Procedure for the synthesis of acid compounds (2S, 3aS, 7aS) - 1 - (S) - alanil - octahidro - 1H indole - 3 - carboxylic acid and application in the synthesis of perindopril.

摘要

Claim 1: procedure for the synthesis of the compounds of formula (1) wherein R represents a H Atom or a protecting Group for the amino function.Wherein the benzyl ester of formula (ii) or (2b); addition of a Salt or Ester of formula (ii) or (2b) with a Mineral acid or an organic acid undergoes reaction with alanine Compound of formula (3), in which R? ? represents a protective Group for the amino function.In the presence of a coupling Agent selected among the following pairs of Reagents and Reagents; hydrochloride (1.3 - dimetilaminopropil) - ethyl - 3 - CARBODIIMIDE hydrochloride (1.3 - dimetilaminopropil) - ethyl - 3 - CARBODIIMIDE hydrochloride / 1-hydroxybenzotriazole (1.3 -, Ethyl - 3 - dimetilaminopropil) - CARBODIIMIDE / 1 - hydroxy - 7 - (1, azabenzotriazol, hydrochloride3-dimethylaminopropyl CARBODIIMIDE) - ethyl - 3 - / N - hidroxisuccinimida, hydrochloride (1.3 - dimetilaminopropil) - ethyl - 3 - hydroxy - 3 - CARBODIIMIDE / 3,4 dihydro - 4 - oxo - 1,2,3 - benzotriazina, hydrochloride (1.3 - dimetilaminopropil) - ethyl - 3 - CARBODIIMIDE / N - hidroxiftalimida, dicyclohexylcarbodiimide 7 / 1 - hydroxy - azabenzot Riazol, dicyclohexylcarbodiimide / N - hidroxisuccinimida, dicyclohexylcarbodiimide / 3 - hydroxy - 34 - dihydro - 4 - oxo - 1,2,3 - dicyclohexylcarbodiimide benzotriazina, hidroxiftalamida hexafluorophosphate / N -, o - (benzotriazole - 1 - il) - 3-amino-3 - tetrametiluronio, hexafluorophosphate (azabenzotriazol - or - 7 - 1 - il) - 3-amino-3 - tetrametiluronio, tetrafluoroborate (benzotriazole or - - 1 - - il) 3-amino-3 - tetrametiluronio, Hex Afluorofosfato of benzotriazole - 1 - il - oxitripirrolidinofosfonio,Hexafluorophosphate benzotriazole - 1 - il - Oxy - tris (dimethylamino) phosphonium hexafluorophosphate (benzotriazole -, or - 1 - il) - 3-amino-3 - (bis tetrametilen) uronio hexafluorophosphate (benzotriazole -, or - 1 - il) - 3-amino-3 - (bis Pentametilen uronio hexafluorophosphate), Chlorine tripirrolidinofosfonio, hexafluorophosphate C Parrot - 3-amino-3 - (bis tetrametilen) offers formamidinio hexafluorophosphate, chlorine -,3 - (bis Pentametilen) formamidinio, N - Ethoxycarbonyl - 2 - ethoxy - 1,2 - or - dihidroquinoleina, tetrafluoroborate cianometilenamino] - [(ethoxycarbonyl) - 3-amino-3 - tetrametiluronio tetrafluoroborate, or - (3,4 dihydro - 4 - oxo - 1,2,3 - benzotriazin IL - 3 - 3-amino-3 - tetrametiluronio tetrafluoroborate), or - (3,4 Dihydro - 4 - Benzotriazin 3 - oxo - 1,2,3 - il) - 3-amino-3 - tetrametiluronio / 1-hydroxybenzotriazole.Tetrafluoroborate or - (3,4 dihydro - 4 - oxo - 1,2,3 - benzotriazin - 3 - yl) - 3-amino-3 - metilmorfolina tetrafluoroborate tetrametiluronio / n, o - (3,4 dihydro - 4 - oxo - 1,2,3 - benzotriazin - 3 - yl) - 3-amino-3 tetrametiluronio / collidine, tetrafluoroborate (1,2 dihydro - or 1 - 2 - oxo - pyridyl) - 3-amino-3 - tetrametiluronio, tetraflu Oroborato o - (1,2 - dihydro - 1 - 2 - oxo - pyridyl) - 3-amino-3 - tetrametiluronio / 1-hydroxybenzotriazole.Hexafluorophosphate (or 1,2 dihydro - 1 - 2 - oxo - pyridyl) - 3-amino-3 - (bis tetrametilen uronio hexafluorophosphate), or - (1,2 - dihydro - 1 - 2 - oxo - pyridyl) - 3-amino-3 - (bis tetrametilen) uronio / 1 - hydroxy benzotriazole, tetrafluoroborate or - (n Succinimidyl) - 3-amino-3 - tetrametiluronio tetrafluoroborate, or - (N - succinimid IL) - 3-amino-3 - bis (tetrafluoroborate uronio, tetrametilen) or - (N - Succinimidyl) - offers,3 - (bis tetrametilen) uronio / 1 - hydroxy benzotriazole, tetrafluoroborate (norbornene or - 5 - - 2.3 - dicarboximido) - 3-amino-3 - tetrametiluronio propanofosfonico acid, anhydride, Imide N - hydroxy - 2.3 - 5 - norbornene acid and N - hydroxy - 1,2 Dihydro pyridine - 2 - oxo - optionally in the presence of a Bas E, to obtain the compound of formula (4a) and (4b), respectively.As if using the compound of formula (ii) or (b) as starting material, in which R? ? is as defined above, which is subjected to a catalytic hydrogenation reaction in the presence of Palladium to obtain the product of formula (1).