CA2389373A1 - Chiral (s- or r-methylphenylglycine) amino acid crystal and method for preparing same - Google Patents

Abstract

The invention concerns chiral amino acid, its preparation method, and the use of said chiral amino acid as intermediate for the synthesis of chiral organic compounds.

Description

CHIRAL AMINO ACID CRYSTAL (S- OR R-METHYLPHENYLGLYCIN) AND PROCESS
OF PREPARATION
Field of the invention The present invention relates to a chiral α-amino acid in the form crystalline, its preparation process, as well as the use of said chiral α-amino acid as as an intermediary in the synthesis of chiral organic compounds.
State of the art io [0002] Amino acids are compounds which are very widely used in a very large number of areas. They are taking an increasingly important place important in the synthesis of compounds for pharmaceutical and veterinary use and phytopharmaceutical.
In these areas of human, animal and plant health, it is constantly is looking for very active products at low doses. A way to combine these of them aspects lies in the fact of using, in the case of compounds having at least minus one asymmetry center, only the optical isomer with activity wanted.
It is therefore necessary to find a simple, economical and effective of 2o synthesize this active optical isomer. This compound generally has a relatively complex chemical structure, so that the center of chirality East introduced during the synthesis, i.e. it is brought by a composed of simpler chemical structure, a synthesis intermediate for example.
2s Among the most preferred chiral intermediates, acids amines chirals occupy a prominent place in these areas of human health, animal and vegetable. The problem is therefore to find methods of synthesis of inexpensive chiral amino acids. easy access from point of industrial view, and with high yields.
[000] Methods for preparing amino acids from hydantoins are known for example in patents JP 60224661 and JP 62103049. These processes drive however to racemic amino acids.
3s [0006] Methods for preparing chiral amino acids are already known in the literature. They are mainly based on resolution methods of mixed racemic by liquid chromatography, resolution using alkaloids or through

-2-WO 01/3260

3 PCT / FR00 / 03064 enzymatic process, as for example in the French patent application no still published n ° 98 06339. These different methods of resolution or preparation of chiral compounds present the problem of leading to products in mixed in the reaction medium without it being possible to easily isolate the desired product.
An additional problem is that the amino acids chirals are of an unsatisfactory degree of purity. Indeed, the synthesis of compounds chemicals developed for human, animal and / or plant health uses imposed very pure purity synthesis intermediates.
1o It is also well known that the purity of such chiral intermediates East difficult to control; it is particularly relatively difficult to purities acceptable for such syntheses, i.e. purities greater than 99%.
However, it is well known that a means of obtaining high purity consists in through 1s example to purify the product in the form of crystal. Among these techniques, one can quote for example the recrystallization, which allows, by dissolution crystal then slow recrystallization to obtain a purity close to 100%.
[0009] A problem is therefore to be able to separate the desired product from the medium 2o reaction, the product having to have a chemical and enantiomeric purity high To obtain this high purity, it is for example advantageous to be able to dispose of the product in crystalline form. However, it is well known to those skilled in the art than obtaining amino acids in the form of crystals is a difficult operation and no described for example for the amino acid called 2-methyl-2-phenylglycine with go 2s of a reaction medium.
General definition of the invention [0010] A first object of the invention consists in providing an α-amino acid chiral in crystalline form, more particularly (S ~ - (+) - methylphenylglycine (or 30 (S ~ - (+) - 2-phenylalanine) or (R) - (-) - methylphenylglycine (or (R) - (-) - 2-phenylalanine) in crystalline form.
A second object of the invention is to propose a process for the preparation of (S ~ - (+) - methylphenylglycine or (R) - (-) - methylphenylglycine, in the form crystalline from chiral hydantoins.
A third object of the present invention is the synthesis of compounds organic chirals prepared from (, S ~ - (+) - methylphenylglycine or (R) - (-) - methylphenylglycine in crystalline form.

Detailed definition of the invention Thus, a first object of the present invention relates to the crystal (, S ~ - (+) - 2-methyl-2-phenylglycine and the crystal of (R) - (-) - 2-methyl-2-phenylglycine s (hereinafter called (, S ~ - (+) - methylphenylglycine and (R) - (-) - methylphenylglycine), characterized in that the single crystal is a system orthorhombic crystalline lens, the mesh parameters of which are a = 5.778 ä, b = 6,692 ä, c = 22,127 ~, of space group P2,2,2 ,, and having four molecules per mesh.
[0012] More particularly, the present invention relates to the crystal of (S ~ - (+) - methylphenylglycine and the crystal of (R) - (-) - methylphenylglycine characterized by the following crystallographic parameters of the single crystal ~ Crystal system: orthorhombic;
Is ~ Mesh parameters: a = 5.778 A a = 90 °;
b = 6.692 (i = 90 °;
c = 22.127 ~ y = 90 °;
~ Asymmetric unit: 1 molecule;
~ Spatial group: P2,2,2,;
~ Number of molecules per cell: 4;
~ Mesh volume: 855.6 A3;
~ Calculated density: 1,282 g / cm3 ~ Absorption coefficient ~: 0.91 cm '(CuKa);
2s The above parameters are obtained by grinding the product and then analysis in order to obtain an experimental reference diagram vis-à-vis 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 evaporation slow; a X-ray diffraction apparatus specially designed for single crystals, all rays 3o of diffractions are analyzed (position, intensity); the settings lenses are finally obtained using computerized calculation programs.
The crystal defined above also has the characteristics following of not be a solvate, i.e. the molecule of (S ~ - (+) -methylphenylglycine or 3s of (R) - (-) - methylphenylglycine is not linked (chemically and / or physically) to a molecule of solvent, and not to contain solvent in the mesh crystalline.

-4_ It has therefore been discovered the possibility of obtaining (, S ') - (+) - methylphenylglycine (pure enantiomer) or (R) - (-) -methylphenylglycine (pure enantiomer) in crystalline form, which has the particular advantage of give this product great chemical and physical stability over time.
In s in particular, (, S ~ - (+) - methylphenylglycine or (R) - (-) -methylphenylglycine under crystalline form has the advantage of not being hygroscopic, this allowing easy handling, storage and handling and therefore a asset major when this product enters, as a raw material, in the synthesis of organic compounds.
Another object of the present invention therefore relates to the method of preparation of (S ~ - (+) - methylphenylglycine (or of (R) - (-) -methylphenylglycine) in crystalline form, characterized in that ~ we solubilize (, S ~ - (+) - methylphenylglycine (respectively Is (R) - (-) - methylphenylglycine), in the form of free amino acid or in the form salified, in a pH zone lower than approximately 4.5 or higher than approximately 9, then ~ it is gradually brought back, by adding a base or an acid respectively, pH value in an area greater than about 4.5 and less than about 9.
The pH value of the reaction medium measured at the start of the reaction of Advantageously, crystallization will either be much less than 4.5, or very greater than 9, very advantageously, either less than 2 or more than 12.
2s In the process described above, it is necessary to carry out adding basic or acid to a perfectly solubilized reaction medium, i.e.
free from any trace of non-soluble compound. So in addition to starting the crystallization at pH values very acidic or very basic, it can be advantageous adding one or more suitable solvents, making it possible to dissolve the (S ~ - (+) - methylphenylglycine or (R) - (-) - methylphenylglycine, in the form of free or salified amino acid. Such solvents are solvents usually used to dissolve amino acids, for example water and / or the methanol and / or ethanol, etc.
3s Under the conditions described above, the first crystals appear when the pH reaches values between approximately 8.5 and 9 or between about 4.5 and 5 pH. These first crystals generally appear without it being necessary initiate crystallization. At this stage of crystallization, the addition of base or acid can advantageously be slowed down or even stopped to allow training, a ripening, optimal crystal growth, this having an influence direct on the physical and chemical quality (yield, purity) of the crystals obtained.
s The crystallization is then continued by continuing the addition of acid or from base until a pH value between about S and 7 is obtained, preferably between about 5 and 6 in order to transform all of the amino acid. The crystallization yield is then optimal.
When the starting reaction medium has a pH value better than 9, the acid used in the crystallization reaction described above can to be an acid mineral or organic. We prefer an acid of mineral type, although an acid organic is also suitable. By way of nonlimiting example, we can cite among 1s the acids which can be used hydrochloric acid or acid sulfuric.
When the starting reaction medium has a pH value lower than

4.5, the base used in the crystallization reaction described above maybe a mineral or organic base. We prefer a mineral type base, although a based zo organic is also suitable. By way of nonlimiting example, one can cite among the bases which can be used, sodium hydroxide or hydroxide potassium.
During crystallization, it may be advantageous to add a compound facilitating the agglomeration of crystals (for better filterability through zs example) This compound is advantageously chosen from the range of compounds who are known to facilitate the agglomeration of crystals. These compounds are so by example chosen from aromatic organic compounds (monochlorobenzene, toluene, etc.).
It is possible to further increase the yields, in quantity of crystals operating the installation reaction from solutions of (S ') - (+) - methylphenylglycine or (R) - (+) - methylphenylglycine strongly amino acid concentrates (free or salified). The crystallization will be thus advantageously carried out from solutions whose concentration in amino acid 3s is between 4% and 50% by volume. Concentrations below also lead to crystal formation, but the yields will less high. The upper limit of 50% is given for information only, but it is well it is understood that concentration values greater than 50% are also compatible with the formation of the desired crystals.
It may also be advantageous to dissolve the s (S ~ - (+) - methylphenylglycine or (R) - (-) - methylphenylglycine, in the form salified, using a solvent, water for example, saturated with salt, for example chloride sodium, sodium sulfate or the like.
In addition, in order to dissolve the entire reaction medium, it can to be 1o also advantageous to heat the reaction medium to obtain a perfect solubility before proceeding to the crystallization step. This stage of heating is particularly suitable when the solvent is saturated with salt. Temperature at which is heated the reaction medium must be sufficient to allow the total solubilization of the amino acid salt as well as of all the entities present in i5 the middle. Advantageously, the reaction medium is heated to a temperature between SO ° C and 100 ° C, preferably between 65 ° C and 85 ° C.
In the case where the reaction medium, containing the solubilized amino acid and to be crystallized, contains other insoluble entities, it is then possible 2o to add a co-solvent. This co-solvent will have the effect of obtaining a medium reactive free of any insoluble material, which is necessary to start the reaction of crystallization. This co-solvent is advantageously chnici marmi 1PC enlvante conventional water-miscible, such as for example an alcohol, such as methanol, ethanol, or solvents such as dimethylformamide or 2s dimethyl sulfoxide.
When the crystallization reaction is complete, the medium reactive containing (S ~ - (+) - methylphenylglycine (or (R) - (-) - methylphenylglycine) under crystal form in suspension, is then filtered, according to methods classics of 3o filtration, then the crystals are washed and dried, according to techniques classics known per se. In the case where the crystallization reaction has been carried out hot it it is then advantageous to carry out the hot filtration, at a temperature noticeably equivalent.
(, S ~ - (+) - methylphenylglycine or (R) - (-) - methylphenylglycine (shapes free or salified forms) to be crystallized, are themselves obtained according to conventional techniques known to those skilled in the art and readily accessible in the literature, the "Chemical Abstracts", as well as in the bases of data electronic.
By way of example, the salt of (, S ~ - (+) - methylphenylglycine or s (R) - (-) - methylphenylglycine can be obtained by hydrolysis of phenylhydantoins, as described in the patent application not yet published N ° 9900202 whose Content is included here by reference. Other examples of preparation of (S ~ - (+) - methylphenylglycine or (R) - (-) - methylphenylglycine are those putting in work of asymmetric synthesis reactions, of splitting, enrichment of 1o balancing, of enzymatic catalysis, as described for example in the request French Patent No. 2,778,671, the content of which is included here by reference. It is well understood that (S ~ - (+) - methylphenylglycine or (R) - (-) - methylphenylglycine who can be implemented in the process of the present invention can to be obtained by any method known to those skilled in the art.
1s (, S ~ - (+) - methylphenylglycine or (R) - (-) - methylphenylglycine under crystalline form as described above find application all particularly interesting as synthesis intermediaries in elaboration of chiral active ingredients useful in particular in therapy or Agriculture.
2o Another object of the present invention therefore relates to the method of preparation of some. 2-imidazoline-5-ones and 2-imidazoline-5-thiones from formula (A) from (, S ~ - (+) - methylphenylglycine or from (R) - (-) - methylphenylglycine substantially obtained in crystal form according to the process of present 2s invention. The compounds of formula (A) defined below are useful especially as phytosanitary products and are described in particular in the request for patent EP-A-0 629 616.
These compounds correspond to the general formula (A) in which y (M) a ~ R

NOT
W ~ N - R4 R ~
NOT

_g_ ~ W represents an oxygen or sulfur atom, or a group S = O;
~ M represents an oxygen or sulfur atom, or a CH2 radical, optionally halogenated;
p is an integer equal to 0 or 1;
s ~ R3 represents:
- hydrogen or a C, -C ~ alkyl radical, optionally halogenated, when p equals 0 or (M) P is a CH2 radical, - an optionally halogenated C, -CZ alkyl radical, when (M) P
represents an oxygen or sulfur atom;
io ~ R4 represents - the hydrogen atom, or - an alkyl radical containing from 1 to 6 carbon atoms, or an alkoxyalkyl, alkylthioalkyl, haloalkyl, cyanoalkyl radical, thiocyanatoalkyl, alkenyl or alkynyl containing from 2 to 6 atoms of 1s carbon, or a dialkylaminoalkyl, alkoxycarbonylalkyl radical, or N-alkylcarbamoylalkyle containing from 3 to 6 carbon atoms, or - an N, N-dialkylcarbamoylalkyl radical containing from 4 to 8 atoms of carbon, or zo - an aryl radical, comprising phenyl, naphthyl, thienyl, furyl, pyridyle, pyrimidyle, pyridazinyle, pyrazinyle, benzothienyle, benzofuryl, quinolinyl, isoquinolinyl, or methylene dioxyphenyl, optionally substituted by 1 to 3 groups chosen from R ~, or an arylalkyl, aryloxyalkyl, arylthioalkyl radical or zs arylsulfonylalkyle, the terms aryl and alkyl having the definitions data above;
~ RS represents - hydrogen, or an alkyl, haloalkyl, alkylsulfonyl radical, haloalkylsulfonyl containing from 1 to 6 carbon atoms or, An alkoxyalkyl, alkylthioakyl, acyl, alkenyl, alkynyl radical, haloacyle, alkoxycarbonyle, haloalkoxycarbonyle, alkoxyalkylsulfonyle, cyanoalkylsulfonyl containing from 2 to 6 carbon atoms or - an alkoxyalkoxycarbonyl, alkylthioalkoxycarbonyl radical, cyanoalkoxycarbonyl containing from 3 to 6 carbon atoms or, 35 - the formyl radical or a cycloalkyl or alkoxyacyl radical, containing alkylthioacyl, cyanoacyl, alkenylcarbonyl, alkynylcarbonyl from 3 to 6 carbon atoms or, - a cycloalkylcarbonyl radical containing from 4 to 8 carbon atoms or, - a phenyl radical; arylalkylcarbonyl, especially phenylacetyl and phenylpropionyl, arylcarbonyl, especially benzoyl, optionally s substituted by 1 to 3 groups from R6, thienylcarbonyl, furylcarbonyl, pyridylcarbonyl, benzyloxycarbonyl, furfuryloxycarbonyl, tetrahydro-furfuryloxycarbonyl, thienylmethoxycarbonyl, pyridylmethoxy-carbonyl, phenoxycarbonyl or phenylthiolcarbonyl, the phenyl radical itself being optionally substituted by 1 to 3 selected groups 1o among R ~, alkylthiolcarbonyl, haloalkylthiolcarbonyl, alkoxyalkylthiol-carbonyl, cyanoalkylthiolcarbonyl, benzylthiolcarbonyl, furfurylthiol-carbonyl, tetrahydrofurfurylthiolcarbonyl, thienylmethylthiolcarbonyl, pyridylmethylthiolcarbonyl, or arylsulfonyl or - a carbamoyl radical optionally mono or disubstituted by 1s - an alkyl or haloalkyl group containing from 1 to 6 carbon atoms, - a cycloalkyl, alkenyl or alkynyl group containing from 3 to 6 atoms of carbon, - an alkoxyalkyl, alkylthioalkyl or cyanoalkyl group containing 2 with 6 carbon atoms or, zo - a phenyl optionally substituted with 1 to 3 group R6;
a sulfamoyl group optionally mono or disubstituted by an alkyl or haloalkyl group containing from 1 to 6 atoms of carbon, - a cycloalkyl, alkenyl or alkynyl group containing from 3 to 6 Zs carbon atoms, - an alkoxyalkyl, alkylthioalkyl or cyanoalkyl group from 2 to 6 carbon atoms or - a phenyl optionally substituted with 1 to 3 group R6;
- an alkylthioalkylsulfonyl group containing from 3 to 8 carbon atoms Or cycloalkylsulfonyl containing from 3 to 7 carbon atoms;
- R4 and R; taken together can also form with the nitrogen atom to which they are attached a pyrrolidino, piperidino, morpholino or piperazino optionally substituted by an alkyl radical containing 1 to 3 carbon atoms.
3s ~ R ~ represents - a halogen atom or - io-an alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio radical, haloalkylthio or alkylsulfonyl containing from 1 to 6 carbon atoms or a cycloalkyl, halocycloalkyl, alkenyloxy, alkynyloxy radical, alkenylthio, alkynylthio containing from 3 to 6 carbon atoms or s - the nitro or cyano group or - an amino radical optionally mono or disubstituted by a radical alkyl or acyl 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 1o optionally substituted by 1 to 3 groups, identical or different, chosen from R ,, and ~ R, represents - a halogen atom chosen from fluorine, chlorine, bromine, iodine or, - an alkyl radical containing from 1 to 6 carbon atoms, or An alkoxy or alkylthio radical containing from 1 to 6 carbon atoms or, - a haloalkoxy or haloalkylthio radical containing from 1 to 6 atoms of carbon or, a nitrile or nitro radical.
The process for preparing the compounds of formula (A) can be represented by the following diagram HzN HZN
(I) (II) (a) CSz +
CSz base HR ~ H
R ~ N ~ N-NHz I
~ S Rs R, NS Rz * N / IM) --a ~ P ~ R
Rz S (d) Rz ~ (e) R, N s O (III) O ~ 'N_R W N-R4 (A) R ~ (IV) Rs 2s diagram in which, the radical R, represents the methyl radical. The radical R, represents the phenyl radical, the radicals R ;, Ra, R5, M, p and W are such that defined for the compounds of formula (A), R represents a hydroxy, alkoxy radical R, ~ R, Rz ~ COOH (b ~ R2 ~ COR

containing from 1 to 6 carbon atoms, benzyloxy, an amino radical, alkylamino or dialkylamino, an alkylamino radical containing from 1 to 6 carbon atoms, and X
represents a leaving group such as a halogen atom, chosen from chlorine, bromine and iodine, or a sulfate radical, or alkylsulfonyloxy or arylsulfonyloxy.
s In the previous diagram ~ steps (a), (b), (c) and (d) are described in patent WO-98/03490 the details of which are incorporated herein by reference;
~ step (e) is described in patent EP-A-0 629 616, the details of which are incorporated herein by reference.
A compound of formula (A) which is very particularly preferred and which can to be synthesized from the amino acid in crystal form according to the present invention is (4S) -4-methyl-2-methylthio-4-phenyl-1-phenylamino-2-imidazoline-S-one, case 1s particular of the compounds of formula (A) for which the carbon atom asymmetric is of configuration S, W represents the oxygen atom, M represents the atom of sulfur, p represents l, R3 represents the methyl radical, R4 represents the radical phenyl, and RS represents hydrogen.
zo The following example is intended to illustrate the present invention and does not must in no case to be understood as having a limiting character.
Example: Formation of crystals of (, S ~ - (+) - methylphenylglycine A basic saline solution comprising the sodium salt of (S) - (+) - methylphenylglycine is brought to about 70 ° C.
The reaction medium is neutralized with sulfuric acid (95%), under slow stirring (300 rpm). The addition of sulfuric acid is carried out on a duration of approximately 5 hours, in two parts (1) about 15% of the total volume of sulfuric acid is added up to 3o that the pH value of the reaction medium goes from 10 to 8.8. The first crystals then appear. The addition of acid is then stopped in order to allow the growth crystals. The reaction medium is maintained for one hour at 72 ° C, below stirring, at pH between 8.8 and 8.6;
(2) the remaining quantity of sulfuric acid is then added during a 3s duration of 4 hours, until a stable pH of value 5 to 6 is obtained during at at least half an hour. If the pH tends to drop below 5, a small amount 20% sodium hydroxide can be added to maintain the pH in a zone between 5 and 7.
The suspension of crystals of (, S ~ - (+) - methylphenylglycine is then filtered at hot (about 70 ° C). The crystals obtained are washed once with water (temperature s 20 to 25 ° C) in order to remove the mother liquors, then once with methanol (temperature 20 to 25 ° C) to remove the water. Amino acid in form crystalline is finally dried under reduced pressure (50 mbar) at 100 ° C to be stored.

Claims (20)

1. Compound which is (S)-(+)-methylphenylglycine in crystalline form, characterized in that the single crystal is an orthorhombic crystal system, whose mesh parameters are a = 5.778 .ANG., b = 6.692 .ANG., c = 22.127 .ANG., group space P2 1 2 1 2 1, and having four molecules per cell. 2. Compound which is (R)-(-)-methylphenylglycine in crystalline form, characterized in that the single crystal is an orthorhombic crystal system, whose mesh parameters are a = 5.778 .ANG., b = 6.692 .ANG., c = 22.127 .ANG., group space P2 1 2 1 2 1, and having four molecules per cell. 3. Compound according to one of claims 1 or 2, characterized by the following crystallographic parameters of the single crystal:
.cndot. Crystal system: orthorhombic;

.cndot. Mesh parameters: a = 5.778 .ANG. .alpha. = 90°;

b = 6.692 .ANG. .beta. = 90°;

c = 22.127 .ANG. .gamma.=90;

.cndot. Asymmetric unit: 1 molecule;

.cndot. Space group: P2 1 2 1 2 1;

.cndot. Number of molecules per cell: 4;

.cndot. Mesh volume: 855.6 .ANG.3;

.cndot. Calculated density: 1.282 g/cm3;

.cndot. Absorption coefficient µ: 0.91 cm-1 (CuK.alpha.); 4. Process for the preparation of (S)-(+)-2-methyl-2-phenylglycine or (R)-(-)-2-methyl-2-phenylglycine in crystalline form, characterized in that that:
.cndot. (S)-(+)-2-methyl-2-phenylglycine (respectively of (R)-(-)-2-methyl-2-phenylglycine), in the form of free amino acid or in salified form, in a pH region below about 4.5 or greater than about 9, then .cndot. gradually reduced, by adding a base or an acid respectively, the pH value in an area above about 4.5 and less than about 9. 5. Method according to claim 4, characterized in that the solubilization is carried out in a zone of pH lower than 2 or higher than 12. 6. Method according to one of claims 4 or 5, characterized in that the amino acid, in free amino acid form or in salified form is solubilized by a solvent. 7. Method according to claim 6, characterized in that the solvent is the water and/or methanol and/or ethanol. 8. Method according to claim 7, characterized in that the solvent is saturated in salt. 9. Method according to one of claims 4 to 8, characterized in that, after the appearance of the first crystals, the addition of base or acid is slowed down or even stopped. 10. Method according to one of claims 4 to 9, characterized in that adding of acid or base is maintained until a pH value between Between about 5 and 7, preferably between about 5 and 6. 11. Method according to one of claims 4 to 10, characterized in that acid used is a mineral or organic acid, preferably a mineral acid, acid hydrochloric or sulfuric acid. 12. Method according to one of claims 4 to 10, characterized in that the base used is an inorganic or organic base, preferably an inorganic base, sodium hydroxide or potassium hydroxide. 13. Method according to one of claims 4 to 12, characterized in that one adds, during crystallization, a compound facilitating the agglomeration of crystals chosen from aromatic organic compounds. 14. Method according to one of claims 4 to 13, characterized in that the crystallization is carried out from solutions whose concentration in amino acid is between 4% and 50% by volume. 15. Method according to one of claims 4 to 14, characterized in that the crystallization is carried out from solutions whose concentration in amino acid is between 4% and 50% by volume. 16. Method according to one of claims 4 to 15, characterized in that the environment reaction is heated to a temperature between 50°C and 100°C, from preferably between 65°C and 85°C. 17. Method according to one of claims 4 to 16, characterized in that one adds a water-miscible co-solvent to the reaction medium. 18. Use of the compounds in crystalline form according to one of the claims 1 to 3 for the preparation of compounds of formula (A):
in which:
.cndot. W represents an oxygen or sulfur atom, or an S=O group;
.cndot. M represents an oxygen or sulfur atom, or a CH2 radical, optionally halogenated;
.cndot. p is an integer equal to 0 or 1;
.cndot. R3 stands for:
- a hydrogen or an optionally halogenated C1-C2 alkyl radical, when p equals 0 or (M)p is a CH2 radical, - an optionally halogenated C1-C2 alkyl radical, when (M)p represents an oxygen or sulfur atom;
.cndot. R4 stands for:
- the hydrogen atom, or - an alkyl radical containing from 1 to 6 carbon atoms, or - an alkoxyalkyl, alkylthioalkyl, haloalkyl, cyanoalkyl radical, thiocyanatoalkyl, alkenyl or alkynyl containing from 2 to 6 carbon atoms carbon, or - a dialkylaminoalkyl, alkoxycarbonylalkyl radical, or N-alkylcarbamoylalkyl containing 3 to 6 carbon atoms, or - an N,N-dialkylcarbamoylalkyl radical containing from 4 to 8 atoms of carbon, or - an aryl radical, comprising phenyl, naphthyl, thienyl, furyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, benzothienyl, benzofuryl, quinolinyl, isoquinolinyl, or methylene dioxyphenyl, optionally substituted with 1 to 3 groups chosen from R6, or - an arylalkyl, aryloxyalkyl, arylthioalkyl or arylsulfonylalkyl, the terms aryl and alkyl having the definitions given above ;
.cndot. R5 stands for:
- hydrogen, or an alkyl, haloalkyl, alkylsulfonyl radical, haloalkylsulfonyl containing 1 to 6 carbon atoms or, - an alkoxyalkyl, alkylthioakyl, acyl, alkenyl, alkynyl radical, haloacyl, alkoxycarbonyl, haloalkoxycarbonyl, alkoxyalkylsulfonyl, cyanoalkylsulfonyl containing 2 to 6 carbon atoms or - an alkoxyalkoxycarbonyl or alkylthioalkoxycarbonyl radical, cyanoalkoxycarbonyl containing 3 to 6 carbon atoms or, - the formyl radical or a cycloalkyl or alkoxyacyl radical, alkylthioacyl, cyanoacyl, alkenylcarbonyl, alkynylcarbonyl containing from 3 to 6 carbon atoms or, - a cycloalkylcarbonyl radical containing 4 to 8 carbon atoms Where, - a phenyl radical; arylalkylcarbonyl, including phenylacetyl and phenylpropionyl, arylcarbonyl, especially benzoyl, optionally substituted with 1 to 3 groups from R6, thienylcarbonyl, furylcarbonyl, pyridylcarbonyl, benzyloxycarbonyl, furfuryloxycarbonyl, tetrahydro-furfuryloxycarbonyl, thienylmethoxycarbonyl, pyridylmethoxy-carbonyl, phenoxycarbonyl or phenylthiolcarbonyl, the phenyl radical being itself optionally substituted by 1 to 3 selected groups from R6, alkylthiolcarbonyl, haloalkylthiolcarbonyl, alkoxyalkylthiol-carbonyl, cyanoalkylthiolcarbonyl, benzylthiolcarbonyl, furfurylthiol-carbonyl, tetrahydrofurfurylthiolcarbonyl, thienylmethylthiolcarbonyl, pyridylmethylthiolcarbonyl, or arylsulphonyl or - a carbamoyl radical optionally mono or disubstituted by:
- an alkyl or haloalkyl group containing from 1 to 6 carbon atoms, - a cycloalkyl, alkenyl or alkynyl group containing 3 to 6 atoms of carbon, - an alkoxyalkyl, alkylthioalkyl or cyanoalkyl group containing 2 with 6 carbon atoms or, - a phenyl optionally substituted by 1 to 3 R6 groups;
- a sulfamoyl group optionally mono or disubstituted by:
- an alkyl or haloalkyl group containing from 1 to 6 carbon atoms carbon, a cycloalkyl, alkenyl or alkynyl group containing from 3 to 6 carbon atoms, - an alkoxyalkyl, alkylthioalkyl or cyanoalkyl group of 2 to 6 carbon atoms or - a phenyl optionally substituted by 1 to 3 R6 groups;
- an alkylthioalkylsulfonyl group containing 3 to 8 carbon atoms or cycloalkylsulfonyl containing 3 to 7 carbon atoms;
- R4 and R5 taken together can also form with the nitrogen atom to which they are attached a pyrrolidino, piperidino, morpholino or piperazino optionally substituted by an alkyl radical containing 1 with 3 carbon atoms.
.cndot. R6 represents - a halogen atom or - an alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio radical, haloalkylthio or alkylsulfonyl containing 1 to 6 carbon atoms or - a cycloalkyl, halocycloalkyl, alkenyloxy, alkynyloxy radical, alkenylthio, alkynylthio containing 3 to 6 carbon atoms or - the nitro or cyano group or - an amino radical optionally mono or disubstituted by a radical alkyl or acyl containing 1 to 6 carbon atoms or alkoxycarbonyl containing 2 to 6 carbon atoms, - a phenyl, phenoxy or pyridyloxy radical, these radicals being optionally substituted by 1 to 3 groups, identical or different, selected from R7, and .cndot. R7 represents:
- a halogen atom chosen from fluorine, chlorine, bromine, iodine or, - an alkyl radical containing from 1 to 6 carbon atoms, or - an alkoxy or alkylthio radical containing from 1 to 6 carbon atoms or, - a haloalkoxy or haloalkylthio radical containing from 1 to 6 atoms of carbon or.
- a nitrite or nitro radical. 19. Use according to claim 18, characterized in that the compound of formula (A) is (4S)-4-methyl-2-methylthio-4-phenyl-1-phenylamino-2-imidazo-line-5-one, special case of compounds of formula (A) for which the atom of asymmetric carbon is of S configuration, W represents the oxygen atom, M
represents the sulfur atom, p represents 1, R3 represents the radical methyl, R4 represents the phenyl radical, and R5 represents hydrogen. 20. Use according to one of claims 18 or 19, characterized in that them compounds of formula (A) are obtained according to the following scheme:
diagram in which the radical R1 represents the methyl radical, the radical R2 represents the phenyl radical, the radicals R3, R4, R5, M, p and W are such than defined for the compounds of formula (A), R represents a hydroxy or alkoxy radical containing 1 to 6 carbon atoms, benzyloxy, an amino radical, alkylamino Where dialkylamino, an alkylamino radical containing 1 to 6 carbon atoms, and X
represents a leaving group such as a halogen atom, chosen from chlorine, bromine and iodine, or a sulphate, or alkylsulfonyloxy or arylsulfonyloxy radical.