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WO2000061574A2 - Procede de production d'amidines - Google Patents

Procede de production d'amidines Download PDF

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Publication number
WO2000061574A2
WO2000061574A2 PCT/EP2000/003018 EP0003018W WO0061574A2 WO 2000061574 A2 WO2000061574 A2 WO 2000061574A2 EP 0003018 W EP0003018 W EP 0003018W WO 0061574 A2 WO0061574 A2 WO 0061574A2
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
amidines
formula
thienylmethylamide
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2000/003018
Other languages
German (de)
English (en)
Other versions
WO2000061574A3 (fr
Inventor
Thomas Zierke
Helmut Mack
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BASF SE
Original Assignee
BASF SE
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by BASF SE filed Critical BASF SE
Priority to JP2000610848A priority Critical patent/JP2002541252A/ja
Priority to CA002369267A priority patent/CA2369267A1/fr
Priority to EP00914182A priority patent/EP1169315A2/fr
Priority to AU35590/00A priority patent/AU3559000A/en
Publication of WO2000061574A2 publication Critical patent/WO2000061574A2/fr
Publication of WO2000061574A3 publication Critical patent/WO2000061574A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • C07K5/04—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
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B43/00—Formation or introduction of functional groups containing nitrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention describes a new process for the preparation of amidines which are not substituted on nitrogen and their salts with inorganic or organic acids, characterized in that corresponding carboxamide amides are reacted with Zn in the presence of carboxylic acids such as formic acid, acetic acid, propionic acid.
  • amidines which are important structural elements in a number of biologically active molecules such as fibrinogen antagonists (L. Alig et al., J. Med. Chem. 1992, 32, 4407), thrombin inhibitors (H. Vieweg et al. ' , Pharmazie 1982, 37, 178) or factor Xa inhibitors (T. Nagahara et al., J. Med. Chem. 1993, 36, 1811) already exist, a large number of synthetic methods already exist.
  • Pinner reaction is the conversion of nitriles via thioamides and S-alkylthioimino esters to amidines (H. Bredereck, Chem. Ber. 1957, 90, 1837). This method is widely used when it comes to building up the amidine functionality in complex compounds such as synthetic thrombin inhibitors (B. Voigt, Pharmazie, 1983, 38, 835). However, the method can only be used for the production of small laboratory quantities.
  • amidines consists in the hydrogenolytic cleavage of the NO bond of carboxylic acid amidoximes (H.Jendralla et al., Tetrahedron 1995, 51, 12047; BD Judkins, Synth. Commun. 1996, 26, 4351) with hydrogen and 5 palladium / carbon catalysts. This method cannot be used for the synthesis of amidines, which may contain functionalities which can be hydrogenated, such as CC double bonds, benzyl-substituted 0 or N atoms, etc.
  • integrin receptor antagonists such as fibrinogen receptor antagonists, or serine protease inhibitors, there in particular thrombin inhibitors, factor Xa inhibitors, factor villa inhibitors, factor IXa inhibitors , 5 urokinase inhibitors, tryplase inhibitors, complement inhibitors (for example Ci s and C ⁇ r ), which contain substituted thienylamidines as structural elements:
  • One of the objects of the invention was to find a method which also enables the preparation of substituted amidines in a simple manner, with good yields and on an industrial scale.
  • Aryl and He arylamidine syntheses are of particular interest, in particular those of thienylamidines.
  • the invention relates to a new generally applicable process for the preparation of amidines which are not substituted on nitrogen and their salts with inorganic or organic acids, characterized in that a corresponding carboxamide amide oxime with Zn in the presence of carboxylic acids such as formic acid, acetic acid, propionic acid, preferably acetic acid, implements.
  • the new process can also be used to prepare substituted thienylamidines, preferably those in which the amidine function is either in the 2-position or 3-position and another substituent in one of the three other positions with respect to sulfur, the substituent in turn via a C, N or O atom is bonded to the thiophene radical.
  • amidines of the formula I can be prepared by the process according to the invention
  • Ci-C ß- alkyl-CO with alkyl meaning straight-chain or branched alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl,
  • Aryl such as phenyl, naphthyl, or heteroaryl such as pyridyl, thienyl, furyl, benzothiazolyl, benzimidazolyl, where these aromatics can optionally be substituted one or more times.
  • substituents are Ci-C ⁇ - alkyl, Ci-Cg-alkoxy, halogen, amino, mono- or di-Ci-C ⁇ - alkylamino.
  • an ⁇ -amino acid fragment in the R or S configuration the N atom of which is protected or unprotected in the usual manner as tert-butoxycarbonyl or benzyloxycarbony derivative, preferably the amino acid fragments 3, 4-dehydroproline, 4,5-dehydro - pipecolic acid, azetidine, proline, pipecolic acid, a dipeptide fragment, optionally substituted one or more times at the N-terminus, consisting of the natural amino acids, the corresponding D-amino acids or the very similar amino acids in the L or D form, preferably combinations of the amino acids 3, 4-dehydroproline , 4,5-dehydropipecolic acid, azetidine, proline, pipecolic acid, phenylalanine, phenylglycine, cyclohexylalanine, cyclohexylglycine, alanine, valine, glycine, particularly preferably combinations of the amino acids azetidine, proline, 3,
  • Carboxylic acid amidoximes of the formula II are used for this
  • n and R have the same meaning as in formula I, with Zn in the presence of carboxylic acids such as formic acid, acetic acid, propionic acid, preferably acetic acid, to give the corresponding amidines of the formula I.
  • carboxylic acids such as formic acid, acetic acid, propionic acid, preferably acetic acid
  • the carboxylic acid amidoximes required to carry out the process according to the invention are prepared by known methods (F. Eloy et al., Chem. Rev. 1962, 62, 155) by reacting the corresponding nitriles with hydroxylamine or preferably its salts, particularly preferably hydroxylamine. Hydrochloride.
  • the corresponding hydroxylamine derivative is preferably used in a 1 to 3-fold excess.
  • the reaction is carried out in an inert solvent.
  • Preferred solvents are alcohols such as methanol, ethanol, n-propanol, iso-propanol or n-butanol, possibly in a mixture with methylene chloride, toluene or water.
  • salts of hydroxylamine are used, at least one equivalent of a stronger base than hydroxylamine itself must be added to release the hydroxylamine.
  • the base can also be used in excess, based on the hydroxylamine salt.
  • inorganic bases such as sodium carbonate (F. Tiemann, Chem. Ber. 17, 1884, 126), metal alcoholates such as sodium methylate or potassium tert-butoxide (BD Judkins, Synth. Commun. 1996, 26, 4351) are particularly suitable as bases but preferably also tert.
  • Amines such as triethylamine (H. Jendralla et al., Tetrahedron 1995, 51, 12047) or diisopropylethylamine in
  • the reaction takes place at room temperature, but to accelerate it can also be heated to the boiling point of the reaction solution, but usually not higher than 80 ° C.
  • the amidines are preferably synthesized by the process according to the invention by converting the carboxamide oximes into an acetic acid solution, where they are reacted by adding metallic zinc, which is usually used as a fine powder.
  • the reaction is usually carried out in a pure acetic acid solution. However, it is also possible to carry out the reaction in, for example, propionic acid solution or in a solvent mixture.
  • alcohols such as methanol, ethanol, n-propanol, isopropanol and n-butanol are suitable.
  • the zinc is used in excess of up to 10 equivalents.
  • the reaction can be carried out in a temperature range from -10 ° C to 70 ° C, a temperature range between 20 and 50 ° C is preferred.
  • the conversion can be checked by means of thin layer chromatography. A reaction time of 2 to 5 hours is usual. But it is also possible to stir at 20 ° C for a long time.
  • Refurbishing is easy. Excess zinc and the resulting zinc salts are filtered off and concentrated.
  • the reaction products can either be isolated and characterized at this stage or can be directly implemented further.
  • any protective groups such as tert-butyl ester or N-tert. -Butoxycarbonyl groups can advantageously be carried out after the solid Zn residues have been separated off without intermediate isolation.
  • the CHC1 2 phase was washed with water, which was adjusted to pH 12 with sodium hydroxide solution. After the phase separation, the water phase was re-extracted with CH 2 C1 2 . The combined CH 2 C1 2 phases were washed neutral and concentrated. Weight: 2.4 g solidified foam I3c-NMR (DMSO; ppm): 158.8 (broadened, amidine)

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)

Abstract

Procédé permettant de produire des amidines non substituées au niveau de l'atome d'azote et leurs sels d'acides inorganiques ou organiques, qui consiste à faire réagir les amidoximes carboxyliques correspondantes avec du Zn en présence d'acides carboxyliques.
PCT/EP2000/003018 1999-04-09 2000-04-05 Procede de production d'amidines Ceased WO2000061574A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2000610848A JP2002541252A (ja) 1999-04-09 2000-04-05 アミジンの製造
CA002369267A CA2369267A1 (fr) 1999-04-09 2000-04-05 Procede de production d'amidines
EP00914182A EP1169315A2 (fr) 1999-04-09 2000-04-05 Procede de production d'amidines
AU35590/00A AU3559000A (en) 1999-04-09 2000-04-05 Method for producing amidines

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE19915930 1999-04-09
DE19915930.0 1999-04-09
DE19933873.6 1999-07-23
DE19933873 1999-07-23

Publications (2)

Publication Number Publication Date
WO2000061574A2 true WO2000061574A2 (fr) 2000-10-19
WO2000061574A3 WO2000061574A3 (fr) 2001-04-26

Family

ID=26052817

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2000/003018 Ceased WO2000061574A2 (fr) 1999-04-09 2000-04-05 Procede de production d'amidines

Country Status (5)

Country Link
EP (1) EP1169315A2 (fr)
JP (1) JP2002541252A (fr)
AU (1) AU3559000A (fr)
CA (1) CA2369267A1 (fr)
WO (1) WO2000061574A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002060861A1 (fr) * 2001-01-29 2002-08-08 Teijin Limited Derives de benzamidine et procede de production de ces derives
WO2006101860A1 (fr) * 2005-03-16 2006-09-28 Janssen Pharmaceutica N.V. Nouveaux composes de thiophene sulfoximine destines a traiter des maladies et des etats pathologiques associes au complement

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2375611A (en) * 1941-08-19 1945-05-08 May & Baker Ltd Production of amidines
US2851490A (en) * 1955-04-20 1958-09-09 Monsanto Chemicals Guanyl aliphatic mono-carboxylic acids
DE19632773A1 (de) * 1996-08-14 1998-02-19 Basf Ag Neue Thrombininhibitoren

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002060861A1 (fr) * 2001-01-29 2002-08-08 Teijin Limited Derives de benzamidine et procede de production de ces derives
WO2006101860A1 (fr) * 2005-03-16 2006-09-28 Janssen Pharmaceutica N.V. Nouveaux composes de thiophene sulfoximine destines a traiter des maladies et des etats pathologiques associes au complement
US7385066B2 (en) 2005-03-16 2008-06-10 Janssen Pharmaceutica N.V. Thiophene sulfoximines, compositions thereof, and methods of treating complement-mediated diseases and conditions
US7868023B2 (en) 2005-03-16 2011-01-11 Janssen Pharmaceutica Nv Thiophene sulfoximines, compositions thereof, and methods of treating complement-mediated diseases and conditions

Also Published As

Publication number Publication date
WO2000061574A3 (fr) 2001-04-26
AU3559000A (en) 2000-11-14
JP2002541252A (ja) 2002-12-03
CA2369267A1 (fr) 2000-10-19
EP1169315A2 (fr) 2002-01-09

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