Hydrochloric Acid → Methyl hydrogen heptane-1,7-dioate

Participants

Reaction Steps

According to a feature of the present invention there is provided, a process for the synthesis of EXOCHELIN 772SM(R) comprising the steps of reacting a mixture of pimelic acid, dimethyl pimelate, hydrochloric acid, methanol and di-n-butyl ether to produce methyl hydrogen pimelate and then mixing the methyl hydrogen pimelate with thionyl chloride and dimethyl formamide to generate methylpimeloyl chloride which was stored for later reaction. This was then added to a suspension of O-benzyl hydroxylamine hydrochloride and triethyl amine in CH2Cl2 to produce O-benzylmethylpimelyl hydroxamate. To a solution of (L)-6-hydroxynorleucine and triethylamine in a tetrahydrofuran (THF)-water mixture a solution of di-tert-butyl dicarbonate in THF was added. An aqueous layer was then acidified to a pH 3 with citric acid and extracted with EtOAc. The organic layer was dried and purified to produce (L)-N-Boc-6-hydroxynorleucine (L)-N-Boc-6-hydroxynorleucine was reacted with allyl bromide to produce (L)-N-Boc-6-hydroxynorleucine allyl ester. To (L)-N-Boc-6-hydroxynorleucine allyl ester and carbon tetrabromide in anhydrous CH2Cl2 was added triphenylphosphine to provide a viscous oil, which was then added to EtOAc/hexane and (L)-N-Boc-6-bromonorleucine allyl ester was recovered. A mixture of (L)-N-Boc-6-bromonorleucine allyl ester, O-benzylmethylpimelyl hydroxamate, potassium iodide (Kl) and potassium carbonate in anhydrous acetone was prepared and (L)-N6-methylpimelyl-N6-(benzyloxy)-N2-Boc-lysine allyl ester was recovered. Trifluoro acetic acid was added to the (L)-N6-methylpimelyl-N6-(benzyloxy)-N2-Boc-lysine allyl ester to form a solid intermediate which was added to (L)-N-(2-(benzyloxy)benzoyl)serine and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline to produce a light brown viscous oil identified as (L)-N6-Methylpimelyl-N6-(benzyloxy)-N2-((L)-N-(2-(benzyloxy)benzoyl)serine)-lysine allyl ester. Thionyl chloride was gradually added to a cooled (−30° C. bath) solution of the lysine allyl ester in anhydrous tetrahydrofuran (THF) and the golden colored oil was then purified to provide a light brown viscous oil identified as (L)-N6-Methylpimelyl-N6-(benzyloxy)-N2-((S)-2-(2-benzyloxy)phenyl)-2-oxazoline-4-carbonyl)-lysine allyl ester. To the solution of oxazoline-lysine allyl ester in anhydrous CH2Cl2 was added morpholine and tetrakis(triphenylphosphine)palladium to provide an acid. To a solution of acid and (L)-Nα-((S)-3-hydroxybutyryl)-α-amino-N-(benzyloxy)caprolactam in anhydrous THF was gradually added diethyl azodicarboxylate. The material isolated was mixed with MeOH, palladium and hydrogen. The mixture was filtered and the solvent was subsequently removed under reduced pressure and co-evaporated with CH2Cl2 to provide an off-white flaky solid determined by NMR analysis indicated to be Exochelin 772SM(R) shown as formula 1a.

Provenance & Evidence