Process for the synthesis of cPLA2 inhibitors
AssigneeWyeth
InventorsChristoph M. Dehnhardt, Sreenivasulu Megati, Ronald S. Michalak, Panolil Raveendranath, Jianxin Ren, Charles C. Wu, Yangzhong Wu
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Abstract
A process for making the compound of formula (I) wherein Ac represents acetate; X represents O or CH2; Y represents C1-C6alkyl; and Z is selected from the group consisting of H, halogen, CN, CHO, CF3, OCF3, OH, C1-C6alkyl, C1-C6alkoxy, C1-C6thioalkyl, NH2, N(C1-C6alkyl)2, NH(C1-C6alkyl), NC(O)—(C1C6alkyl), and NO2. In his process, a compound of formula (II) is reacted with hydrazine to form a primary alkylamine, and then the primary alkylamine is reacted with acetic anhydride, to produce the compound of formula (I).
Claims8
A process for preparing a compound of formula (IV):
- in purified form,
- the process comprising converting a compound of formula (III):
- to the compound of formula (IV) by:
- using an alkali solution to remove the Y from the ester group in the compound of formula (III), thereby forming a carboxylic acid intermediate;
- purifying the carboxylic acid intermediate by slurrying the carboxylic acid intermediate in an organic solvent;
- using an alkali solution to hydrolyze the N-acetyl amide bond in the purified carboxylic acid intermediate, thereby forming an amino acid intermediate;
- and then,
- reacting the amino acid intermediate with R-A-(CH2)n—S(O)2Cl to form the compound of formula (IV);
- wherein:
- n represents an integer from 0 to 4;
- A is a chemical bond, —S—, —O—, —S(O)—, —S(O)2—, —NH—, —C═C—,
- R is a moiety selected from the group consisting of C1-C6 alkyl, C1-C6 fluorinated alkyl, C3-C6 cycloalkyl, tetrahydropyranyl, camphoryl, adamantyl, —CN, —N(C1-C6 alkyl)2, phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, napthyl, morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl, imidazolyl, piperizinyl, thiazolidinyl, thiomorpholinyl, tetrazole, indolyl, benzoxazolyl, benzofuranyl, imidazolidine-2-thionyl, 7,7,dimethyl-bicyclo[2.2.1]heptan-2-onyl, benzo[1,2,5]oxadiazolyl, 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, piperazin-2-onyl or pyrrolyl groups, each optionally substituted by from 1 to 3 substituents independently selected from halogen, —CN, —CHO, —CF3, —OCF3, —OH, C1-C6 alkyl, C1-C6 alkoxy, —NH2, —N(C1-C6 alkyl)2, —NH(C1-C6 alkyl), —NH—C(O)—(C1-C6 alkyl), —NO2, —SO2(C1-C3 alkyl), —SO2NH2, —SO2NH(C1-C3 alkyl), —SO2N(C1-C3 alkyl)2, —COOH, —CH2—COOH, —CH2—NH(C1-C6 alkyl), —CH2—N(C1-C6 alkyl)2, —CH2—NH2, pyridinyl, 2-methyl-thiazolyl, morpholino, 1-chloro-2-methyl-propyl, C1-C6 thioalkyl, phenyl optionally substituted with one or more halogen atoms, benzyloxy, (C1-C3 alkyl)C(O)CH3, (C1-C3 alkyl)OCH3, —C(O)NH2,
- X represents O or CH2;
- Y represents C1-C6 alkyl;
- and
- Z is selected from the group consisting of H, halogen, —CN, —CHO, —CF3, —OCF3, —OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, —NH2, —N(C1-C6 alkyl)2, —NH(C1-C6 alkyl), —NHC(O)—(C1-C6 alkyl), and —NO2;
- wherein the process is carried out without the use of chromatography.
Dependencies are inferred from the claim text.