Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
  • C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
  • C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala

Definitions

• the present invention relates to a process for the synthesis of (2S, 3aS, 7aS) - perhydroindole-2-carboxylic acid, and its application to the synthesis of perindopril and its pharmaceutically acceptable salts.
• the present invention relates to a new process for the synthesis of the compound of formula (I): H
• Perindopril as well as its salts, have interesting pharmacological properties. Their main property is to inhibit the angiotensin I converting enzyme (or kininase II), which on the one hand prevents the transformation of the decapeptide angiotensin I into octapeptide angiotensin II (vasoconstrictor), and on the other hand to prevent the degradation of bradykinin (vasodilator) into an inactive peptide. These two actions contribute to the beneficial effects of perindopril in cardiovascular diseases, especially high blood pressure and heart failure.
• angiotensin I converting enzyme or kininase II
• patent EP 0 037 231 uses as indole 2-carboxylic acid, which is subjected to a catalytic hydrogenation on rhodium to give a mixture of the two cis endo isomers of respective configurations (2S, 3aS, 7aS) and ( 2R, 3aR, 7aR).
• This mixture is then separated in a particularly laborious manner: synthesis of the N-benzoyl derivative, fractional crystallization of the salt of the diastereoisomer with the (S) - ⁇ -phenyl-ethylamine, release of the two derivatives (S, S, S) and (R, R, R) N-benzoylated, then elimination of the benzoyl group, followed by passage through an ion exchange column and recrystallization.
• Patent EP 0 115 345 for this same separation, uses several stages requiring the esterification of the carboxylic acid function with benzyl alcohol, the salification of the amino ester with N-benzyloxycarbonyl- (S) -phenylalanine, separation by fractional crystallization of the (S, S, S) isomer, the release of the amino function optionally followed by the release of the carboxylic acid group.
• the patents EP 0 308 339 and EP 0 308 341 also use as starting material indole 2-carboxylic acid, which is initially reduced to indoline 2-carboxylic acid, to give a mixture of indoline carboxylic acid 2R and 2S , which are then separated by fractional crystallization. The 2S isomer is then subjected to catalytic hydrogenation to yield the compound of formula (I).
• the applicant has now developed a new process for the synthesis of the compound of formula (I), from a particularly inexpensive raw material, which allows the selective obtaining of the diastereoisomer (S, S, S) with a good yield and excellent purity.
• the present invention relates to a process for the synthesis of the compound of formula (I), characterized in that the 2- (hydroxymethyl) -cyclohexanone of formula (III) is condensed:
• non-limiting non-cyclic amines such as triethylamine, diisopropylamine, diisopropylethylamine and cyclic amines such as piperidine, morpholine, pyrrolidine, may be mentioned without limitation.
• pyridine non-limiting non-cyclic amines such as triethylamine, diisopropylamine, diisopropylethylamine and cyclic amines such as piperidine, morpholine, pyrrolidine.
• the preferred organic base is piperidine.
• chiral amines which can be used in the process according to the invention, non-limiting mention may be made of ⁇ -methylbenzylamine, l- (l-naphthyl) -ethylamine, ephedrine, ⁇ - chymotrypsin, sec-butylamine, 1-amino-2-methylbutane, N, N-dimethyl-1-phenylethylamine, 1-cyclohexylethylamine, cycloserine, 2- (methoxymethyl) - pyrrolidine, ⁇ -dimethylamino- ⁇ -caprolactam, isobomylamine, l- (4-nitrophenyl) - ethylamine, ⁇ -amino- ⁇ -caprolactam, 2-amino-l-butanol, l-amino-2-propanol, cinchonidine, cinchonine, N-methyl-ephedrine , phenylamine
• the preferred chiral amines are ⁇ -methylbenzylamine and l- (l-naphthyl) -ethylamine.
• the compound of formula (I) thus obtained has very good chemical and enantiomeric purity, which makes its use particularly advantageous in the synthesis of perindopril of formula (II).
• Stage B Acid (2RS, 3aRS, 7aRS) -perhydroindole-2-carboxylic: In a hydrogenator, place 200 g of the compound obtained in the previous stage, in solution in acetic acid, then 5 g of Pd / C at 10%. Hydrogenate under pressure of 4 bars at room temperature, until the theoretical amount of hydrogen has been absorbed. Remove the catalyst by filtration, then evaporate the solvent. The residue thus obtained is crystallized, to yield the expected product.
• a precipitate is formed, which is drained, washed and then dried, to yield the expected product with a chemical purity of 98% and an enantiomeric purity of 99%.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Genetics & Genomics (AREA)
• Biochemistry (AREA)
• Biophysics (AREA)
• General Health & Medical Sciences (AREA)
• Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Molecular Biology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Life Sciences & Earth Sciences (AREA)
• Indole Compounds (AREA)
• Peptides Or Proteins (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=28459642

Family Applications (1)

Country Status (10)

Cited By (4)

Families Citing this family (3)

Citations (2)

• 2003
  • 2003-06-13 SI SI200330034T patent/SI1354876T1/xx unknown
  • 2003-06-13 DK DK03291420T patent/DK1354876T3/da active
  • 2003-06-13 AT AT03291420T patent/ATE294161T1/de active
  • 2003-06-13 ES ES03291420T patent/ES2240921T3/es not_active Expired - Lifetime
  • 2003-06-13 DE DE60300558T patent/DE60300558T2/de not_active Expired - Lifetime
  • 2003-06-13 PT PT03291420T patent/PT1354876E/pt unknown
  • 2003-06-13 EP EP03291420A patent/EP1354876B1/fr not_active Expired - Lifetime
• 2004
  • 2004-06-09 WO PCT/FR2004/001427 patent/WO2005003091A1/fr not_active Ceased
  • 2004-06-10 MY MYPI20042237A patent/MY142634A/en unknown
  • 2004-06-11 AR ARP040102021A patent/AR044670A1/es not_active Application Discontinuation

Patent Citations (2)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events