Synthesis Of Perindopril And Its Intermediates

Perindopril, a non-thiohydroxy ACE inhibitor, launched in France in 1989, in used for the treatment of hyperpiesia and congestive heart failure with high activity, less side-effect and lower tolerance. The purpose of our work is to discover a practical synthesis of perindopril.The route of active ester was designed and researched in this paper on the basis of referesces from L-norvaline and (2S,3aS,7aS)-2-carboxyoctahydroindole. The structure of perindopril eburmine was confirmed by the application of ¹H-NMR, ¹³C-NMR and IR spectra.With valeric acid as the initial material, acyl chloridation and α-position bromization were completed in one-pot to achieve α-brominevaleryl chloride with 84.7% yield. Then the aminolysis of α-brominevaleryl chloride with ammonia in the autoclave producted in 88.7% yield at 100℃ and 5.1MPa. Rather than the aminolysis at high pressure and temperature in the autoclave, the tube aminolysis technology was adopted in the paper, and at the appropriate conditions of 90 ℃, 6.5MPa, 10mins residence-time and n_NH3 : n_{brominevalerylchloride} =12, the yield ofDL-norvaline amide was 89.2%.A chiral resolving reagent L-tartaric acid was used, and DL-norvaline amide was resolved by separating the salt of L-norvaline amide L-tartaric acid. ThenL-norvaline was achieved with [a]_D²⁰=+22.6(c=10, 20% hydrochloric acid) viacation-exchange and hydrolysis on a D001 macroporous strong acidic cation exchange resin. The total yield over those three steps was 26.7%. The D-norvalinewas also achieved with [a]_D²⁰=-21.75(c=10, 20% hydrochloric acid) from thetreatment of the exhaust liquid with D-tartaric acid. The recovery of L-tartaric acid and D-tartaric acid were 33.3% and 53.3% respectively and the resin could also be reused.Ethyl L-norvaline ester hydrochloride was prepared by two routes, with the regent of SOCl₂ and HCl, giving the yield of 92.4% and 83.5%, respectively. On the other hand, with the catalyst of D001 macroporous strong acidic cation exchange resin, ethyl L-norvaline ester was also prepared with the yield of 85.3%.Catalyzed by 5%Pd-C, N-[(S)-1-carbethoxybutyl]-(S)-alanine was synthesized via reductive amination at 0.5MPa and 20℃ with the yield of 79.9% and[α]_D²⁰=+4.6(c=1,EtOH).In order to explain the mechanism of the stereoselective of the reductive amination, a conjecture was put forward in the paper. We considered that because of intramolecular hydrogen-bonding, the structure of 8-cyclic ring-like was formed in the imine molecule which caused the stereoselective of the reductive amination.(S)-2-Carboxyindoline was prepared with two routes, chiral resolution and rational synthesis. By using chiral resolution, (S)-2-carboxyindoline was proposed which starting from o-nitrotoluene and diethyl oxalate, via condensation, nitro-group reduction, heterocyclic reduction, hydrolysis, 2-Carboxyindoline was achieved with 40.6% yield. Especially, using 10% Pt-C as catalysts, the pyrrole was reduced easily with hydrogen at 160℃ and 6.2 MPa, the catalysts also could be reclaimed. (S)-2-carboxyindoline was prepared from resolution with L-carnitine oxalate as chiral reagent, after converted to acid chloride, through the steps of esterification, fractional crystallization, hydrolysis, the product was achieved with 32.0% yield and[α] ₅₈₉²⁰, = -26.5(c = 1.0, DMSO).By using rational synthesis, (S)-2-carboxyindoline was proposed which starting from L-phenylalanine, via chlorination, cyclization and reduction, 2-carboxyindolinewas achieved with 30.1 % yield and [α]₅₈₉²⁰ = -27.5(c = 1.0, DMSO).(2S,3aS,7aS)-2-Carboxyoctahydroindole was synthesized by reduced the (S)-2-carboxyindoline with 5%Pd-C, and the reaction conditions were 40℃, 6.0MPa and 10h. The yield was 75%. Catalyzed by para-toluensulfonate, the para-toluensulfonate of the benzyl ester of (2S,3aS,7aS)-2-carboxyoctahydroindole was synthesized from (2S,3aS,7aS)-2-carboxyoctahydroindole and benzyl alcoholwith the yield of 90.6%.Finally, perindopril eburmine was prepared from the N-[(S)-1-carbethoxybutyl]-(S)-alanine and the para-toluensulfonate of the benzyl ester of (2S,3aS,7aS)-2-carboxyoctahydroindole, via condensation, catalytic hydrogenation, forming salt. The yield of condensation was 81%. Especially, using 5% Pd-C as catalysts, the product of condensation reaction was reduced easily with hydrogen, and then forming salt with tert-butylamine. The yield for these two steps was 82.8%.