Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
  • C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
  • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/90—Carboxylic acid amides having nitrogen atoms of carboxamide groups further acylated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers

Definitions

• the present invention relates to a chiral ⁇ -amino acid in crystalline form, its preparation process, as well as the use of said chiral ⁇ -amino acid as an intermediate for the synthesis of chiral organic compounds.
• Amino acids are compounds which are very widely used in a very large number of fields. In particular, they are playing an increasingly important role in the synthesis of compounds for pharmaceutical, veterinary and phytopharmaceutical use. In these fields of human, animal and plant health, very active products are constantly sought at low doses.
• One way to combine these two aspects is to use, in the case of compounds having at least one center of asymmetry, only the optical isomer having the desired activity.
• This compound generally has a relatively complex chemical structure, so that the center of chirality is introduced during the synthesis, that is to say that it is provided by a compound with a simpler chemical structure, a synthesis intermediate. for example.
• chiral amino acids occupy a prominent place in these areas of human, animal and plant health.
• the problem that arises is therefore to find methods of synthesizing chiral amino acids which are inexpensive, of easy access from the industrial point of view, and whose yields are high.
• a problem is therefore to be able to separate the desired product from the reaction medium, the product having to have a high chemical and enantiomeric purity
• the product having to have a high chemical and enantiomeric purity
• it is for example advantageous to be able to have the product in crystalline form.
• obtaining amino acids in the form of crystals is a difficult operation and not described, for example for the amino acid called 2-methyl-2-phenylglycine from a medium. reaction.
• a first object of the invention consists in providing a chiral ⁇ -amino acid in crystalline form, more particularly (S) - (+) - methylphenylglycine (or (S) - (+) - 2-phenylalanine) or the (7?) - (-) - methylphenylglycine (or
• a second object of the invention is to propose a process for the preparation of
• a third object of the present invention is the synthesis of chiral organic compounds prepared from (S) - (+) - methylphenylglycine or
• the above parameters are obtained by grinding the product and then analyzed in order to obtain a reference experimental diagram with respect to the resolution of the structure: from this powder is synthesized a single crystal in a solvent or a suitable solvent mixture, for example water, by very slow evaporation; an X-ray diffraction device specially designed for single crystals, all the diffraction lines are analyzed (position, intensity); the crystal parameters are finally obtained using computerized calculation programs.
• a solvent or a suitable solvent mixture for example water
• the crystal defined above also has the following characteristics of not being a solvate, that is to say that the molecule of (S) - (+) - methylphenylglycine or of (_?) - (-) -methylphenylglycine is not linked (chemically and / or physically) to a solvent molecule, and to not contain any solvent in the crystal lattice. It has therefore been discovered the possibility of obtaining (S) - (+) - methylphenylglycine (pure enantiomer) or (_ ⁇ ) - (-) - methylphenylglycine (pure enantiomer) in crystalline form, which has the particular advantage of giving this product great chemical and physical stability over time.
• (S) - (+) - methylphenylglycine or (_ /?) - (-) - methylphenylglycine in crystalline form has the advantage of not being hygroscopic, this allowing handling, storage and easy handling and therefore a major advantage when this product enters, as a raw material, in the synthesis of organic compounds.
• Another object of the present invention therefore relates to the process for the preparation of (S) - (+) - methylphenylglycine (or of (i?) - (-) - methylphenylglycine) in crystalline form, characterized in that than :
• the pH value is gradually reduced, by adding a base or an acid respectively, to an area greater than approximately 4.5 and less than approximately 9.
• the pH value of the reaction medium measured at the start of the crystallization reaction will advantageously be either much less than 4.5, or very much greater than 9, very advantageously, either less than 2 or greater than 12.
• the first crystals appear when the pH reaches values between about 8.5 and 9 or between about 4.5 and 5 pH. These first crystals generally appear without the need initiate crystallization.
• the addition of base or acid can advantageously be slowed down or even stopped to allow formation, ripening, optimal growth of the crystals, this having a direct influence on the physical and chemical quality (yield, purity) of the crystals obtained.
• the crystallization is then continued by continuing the addition of acid or base until a pH value of between approximately 5 and 7 is obtained, preferably between approximately 5 and 6 in order to transform all of the crystal into crystal. amino acid.
• the crystallization yield is then optimal.
• the acid used in the crystallization reaction described above can be a mineral or organic acid.
• a mineral type acid is preferred, although an organic acid is also suitable.
• the base used in the crystallization reaction described above can be an inorganic or organic base.
• a mineral type base is preferred, although an organic base is also suitable. Mention may be made, by way of nonlimiting example, of the bases which can be used, sodium hydroxide or potassium hydroxide.
• a compound facilitating the agglomeration of the crystals (for better filterability for example)
• This compound is advantageously chosen from the range of compounds which are known to facilitate l agglomeration of crystals. These compounds are thus for example chosen from aromatic organic compounds (monochlorobenzene, toluene, etc.).
• reaction medium in order to dissolve the entire reaction medium, it may also be advantageous to heat the reaction medium to obtain perfect solubility before proceeding to the crystallization step.
• This heating step is particularly suitable when the solvent is saturated with salt.
• the temperature to which the reaction medium is heated must be sufficient to allow the total solubilization of the amino acid salt as well as of all the entities present in the medium.
• the reaction medium is heated to a temperature between 50 ° C and 100 ° C, preferably between 65 ° C and 85 ° C.
• reaction medium containing the dissolved amino acid and to be crystallized
• a co-solvent will have the effect of obtaining a reaction medium free of any insoluble material, which is necessary to start the crystallization reaction.
• This co-solvent is advantageously chosen from conventional solvents miscible with water, such as for example an alcohol, such as methanol, ethanol, or also solvents such as dimethylformamide or dimethylsulfoxide.
• the reaction medium containing the (S) - (+) - methylphenylglycine (or (?) - (-) - methylphenylglycine) in the form of a crystal in suspension is then filtered, according to conventional filtration methods, then the crystals are washed and dried. according to conventional techniques known per se.
• the salt of (S) - (+) - methylphenylglycine or (i?) - (-) - methylphenylglycine can be obtained by hydrolysis of phenylhydantoins, as described in the patent application not yet published N ° 9900202 the content of which is included here by reference.
• Other examples of preparation of (S) - (+) - methylphenylglycine or of (i?) - (-) - methylphenylglycine are those using asymmetric synthesis, splitting, balancing enrichment, catalysis reactions enzymatic, as described for example in French patent application No. 2778671, the content of which is included here by reference.
• Another object of the present invention therefore relates to the process for the preparation of certain 2-imidazoline-5-ones and 2-imidazoline-5-thiones of formula (A) from (S) - (+) - methylphenylglycine or (?) - (-) - methylphenylglycine substantially obtained in crystal form according to the process of the present invention.
• the compounds of formula (A) defined below are useful in particular as phytosanitary products and are described in particular in patent application EP-A-0 629 616.
• M represents an oxygen or sulfur atom, or a CH 2 radical, optionally halogen
• arylalkylcarbonyl in particular phenylacetyl and phenylpropionyl
• arylcarbonyl in particular benzoyl, optionally substituted with 1 to 3 groups among R thienylcarbonyl, furylcarbonyl, pyridylcarbonyl, benzyloxycarbonyl, furfuryloxycarbonyl, tetrahydro-furfuryloxycarbonyl, thiénylméthoxycarbonyle, pyridylméthoxy- carbonyl, phenoxycarbonyl or phénylthiolcarbonyle, the phenyl radical being itself optionally substituted with 1 to 3 groups chosen from R 1, alkylthiolcarbonyl, haloalkylthiolcarbonyl, alkoxyalkylthiolcarbonyl, cyanoalkylthiolcarbonyl, benzylthiolcarbonyl, furfurylthi
• - a carbamoyl radical optionally mono or disubstituted by: - an alkyl or haloalkyl group containing from 1 to 6 carbon atoms,
• alkylthioalkylsulfonyl group containing from 3 to 8 carbon atoms or cycloalkylsulfonyl containing from 3 to 7 carbon atoms;
• R 4 and R 5 taken together can also form with the nitrogen atom to which they are attached a pyrrolidino, piperidino, morpholino or piperazino group optionally substituted by an alkyl radical containing from 1 to 3 carbon atoms.
• R 6 represents:
• halogen atom or - an alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio or alkylsulfonyl radical containing from 1 to 6 carbon atoms or
• cycloalkyl radical halocycloalkyle, alkenyloxy, alkynyloxy, alkenylthio, alkynylthio containing from 3 to 6 carbon atoms or
• an amino radical optionally mono or disubstituted by an alkyl or acyl radical containing from 1 to 6 carbon atoms or alkoxycarbonyl containing from 2 to 6 carbon atoms,
• a phenyl, phenoxy or pyridyloxy radical these radicals being optionally substituted with 1 to 3 groups, identical or different, chosen from R 7 , and
• R 7 represents:
• halogen atom chosen from fluorine, chlorine, bromine, iodine or,
• haloalkoxy or haloalkylthio radical containing from 1 to 6 carbon atoms or,
• the radical R represents the methyl radical.
• the radical R 2 represents the phenyl radical
• the radicals R ,, R 4 , R ,, M, p and W are as defined for the compounds of formula (A)
• R represents a hydroxy, alkoxy radical containing from 1 to 6 carbon atoms, benzyloxy, an amino, alkylamino or dialkylamino radical, an alkylamino radical containing from 1 to 6 carbon atoms
• X represents a leaving group such as a halogen atom, chosen from chlorine, bromine and iodine, or a sulfate radical, or alkylsulfonyloxy or arylsulfonyloxy.
• step (e) is described in patent EP-A-0 629 616, the details of which are incorporated here by reference.
• a very particularly preferred compound of formula (A) which can be synthesized from the amino acid in crystal form according to the present invention is (4S) -4-methyl-2-methylthio-4-phenyl- l-phenylamino-2-imidazoline-5-one, special case of the compounds of formula (A) for which the asymmetric carbon atom is of configuration S, W represents the oxygen atom, M represents the sulfur atom , p represents 1, R 3 represents the methyl radical, R 4 represents the phenyl radical. and R 5 represents hydrogen.
• a basic saline solution comprising the sodium salt of (S) - (+) - methylphenylglycine is brought to approximately 70 ° C.
• reaction medium is neutralized with sulfuric acid (95%), with slow stirring (300 revolutions / minute).
• sulfuric acid is carried out over a period of approximately 5 hours, in two parts:
• the suspension of crystals of (S) - (+) - methylphenylglycine is then filtered hot (around 70 ° C).
• the crystals obtained are washed once with water (temperature 20 to 25 ° C) to remove the mother liquors, then once with methanol (temperature 20 to 25 ° C) to remove the water.
• the amino acid in crystalline form is finally dried under reduced pressure (50 mbar) at 100 ° C to be stored.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Applications Claiming Priority (3)

Publications (1)

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• 1999
  • 1999-11-05 FR FR9914196A patent/FR2800734B1/fr not_active Expired - Fee Related
• 2000
  • 2000-11-03 AU AU12869/01A patent/AU1286901A/en not_active Abandoned
  • 2000-11-03 WO PCT/FR2000/003064 patent/WO2001032603A1/fr not_active Application Discontinuation
  • 2000-11-03 JP JP2001534757A patent/JP2003523322A/ja not_active Withdrawn
  • 2000-11-03 BR BR0015216-1A patent/BR0015216A/pt not_active IP Right Cessation
  • 2000-11-03 EP EP00974643A patent/EP1226111A1/fr not_active Withdrawn
  • 2000-11-03 CA CA002389373A patent/CA2389373A1/fr not_active Abandoned

Non-Patent Citations (1)

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