BE889757A - NEW OXAZOLIDINE -2,4- DIONES SUBSTITUTED IN POSITION 5 PROVIDED WITH HYPOGLYCEMIC ACTIVITY - Google Patents

Description

       

    <EMI ID = 1.1>

  
The present invention relates to certain derivatives killed in position 5 endowed with hypoglycemic activity

  
  <EMI ID = 2.1>

  
Although insulin was discovered early and despite its subsequent widespread use in the treatment of diabetes, despite also the discovery and more recent use of sulfonylureas, (e.g. chlorpropamide, tolbutamide, acetohexamide, tolazamide) and biguanides (e.g. phenformin)

  
  <EMI ID = 3.1>

  
diabetes remains less than satisfactory. The use of insulin, necessary for a large percentage of diabetics in whom the available synthetic hypoglycemic agents are not effective, requires multiple daily injections which the patient ordinarily makes himself. Determining the correct insulin dose requires frequent estimates of sugar levels

  
in the urine or blood. Administering an excessive dose of insulin causes hypoglycemia, with effects ranging from moderate abnormalities in blood glucose to coma or even death. When a synthetic hypoglycemic agent is effective, it is preferred over insulin, being more convenient to administer and less likely to cause severe hypoglycemic reactions. However, the hypoglycaemics available in the clinic are unfortunately accompanied by other toxic manifestations which limit their use. In any case, where one of these agents can fail in an indi- vidual case

  
another can succeed. Continued need for agents

  
  <EMI ID = 4.1>

  
can succeed where others fail, is clearly evident.

  
In addition to the hypoglycemic agents mentioned above, this type of activity has been attributed to various other compounds, a review of which was recently published by Blank / Burger's

  
  <EMI ID = 5.1>

  
  <EMI ID = 6.1>

  
killing variants of the present invention are new compounds: this is so despite the fact that

  
  <EMI ID = 7.1>

  
various citations as an intermediate compound for obtaining certain antibacterial agents of the type

  
  <EMI ID = 8.1>

  
  <EMI ID = 9.1>

  
The Applicant has just discovered, as indicated in detail below, that some of these compounds had

  
  <EMI ID = 10.1>

  
conversely, one of the preferred embodiments of the present invention, namely 5- (2-chloro-6-

  
  <EMI ID = 11.1>

  
In addition, no antidepressant activity was noted for this compound; on the contrary, at doses higher than those for which it is endowed with hypoglycemic activity, this compound. has been depressed.

  
  <EMI ID = 12.1>

  
for known 5-aryloxazolidine-2,4-diones is repro-

  
  <EMI ID = 13.1>

  
these determinations are indicated in detail in the following. It will be noted that the related phenyl compound has good activity at a dose of 25 mg / kg. The replacement of the phenyl ring by a methoxy group in position 4 leads to a total decrease in activity, even

  
at a dose of 100 mg / kg. In addition, the analogues 2,4dimethoxy and 2,3-dimethoxy are also devoid of activity at the tested dose of 10 mg / kg. It is therefore surprising and unexpected to find that, when the methoxy group occupies position 2, alone or with other groups chosen in positions 5 or 6, a remarkable hypoglycemic activity ensues at doses for which the phenyl compound -same and other known analogues are devoid of activity.

  
  <EMI ID = 14.1>

  
  <EMI ID = 15.1>

  
in the glucose tolerance test in rats
  <EMI ID = 16.1>
 (a) See the text. (b) Other counterparts are known <EMI ID = 17.1>

  
58, pages 63-99. (1958). (c) See Clark-Lewis, Loc. cit. 5 (d) King and Clark-Lewis, J. Chem. Soc. pages 3077-3079
(1951). (e) Najer et al., Bull. Soc. Chim.

  
France, pages 1226-1230 (1961); Chem. Abs. 55, pages
27268-27269. (f) Riebsomer et al, J. Am. Chem.

  
Soc. 61, pages 3491-3493 (1939). (g) German patent

  
  <EMI ID = 18.1>

  
as inactive.

  
In addition, the substitution of an amino group in position 4 of the phenyl compound to produce the known 5- (4 aminophenyl) oxazolidine-2,4-dione unevenly leads to inactivity, even at the dose of 100 mg / kg,

  
while the analogous 2-acetamidophenyl derivative of the present invention has an activity comparable to that of the 2-iaethoxy compounds. Similarly, the substitution of a halogen
(chloro) in position 4 reduces activity, while <EMI ID = 19.1>

  
remarkable activity, again comparable to 2-methoxy compounds.

  
  <EMI ID = 20.1>

  
acids suitable for the formation of acid addition salts with basic hypoglycemic biguanides

  
(see United States patent n [deg.] 2,961,377).

  
  <EMI ID = 21.1>

  
present invention.

  
A group of derivatives of

  
  <EMI ID = 22.1>

  
Aldose reductase, which therefore find utility in

  
treatment of certain complications of diabetes (patent

  
  <EMI ID = 23.1>

  
  <EMI ID = 24.1>

  
diones (the aryl group of which comprises 6 to 12 carbon atoms, unsubstituted or substituted with one or more halogen atoms or methyl or methoxy radicals) is described in another patent from the United States of America

  
  <EMI ID = 25.1>

  
The utility of these compounds, which are the isomers of various compounds of the present invention, is not specified.

  
The present invention relates to compounds of formula

  

  <EMI ID = 26.1>


  
in which (1)

  
R is hydrogen, an alkanoyl residue in Cl-C4

  
  <EMI ID = 27.1>

  
R "is a group

  
of formula
  <EMI ID = 28.1>
 in which

  
  <EMI ID = 29.1>

  
thio, chloro or fluoro; and

  
  <EMI ID = 30.1>

  
hydrogen or a methyl, bromo, chloro, fluoro, cyano, nitro or trifluoromethyl residue; and

  

  <EMI ID = 31.1>


  
in which

  
R has the definition given above;

  
  <EMI ID = 32.1>

  

  <EMI ID = 33.1>


  
Y is hydrogen or methyl, benzyloxy,

  
  <EMI ID = 34.1>

  
  <EMI ID = 35.1>

  
Y is the fluoro or chloro residue; -

  
and cationic, pharmaceutically acceptable salts, of compounds (1) and (2) when R is hydrogen.

  
  <EMI ID = 36.1>

  
compounds mainly resides in the compounds in which R is hydrogen and that those in which

  
  <EMI ID = 37.1>

  
removed by hydrolysis under physiological conditions, giving the fully active compounds in which

  
R is hydrogen.

  
The term "pharmaceutically acceptable cationic salts" is used to refer to salts in the form of the alkali metal salts (e.g. sodium and potassium, alkaline earth metal salts
(e.g. calcium and magnesium, aluminum salts, ammonium salts and organic amine salts such

  
  <EMI ID = 38.1>

  
The compounds of the present invention have hypoglycemic activity, which reflects their clinical utility in lowering the blood glucose level of

  
hyperglycemic mammals, including humans, at normal values. They have the particular advantage of lowering blood glucose levels within a normal range without risking causing hypoglycemia. The compounds of the present invention were subjected to tests of hypoglycemic (anti-hyperglycemic) activity in rats, using the so-called glucose tolerance test, as described in detail below.

  
Compounds appreciated for their very good hypoglycemic activity are those in which R is hydrogen, or their acceptable salts

  
  <EMI ID = 39.1>

  

  <EMI ID = 40.1>


  
(the)

  
in which R has the definition given above, R 'is a group

  

  <EMI ID = 41.1>


  
  <EMI ID = 42.1>

  
  <EMI ID = 43.1>

  
cyano or methyl;

  
and their pharmaceutically acceptable cationic salts when R is hydrogen. The known analogs of these compounds are either devoid of hypoglycemic activity or at least endowed with less activity than the related phenyl compound; on the other hand, these compounds have a surprising and surprisingly high degree of activity. As shown in Table II, all show activity at a rate of 5 mg / kg or less, at which rate all known compounds, including the basic phenyl compound, are inactive. Due to their particularly remarkable level of activity, phenyl compounds of extraordinary value in the

  
  <EMI ID = 44.1>

  
a residue. C1 or C2 alkoxy and X2 is hydrogen, chlorine or fluorine, in particular:

  
  <EMI ID = 45.1>

  
  <EMI ID = 46.1>

  
are all new, the preferred compounds are those in which Riel is a group of formula:

  

  <EMI ID = 47.1>


  
where Y is 1 [deg.] hydrogen, a methyl, methoxy or fluoro residue

  
  <EMI ID = 48.1>

  
remains methoxy. We particularly appreciate the 5- (2-

  
  <EMI ID = 49.1>

  
extraordinarily high hypoglycemic activity.

TABLE II

  
  <EMI ID = 50.1>

  
in the glucose tolerance test in rats
  <EMI ID = 51.1>
(a) 14 after 2 hours, (b) 13 after 2 hours. (c) Preliminary tests have shown an absence of activity at this level. . The compounds of the present invention are prepared <EMI ID = 52.1>

  
which

  
  <EMI ID = 53.1>

  
  <EMI ID = 54.1>

  
methyl or ethyl);

  
R <3> is hydrogen, a lower alkyl residue or a phenyl residue and

  
R 4 is hydrogen or an acyl residue such as acetyl or benzoyl.

  
A particularly convenient synthesis for compounds of the present invention is to go through the carboximidate (3). The latter compound is reacted with phosgene in an inert solvent such as titrahydrofuran in the presence of 2 to 2.3 equivalents of a tertiary amine (for example triethylamine, N & methylmorpholine). Another equivalent of tertiary amine is used if the carboximidate is introduced in the form of

  
  <EMI ID = 55.1>

  
reaction temperature is not critical, but

  
  <EMI ID = 56.1>

  
are preferable during the initial stages of the reaction, in particular if it is desired to isolate the intermediate 4-alkoxyoxazole-2one (4). The isolation of this intermediate compound is carried out by simple evaporation of the reaction mixture to dryness. By subsequent reaction to temples

  
  <EMI ID = 57.1>

  
aqueous, the intermediate compound (4) is converted to the desired oxazolidine-2t4-dione. When a primary or secondary amine function must exist in the final product, this functionality is introduced via an oxazolidine-2,4-dione carrying a selectively reducible group (for example by catalytic hydrogenation or

  
  <EMI ID = 58.1>

  
daire. For example, a substituted nitro or hydroxylamino function can be used as a precursor of an amino function.

  
  <EMI ID = 59.1>

  
  <EMI ID = 60.1>
  <EMI ID = 61.1>
 The carboximidate (3) is advantageously prepared from the corresponding aldehyde according to the diagram

  

  <EMI ID = 62.1>


  
(13)

  
The aldehyde (11) is converted to cyanohydrin

  
(13) by conventional methods (e.g. passing through the bisulfite adduct which is brought to

  
  <EMI ID = 63.1>

  
aqueous phase and an organic phase). Alternatively, the aldehyde is converted to trimethylsilyl-cyanohydrin

  
(12) by reaction with trimethylsilylcarbonitrile in the presence of a catalytic amount of a Lewis acid,

  
  <EMI ID = 64.1>

  
of the reaction (e.g. methylene chloride, ether) is generally used when the aldehyde is solid, but it is optional when the aldehyde is liquid. The reaction temperature is not determined.

  
  <EMI ID = 65.1>

  
allow to develop at room temperature for

  
several hours or several days, depending on the time required to obtain a total reaction. Where appropriate, the trimethylsilyl ether can be hydrolyzed to cyanohydrin, advantageously at reduced temperature
(eg -10 [deg.] C) in a two phase system comprising a strong aqueous acid and an organic solvent.

  
We convert either cyanohydrin (13) or <EMI ID = 66.1>

  
by alcohol catalyzed by a strong cide (using strictly anhydrous conditions). A practical method is to simply dissolve the nitrile in Alcohol which has been saturated with hydrogen chloride and allow the solution to stand until the formation

  
  <EMI ID = 67.1>

  
decisive, although fairly low temperatures
(for example from 0 to 25 [deg.] C) generally lead to more optimal results.

  
The aldehydes necessary for the above syntheses

  
  <EMI ID = 68.1>

  
by methods described in the literature, such as the Sommelet reaction / for example o-tolualdehyde,

  
  <EMI ID = 69.1>

  
1945, page 156; 1-naphtaldëhyde, Angyal et al., Org. Syntheses 30, page 67 (1950); 2-naphthal-

  
  <EMI ID = 70.1>

  
diazonium by halogen, / for example m-chlorobenzal-

  
dehyde and m-bromobenzaldehyde, Buck and Ide, Org.

  
  <EMI ID = 71.1>

  
example 2-naphthaldehyde, Hershberg and Cason, Org. Summaries
21, page 84 (1941) 7, the reduction of nitriles according to Stephen &#65533; for example m-tolualdehyde, Bowen and Wilkinson,

  
  <EMI ID = 72.1>

  
Other methods are indicated in the Preparations described in detail below.

  
Another suitable precursor for the oxazolidine-2,4-diones of the present invention having no

  
of primary or secondary amino function is α-hydroxyamide (5). The latter compound is converted into the desired oxazolidine2,4-dione (1), either by reaction with an alkyl chloroformate in the presence of a basic catalyst

  
such as potassium carbonate, either by reaction with

  
a dialkyl carbonate in the presence of a more strongly basic catalyst such as sodium methylate or

  
  <EMI ID = 73.1>

  
suitable as solvent for the latter reaction,

  
using 1 to 3 equivalents of both dialkyl carbonate and base, preferably 2 to 3 equivalents

  
of each. When a primary or secondary amino function is desired in the final product, this functionality is introduced via an oxazolidine-2,4dione containing a suitable precursor group, as described above.

  
The desired alpha hydroxy amide. is advantageously prepared from cyanohydrin (13) or from an alpha-hydroxy acid or ester (6):

  

  <EMI ID = 74.1>


  
Suitable conditions for the hydrolysis of

  
cyanohydrin (13) consists of treating cyanohydrin in formic acid with an excess of concentrated hydrochloric acid. A temperature range of 0 to 75 [deg.] C is generally satisfactory, depending on the stability of the individual amide in this medium. If necessary, an intermediate formic acid ester of (5) can be isolated under these conditions. Excessive acid hydrolysis can be prevented by monitoring the reaction by thin layer chromatography, as detailed below. Practical conditions for the aminolysis of the ester (6) are to simply heat the ester in hot concentrated ammonium hydroxide.

  
The alpha-hydroxy ester (6) itself can

  
  <EMI ID = 75.1>

  
zolidine -2,4-dione desired. The ester is reacted with urea (or one of certain substituted ureas

  
  <EMI ID = 76.1>

  
in the presence of a basic catalyst such as ethylate

  
sodium (preferably 1 equivalent) in alcohol

  
at a temperature of 50-110 [deg.] C. The ester to be used for this purpose is by no means limited to a simple lower alkyl ester but may consist of any

  
  <EMI ID = 77.1>

  

  <EMI ID = 78.1>


  
and the urea can be replaced by a urethane.

  
Two other precursors which are suitable for

  
  <EMI ID = 79.1>

  
thio compounds (7) and (8). The compound 2-thioxo (7) is converted into the desired oxazolidine-2,4-diones under oxidizing conditions, for example in the presence of the mercuric ion, of bromine or of aqueous chlorine or of aqueous hydrogen peroxide, usually in excess

  
and in the presence of a cosolvent such as a lower alcohol The reaction temperature is not decisive,

  
  <EMI ID = 80.1>

  
concurrent oxidation at the nitrogen level tends to reduce yields and complicates the isolation of the desired product.

  
  <EMI ID = 81.1>

  
alkylthio (8) compounds by simple hydrolysis catalyzed by an acid or a base. Appropriate conditions consist in using aqueous hydrochloric acid in a temperature range of 0 to 50 [deg.] C.

  
  <EMI ID = 82.1>

  
generally carried out in an aqueous acid medium by the action

  
  <EMI ID = 83.1>

  
  <EMI ID = 84.1>

  
(1968); Chem. Abstr. 69, 52050k7. 2-alkylthio compounds

  
  <EMI ID = 85.1>

  
placed 2-thioxo (7), for example with an alkyl halide or a dialkyl sulphate, preferably in the presence of at least two equivalents of a base such as an alcoholate

  
  <EMI ID = 86.1>

  
product of this reaction.

  
Another advantageous precursor is the derivative of 2-imino-oxazolidine-4-one (9), easily hydrolyzed to oxazolidine-2,4-dione ,. preferably under conditions

  
  <EMI ID = 87.1>

  
obtained by condensation of the alpha-hydroxyl ester

  
(6) with guanidine or with thiourea in the presence of an equivalent of a strong base such as a sodium alcoholate, by ammonolysis of the 2-alkoxylated compound (isomer

  
of compound 4) or of 2-thioalkylated compound (8), by cyclization, under the action of an alkali, suitable alpha-halogenides ides (R CHZCONHCONHR where Z is a halogen such as chloro or bromine) or by condensation of suitable alkyl alpha haloacetates (RCHZCOOR) with urea or

  
  <EMI ID = 88.1>

  
4-imino derivatives (isomers of compound 9). These latter compounds are also easily hydrolyzed to oxazolidine-

  
  <EMI ID = 89.1>

  
dione desired.

  
Dialuric acids and acyl-dialuric acids (10) are also very useful as precursors

  
  <EMI ID = 90.1>

  
are readily converted, under moderately basic conditions, to the desired oxazolidine-2,4-diones. Methods suitable for the preparation of precursor dialuric acids (10) are illustrated in the diagram

  
124

  
(II), on which the substituents R, R and R. have the

  
  <EMI ID = 91.1>

  
  <EMI ID = 92.1>

DIAGRAM II

  

  <EMI ID = 93.1>
 

  
A general process for the preparation of dialuric acids which are suitable as precursors of the oxazolidine2,4-diones of the present invention consists in starting from the malonic esters (14), which involves the two stages of condensation with urea catalyzed by a base and oxidation to the hydroxy or acyloxyl compound. When the first step is an oxidation, the intermediate compound is a derivative of tartronic acid (15), while when the first step is a condensation, the compound

  
  <EMI ID = 94.1>

  
contains an amino function (for example 2-aminophenyl), it is preferable to conduct the oxidation as a first step. avoiding possible complications of sulfur oxidation. When a condensation constitutes the second stage, the dialuric acid is ordinarily not isolated, at least in the pure form, and it is further transformed, under the basic conditions of the condensation, into

  
  <EMI ID = 95.1>

  
The substituted malonic esters necessary for the above syntheses, when they are not commercially available, are obtained by methods described in the literature, for example by alpha-alcoholysis.

  
  <EMI ID = 96.1>

  
A less general process for the preparation of suitable intermediate dialuric acid is to

  
  <EMI ID = 97.1>

  
electrons, for example an alkoxybenzene with C or C alkoxy group &#65533; or a methoxynaphthalene, with alloxane hydrate. The reaction takes place. in para position when this position is free, otherwise it takes place in ortho position. For example :

  

  <EMI ID = 98.1>


  
Another process is currently available

  
for the preparation of certain intermediate dialuric acids.

  
This process, preferable when the suitable starting compounds are easy to obtain, involves the reaction of alloxane (preferably in the anhydrous form) with the organometallic derivatives suitably chosen (for example organolithium, Grignard reagent). For example :

  

  <EMI ID = 99.1>


  
Protective measures are necessary when using this process for the preparation of certain

  
  <EMI ID = 100.1>

  
killing which is not compatible with organometallic reactions, for example an acyl group is protected in the form of its ethylenic etal. In other cases,

  
  <EMI ID = 101.1>

  
for the latter syntheses passing through the alloxane are commercially available or can be obtained by methods described in the literature.

  
  <EMI ID = 102.1>

  

  <EMI ID = 103.1>


  
(where Ox is the abbreviation used to designate the nucleus

  
  <EMI ID = 104.1>

  
at a temperature in the range of 80 to 170 [deg.] C. Potassium tert-butoxide, sodium hydride, sodium or another similar strong base can replace

  
  <EMI ID = 105.1>

  

  <EMI ID = 106.1>


  
  <EMI ID = 107.1>

  
other groups may thus be introduced by repla &#65533; cementation of a halogen, for example:

  

  <EMI ID = 108.1>
 

  
We conduct this last reaction by making act

  
  <EMI ID = 109.1>

  
  <EMI ID = 110.1>

  
125 to 175 [deg.] C, advantageously at the reflux temperature of the solvent.

  
It is obvious to those skilled in the art that the method of choice for obtaining the oxazolidine-2,4-diones of the

  
  <EMI ID = 111.1>

  
other depending on factors such as the availability of starting materials, yields, the ability to remove unwanted impurities from the end products, the chemical nature of the substituent groups contained in the end products, etc.

  
The pharmaceutically acceptable cationic salts of the compounds of the present invention are easy to prepare by reacting the acid forms with a suitable base, usually in an equivalent amount, in a cosolvent. Representative bases are sodium hydroxide, sodium methylate, sodium ethylate, sodium hydride, potassium methylate, magnesium hydroxide, calcium hydroxide, benzathine,

  
  <EMI ID = 112.1>

  
benethamine, diethylamine, piperazine and tromethamine. The salt is isolated by dry concentration or by addition of a non-solvent. In some cases, salts can be prepared by mixing a solution of the acid with a solution of a salt different from the cation (sodium ethylhexanoate, magnesium oleate), using a solvent in which the desired cationic salt precipitates or can otherwise be isolated by concentration and addition of a non-solvent.

  
The 3-acylated derivatives of the present invention are easily prepared using standard acylation conditions, for example the reaction of the oxazolidine2,4-dione salt (in its own form or advantageously formed

  
in situ by adding an equivalent of a tertiary amine

  
  <EMI ID = 113.1> an equivalent of acid chloride or acid anhydride

  
  <EMI ID = 114.1>

  
with the suitable organic isocyanate, optionally in the presence of a catalytic amount of a base consisting of a tertiary amine. In both cases, the reaction is carried out in an inert solvent such as

  
toluene, tetrahydrofuran or methylene chloride, The temperature is not critical and can be chosen

  
  <EMI ID = 115.1>

  
obvious to those skilled in the art that such acylation is complicated by concurrent or even selective acylation

  
  <EMI ID = 116.1>

  
can be selectively acetylated at the 2-amino group and, where appropriate, the 3-acyl group can be introduced subsequently by one of the general methods described above.

  
  <EMI ID = 117.1>

  
of the present invention are asymmetrical and therefore capable of existing in two optically active enantiomeric forms. The racemic compounds of the present invention, which are acids, form salts with organic amines. These racemic forms are therefore generally capable of being resolved into the optically active forms by the conventional method of forming diastereoisomeric salts.

  
with optically active amines, now separable

  
by selective crystallization. Mention is made, by way of example, of the crystallization of the (+) enantiomer of 5- (5-chloro-2-methoxy) oxazolidine-2,4-dione in the form of the salt of lcinchonidine in ethanol and the recovery of l '(-) corresponding enantiomer in the mother liquor. There are generally

  
  <EMI ID = 118.1>

  
activity than the other.

  
The reactions used to prepare the compounds of the present invention can generally be controlled by conventional methods of thin layer chromatography using commercially available plates.

  
Suitable eluents are common solvents such as. chloroform, ethyl acetate or hexane or their suitable mixtures which differentiate the starting materials, the products, the by-products and, in some cases, the intermediate products. The application of these methods, which are well known in the art, makes it possible to further improve the methodology of the particular examples illustrated in detail in what '. follows, for example, the choice of the most suitable reaction times and temperatures, while facilitating the choice of the optimal processes.

  
The oxazolidine-2,4-diones of the present invention are readily adapted for clinical use as agents

  
  <EMI ID = 119.1>

  
this clinical use is defined by the tolerance test

  
glucose described below. Uncastrated male albino rats are the test animals used for these experimental purposes. Test animals are fasted for about 18-24 hours. Weigh the rats, number them and note the results in groups of five or six as necessary. Each group of animals is then administered intraperitoneally with glucose (1 g per kg) and, orally, water (controls) or the compound (

  
a concentration usually chosen in the range of 0.1 to 100 mg / kg. Blood glucose levels are noted
(mg / 100 ml) in blood samples taken from the tail over a 3 hour period from the control and treated groups. With equivalent blood glucose levels at time zero in the control groups and the treated groups, the percentage of reduction in blood glucose after 0.5 hour, one hour, 2 hours and 3 hours is calculated from the expression:

  

  <EMI ID = 120.1>
 

  
  <EMI ID = 121.1>

  
  <EMI ID = 122.1>

  
These tables show the percentage of reduction

  
blood glucose at times 0.5 hours and 1 hour. A decrease in blood glucose of 9% or more reflects

  
  <EMI ID = 123.1>

  
statistic in this test. The compounds which show significant activity only after 2 hours or 3 hours have this activity indicated in "remark".

  
  <EMI ID = 124.1>

  
humans, orally or parenterally. Oral administration is preferred, which is more convenient and avoids the pain and irritation of an injection. However, in cases where the patient cannot swallow medication, or when absorption

  
as a result of oral administration is disrupted, by

  
for example due to illness or other abnormality, it is essential that the medication be administered parenterally. For either of these two routes, the dosage is in the range of about 0.10 to about
50 mg / kg of body weight of the subject per day, preferably about 0.10 to about 10 mg / kg of body weight per day, which is administered in one or more doses. However, the optimal dosage for the individual subject in treatment is determined by the attending physician, generally lower doses being administered initially and then gradually increased in order to determine the most suitable dosage. This dosage varies according to the particular compound being used and the subject being treated.

, TABLE III

  
  <EMI ID = 125.1>
  <EMI ID = 126.1>
 Table III (Continued)
  <EMI ID = 127.1>
 Table III (Continued)
  <EMI ID = 128.1>
  <EMI ID = 129.1> levorotatory tiomer. (e) 10 after 2 hours. (f) 19 after 2 hours.

  
  <EMI ID = 130.1>

  
results for certain preferred compounds are given in Table II. (j) 9 after 2 hours. (k) 12 after 2

  
  <EMI ID = 131.1> <EMI ID = 132.1>

  
Hypoglycemic activity of oxazolidine-2,4-diones in the test

  
  <EMI ID = 133.1>
  <EMI ID = 134.1>
 The compounds can be used in pharmaceutical preparations which contain them or which contain one of their pharmaceutically acceptable acid salts, in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers are inert solid fillers or diluents and sterile aqueous or organic solutions. The active compound

  
  <EMI ID = 135.1>

  
sufficient to provide the desired dosage within the range defined above. Thus, for oral administration, the compounds can be combined with a solid or liquid carrier or diluent suitable for forming capsules, tablets, powders, syrups, solutions, suspensions, etc. The pharmaceutical compositions can optionally contain additional components such as perfumes, sweeteners, excipients, etc. For parenteral administration, the compounds can be combined with sterile aqueous or organic media to form solutions

  
or injectable suspensions. For example, solutions may be used in sesame oil or in peanut oil, in aqueous propylene glycol, etc., as well as aqueous solutions of water-soluble addition salts.

  
pharmaceutically acceptable acids of the compounds. The solutions for injection prepared in this way can then be administered intravenously.

  
  <EMI ID = 136.1>

  
blood, intramuscular administration being preferable in humans.

  
It has also been discovered that certain other oxazolidine-2,4-diones substituted in position 5 are endowed with a beneficial hypoglycemic activity. These compounds include certain 5-pyrryloxazolidine-2,4diones, in particular those which are substituted on the nitrogen of the pyrrole nucleus by a lower alkyl or phenyl group; as well as certain pyridine derivatives, <EMI ID = 137.1>

  
isoxazole, the substitution of which has configurations similar to those of the above phenyl derivatives.

  
The oxazolidine-2,4-diones referred to in the preceding paragraph, as well as their pharmaceutically acceptable salts and their 3-acyl derivatives, are prepared in the same way and suitable for clinical use in patients with mammals as anti-diabetic agents by the same method of administration and according to the

  
  <EMI ID = 138.1>

  
following, given without limitation.

  
EXAMPLE 1

  
  <EMI ID = 139.1>

  
Reiche and Collaborators, Ber. 93, page 88 (1960) 7 in
150 ml of methylene chloride and the solution is cooled to 0-5 [deg.] C. 500 mg of zinc iodide are added, then 21.8 g (0.22 mole) of -trimethylsilylcarbonitrile are added dropwise. The reaction mixture is stirred for approximately
65 hours at room temperature. It is washed twice with saturated sodium bicarbonate, it is dried over anhydrous sodium sulfate, it is filtered and it is evaporated.

  
  <EMI ID = 140.1>

  
EXAMPLE 3

  
  <EMI ID = 141.1>

  
ethyl in 500 ml of tetrahydrofuran, the suspension is cooled to 0-5 [deg.] C and triethylamine (23.6 g, 0.234 mole) is added. Phosgene is passed for 30 minutes through the reaction mixture with stirring. We continue

  
  <EMI ID = 142.1>

  
reaction mixture on 1 liter of crushed ice and the product is extracted into 3 portions of chloroform. The combined chloroform extracts are washed with brine,

  
  <EMI ID = 143.1>

  
dione (6.4 g, 42%; melting point 175-177 [deg.] C; m / e 207).

  
  <EMI ID = 144.1>

  
is obtained from the toluene mother liquor.

  

  <EMI ID = 145.1>


  
EXAMPLE 4

  
  <EMI ID = 146.1>

  
Following the procedure of Example 1, 2-ethoxybenzaldehyde (25 g, 0.166 mole) is converted

  
  <EMI ID = 147.1>

  
Following the procedure of Example 2, 40 g of 2- (2-ethoxyphenyl) -2-trimethylsiloxyethane- are converted.

  
  <EMI ID = 148.1>

  
  <EMI ID = 149.1>

  
phosgene in accordance with the procedure of Example 3.

  
To isolate the product, the reaction mixture is evaporated

  
dry and the solid residue is distributed between 500 ml of water and
500 ml of chloroform. The aqueous phase is washed with two new portions of chloroform. The combined chloroform phase and washers are dehydrated

  
over anhydrous magnesium sulfate, filtered, evaporated

  
  <EMI ID = 150.1>

  

  <EMI ID = 151.1>


  
EXAMPLE 7

  
  <EMI ID = 152.1>

  
With the difference that a reaction time of 16 hours is used, the procedure of Example 1 is repeated to react the 2-fluorobenzaldehyde (10 g, 0.081 mole) in 50 ml of methylene chloride with trimethyl -

  
  <EMI ID = 153.1>

  
zinc (300 mg) to obtain 2- (2-fluorophenyl) -2-

  
  <EMI ID = 154.1>

  
ethyl midate

  
Following the procedure of Example 2, we

  
  <EMI ID = 155.1>

  
129-131 [deg.] C '(decomposition) /.

  

  <EMI ID = 156.1>


  
EXAMPLE 9

  
  <EMI ID = 157.1>

  
Following the procedure of Example 3, with the difference that a reaction time of 2 hours at room temperature is used after the step of introducing phosgene, hydrochloride of 1- (2-

  
  <EMI ID = 158.1>

  

  <EMI ID = 159.1>


  
EXAMPLE 10

  
  <EMI ID = 160.1>

  
Following the procedure of Example 7, 5-chloro-2-methoxybenzaldehyde (6 g, 35 mmol) in 100 ml of methylene chloride is reacted with trimethylsilylcarbonitrile (4.16 g, 42 mmol) in the presence of 200 mg of zinc chloride. The reaction mixture is diluted with 50 ml of methylene chloride immediately before

  
  <EMI ID = 161.1>

  
Method A

  
Following the procedure of Example 2,

  
  <EMI ID = 162.1>

  
siloxyethanenitrile (9 g) in 250 ml of saturated ethanolic hydrogen chloride, in 1- hydrochloride (S-chloro-2-

  
  <EMI ID = 163.1>

  
The hydrochloride is transformed into the free base by partitioning between methylene chloride and saturated sodium bicarbonate. The chloromethylenic phase is washed twice with additional bicarbonate and then with brine, dried over anhydrous magnesium sulfate, filtered and evaporated, taking the free base as product as a viscous oil L5.62 g, 70% , m / e 245/243;

  
  <EMI ID = 164.1>

  
Method B

  
100 ml of ethanol are cooled in a water and ice bath and hydrochloric gas is passed through for one minute. 4 g of 2- (5chloro-2-methoxy) -2-trimethylsiloxyethanenitrile are suspended in cold ethanolic hydrogen chloride. 50 ml are added

  
carbon tetrachloride to dissolve the nitrile and the cold mixture is stirred for 2 minutes and concentrated to dryness to obtain 2.58 g of cyanohydrin of 5chloro-2-methoxybenzaldehyde melting at 71-74 [deg.] C, m / e 199 /

  
  <EMI ID = 165.1>

  
  <EMI ID = 166.1>

  
ethanolic saturated at 0-5 [deg.] C and the solution is maintained

  
  <EMI ID = 167.1>

  
to get the raw product. By recrystallization from a mixture of ethanol and ether, the hydrochloride is obtained

  
  <EMI ID = 168.1>

  
Following the procedure of Example 9, with the difference that only 2 equivalents of triethylamine are used, and that the product is extracted in methylene chloride, after deactivation on ice, one trans- <EMI ID = 169.1>

  

  <EMI ID = 170.1>


  
14.2 g (0.05 mole) of chlorhy- are suspended

  
  <EMI ID = 171.1>

  
ethyl carboximidate-in 350 ml of tetrahydrofuran and the suspension is cooled in an ice bath. We add
16.2 g (0.16 mole) of triethylamine and phosgene is passed through the cold reaction mixture for 2 hours, and at this time, thin layer chromatography (ethyl acetate: chloroform 1: 1) n ' indicates that the

  
  <EMI ID = 172.1>

  
between ethyl acetate. and water. The ethyl acetate phase is washed with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated to give the intermediate compound (m / e 271/269). The reaction mixture is allowed to warm to room temperature while continuing the passage of phosgene for one hour, while stirring at room temperature for 16 hours. We slowly pour the

  
  <EMI ID = 173.1>

  
milk three times with 250 ml portions of chloride

  
methylene. The combined extracts are washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give the product (14.7 g). Aliquots are variously recrystallized in

  
a mixture of ethyl acetate and toluene and a mixture of acetone and hexane. Most of the product (14.2 g) <EMI ID = 174.1>

  
sodium IN, the product is extracted with toluene (one portion of 140 ml and two portions of 50 ml), it is treated with activated carbon, it is filtered and it is reprecipitated by pouring it into 100 ml of 3N hydrochloric acid with stirring -

  
  <EMI ID = 175.1>

  
Following the procedure of Example 1, but using a reaction time of 4 days at room temperature, 9.5 g (0.062 mole) of 5fluoro-2-methoxybenzaldehyde in 50 ml of methylene chloride are reacted. with 7.3 g (0.074 mole) of trimethylsilylcarbonitrile in the presence of a catalytic amount of iodide of

  
  <EMI ID = 176.1>

  
  <EMI ID = 177.1>

  
  <EMI ID = 178.1>

  
Following the procedure of Example 2, but using a reaction time of only 2 hours at

  
  <EMI ID = 179.1>

  

  <EMI ID = 180.1>


  
EXAMPLE 15

  
  <EMI ID = 181.1>

  
39

  
  <EMI ID = 182.1>

  

  <EMI ID = 183.1>


  
EXAMPLE 16

  
  <EMI ID = 184.1>

  
Cool in an ice bath 15 g (0.107 mole)

  
of 2-chlorobenzaldehyde. 500 mg of zinc iodide is added with stirring, then 12.7 g (0.128 mol) are added dropwise

  
  <EMI ID = 185.1>

  
16 hours at room temperature, diluted with methylene chloride, washed with three portions of saturated sodium bicarbonate then with brine, dried over anhydrous magnesium sulfate and dried

  
  <EMI ID = 186.1>

  
EXAMPLE 17

  
  <EMI ID = 187.1>

  
ethyl midate

  
Following the procedure of Example 2, the 2- (2-chlorophenyl) -2-trimethylsiloxyethanenitrile is transformed
(15 g) in 375 ml of hydrogen chloride than thanolic

  
  <EMI ID = 188.1>

  
ethyl methanecarboximidate L13.4 g, 85%; melting point 127-129 [deg.] C (decomposition). ; infrared spectrum (KBr)

  
  <EMI ID = 189.1>

  
tetrahydrofuran and the mixture is cooled in an ice and water bath. 16.77 g (0.166 mole) of triethylamine is added and phosgene is passed through the mixture with stirring for 45 minutes at 0 [deg.] C. After having kept the mixture for another hour at the same temperature, it is poured slowly over a liter of crushed ice, isolating the product and recrystallizing it from toluene in accordance with Example 3 to obtain 5- (2-

  
  <EMI ID = 190.1>

  
106-108 [deg.] C).

  

  <EMI ID = 191.1>


  
EXAMPLE 19

  
  <EMI ID = 192.1>

  
Following the procedure of Example 16, 25 g (0.178 mole) of 3-chlorobenzaldehyde is reacted

  
  <EMI ID = 193.1>

  
ethyl midate

  
Following the procedure of Example 2, 10 g of 2- (3-chlorophenyl) -2-trimethylsiloxyethanenitrile are transformed into 250 ml of hydrogen chloride ethano-

  
  <EMI ID = 194.1>

  
EXAMPLE 21

  
  <EMI ID = 195.1>

  
Following the procedure of Example 3, 9 g (38 moles) of 1- (3-chloro- hydrochloride) are transformed.

  
  <EMI ID = 196.1>

  
melting point 142-144 [deg.] C).

  

  <EMI ID = 197.1>


  
EXAMPLE 22

  
  <EMI ID = 198.1>

  
3.4 g (0.019 mol) of 2-methoxy-5nitrobenzaldehyde are dissolved in 125 ml of methylene chloride.

  
Zinc iodide (50 mg) is added, followed by trimethylsilylcarbonitrile and the mixture is stirred for 2 hours at room temperature. The reaction mixture is washed with two portions of saturated sodium bicarbonate, then a portion of brine, it is dried over sulphate

  
anhydrous magnesium, filtered and then concentrated to

  
  <EMI ID = 199.1>

  
EXAMPLE 23

  
Ethyl methanecarboximidate hydrochloride

  
Following the procedure of Example 3, but

  
  <EMI ID = 200.1>

  
siloxyethanenitrile in 150 ml of saturated ethanolic hydrogen chloride, in 1-hydroxy-1- (2-

  
  <EMI ID = 201.1>

  
EXAMPLE 24

  
  <EMI ID = 202.1>

  
ethyl phenyl) methanecarboximidate (4.5 g, 0.015 mole)

  
in 400 ml of tetrahydrofuran in crude product. By recrystallization from ethanol, 5- (2-methoxy-

  
  <EMI ID = 203.1>

  

  <EMI ID = 204.1>


  
EXAMPLE 2 5

  
  <EMI ID = 205.1>

  
in 50 ml of ether and the solution is cooled in an ice and water bath. 300 mg of zinc iodide are added and then drop

  
  <EMI ID = 206.1>

  
The reaction mixture is stirred for 16 hours at room temperature, diluted with 200 ml of ether,

  
  <EMI ID = 207.1>

  
and a portion of brine, 1 1 deg. dehydrate over anhydrous magnesium sulfate, filter and concentrate for

  
  <EMI ID = 208.1>

  
ethyl midate

  
Following the procedure of Example 2, we

  
  <EMI ID = 209.1>

  
EXAMPLE 27

  
  <EMI ID = 210.1>

  
Following the procedure of Example 3, with the difference that a reaction time of 16 hours at room temperature is used after cold passage of phosgene and that the product is extracted with methylene chloride after deactivation on crushed ice, 16 g (0.068 mole) of 1- (3-

  
  <EMI ID = 211.1>

  
5- (3-fluorophenyl) oxazolidine-2, 4-dione recrystallized from toluene (7.51 g, 56%; melting point 147-149 [deg.] C).

  

  <EMI ID = 212.1>


  
EXAMPLE 28

  
  <EMI ID = 213.1>

  
Following the procedure of Example 16,

  
with the difference that we use a reaction time of

  
5 days at room temperature, react 15 g
(0.125 mole) of 2-methylbenzaldehyde with 14.9 g (0.15 mole) of trimethylsilylcarbonitrile to produce 2- (2-methylphenyl) -2-trimethylsiloxyethanenitrile as

  
  <EMI ID = 214.1>

  
123-125 [deg.] C (decomposition)? m / e 1937.

  

  <EMI ID = 215.1>


  
EXAMPLE- 30

  
  <EMI ID = 216.1>

  
recrystallized from toluene (9.1 g, 77%, melting point 111-113 [deg.] C (m / e 191).

  

  <EMI ID = 217.1>
 

  
EXAMPLE 31

  
  <EMI ID = 218.1>

  
Following the procedure of Example 16, 10 g (0.057 mole) of 2-trifluoromethylbenzaaldehyde are reacted with 6.73 g (0.068 mole) of trimethylsilylcarbonitrile in the presence of 250 mg of zinc iodide to obtain

  
  <EMI ID = 219.1>

  
saturated ethanolic hydrogen chloride, 1-hydroxy-1-
(2-trif luoromethylphenyl) methanecarboximidate, ethyl

  
  <EMI ID = 220.1>

  
2,4-dione recrystallized from toluene (5.3 g, 54%; melting point 91-93 [deg.] C; m / e 245).

  

  <EMI ID = 221.1>


  
  <EMI ID = 222.1>

  
  <EMI ID = 223.1> 45

  
  <EMI ID = 224.1>

  
Following the procedure of Example 2, 15 g of 2- (3-phenoxyphenyl) -2-trimethylsiloxyethanenitrile are transformed into 350 ml of hydrogen chloride ethano-

  
  <EMI ID = 225.1>

  

  <EMI ID = 226.1>


  
  <EMI ID = 227.1>

  
  <EMI ID = 228.1>

  
Following the procedure of Example 1, 2-benzyloxybenzaldehyde (25 g, 0.118 mol) in 250 ml of methylene chloride is reacted with trimethyl-

  
  <EMI ID = 229.1>

  
zinc (500 mg) to obtain 2- (2-benzyloxyphenyl) 2-trimethylsiloxyethanenitrile in the form of an oil L35.6 g, m / e 311, infrared spectrum (CH2C12) 1605, 1493,

  
  <EMI ID = 230.1>

  
Following the procedure of Examples 2 and 11
(Method A), 20 g of 2- (2-benzyloxyphenyl) 2-trimethylsiloxyethanenitrile are transformed into 500 ml of chloride <EMI ID = 231.1>

  
Ethyl 1-hydroxymethanecarboximidate in the form of a viscous oil L13.2 g, 72% m / e 285 infrared spectrum

  
  <EMI ID = 232.1>

  
recrystallized from toluene (7.23 g, 55%; melting point 191-193 [deg.] C; m / e 283).

  

  <EMI ID = 233.1>


  
  <EMI ID = 234.1>

  
  <EMI ID = 235.1>

  
ethyl

  
Following the procedures of Examples 2 and

  
  <EMI ID = 236.1> <EMI ID = 237.1>

  
fusion 93-96 [deg.] C). A second recrystallization from toluene gives the purified product (4.9 g, 53% in total melting point 97-99 [deg.] C, m / e 245).

  

  <EMI ID = 238.1>


  
  <EMI ID = 239.1>

  
  <EMI ID = 240.1>

  
methylbenzaldehyde in 50 ml of methylene chloride with 1.27 g (12.8 mmol) of trimethylsilylcarbonitrile in the presence of 50 mg of zinc iodide to obtain 2- (5-

  
  <EMI ID = 241.1>

  
Saturate 100 ml of ethanol of hydrogen chloride at 0 [deg.] C. 2.9 g of 2- (5-chloro-

  
  <EMI ID = 242.1>

  
about 1 hour, it is evaporated to dryness and the residue is triturated with ether to obtain the hydrochloride of

  
  <EMI ID = 243.1> <EMI ID = 244.1>

  
Following the procedure of Example 9, with the difference that methylene chloride is used in place of chloroform for the extraction of the product after

  
  <EMI ID = 245.1>

  
reaction mixture slowly on 1 liter of crushed ice.

  
The aqueous phase is separated and extracted with three portions of methylene chloride. After gathering the

  
  <EMI ID = 246.1>

  
  <EMI ID = 247.1>

  
it is extracted with ether and acidified with 1 [deg.] 3N hydrochloric acid to precipitate the desired product (1.81 g,
83%, melting point 184-186 [deg.] C). By recrystallization in

  
  <EMI ID = 248.1>

  
purified phenyl) oxazolidine-2,4-dione (1.57 g, yield otal 72%; melting point 187-189 [deg.] C).

  

  <EMI ID = 249.1>


  
  <EMI ID = 250.1>

  
  <EMI ID = 251.1>

  
Following the procedure of Example 25,

  
with the difference that a reaction time of one hour at room temperature is used, 2-chloro is reacted

  
  <EMI ID = 252.1>

  
ether with trimethylsilylcarbonitrile (4.30 g, 0.042 mole) in the presence of zinc iodide (100 mg), which gives

  
  <EMI ID = 253.1>

  
nitrile in the form of an oil (5.62 g, 99%, resonance <EMI ID = 254.1>

  
the difference that one maintains the reactional mixture during one hour only at 0-8 [deg.] C,, one transforms the

  
  <EMI ID = 255.1>

  

  <EMI ID = 256.1>


  
EXAMPLE 48

  
  <EMI ID = 257.1>

  
Following the procedure of Example 9, 1- (2-chloro-6-methoxyphenyl) hydrochloride is transformed -

  
  <EMI ID = 258.1>

  
acetone displaced by ethyl acetate, as detailed in Example 92 given below, is used to further purify the product.

  
  <EMI ID = 259.1>

  
  <EMI ID = 260.1>

  
Following the procedure of Example 25, except that a reaction time of 2.5 hours at room temperature is used, 2chloro-6-fluorobenzaldehyde (10 g, 0.063 mol) is reacted in 150 ml

  
  <EMI ID = 261.1>

  
0.126 mol) in the presence of zinc iodide (100 mg) for <EMI ID = 262.1>

  
Following the procedure of Example 2, with the difference that a reaction time of only 40 minutes is used at 0-5 [deg.] C, 2- (2-chloro-6-

  
  <EMI ID = 263.1>

  
incompletely anhydrous from the previous example in 540 ml of saturated ethanolic hydrogen chloride to produce

  
  <EMI ID = 264.1>

  
EXAMPLE 51

  
  <EMI ID = 265.1>

  
ethyl and 16.8 g (23.3 ml, 0.167 mol) of triethylamine in 560 ml of, tetrahydrofuran and the solution is cooled to 0 [deg.] C. Phosgene is bubbled through the reaction mixture for 35 minutes. The mixture is then stirred for 2.5 hours at room temperature, poured into 600 ml of crushed ice and extracted with three portions of ethyl acetate. The combined extracts are washed with water, with brine, dried over anhydrous magnesium sulfate, filtered and evaporated under

  
empty giving 14.4 g of product. By recrystallization from toluene, the. 5- (2-chloro-6-fluorophenyl)

  
  <EMI ID = 266.1>

  
  <EMI ID = 267.1>

  

  <EMI ID = 268.1>


  
EXAMPLE 52

  
  <EMI ID = 269.1>

  
15 g (0.069 mol) of 5-bromo-2-methoxybenzaldehyde are reacted in 100 ml of methylene chloride

  
  <EMI ID = 270.1>

  
mole) in the presence of 100 mg of zinc iodide in accordance with Example 1. After 24 hours at room temperature, the reaction mixture is diluted with 100 ml of methylene chloride and the mixture is further isolated in accordance with

  
  <EMI ID = 271.1>

  
trimethylsiloxyethanenitrile L21.1 g, solids; Rf (ethyl acetate / chloroform 1: 1) 0.78; resonance

  
  <EMI ID = 272.1>

  
EXAMPLE 53

  
  <EMI ID = 273.1>

  
siloxyethanenitrile (20 g) in 500 ml of ethanolic hydrogen chloride saturated with 1- (5-

  
  <EMI ID = 274.1>

  
ethyl (17.4 g, solid, proton magnetic resonance / CDCl3 ': DMSO 1: 1) 1.5 (3H), 4.0 (3H), 4.6 (2H),

  
  <EMI ID = 275.1>

  
Following the procedure of Example 3, react with phosgene 16 g (0.049 mole) of 2- (5-

  
  <EMI ID = 276.1>

  
in 320 ml of tetrahydrofuran. After shaking for
16 hours at room temperature, the reaction mixture is deactivated in 1 liter of crushed ice and. it is extracted with two 500 ml portions of ethyl acetate.

  
After having combined the extraction phases in] ethyl acetate, they are rinsed with two 200 ml portions of brine, they are dried over anhydrous magnesium sulfate, they are filtered and they are evaporated to dryness. The solids are recrystallized from toluene in

  
  <EMI ID = 277.1>

  
Purified 2,4-dione melting at 166-167 [deg.] C.

  

  <EMI ID = 278.1>


  
EXAMPLE 55

  
  <EMI ID = 279.1>

  
Following the procedure of Example 1, 10 g (0.054 mole) of 5-chloro-2-ethoxybenzaldehyde in 100 ml of methylene chloride are reacted with 6.4 g

  
  <EMI ID = 280.1>

  
presence of 100 mg of zinc iodide. After 2.5 hours at room temperature, the isolation is carried out in accordance with

  
  <EMI ID = 281.1>

  
EXAMPLE 56

  
  <EMI ID = 282.1>

  
ethyl

  
Following the procedure of Example 2, but

  
  <EMI ID = 283.1>

  
siloxyethanenitrile in 350 ml of saturated ethanolic hydrogen chloride, produces it in the form of the hydrochloride. In solvent, the procedure of Example 11, except for the use of chloroform instead of methylene chloride, the hydrochloride is converted into the

  
  <EMI ID = 284.1> (two triplets, 6H), 3.8-4.6 (two quadruplets, 4H), 5.5

  
  <EMI ID = 285.1>

  
for 2 hours at room temperature, is also isolated, in accordance with Example 54 by substituting the chloroform for ethyl acetate to obtain 5- (5-

  
  <EMI ID = 286.1>

  

  <EMI ID = 287.1>


  
  <EMI ID = 288.1>

  
  <EMI ID = 289.1>

  
0.06 mol) in 120 ml of methylene chloride with

  
  <EMI ID = 290.1>

  
presence of zinc iodide (150 mg) to obtain 2- (2-

  
  <EMI ID = 291.1>

  
Following the procedure of Example 56, 14 g of 2- (2-ethoxy-5-fluorophenyl) -2trimethylsilylethanenitrile in 420 ml of saturated ethanolic hydrogen chloride are converted into 1- (2-

  
  <EMI ID = 292.1> <EMI ID = 293.1>

  
Following the procedure of Example 27 and using chloroform as an extractant,

  
  <EMI ID = 294.1>

  
Ethyl 1-hydroxymethanecarboximidate (11 g) in crude product (11.3 g). By recrystallization from isopro- alcohol

  
  <EMI ID = 295.1>

  

  <EMI ID = 296.1>


  
  <EMI ID = 297.1>

  
  <EMI ID = 298.1>

  
Following the procedure of Example 1, 15 g (0.1 mole) of 2-methoxy-5-methylbenzaldehyde in 300 ml of methylene chloride are reacted with 19.8 g (0.2 mole) of trimethylsilylcarbonitrile in the presence of 200 mg of iodide

  
  <EMI ID = 299.1> By following the procedure of Example 3, and using a stirring time of 16 hours at room temperature before deactivation, it is transformed

  
  <EMI ID = 300.1>

  
oxazolidine-2,4-dione recrystallized from toluene

  
  <EMI ID = 301.1>

  
using a stirring time of 16 hours at room temperature, 8.2 g (0.059 mole) of

  
  <EMI ID = 302.1>

  
methylene with trimethylsilylcarbonitrile (8.9 g, 0.09 mole) in the presence of zinc iodide (100 mg) to obtain

  
  <EMI ID = 303.1>

  
nitrile in the form of an oil (13.6 g, proton magnetic resonance / CDCl3 comprises a peak at 0.2 ppm due to the protons of the trimethylsilyl group.

EXAMPLE '65

  
  <EMI ID = 304.1>

  
By following the procedure of Example 2 and by

  
  <EMI ID = 305.1>

  
solid ethyl / 4.4 g, proton magnetic resonance /

  
  <EMI ID = 306.1>

  
Following the procedure of Example 63, but using 3 instead of 3.2 equivalents of triethyl- <EMI ID = 307.1>

  
as a crude product (1.36 g). By recrystallization from a mixture of carbon tetrachloride and chloroform

  
  <EMI ID = 308.1>

  
oxazolidine-2,4-dione (m / e 209; the magnetic resonance of the protons indicates a contamination of approximately 10% by an isomeric product).

  

  <EMI ID = 309.1>


  
EXAMPLE, 67

  
  <EMI ID = 310.1>

  
ethanenitrile

  
Following the procedure of Example 64, we

  
  <EMI ID = 311.1>

  
methylbenzaldehyde in 25 ml of methylene chloride with 0.5 g (0.6 ml, 4.5 mmol) of trimethylsilylcarbonitrile in the presence of zinc iodide (10 mg) to form the

  
  <EMI ID = 312.1>

  
Proton magnetic nance (CH2C12) exhibits a loss of the aldehyde peak at 10 ppm7.

  
EXAMPLE 68

  
  <EMI ID = 313.1> <EMI ID = 314.1>

  

  <EMI ID = 315.1>


  
EXAMPLE 70

  
  <EMI ID = 316.1>

  
ethanenitrile

  
Following the procedure of Example 64, we

  
  <EMI ID = 317.1>

  
EXAMPLE 71

  
  <EMI ID = 318.1>

  
ethyl carboxymidate / 1.74 g, 91%; Fusion point
132-134 [deg.] C (decomposition); infrared spectrum (KBr)

  
  <EMI ID = 319.1>

  
Following the procedure of Example 63, 1.5 g (5.7 mmol) of 1- (3-

  
  <EMI ID = 320.1>

  
oxazolidine-2,4-dione recrystallized from toluene

  
(0.84 g, 57%; melting point 177-179 [deg.] C; infra-spectrum

  
  <EMI ID = 321.1>

  
EXAMPLE 73

  
  <EMI ID = 322.1>

  
Following the procedure of Example 1 and using a reaction time of one hour at room temperature, react 1.3 g (7.7 mmol) of 2-ethoxy-6-fluorobenzaldehyde in 30 ml. chloride

  
  <EMI ID = 323.1>

  
Following the procedure of Example 66 and

  
using a reaction time of 3 hours at room temperature, it is converted into a crude product 0.56 g

  
  <EMI ID = 324.1>

  
tetrahydrofuran. By recrystallization from toluene, there is obtained purified 5- (2-ethoxy-6-fluorophenyl) oxazolidine-2,4dione (147 mg, melting point 127-128 [deg.] C).

  
  <EMI ID = 325.1>

  
  <EMI ID = 326.1>

  
25 g (0.24 mole) of benzaldehyde is cooled in an ice and water bath. 500 mg of iodide of

  
  <EMI ID = 327.1>

  
silylcarbonitrile. The reaction mixture is stirred at room temperature for 16 hours, diluted with
100 ml of chloroform, washed with three portions of saturated sodium bicarbonate, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness to obtain 46.1 g

  
  <EMI ID = 328.1>

  
of ethyl

  
Following the procedure of Example 2,

  
  <EMI ID = 329.1>

  
siloxyethanenitrile in 750 ml of saturated ethanolic hydrogen chloride, in ethyl 1-hydroxy-1-phenylmethanecarboximidate hydrochloride L42.2 g, 89%,

  
  <EMI ID = 330.1>

  
The free base is prepared by distributing 20 g of the hydrochloride between 500 ml of methylene chloride and

  
  <EMI ID = 331.1>

  
lenique, washed twice with sodium hydroxide

  
  <EMI ID = 332.1>

  
anhydrous magnesium sulphate, filtered and concentrated

  
  <EMI ID = 333.1>

  
ethyl carboxididate (12.1 g, melting point 65-67 [deg.] C).

  
EXAMPLE 78

  
  <EMI ID = 334.1>

  
Following the procedure of Example 3, at

  
the difference that we use a reaction time of 16 hours at room temperature and that we then pass phcsgene to cold, we transform 22 g (0.102 mole)

  
  <EMI ID = 335.1>

  
ethyl in 450 ml of tetrahydrofuran to 5-phenyloxazolidine-2,4-dione recrystallized from toluene

  
  <EMI ID = 336.1>

  
Following the procedure of Example 16 and using a reaction time of 64 hours, we make bU

  
  <EMI ID = 337.1>

  
8.91 g (0.09 mole) of trimethylsilylcarbonitrile in the presence of 200 mg of zinc iodide to produce

  
  <EMI ID = 338.1>

  
in the form of an oil (15.4 g, 88% m / e 233).

EXAMPLE 80

  
  <EMI ID = 339.1>

  
siloxyethanenitrile with 350 ml of saturated ethanolic hydrogen chloride to obtain 1- (2,5-

  
  <EMI ID = 340.1>

  
sition); m / e 2017.

  
  <EMI ID = 341.1>

  
  <EMI ID = 342.1>

  
Following the procedure of Example 9 and using methylene chloride as solvent, we

  
  <EMI ID = 343.1>

  
phenyl) -oxazolidine-2,4-dione recrystallized from toluene (5.82 g; melting point 134-136 [deg.] C, melting point

  
  <EMI ID = 344.1>

  
Following the procedure of Example 1 and using a stirring time of 2.5 hours at room temperature, 33 g (0.22 mole) of 2nitrobenzaldehyde in 400 ml of methylene chloride are reacted.

  
  <EMI ID = 345.1>

  
EXAMPLE 83

  
  <EMI ID = 346.1>

  
ethyl midate

  
Following the procedure of example 2, using a reaction time of one hour at 0-5 [deg.] C, reacting 54.0 g (0.216 mole) of 2- (2- nitrophenyl) -2-

  
  <EMI ID = 347.1>

  
Following the procedure of Example 66, 49 g (0.188 mole) of 1-hydroxy hydrochloride are transformed.

  
  <EMI ID = 348.1>

  
  <EMI ID = 349.1>

  

  <EMI ID = 350.1>


  
  <EMI ID = 351.1>

  
  <EMI ID = 352.1>

  
5.0 g (22.5 mmol) of 5- (2-nitrophenyl) oxazolidine-2,4-dione are taken up in a mixture of 11.5 ml of methanol and 12.3 ml of concentrated hydrochloric acid. We add

  
iron powder (3.77 g, 67.5 mmol) in 30 minutes, during which time an exothermic reaction takes

  
the temperature at reflux and the mixture becomes homogeneous.

  
The mixture is allowed to cool to room temperature

  
and stirred for 3 hours. Another 1.2 g of powdered iron are added and the mixture is stirred for 0.5 hour,

  
it is poured into 100 ml of water and extracted with three portions of ethyl acetate. After having combined the extraction phases with ethyl acetate, they are rinsed with water and. brine, they are dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to obtain a solid foam. The crude product is taken up in 55 ml of ethanol, it is

  
  <EMI ID = 353.1>

  
for 10 minutes (crystallization begins at this stage), dilute with ether and filter to collect 5- (2-aminophenyl) oxazolidine-2,4-dione hydrochloride

  
  <EMI ID = 354.1>

  
m / e 1927.

  

  <EMI ID = 355.1>


  
EXAMPLE 86

  
  <EMI ID = 356.1>

  
sodium acetate then, drop by drop, 449 mg (0.41 ml, 4.37 mmol) of acetic anhydride. The reaction mixture is stirred at room temperature for 16 hours, poured into 50 ml of water and extracted with three portions of ethyl acetate. The collected extracts

  
  <EMI ID = 357.1>

  
brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness under vacuum (0.72). by recrystallization from ethyl acetate, we obtain in two

  
  <EMI ID = 358.1>

  

  <EMI ID = 359.1>


  
  <EMI ID = 360.1>

  
  <EMI ID = 361.1> <EMI ID = 362.1>

  
position); infrared spectrum (KBr) 3175, 2899, 1681,

  
  <EMI ID = 363.1>

  

  <EMI ID = 364.1>


  
EXAMPLE 89

  
  <EMI ID = 365.1>

  
Following the procedure of Example 27, but using 3 instead of 3.2 equivalents of triethyl-

  
  <EMI ID = 366.1>

  
m / e 252).

  

  <EMI ID = 367.1>


  
EXAMPLE 90

  
  <EMI ID = 368.1> <EMI ID = 369.1>

  
using a reaction time of 16 hours at room temperature, 2,6-difluorobenzaldehyde (9.1 g, 0.064 mole) in 100 ml of methylene chloride is reacted with trimethylsilylcarbonitrile (7.13 g, 0.072 mole ) in the presence of 100 mg of zinc iodide for

  
  <EMI ID = 370.1>

  
ethanenitrile (14.3 g, 0.059 mole) in 360 -, nor of saturated ethanolic hydrogen chloride, in 1- hydrochloride

  
  <EMI ID = 371.1>

  
13.1 g, 88%; melting point 135-137 [deg.] (decomposition);

  
  <EMI ID = 372.1>

  

  <EMI ID = 373.1>


  
EXAMPLE 92

  
  <EMI ID = 374.1>

  
500 ml of tetrahydrofuran in crude product. The crude product is recrystallized from approximately 60 ml of isopropanol to give the purified 5- (2,6-difluorophenyl) oxazolidine-2,4-dione / 5.8 g, 57%; melting point 196-198 [deg.] C, m / e
213; infrared spectrum (KBr) 3175, 1812, 1739, 1361,

  
  <EMI ID = 375.1>

  
ethanenitrile The procedure of Example 1 is followed, with the difference that a reaction time of 4 days at room temperature is used to react the 3-

  
  <EMI ID = 376.1>

  
in 25 ml of methylene chloride with trimethylsilylcarbonitrile (535 mg, 5.4 mmol) in the presence of zinc iodide (10 mg) to produce 2- (3-chloro-6-

  
  <EMI ID = 377.1>

  
  <EMI ID = 378.1>

  
EXAMPLE 94

  
  <EMI ID = 379.1>

  
EXAMPLE 95

  
  <EMI ID = 380.1>

  
Following the procedure of Example 27, 1- (3-chloro-6-methoxy-2- hydrochloride) is transformed

  
  <EMI ID = 381.1>

  
in toluene (470 mg, 54%; melting point 193-195 [deg.] C).

  

  <EMI ID = 382.1>


  
EXAMPLE 96

  
  <EMI ID = 383.1> <EMI ID = 384.1>

  
salt and ice, 3 mi of concentrated hydrochloric acid.

  
2.2 g of 5-chloro-2- cyanohydrin are suspended

  
  <EMI ID = 385.1>

  
Example 11) in 5 ml of ether and the suspension is added to cold acid. Hydrogen chloride gas is passed through

  
  <EMI ID = 386.1>

  
3 hours. The reaction mixture is quenched in 50 ml of water and extracted with 3 portions of ethyl acetate.

  
The combined extracts are dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. By trituration of the solids with ether, we obtain

  
  <EMI ID = 387.1>

  
53%; melting point 12l-123 [deg.] C, m / e 217/215).

  

  <EMI ID = 388.1>


  
  <EMI ID = 389.1>

  
  <EMI ID = 390.1>

  
(1.0 g, 4.6 = moles) and the mixture is stirred for a few minutes to obtain dissolution, then it is refluxed for 16 hours and, at this time, thin layer chromatography (ethyl acetate chloroform 1: 1) indicates the presence of some unreacted starting material. The addition of an additional amount of diethyl carbonate (625 mg) and potassium tert-butoxide (100 mg) and an additional reflux time of 2.5 hours do not seem to reduce the

  
starting acetamide level. The reaction mixture is allowed to cool to room temperature, poured into excess IN hydrochloric acid cooled with ice and

  
  <EMI ID = 391.1>

  
  <EMI ID = 392.1> <EMI ID = 393.1>

  
bicarbonate pooled are slowly poured into excess IN hydrochloric acid to.precipitate the 5-

  
  <EMI ID = 394.1>

  
41.6 g (0.4 mole) of sodium bisulfite is added to a suspension with stirring of 2-chloro-6-methoxybenzaldehyde (38.9 g, 0.23 mole) in 550 ml of water. The mixture is heated to 50-55 [deg.] C for one hour, to 65-
68 [deg.] C for 20 minutes, then it is cooled to 10 [deg.] C. A solution of 38.7 g (0.57 mole) of potassium cyanide in 200 ml of water is added over 15 minutes while maintaining the temperature at 10-13 [deg.] C. No notable exothermic reaction is observed. The mixture is stirred for 15 minutes in an ice and water bath, the bath is removed and

  
  <EMI ID = 395.1>

  
temperature rises to 18 [deg.] C. The reaction mixture is extracted with 2 portions of 100 ml of methylene chloride. The combined chloromethylenic extracts are washed with

  
150 ml of water. The 150 ml aqueous extract is rinsed with

  
100 ml of fresh methylene chloride. All the organic phases are combined, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give an oil which, by scraping, gives the cyanhydrin

  
  <EMI ID = 396.1>

  
A variant preparation of this compound is given in process B of Example 11.

  
EXAMPLE 99

  
  <EMI ID = 397.1>

  
22.2 g (0.113 mole) of 2-chloro-6-methoxybenzaldehyde cyanohydrin are dissolved in 39.4 ml of formic acid at 22 [deg.] C. The mixture is cooled to 10 [deg.] C in an ice-water bath and added dropwise over 27 minutes
39.4 ml concentrated hydrochloric acid, maintaining <EMI ID = 398.1>

  
in 10 minutes at 220 ml of water, period during which a moderate heat release is observed. The deactivated reaction mixture is extracted with 235 ml of methyl isobutyl ketone in three portions. The combined organic phases are dried over 4 g of anhydrous sodium sulfate, treated with 1 g of activated carbon, filtered through a Buchner funnel previously coated with diatomaceous earth and evaporated under vacuum with displacement.

  
  <EMI ID = 399.1>

  
Crystalline 2-formoxyacetamide L17.7 g, melting point
70-73 [deg.] C, proton magnetic resonance / CDC13 / delta

  
  <EMI ID = 400.1>

  
Method A

  
700 mg (3.5 mmol) of 2-chloro-6-methoxybenzaldehyde cyanohydrin are dissolved in 1.6 ml of formic acid. 1.6 ml of concentrated hydrochloric acid are added

  
and the mixture is stirred at 20 [deg.] C for 4 hours while carrying out a control by thin layer chromatography (chloroform: methanol 49: 1). The reaction mixture is then extracted twice with 25 ml portions

  
  <EMI ID = 401.1>

  
extraction with ethyl acetate, they are stirred with 25 ml

  
  <EMI ID = 402.1>

  
hydrolysis of the intermediate formic ester. The organic phase is separated, dried over anhydrous magnesium sulfate and evaporated to give an oil which, by

  
  <EMI ID = 403.1>

  
(500 mg, 65%; melting point 116-118 [deg.] C). Method B

  
  <EMI ID = 404.1>

  
moderately. The resulting solution is equilibrated with 30 ml of saturated sodium bicarbonate, by stirring for 30 minutes. The ethyl acetate phase is separated, dried over anhydrous magnesium sulfate, treated with activated carbon, filtered through a bed of diatomaceous earth and concentrated in vacuo to give a foam. By trituration with hexane, we obtain

  
  <EMI ID = 405.1>

  
proton magnetic resonance / CDC13 / delta. peak disappearing at 7.9 ppm, includes two doublets between 5.1 and 5.9 ppm (OH-CH split) which merge into a singlet

  
  <EMI ID = 406.1>

  
EXAMPLE 101

  
  <EMI ID = 407.1>

  
Method A

  
17.4 g (0.071 mole) of 2- (2-chloro-6-) are mixed

  
  <EMI ID = 408.1>

  
22.6 g (0.23 mole) of dimethyl carbonate and stirred

  
mixing for 30 minutes. We add in portions

  
12.9 g (0.24 mole) of sodium methylate in 30 minutes, a period during which the temperature rises from 22 [deg.] To
55 [deg.] C. After 15 minutes, the reaction mixture is poured into 260 ml of cold water with stirring. 1.7 g of activated carbon are added, the mixture is stirred for 10 minutes and filtered through a pad of diatomaceous earth with 80 ml of cold water for transfer and washing. We adjust

  
the pH to a value lower than 1 by the addition of 30 ml of concentrated hydrochloric acid, period during which

  
  <EMI ID = 409.1>

  
crude product by filtration and partially dried to a weight of 27 g in an air oven at 40 [deg.] C. The partially dried product is dissolved in 150 ml of acetone at 50 [deg.] C and clarified by filtration. We eliminate half

  
acetone by distillation and the second half is removed while adding 150 ml of ethyl acetate. Final-

  
  <EMI ID = 410.1>

  
  <EMI ID = 411.1> it is granulated for one hour. After filtration, washing

  
  <EMI ID = 412.1>

  
new filtration and air drying at 40 [deg.] C, we obtain

  
  <EMI ID = 413.1>

  
purified (13.1 g, 67%; melting point 203-205 [deg.] C).

  
Method B

  
2.50 g (22 mmol) of tert-butylate are taken up.

  
  <EMI ID = 414.1>

  
heat it. mix at reflux for 1.5 hours. The reaction mixture is cooled and deactivated by

  
  <EMI ID = 415.1>

  
with two 100 ml portions of chloroform. The combined organic extracts are washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give an oil which crystallizes under the vacuum of the pump - By recrystallization from 100 ml of toluene,

  
  <EMI ID = 416.1>

  
Method C

  
By following the procedure of method A of this

  
  <EMI ID = 417.1>

  
melting point 204-205 [deg.] C; proton magnetic resonance / DMSO / delta 3.80 (s, 3H), 4.20 (s, wide, 1H), 6.40

  
  <EMI ID = 418.1>

  

  <EMI ID = 419.1>
 

  

  <EMI ID = 420.1>


  
EXAMPLE 102

  
  <EMI ID = 421.1>

  
33.4 g (0.2 mole) of 2chloro-6-fluorobenzaldehyde are suspended in 300 ml of water, added

  
  <EMI ID = 422.1>

  
  <EMI ID = 423.1>

  
methylene and again cooled to 6 [deg.] C. Then we add
40.7 g (0.6 mole) of potassium cyanide in 200 ml of water in a two-phase system with stirring. The temperature

  
  <EMI ID = 424.1>

  
  <EMI ID = 425.1>

  
the aqueous phase with two 100 ml portions of fresh methylene chloride. The organic phase and the combined chloromethylenic extracts are washed with 200 ml of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo giving

  
  <EMI ID = 426.1>

  
  <EMI ID = 427.1>

  
  <EMI ID = 428.1>

  
The cyanohydrin of Example 102 (5.0 g) is dissolved in 10 ml of formic acid. 10 ml of concentrated hydrochloric acid are added in portions and the mixture is stirred at

  
room temperature for 2.5 hours, pour it

  
on 180 ml of crushed ice and extracted with two portions of ethyl acetate. The combined extracts are washed with

  
  <EMI ID = 429.1>

  
dehydrated over anhydrous magnesium sulfate, filtered and evaporated to give a solid product (4.4 g). By recrystallization from toluene, 2- (2-chloro-6-

  
  <EMI ID = 430.1>

  

  <EMI ID = 431.1>


  
  <EMI ID = 432.1>

  
  <EMI ID = 433.1>

  
Method A

  
26.7 g (0.13 mole) of 2- (2-chloro-6fluorophenyl) -2-hydroxyacetamide are mixed with 200 ml of methanol. ) 33.7 g (0.37 mole) of dimethyl carbonate are added and the mixture is stirred for a few minutes to obtain dissolution. 20.6 g are added in 25 minutes

  
  <EMI ID = 434.1>

  
hours, the reaction mixture is poured into 1 liter of ice and water. The deactivated reaction mixture is strongly acidified by the dropwise addition of 6N hydrochloric acid and the precipitated product is collected by

  
  <EMI ID = 435.1>

  
partially dried product is taken up in 100 ml of acetone, treated with activated carbon, filtered with 20 ml of acetone

  
for transfer and washing, diluted with 120 ml of ethyl acetate, evaporated in vacuo to half its volume, diluted with 80 ml of fresh ethyl acetate, evaporated in vacuo to a volume of 100 ml , diluted slowly and with stirring with 100 ml of hexane, granulated and filtered giving
18.8 g of 5- (2-chloro-6-fluorophenyl) oxazolidine-2,4-dione

  
  <EMI ID = 436.1>

  
(6.7 g in total) are obtained by concentration of the mother liquor.

  
Method B

  
3 g (15 mmol) of 2- (2-chloro-6fluorophenyl) -2-hydroxyacetamide are taken up in 40 ml of tertiobutanol and 2.7 g (2.5 ml, 30 mmol) of dimethyl carbonate. 3.4 g (30 mmol) of potassium tert-butoxide are added in portions and the reaction mixture is heated at reflux for 65 minutes, allowed to cool to room temperature, deactivated by adding in portions of 60 ml of 'hydrochloric acid

  
  <EMI ID = 437.1>

  
3 portions of ethyl acetate. The combined organic extracts are washed with water, washed with brine, dried over anhydrous magnesium sulfate, filtered

  
  <EMI ID = 438.1>

  
oxazolidine-2,4-dione (3.5 g). The purified product is obtained by recrystallization from toluene (3.0 g,

  
  <EMI ID = 439.1>

  
  <EMI ID = 440.1>

  
  <EMI ID = 441.1>

  
  <EMI ID = 442.1>

  
and continue to heat at 50 [deg.] C for 1.5 hours. The mixture is cooled to 0 ° C., it is covered with 150 ml of ether and a mixture of sodium cyanide (4.66 g, 0.095 mol) and

  
100 ml of ether. The two phase system is stirred at 0 [deg.] C for one hour. The organic phase is separated and the aqueous phase is extracted with two additional portions of ether. The organic phases are collected, washed

  
in brine, dehydrated over anhydrous magnesium sulfate, filtered and concentrated to dryness giving the

  
  <EMI ID = 443.1>

  
melting point 79-82 [deg.] C;. infrared spectrum (KBr) 3333,

  
  <EMI ID = 444.1>

  
The cyanhydrin of 2,6-dichlorobenzaldehyde (10 g, 0.049 mole) is dissolved in 30 ml of formic acid. Concentrated hydrochloric acid (30 ml) is added in

  
3 minutes and the mixture is stirred at room temperature for 2.5 hours. The reaction mixture is poured onto
300 ml of crushed ice and extracted with three portions of ethyl acetate. The organic extracts are collected, <EMI ID = 445.1>

  
IN sodium and brine, dehydrated over anhydrous magnesium sulfate, filtered and concentrated to give

  
  <EMI ID = 446.1>

  
melting point 155-158 [deg.] C; infrared spectrum (KBr) 3390,

  
  <EMI ID = 447.1>

  
5.16 g (0.046 mole) of potassium tert-butoxide is dissolved in 60 ml of tert-butanol. 4.14 g are added
(0.046 mole) of dimethyl carbonate, then 5 g (0.023

  
  <EMI ID = 448.1>

  
let cool to room temperature. We add

  
  <EMI ID = 449.1>

  
extract the mixture with three portions of methylene chloride. The collected organic extracts are washed

  
in brine, dehydrated over anhydrous magnesium sulfate, filtered and concentrated to dryness. By recrystallization of

  
  <EMI ID = 450.1>

  
purified oxazolidine-2,4-dione (3.15 g, 50%; melting point 151-153 [deg.] C), infrared spectrum (KBr) 1818, 1739,

  
  <EMI ID = 451.1>

  

  <EMI ID = 452.1>


  
  <EMI ID = 453.1>

  
  <EMI ID = 454.1>

  
22 g (0.096 mol) of 5- (2-chloro-6fluorophenyl) oxazolidine-2,4-dione are taken up in a mixture of

  
100 ml of dimethyl sulfoxide and 31.5 ml of methanol. 10.8 g (0.2 mole) of sodium methylate are added over approximately 4 minutes, during which time the temperature of the reaction mixture rises to 57 ° C. For convenience, the reaction mixture is allowed to stand for 16 hours at room temperature before heating to 106 [deg.] C for 5 hours. After cooling to 65 [deg.] C, the reaction mixture is deactivated by pouring it into 450 ml of ice and water, it is treated with activated carbon, it is filtered and it is made strongly acid with concentrated hydrochloric acid. The precipitated product is collected by filtration and the wet cake is suspended in
100 ml of toluene. Water is removed by azeotropic distillation under vacuum.

   The residual suspension is dissolved by the addition of 100 ml of acetone and by heating. After clarification, the acetone is removed

  
by vacuum evaporation (final volume 70 ml). 5- (2-chloro-6-methoxyoxazolidine-2,4- is obtained by filtration

  
  <EMI ID = 455.1>

  
second crop (0.9 g) of lower melting point is obtained from the mother liquor.

  
  <EMI ID = 456.1>

  
  <EMI ID = 457.1>

  
(18.8 mmol) of potassium tert-butoxide and the reaction mixture is heated in an oil bath maintained at 155 [deg.] C for 4 hours. The reaction mixture is allowed to cool to room temperature, poured into 200 ml of IN hydrochloric acid and extracted with three portions of ethyl acetate. The combined organic extracts are washed with water and then with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. The solids are taken up in hydroxide

  
  <EMI ID = 458.1>

  
purified oxazolidine-2,4-dione (1.32 g, 62%; melting point 138-142 [deg.] C). For analysis, the product is recrystallized from toluene (930 mg collected; melting point 139-1410C).

  

  <EMI ID = 459.1>
 

  
EXAMPLE 110

  
  <EMI ID = 460.1>

  
234 mg (2.1 mmol) of potassium tert-butoxide are taken up in 2.0 ml of dimethyl sulfoxide. 0.16 ml (146 mg, 3.0 mmol) of methylmercaptan is condensed and added to the reaction mixture. Finally, we add 229 mg
(1.0 mmol) of 5- (2-chloro-6-fluoro) oxazolidine-2,4-dione

  
  <EMI ID = 461.1>

  
hours, let it cool to room temperature,

  
  <EMI ID = 462.1>

  
the extract with three portions of ethyl acetate. The combined organic extracts are washed with two portions of water and one portion of brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give an oil (223 mg). By crystallization in the mixture

  
  <EMI ID = 463.1>

  
  <EMI ID = 464.1>

  
  <EMI ID = 465.1>

  
the reaction mixture is heated to reflux for 22 hours. To complete the reaction, we add again

  
0.1 portion (752 mg) of cuprous cyanide and reflux is continued for another 7 hours. The reaction mixture is allowed to cool to room temperature and is removed

  
  <EMI ID = 466.1>

  
under vacuum. The residue is distributed between 250 ml of acetate

  
  <EMI ID = 467.1>

  
organic phase, washed successively with 2 portions

  
  <EMI ID = 468.1>

  
100 ml of 10% ferric chloride in 3N hydrochloric acid and once with brine, it is dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. By recrystallization from a toluene / methanol mixture, the 5- (5-cyano-2-

  
  <EMI ID = 469.1>

  
(3.32 and 0.45 g, 58%; melting point 207-2090C; m / e
232).

  
  <EMI ID = 470.1>

  
  <EMI ID = 471.1>

  
3.95 g (0.06 mole) of potassium cyanide, 4.85 g (0.05 mole) of potassium thiocyanate and 6 ml of water are mixed and the mixture is stirred in an ice and water bath . 5.3 g (0.05 mol) of benzaldehyde are added dropwise. After stirring for 20 minutes, a practically homogeneous light yellow solution is obtained.

  
Continuing the cooling in a water and ice bath, 20.5 ml of 30% hydrochloric acid are added dropwise over 20 minutes. The resulting cloudy yellow solution is heated in a boiling water bath for

  
1 hour, resulting in the separation of an oil that is. less dense than the solution. The mixture is allowed to cool to room temperature, diluted with 50 ml

  
of water and the resulting solids are collected
(6.23 g) by filtration. By recrystallization from water, the crude 5-phenyloxazolidine-4-one-2-thione is obtained

  
  <EMI ID = 472.1>

  
dione (see the following example). The first and second harvests are collected and recrystallized a second time from water (melting point 132-135 [deg.] C, the melting point indicated in the literature is 130 [deg.] C) :.

  
EXAMPLE 113

  
  <EMI ID = 473.1>

  
In an initial recrystallization from water, described in the previous example, a third crop of product is obtained which consists of 5-phenyloxazolidine-

  
  <EMI ID = 474.1>

  

  <EMI ID = 475.1>
 

  
  <EMI ID = 476.1>

  
dione by the method of example 149.-

  
EXAMPLE 114

  
  <EMI ID = 477.1>

  
Butyllithium in hexane is added in 10 minutes

  
(2.4 M, 10 ml, 24 mmol) keeping the temperature between -70 and -60 [deg.] C. 3.14 g (20 mmol) of phenyl bromide are added over 20 minutes, maintaining the temperature

  
  <EMI ID = 478.1>

  
room temperature, then it is cooled to 5 [deg.] C. We add

  
  <EMI ID = 479.1>

  
organic phase. The aqueous phase is extracted with 35 ml of ethyl acetate. The combined organic extracts are washed with 10 ml of water, dried over anhydrous sodium sulfate and concentrated to give 5-hydroxy-

  
  <EMI ID = 480.1>

  
As a variant, we transform bromide from

  
  <EMI ID = 481.1>

  
corresponding by reaction with magnesium turn. The reagent is cooled and reacted with anhydrous alloxane as described above.

  
By the same procedures, the 2-bromanisole, the 2-ethoxy bromide, are respectively converted.

  
  <EMI ID = 482.1>

  
  <EMI ID = 483.1>

  
pyrimidinetrione.

  
EXAMPLE 115

  
  <EMI ID = 484.1>

  
(1H, 3Hp5H) -pyrimidine-trione in 15 ml of hydroxide

  
  <EMI ID = 485.1>

  
15 minutes, extracted with ethyl acetate, slightly acidified with about 1 ml of glacial acetic acid and extracted with 25 ml of ethyl acetate. The last ethyl acetate extract is rinsed with about 6.5 ml of water, filtered through a bed of anhydrous magnesium sulfate and evaporated to give 5-phenyloxazolidine2,4-dione.

  
Following the same procedure, the other pyrimidinetriones of the previous example are converted into the following compounds:

  
5- (2-methoxyphenyl) oxazolidine-2, 4-dione

  
  <EMI ID = 486.1>

  
2.4 g of 4-methylanisole and alloxane hydrate are dissolved in 25 ml of hot ethanol. We add 3 ml <EMI ID = 487.1>

  
for 15 minutes. The mixture is cooled and the ethanol is distilled off, adding 15 ml at the same time.

  
  <EMI ID = 488.1>

  
a solution of 830 mg of sodium hydroxide in 25 ml

  
methanol and stirred. mixing at room temperature

  
  <EMI ID = 489.1>

  
fusion 224-226 [deg.] C (decomposition) ^. By recrystallization from absolute ethanol and from isopropyl ether,

  
  <EMI ID = 490.1>

  

  <EMI ID = 491.1>


  
EXAMPLE 119

  
  <EMI ID = 492.1>

  
a mixture of 300 ml of ethyl acetate and 200 ml of tetrahydrofuran and the solution is clarified by filtration

  
  <EMI ID = 493.1>

  
and washing. The mother liquor, now at room temperature, is diluted with 100 ml of ethyl acetate,

  
  <EMI ID = 494.1>

  
sodium in 25 ml of methanol. 4.3 ml of water are added and crystallization is started by scraping or seeding. After granulation for 4 hours, the desired sodium salt (21 g) is obtained by filtration.

  
By redispersion in a mixture of 200 ml of ethyl acetate and 5 ml of water, the sodium salt is obtained

  
  <EMI ID = 495.1>

  
(19.6 g, melting point 96-98 [deg.] C).

  

  <EMI ID = 496.1>


  
The water is removed by vacuum drying for 3

  
  <EMI ID = 497.1>

  

  <EMI ID = 498.1>


  
The free acid (6.86 g) is separated from the liquor by partial evaporation, extraction with excess sodium hydroxide and acidification of the basic extract with 6N hydrochloric acid.

  
EXAMPLE 120

  
  <EMI ID = 499.1>

  
Method A

  
By operating at room temperature,

  
  <EMI ID = 500.1>

  
phêny]) oxazolidine-2,4-dione in 25 ml of 1,2-dichloroethane. 505 mg (0.7 ml, 5 mmol) of triethylamine are added and the mixture is stirred for one minute to obtain dissolution. 393 mg (0.36 ml, 5 mmol) of acetyl chloride are added and the mixture is stirred for one hour. The reaction mixture is concentrated to 5 ml and the solid is precipitated by the addition of about 25 ml of ether. The isolated solid material is distributed between chloroform and saturated sodium bicarbonate. The sentence

  
  <EMI ID = 501.1>

  
then with brine, dehydrated over anhydrous magnesium sulfate and evaporated to give 3-acetyl-5-

  
  <EMI ID = 502.1>

  
64%; melting point 161-164 [deg.] C; proton magnetic resonance / DMSO-d6 / delta 2.5 (s, 3H), 3.9 (s, 3H), 6.0

  
  <EMI ID = 503.1>

  
By the same procedure, replacing acetyl chloride with an equivalent amount of chloride

  
  <EMI ID = 504.1>

  
Method B

  
  <EMI ID = 505.1>

  
Add excess acetic anhydride (4 drops) and

  
  <EMI ID = 506.1>

  
(ethyl acetate: chloroform 1: 1; melting point 160-

  
  <EMI ID = 507.1>

  
dine-2,4-dione.

  
EXAMPLE 121

  
  <EMI ID = 508.1>

  
dine-2,4-dione

  
1.21 g (5 immoles) of 5- (5-

  
  <EMI ID = 509.1>

  
amine then 626 mg (5 mmol) of isocyanatocyclohexane. The reaction mixture is stirred for 19 hours at room temperature, washed successively with two

  
  <EMI ID = 510.1>

  
hydrochloric acid IN and once with brine, it is dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. By recrystallization in

  
  <EMI ID = 511.1>

  
  <EMI ID = 512.1>

  
By following the same procedure, and by replacing

  
  <EMI ID = 513.1>

  
EXAMPLE 122

  
  <EMI ID = 514.1>

  
  <EMI ID = 515.1>

  
708 mg (5 moles) of ethyl chloroformate and the reaction mixture is refluxed for 4.5 hours, kept for 18 hours at room temperature, clarified by filtration and concentrated to obtain an oil. The oil is crystallized by trituration with a small amount of ether (1.02 g) and recrystallized from a mixture of ethyl acetate and <EMI ID = 516.1> <EMI ID = 517.1>

  
(920 mg, 59%;: melting point 100-103 [deg.] C, m / e 315/313).

  

  <EMI ID = 518.1>


  
Following the same procedure, but replacing the ethyl chloroformate by an amount

  
  <EMI ID = 519.1>

  
hydrofuran. 613 mg (0.57 ml, 6 mmol) of acetic anhydride are added and the solution is stirred at room temperature for 44 hours. The reaction mixture is concentrated.

  
  <EMI ID = 520.1>

  
form and saturated sodium bicarbonate. We wash the

  
chloroform phase with fresh bicarbonate then brine, it is dried over anhydrous magnesium sulfate, filtered and concentrated to a solid. By resuspending the residue in approximately 50 ml

  
  <EMI ID = 521.1>

  
  <EMI ID = 522.1>

  
the mixture is stirred for 3 hours at room temperature, during which time the dissolution takes place.

  
  <EMI ID = 523.1> ethane, the solution is washed with two portions of saturated sodium bicarbonate, then with brine, it is dried over anhydrous magnesium sulfate, filtered and concentrated to obtain the product. By recrystallization from a mixture of chloroform and

  
  <EMI ID = 524.1>

  
300/2987.

  
EXAMPLE 125

  
  <EMI ID = 525.1>

  
2,4-dione

  
542 mg (2.06 moles) of sodium salt is mixed

  
  <EMI ID = 526.1>

  
reflux the mixture for 3 hours, allow to cool to room temperature, stir for

  
  <EMI ID = 527.1>

  
purified oxazolidine-2,4-dione (212 mg, melting point
196-200 [deg.] C) ..

  
EXAMPLE 126

  
  <EMI ID = 528.1>

  
Salt crystallizes by slow cooling to temperature

  
ethanol

  
  <EMI ID = 529.1>
-58.6 [deg.]). We put the solid matter aside. The mother liquor is distributed between ethyl acetate and acid <EMI ID = 530.1>

  
anhydrous magnesium sulfate, filtered and evaporated to dryness (520 mg). This residue is taken up in 20 ml of methanol and it is recrystallized by adding 30 ml of water. After 20 minutes, a first harvest is collected

  
  <EMI ID = 531.1>

  
optical equal to 73%. By recrystallization of 50 mg of this product in 1 ml of methanol and 1.5 ml of water, a material of optical purity equal to 385% is obtained (25.4 mg, point

  
  <EMI ID = 532.1>

  
The solid salt previously set aside is decomposed by partitioning between chloroform and IN hydrochloric acid, which gives 0.488 g of solid material by evaporation of the dehydrated chloroform phase. This last solid material is taken up in 20 ml of methanol and the

  
  <EMI ID = 533.1>

  
dinner is triggered by the addition of 30 ml of water. The product is obtained in two harvests: 182.4 mg, point of

  
  <EMI ID = 534.1>

  
  <EMI ID = 535.1>

  
  <EMI ID = 536.1>

  
rotary power equal to +27.06 [deg.] has essentially an optical purity of 100%.

  
EXAMPLE 127

  
  <EMI ID = 537.1>

  
By following the procedure of Example 7 and by

  
  <EMI ID = 538.1>

  
in 100 ml of ether with 15.8 g (0.16 mole) of trimethylsilylcarbonitrile in the presence of zinc iodide (0.266 g)

  
  <EMI ID = 539.1> EXAMPLE 128

  
  <EMI ID = 540.1>

  
ethyl

  
Following the procedure of Example II,

  
  <EMI ID = 541.1>

  
delta: 1.0 (t, 3H), 3.8-4.3 (q and s, 5H), 6.0 (s, 1H),

  
  <EMI ID = 542.1>

  
EXAMPLE 129

  
  <EMI ID = 543.1>

  
Following the procedure of Example 12, with the difference that 2.3 is used instead of 2.0 equivalents of triethylamine, it is transformed into crude product.

  
  <EMI ID = 544.1>

  
furan. By recrystallization from a mixture of ethyl acetate and toluene, the 5- (2-methoxy-lnaphthyl) oxazolidine-2,4-dione obtained is obtained in two harvests

  
  <EMI ID = 545.1>

  

  <EMI ID = 546.1>


  
EXAMPLE 130

  
  <EMI ID = 547.1>

  
Following the procedure of the example
127, 4.5 g (22.5 mmol) of 2-ethoxynaphthaldehyde in 50 ml of ether are reacted with 2.6 g (27 mmol)

  
  <EMI ID = 548.1>

  
  <EMI ID = 549.1>

  
  <EMI ID = 550.1>

  
EXAMPLE 131

  
  <EMI ID = 551.1>

  
ethyl carboximidate

  
Following the procedure of Example 2,

  
  <EMI ID = 552.1>

  
naphthyl) -2-trimethylsiloxyethanenitrile in 140 ml of ethanol saturated with hydrogen chloride, in 5.0 g of

  
  <EMI ID = 553.1>

  
ethyl carboximidate melting at 110-112 [deg.] C).

  
EXAMPLE 132

  
  <EMI ID = 554.1>

  
Following the procedure of Example 3, and using a reaction time of 64 hours at room temperature, then passing cold phosgene, 5.0 g (16.1 mmol) of hydrochloride are transformed.

  
  <EMI ID = 555.1>

  
ethyl in 200 ml of tetrahydrofuran in 5- (2-ethoxy1-naphthyl) oxazolidine-2,4-dione recrystallized from. toluene (0.57 g, melting point 221-224 [deg.] C, m / e 271).

  
EXAMPLE 133

  
  <EMI ID = 556.1>

  
Following the procedure of the example
127 and using a reaction time of 48 hours, reacting 9.0 g (0.034 mole) of 2-benzyloxy-1naphthaldehyde in 80 ml of ether with 4.0 g (0.041 mole)

  
  <EMI ID = 557.1>

  
ethyl carboximidate

  
Following the procedure of Example 2,

  
  <EMI ID = 558.1>

  
naphthyl) -2-trimethylsiloxyethanenitrile in 190 ml of chloride [pound]. saturated ethanolic hydrogen as hydrochloride

  
  <EMI ID = 559.1>

  
  <EMI ID = 560.1>

  
  <EMI ID = 561.1>

  
  <EMI ID = 562.1>

  
Following the procedure of Example 27, with the difference that 2.1 equivalents are used instead of 3.2 equivalents of triethylamine, 4.0 g are transformed.

  
  <EMI ID = 563.1>

  

  <EMI ID = 564.1>


  
EXAMPLE 136

  
  <EMI ID = 565.1>

  
  <EMI ID = 566.1>

  
14 mmol) of trimethylsilylcarbonitrile in the presence of

  
  <EMI ID = 567.1>

  
  <EMI ID = 568.1>

  
2-trimethylsiloxyethanenitrile.

  
EXAMPLE 137

  
  <EMI ID = 569.1>

  
ethyl carboximidate

  
  <EMI ID = 570.1>

  
naphthyl) -2-trimethylsiloxyethanenitrile in 85 ml of saturated ethanolic hydrogen chloride and the solution is stirred for one hour at the same temperature. <EMI ID = 571.1>

  
  <EMI ID = 572.1>

  
proton magnetic resonance / DMSO / delta 1,2 (t, 3H),

  
  <EMI ID = 573.1>

  
By the same procedure, the corresponding chlorine compound of the previous example is transformed into

  
  <EMI ID = 574.1>

  
The procedure of Example 3 is followed; with the difference that a reaction time of 16 hours is used after the passage of a stream of phosgene and

  
  <EMI ID = 575.1>

  
2,4-dione recrystallized from toluene (1.63 g, point of

  
  <EMI ID = 576.1>

  
recrystallize the product from toluene (1.15 g, melting point 152-154 [deg.] C).

  

  <EMI ID = 577.1>


  
Following the same procedure, the chlorine compound of the previous example is transformed into

  
  <EMI ID = 578.1>

  
  <EMI ID = 579.1>

  
difference that we use a reaction time of 12 hours

  
  <EMI ID = 580.1>

  
methylene with 0.40 g (3.9 mmol) of trimethylsilylcarbonitrile in the presence of 10 mg of zinc iodide to obtain

  
  <EMI ID = 581.1>

  
nitrile (Rf 0.35, chloroform).

  
  <EMI ID = 582.1>

  
  <EMI ID = 583.1>

  
  <EMI ID = 584.1>

  
and ether, we obtain an analytical sample (point of

  
  <EMI ID = 585.1>

  

  <EMI ID = 586.1>


  
EXAMPLE: 1'4 2

  
  <EMI ID = 587.1>

  
naphthaldehyde in 80 ml of ether with 1.2 g (12.7 mmol) of trimethylsilylcarbonitrile in the presence of 50 mg of iodide

  
  <EMI ID = 588.1>

  
  <EMI ID = 589.1>

  
  <EMI ID = 590.1>

  
  <EMI ID = 591.1>

  
ethyl Following the procedures of Examples 2 and 11 (method A), with the difference that the duration of

  
  <EMI ID = 592.1>

  
  <EMI ID = 593.1>

  
form of an oil L3.2 g; proton magnetic resonance /

  
  <EMI ID = 594.1>

  
  <EMI ID = 595.1>

  
EXAMPLE 144

  
  <EMI ID = 596.1>

  
of tetrahydrofuran into the desired product. To isolate the product, the reaction mixture is deactivated by pouring it slowly into 200 ml of crushed ice and it is extracted with

  
  <EMI ID = 597.1>

  
287).

  
  <EMI ID = 598.1>

  
  <EMI ID = 599.1>

  
  <EMI ID = 600.1>

  
  <EMI ID = 601.1>

  
ethyl carboximidate

  
Following the procedure of Example 2

  
  <EMI ID = 602.1>

  
  <EMI ID = 603.1>

  
siloxyethanenitrile in 200 ml of saturated ethanolic hydrogen chloride, in 1- (7-fluoro-l-) hydrochloride

  
  <EMI ID = 604.1>

  
melting point 135-138 [deg.] C '; proton magnetic resonance / CDC13 / delta: 1.2 (t, 3H), 3.9-4.2 (q, 2H), 5.6

  
  <EMI ID = 605.1>

  
Following the same procedure, the corresponding chlorine compound of the example is transformed

  
  <EMI ID = 606.1>

  
EXAMPLE 147

  
  <EMI ID = 607.1>

  

  <EMI ID = 608.1>


  
Following the same operating mode, the corresponding chlorine compound from the previous example is transformed into.

  
  <EMI ID = 609.1>

  
Mixing potassium cyanide (4.9 g, 0.077 mole) and potassium thiocyanate (6.2 g, 0.064

  
  <EMI ID = 610.1>

  
10 g (0.064 mole) of 2-naphthaldehyde are added dropwise over 20 minutes. Then added 31.2 ml of acid <EMI ID = 611.1>

  
for 1.5 hours. , it is allowed to cool to room temperature, it is poured into 100 ml of water and filtered. We share the solids between 150 ml

  
  <EMI ID = 612.1>

  
The chloroform phase is extracted with two portions of
80 ml of fresh 5% bicarbonate, then they are combined with the initial bicarbonate phase, the mixture is acidified and the product is collected by filtration (8.0 g in the wet state). By recrystallization from toluene, we obtain

  
  <EMI ID = 613.1>

  
EXAMPLE 149

  
  <EMI ID = 614.1>

  
diluted with chloroform and water and the organic phase is separated. The organic phase is extracted with saturated sodium bicarbonate. The bicarbonate phase is carefully acidified with dilute hydrochloric acid and the precipitated product is collected by filtration. By recrystallization from toluene, the

  
  <EMI ID = 615.1>

  

  <EMI ID = 616.1>


  
EXAMPLE 150

  
  <EMI ID = 617.1> 7D

  
  <EMI ID = 618.1>

  
Following the procedure of the example
149, 2.0 g (8.2 mmol) of 5- (l-naphthyl) are transformed

  
  <EMI ID = 619.1>

  

  <EMI ID = 620.1>


  
EXAMPLE 152

  
  <EMI ID = 621.1>

  
benzaldehyde and 200 mg zinc iodide with 10 0 ml

  
  <EMI ID = 622.1>

  
carbonitrile and the mixture is stirred overnight. The reaction mixture is diluted with 100 ml of ether and is then isolated by the operations of Example 1 to

  
  <EMI ID = 623.1>

  
nitrile in the form of an oil (31.7 g).

  
  <EMI ID = 624.1>

  
  <EMI ID = 625.1>

  
Following the procedure of Example 2,

  
  <EMI ID = 626.1>

  
  <EMI ID = 627.1>

  
magnetic of the protons / DMSO / delta: 1, 2. (t, 3H), 4.6 (q, 2H),

  
  <EMI ID = 628.1>

  
EXAMPLE 154

  
  <EMI ID = 629.1>

  
Following the procedure of Example 1, but using a reaction time of 48 hours at room temperature, after the passage of phosgene, we

  
  <EMI ID = 630.1>

  
1200 ml of 5- (4-fluorophenyl) oxazolidine-2,4-dione tetrahydrofuran recrystallized from toluene

  
  <EMI ID = 631.1>

  

  <EMI ID = 632.1>


  
A second harvest is obtained by recrystall-

  
  <EMI ID = 633.1>

  
EXAMPLE 155

  
  <EMI ID = 634.1>

  
dione

  
We combine and mix for 30 minutes the

  
  <EMI ID = 635.1>

  

  <EMI ID = 636.1>


  
  <EMI ID = 637.1>

  
solvated).

  
The mixture is ground (1.016 mm tray) and kneaded for another 30 minutes. Add magnesium stearate and sodium lauryl sulfate as a 90/10 mixture (1.00 g) and knead this mixture for
20 minutes. The formulation is loaded into capsules

  
gelatin (500 mg load weight) so as to obtain 250 mg capsules.

  
Larger loading weights in larger capsules are used to prepare more powerful capsules.

  
We use the same procedure for

  
  <EMI ID = 638.1>

  
following:

  

  <EMI ID = 639.1>


  
  <EMI ID = 640.1>

  
  <EMI ID = 641.1>

  
power.

EXAMPLE 15 6

  
Tablets

  
A base for tablets is prepared by mixing the following ingredients in the proportions indicated by weight:

  

  <EMI ID = 642.1>


  
A sufficient amount of 5- (2chloro-6-methoxyphenyl) oxazolidine-2,4-dione sodium salt dihydrate is incorporated into this tablet base to form tablets containing 50 mg, 100 mg or 250 mg of active drug ( equivalent weight to free acid). The portion of the mixture which returns to the active substance is within the limits of 1-0.167 to 1-1, for example, at the extremes,
62.0 mg of sodium salt dihydrate and 300 mg of mixture in a 50 mg tablet or 310 mg of sodium salt dihydrate and 250 mg of mixture in a 250 mg tablet.

EXAMPLE 157

  
Injection preparation

  
  <EMI ID = 643.1>

  
phenyl) oxazolidine-2,4-dione sterile is loaded dry into vials so that each vial contains 632.0 mg of sodium salt dihydrate (equivalent to 550 mg of free acid. Before use. sterile water for injectables (11 ml) and shake the mixture to form a solution containing 50 mg / ml

  
of active drug, which is suitable for intravenous, intramuscular or subcutaneous injection.

  
Alternatively, vials are loaded by a lyophilization process. Two ml of a sterile aqueous solution containing 341 mg / ml of monohydrated sodium salt are introduced into each flask. The vials are freeze-dried on trays.

  
PREPARATION 1

  
  <EMI ID = 644.1>

  
drop by drop 30 g (17.4 ml, 0.16 mole) of titanium tetrachloride. After 10 minutes, 12.7 g (0.088 mole) of 1,1-dichloromethyl and methyl ether are added dropwise and the reaction mixture is stirred for
90 minutes at 0-10 [deg.] C, then deactivate it in bicar-

  
excess saturated sodium bonate and methylene chloride. The organic phase is separated and combined with another chloromethylenic extract of the aqueous phase. The combined organic phases are rinsed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo

  
  <EMI ID = 645.1>

  
13.1 g (0.084 mole) of ethyl iodide and 10.6 g (0.077 mole) of anhydrous potassium carbonate in 130 ml of acetone and the mixture is heated with stirring at reflux for 16 hours. The reaction mixture is filtered and the filtrate is evaporated to dryness. The residue is taken up in 300 ml of chloroform, the solution is washed successively with two portions

  
  <EMI ID = 646.1>

  
PREPARATION 3

  
  <EMI ID = 647.1>

  
"Following the procedure of Preparation 1 and using a reaction time of 2.5 hours at 0 [deg.] C, after the end of the addition of the reagents,

  
  <EMI ID = 648.1>

  
3 and using a reaction time of 2 hours at

  
  <EMI ID = 649.1>

  
. PREPARATION 5 <EMI ID = 650.1>

  
  <EMI ID = 651.1>

  
methylanisole in 300 ml of methylene chloride. We

  
  <EMI ID = 652.1>

  
aqueous phase with two other portions of methylene chloride. The combined organic extracts are washed with brine, dried over anhydrous sulfate

  
  <EMI ID = 653.1>

  
PREPARATION 6

  
  <EMI ID = 654.1>

  
1 and allowing the reaction mixture to warm to ambient temperature with stirring for 16 hours after the addition of the reagents is complete,

  
  <EMI ID = 655.1>

  
Following the procedure of Preparation 5, 2.0 g (14.2 mmol) of 2-fluoro-4-methylanisole in 70 ml of methylene chloride is transformed into crude product.

  
  <EMI ID = 656.1>

  
  <EMI ID = 657.1>

  
  <EMI ID = 658.1>

  
we obtain ;, as a minor component, the least polar of

  
  <EMI ID = 659.1>

  
50 g of sodium hydroxide are dissolved in

  
  <EMI ID = 660.1>

  
  <EMI ID = 661.1>

  
mix for 2 hours. The addition of 30 ml of chloroform and heating under reflux for 2 hours are repeated twice. The reaction mixture is allowed to cool to room temperature and the crude product is collected in the form of the sodium salt, by filtration. The crude product is taken up in water and the solution is

  
  <EMI ID = 662.1>

  
6.6 g of product in the free phenolic form. This

  
  <EMI ID = 663.1>

  
silica, the eluent being a mixture of methylene chloride and hexane at 1: 1. The column is checked by thin layer chromatography. The fractions containing the pure product are combined and evaporated to dryness, giving the

  
  <EMI ID = 664.1>

  
melting point 80-83 [deg.] C, Rf 0.49 (methylene chloride:

  
  <EMI ID = 665.1>

  
2.5 g (0.014 mol) of 3-chloro-5fluoro-2-hydroxybenzaldehyde are taken up in 25 ml of acetone. Potassium carbonate (2.48 g, 0.018 mole) and methyl iodide (2.55 g, 0.018 mole) are successively added and the mixture is stirred for 16 hours at room temperature. The reaction mixture is filtered and the filtrate is concentrated to obtain an oil. The oil is distributed between methylene chloride and water. The organic phase is washed successively with fresh water,

  
  <EMI ID = 666.1>

  
on anhydrous magnesium sulfate and concentrated giving

  
  <EMI ID = 667.1>

  
melting at 59-62 [deg.] C.

  
PREPARATION 10

  
  <EMI ID = 668.1>

  
Following the procedure of preparation 9, react with chloroform (3 portions. Of 58 ml) <EMI ID = 669.1> sodium and 133 ml of water. The reaction mixture is cooled and filtered. The resulting solid materials are distributed between saturated brine and ethyl acetate,

  
  <EMI ID = 670.1>

  
diluted and separating the ethyl acetate phase which is

  
  <EMI ID = 671.1>

  
concentrated hydrochloric acid and this filtrate is extracted with ethyl acetate. The first and second

  
  <EMI ID = 672.1>

  
water then brine, dehydrated over anhydrous magnesium sulfate, filtered and evaporated into partial crude product-

  
  <EMI ID = 673.1> <EMI ID = 674.1>

  
with a mixture of hexane and ether, at 6: 1, with control by thin layer chromatography. The least polar component is collected in the first fractions which are combined and evaporated, giving 2-fluoro-6hydroxybenzaldehyde in the form of an oil which

  
  <EMI ID = 675.1>

  
(chloroform: hexane 2: 127-

  
PREPARATION 11

  
2-ethoxy-6-fluorobenzaldehyde

  
Following the procedure of Preparation 9, 1.4 g (10 mmol) of 2-fluoro-6-hydroxybenzaldehyde, 1.7 g (11 mmol) of ethyl iodide are transformed and

  
  <EMI ID = 676.1>

  
2-ethoxy-6-fluorobenzaldehyde acetone in the form

  
  <EMI ID = 677.1>

  
51.5 g (0.030 mole) of 2-chloro-6- are taken up.

  
fluorobenzaldehyde in 500 ml of methanol. We add
14.4 g (0.35 mole) of sodium hydroxide and the

  
  <EMI ID = 678.1>

  
hours: The mixture is allowed to cool to room temperature and the volume is reduced to 200 ml by vacuum distillation. 400 ml of water and 200 ml of methylene chloride are added and the system is balanced in two phases. The organic phase is separated and the aqueous phase is

  
  <EMI ID = 679.1>

  
methylene. The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the methylene chloride is distilled off at atmospheric pressure with displacement by 450 ml

  
  <EMI ID = 680.1>

  
product, initially present in the form of an oil,

  
  <EMI ID = 681.1>

  
mix at room temperature, granulate for <EMI ID = 682.1>

  
25 g (0.163 mole) of p-nitroanisole are dissolved

  
  <EMI ID = 683.1>

  
solution at 10 [deg.] C. 61.8 g (36 ml, 0.326 mole) of titanium tetrachloride are added, followed by addition of

  
  <EMI ID = 684.1>

  
the mixture warm to room temperature and stirred for 42 hours. The reaction mixture is diluted

  
  <EMI ID = 685.1>

  
500 ml portions of methylene chloride. The organic extracts are combined, washed with 2 portions of water and one portion of brine, dehydrated over anhydrous magnesium sulfate, filtered and concentrated. an oil
(20 g). The oil is chromatographed on 600 g of gel.

  
  <EMI ID = 686.1>

  
of methylene and hexane at 2: 1, and 15 ml fractions are collected by carrying out the control by thin layer chromatography. The fractions 79-185 containing the pure product are combined and evaporated, giving

  
3.8 g of 2-methoxy-5-nitrobenzaldehyde (melting point
87-89 [deg.], The literature indicates a melting point of
89-90 [deg.]).

  
  <EMI ID = 687.1>

  
2,6-difluorobenzaldehyde

  
25 g (0.22 mole) of 1,3-difluorobenzene are dissolved in 150 ml of tetrahydrofuran and the solution is cooled to -50 [deg.] C. 99 ml of 2.3M butyl lithium in hexane (0.228 mol) are added over 20 minutes while maintaining

  
  <EMI ID = 688.1>

  
at the same temperature, it is added in 20 minutes at -50 [deg.] C
29.7 g (0.22 mole) of N-methylformanilide in 50 ml of tetrahydrofuran. After stirring for a further 1.5 hours at -50 ° C., the reaction mixture is slowly poured into

  
  <EMI ID = 689.1>

  
three portions of ether. The combined organic extracts are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in an oil. The oil is distilled. The average fractions are combined to give 18.2 g of 2,6-difluorobenzaldehyde (58%; point

  
  <EMI ID = 690.1>

  
PREPARATION 15 4-chloro-3-methylanisole

  
28.5 g (0.2 mole) of 4-chloro-3- are dissolved

  
  <EMI ID = 691.1>

  
(0.24 mole) of potassium carbonate then 34.1 g (0.24 mole) of methyl iodide and the mixture is stirred for
16 hours at room temperature. The reaction mixture is filtered and the filtrate is evaporated to obtain an oil containing solids. This residue is partitioned between methylene chloride and water. The organic phase is separated, washed successively with

  
  <EMI ID = 692.1>

  
of water and a portion of brine, it is dried over anhydrous magnesium sulfate and concentrated to obtain 4-chloro-3-methylanisole in the form of a

  
  <EMI ID = 693.1>

  
PREPARATION 16

  
  <EMI ID = 694.1>

  
15.4 g (0.10 mole) of 4-chloro-3methylanisole are taken up in 200 ml of methylene chloride and the solution is cooled to 0 [deg.] C. 37.9 g (0.2 mole) of titanium tetrachloride are added, followed by 13.8 g (0.12 mole) of 1,1-dichloromethyl methyl ether, each over a period of 2 minutes. The reaction mixture is stirred at room temperature for one hour, poured onto 500 ml of ice and water and the organic phase is separated. The aqueous phase is extracted with two portions of fresh methylene chloride and these extracts are combined with the original organic phase. The phases

  
  <EMI ID = 695.1> tees on anhydrous magnesium sulfate. filtered and

  
  <EMI ID = 696.1>

  
  <EMI ID = 697.1>

  
compounds are separated by chromatography on 1 kg of silica gel, elution being carried out with a mixture of methylene chloride and hexane at 1: 1; 15 ml fractions are collected and the control carried out by thin layer chromatography. Fractions 115-140 are combined and evaporated to dryness, giving the unwanted 0.35 Rf isomer (860 mg, melting point 86-88 [deg.] C).

  
  <EMI ID = 698.1>

  
  <EMI ID = 699.1>

  
  <EMI ID = 700.1>

  
  <EMI ID = 701.1>

  
Naphthaldehyde with 120 ml of acetone, 9.9 g (0.063 mole) of iodethane and 8.0 g (0.058 mole) of anhydrous potassium carbonate and the mixture is heated at reflux for 48 hours. The reaction mixture is allowed to cool to room temperature, filtered and the filtrate is evaporated to dryness (9.0 g). By recrystallization from ether

  
  <EMI ID = 702.1>

  
purified in two harvests (4.5 g and 0.5 g, melting point
106-109 [deg.] C).

  
  <EMI ID = 703.1>

  
  <EMI ID = 704.1>

  
Following the procedure of Preparation 17, replacing the ethyl iodide with the equivalent benzyl bromide (10.7 g, 0.063 mol) and recrystallizing the crude product from an ether mixture <EMI ID = 705.1>

  
in 200 ml of methylene chloride with 25.5 g (14.7 ml, 0.136 mole) of titanium tetrachloride and 10.1 g (0.088

  
  <EMI ID = 706.1>

  
chromatograph the residue on 400 g of silica gel, eluting initially with a mixture of hexane and chloroform at 3: 1, then with a mixture of hexane and chloroform at 3: 2. The column is checked by thin layer chromatography. The fractions

  
  <EMI ID = 707.1>

  
chloroform 3: 2) 7 are combined and evaporated to dryness, giving the purified 2-fluoro-1-naphthaldehyde (2.8 g, melting point 60-62 [deg.] C).

  
By the same procedure, we transform the

  
  <EMI ID = 708.1>

  
chloro-1-naphthaldehyde.

  
  <EMI ID = 709.1>

  
  <EMI ID = 710.1>

  
Following the procedure of the preparation

  
  <EMI ID = 711.1>

  
  <EMI ID = 712.1>

  
  <EMI ID = 713.1>

  
with 52.6 g (30.5 ml, 0.28 mole) of titanium tetrachloride and 24.1 g (0.2 1 mole) of methyl ether and 1,1-dichloromethyl. The crude product obtained in the form of an oil is distilled, giving 12.2 g of distillate

  
  <EMI ID = 714.1>

  
crystalline separates from the distillate. Purified 2-methyl-1-naphthaldehyde is obtained by filtration (0.53 g, melting point 48-50 [deg.] C).

  
PREPARATION 21

  
  <EMI ID = 715.1>

  
in 150 ml of methylene chloride with 19.7 g (11.4 ml,
104 mmol) of titanium tetrachloride and 8.9 g (78 mmol) of methyl ether and 1,1-dichloromethyl. The resulting crude product is recrystallized from toluene, which

  
  <EMI ID = 716.1>

  
melting point 285-288 [deg.] C).


    

Claims (1)

1. Racemic or optically active compound, characterized in that it corresponds to the formula:  <EMI ID = 717.1> where: <EMI ID = 718.1>  <EMI ID = 719.1>  <EMI ID = 720.1>  <EMI ID = 721.1> carbamoyl;  <EMI ID = 722.1>  <EMI ID = 723.1>  or Z is the fluoro radical  <EMI ID = 724.1> chloro, phenoxy, nitro or trifluoromethyl;  <EMI ID = 725.1> phenoxy, nitro or trifluoromethyl;  <EMI ID = 726.1>  <EMI ID = 727.1> fluoro,  <EMI ID = 728.1> hydrogen, a methyl, bromo, chloro, fluoro, cyano, nitro or trifluoro-radical  <EMI ID = 729.1> methyl radical, Z represents something other than a 5-methyl radical; there is hydrogen, a methyl radical, benzyloxy, C1 or C2 alkoxy, chloro, bromo or fluoro,  <EMI ID = 730.1>  <EMI ID = 731.1> this compound. which can also be in the form of a pharmaceutically acceptable salt when R is hydrogen. 2. Compound according to claim 1, characterized in that R is hydrogen. 3. Compound according to claim 2, characterized in that R is a rest of formula:  <EMI ID = 732.1>  <EMI ID = 733.1> R is a remainder of formula:  <EMI ID = 734.1>   <EMI ID = 735.1>  <EMI ID = 736.1>  <EMI ID = 737.1> fluoro, cyano or methyl. 4. Compound according to claim 3, characterized in that R is the remainder of formula:  <EMI ID = 738.1> 5. Compound according to claim 3, characterized  <EMI ID = 739.1>  <EMI ID = 740.1>  <EMI ID = 741.1> by the fact that R is the remainder of formula:  <EMI ID = 742.1> 7. Compound according to claim 3, characterized in that B <1> -is the remainder of formula:  <EMI ID = 743.1> 8. Compound according to Claim 3, characterized in that R is a residue of formula:  <EMI ID = 744.1> y is hydrogen or a methoxy, methyl radical or fluoro and  <EMI ID = 745.1> Y and Y are both a methoxy residue.  <EMI ID = 746.1> formula :  <EMI ID = 747.1> in which :  <EMI ID = 748.1> R6 is a remainder of formula:  <EMI ID = 749.1>  or  <EMI ID = 750.1>  <EMI ID = 751.1>  <EMI ID = 752.1>  <EMI ID = 753.1> trifluoromethyl;  <EMI ID = 754.1> methylthio, chloro or fluoro;  <EMI ID = 755.1> hydrogen or a methyl, bromo, chloro, fluoro, cyano, nitro or trifluoro-radical  <EMI ID = 756.1> 10. Compound, characterized in that it corresponds to the formula:  <EMI ID = 757.1> in which :  <EMI ID = 758.1> R7 is a remainder of formula:  <EMI ID = 759.1>  or V is the fluoro radical: V is the benzyloxy, chloro, phencxy radical, nitro or trifluoromethyl;  <EMI ID = 760.1> trifluoromethyl;  <EMI ID = 761.1> tion that when V <3> is the methoxy radical  <EMI ID = 762.1> something other than hydrogen;  <EMI ID = 763.1> oxy, C alkoxy or C2 'chloro, bromo or fluoro:  <EMI ID = 764.1>  <EMI ID = 765.1> 11. Compound, characterized in that it corresponds to the formula  <EMI ID = 766.1> or  <EMI ID = 767.1>  <EMI ID = 768.1>    <EMI ID = 769.1> T is the fluoro radical;  <EMI ID = 770.1> nitro or trifluoromethyl; T <2> is the benzyloxy, phenoxy, nitro or trifluoromethyl; <EMI ID = 771.1> gene or methyl, bromine, chloro, fluoro, cyano, nitro or trifluoromethyl radical; Y represents hydrogen or a methyl radical,  <EMI ID = 772.1> or fluoro;  <EMI ID = 773.1>  <EMI ID = 774.1> 12. Compound, characterized in that it corresponds to the formula  <EMI ID = 775.1>  <EMI ID = 776.1> 13. Compound, characterized in that it corresponds to the formula:  <EMI ID = 777.1> in which :  <EMI ID = 778.1> laughing or benzoyl and R has the definition given above. 14. Compound, characterized in that it corresponds to the formula:  <EMI ID = 779.1> 'in which :  <EMI ID = 780.1> or phenyl; and  <EMI ID = 781.1>  <EMI ID = 782.1> or Q is the fluoro radical?  <EMI ID = 783.1> chloro, - phenoxy, nitro or trifluoromethyl <EMI ID = 784.1> phenoxy, nitro or trifluoromethyl;  <EMI ID = 785.1> methylthio, chloro or fluoro;  <EMI ID = 786.1> gene or methyl, bromo, chloro, fluoro, cyano, nitro radical. or trifluoromethyl: Y is hydrogen or methyl, benzyl-  <EMI ID = 787.1> fluoro;  <EMI ID = 788.1>  <EMI ID = 789.1> provided that when R <3> is hydrogen, R represents something other than the 2-chlorophenyl radical. 15. A method for lowering blood sugar in a hyperglycemic mammal, characterized in that it consists in administering an amount, lowering the blood glucose level, of a racemic or optically active compound according to claim 1.