-thiazolidine-4-carboxylate, introduction of a formyl protective group to give 2S,4S-methyl 2-tert-butyl-1,3-thiazolidine-3-formyl-4-carboxylate, reaction at −78° C. with lithium diisopropylamide to give the corresponding enolate and quenching of the enolate with methyl iodide. The yield of (S)-α-methylcysteine starting from (S)-cysteine methyl ester is in this case only 29%. In addition to the low yield of (S)-α-methylcysteine, the laborious process steps and especially the starting material (S)-cysteine methyl ester hydrochloride, a compound which is unnatural, commercially unavailable and therefore not to be taken into consideration for industrial syntheses, are significant disadvantages of this preparation variant.

Workup

  1. customAn important intermediate compound for the synthesis of the abovementioned target compounds
  2. customprepared
  3. customto give

Sources & evidence

ORD record
ord-f6b16ae3a6d44e658cb7011b9e21eb1d
Source dataset
uspto-grants-2005_05
Patent number
US06894170B2

Reaction notes

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