BE889758A - OXAZOLIDINE-2,4-DIONES SUBSTITUTED IN POSITION 5 WITH HYPOGLYCEMIC ACTION - Google Patents

Description

       

    <EMI ID = 1.1>

  
position 5 with hypoglycemic action The present invention relates to certain derivatives of 5-furyl, 5-thienyl, 5-chromanyl, 2,3-dihydrobenzo-

  
  <EMI ID = 2.1>

  
as hypoglycemic agents.

  
Despite the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the subsequent discovery and use of sulfonylureas (e.g. chlcrpropamide, tolbutaxai.de, acetohexamide, tolazamide) and biguanides (e.g. <EMI ID = 3.1> the treatment of diabetes remains less than satisfactory. The use of insulin, necessary for a high percentage of diabetics in whom hypo agents Synthetic blood sugar available is not effective, requires multiple daily injections, usually done by the patient himself. Determination of the proper insulin dosage requires frequent estimates of sugar in or in the urine. the blood. Administration of an excessive dose of insulin causes hypoglycemia, with excess ranging from anomaly

  
  <EMI ID = 4.1>

  
  <EMI ID = 5.1>

  
to administer and less likely to cause severe hypoglycenic reactions. However, clinically available hypoglycaemics are unfortunately accompanied by other toxic manifestations which limit their use. In any case, when one of these agents can fail in an individual case, another can succeed. A continuing need for hypoglycemic agents which may be less toxic or which may succeed where others fail is clearly evident.

  
In addition to the hypoglycemic agents mentioned above, various other compounds have this type of activity, as recently reported by <EMI ID = 6.1>

  
part II, John Wiley and Sons, New York (1979), pages
1057-10807.

  
  <EMI ID = 7.1>

  
well-known class of compounds / for further details, see Clark-Lewis, Chem. Rev. 58, pages 53-99

  
  <EMI ID = 8.1>

  
mentions 5-phenyloxazolidine-2,4-dione, considered by various authors to be an intermediate compound

  
  <EMI ID = 9.1>

  
  <EMI ID = 10.1>

  
anti-depressive agents (United States patent

  
  <EMI ID = 11.1>

  
2,4-dione LReibsomer et al., J. Am. Chem. Soc.

  
  <EMI ID = 12.1>

  
Gazz. chem. ital. 16, 357 (1886); Ber. 19, 1708-1714

  
  <EMI ID = 13.1>

  
of known previous activity, displays only relatively weak hypoglycemic activity (see Table 1 below).

  
Oxazolidine-2,4-dione and substituted oxazolidine-2,4diones (more particularly derivatives

  
  <EMI ID = 14.1>

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

  
  <EMI ID = 15.1> determined that neither oxazolidine-2,4-dione itself, nor

  
  <EMI ID = 16.1>

  
hypoglycemic activity of the compounds of the present invention.

  
  <EMI ID = 17.1>

  
  <EMI ID = 18.1>

  
aldose reductase, thus finding utility in the treatment of certain complications of diabetes (patent

  
  <EMI ID = 19.1>

  
A process for the synthesis of 3-aryloxazolidine2,4-diones (where the aryl group contains 6 to 12 carbon atoms and may or may not have one or more substituents chosen between halogen atoms and methyl or methoxy radicals) is the subject of another recent patent of the United States of America, bearing the n [deg.]

  
4,220,787). The usefulness of these compounds is not specified.

  
The present invention relates to compounds of formula:

  

  <EMI ID = 20.1>


  
(1)

  
in which

  
  <EMI ID = 21.1>

  
(for example formyl, acetyl, isobutyryl), benzoyl,

  
  <EMI ID = 22.1>

  
  <EMI ID = 23.1>

  

  <EMI ID = 24.1>


  
  <EMI ID = 25.1>

  
is hydrogen, a C1 to C4 alkyl or phenyl residue and X is a halogen residue (fluoro, chloro, bromo or iodo); these formulas including 2- or 3pyrrolyl or indolyl derivatives, with substituents such as those which have been specified;
(b) a remainder of formula:

  

  <EMI ID = 26.1>


  
  <EMI ID = 27.1>

  
  <EMI ID = 28.1>

  
Y "is hydrogen or a halo radical:
(c) a remainder of formula:

  

  <EMI ID = 29.1>


  
  <EMI ID = 30.1>

  
  <EMI ID = 31.1>

  
or a halogen radical: <EMI ID = 32.1>

  

  <EMI ID = 33.1>


  
wherein W is hydrogen or a halogen radical and n is 1 or 2; this formula encompassing

  
  <EMI ID = 34.1>
(e) a remainder of the formula
  <EMI ID = 35.1>
 in which Q is. sulfur or oxygen and V is

  
  <EMI ID = 36.1>
(f) a remainder of formula:,
  <EMI ID = 37.1>
 wherein Q is sulfur or oxygen; and V is

  
  <EMI ID = 38.1>

  

  <EMI ID = 39.1>
 

  
in which Y is sulfur or oxygen X is <EMI ID = 40.1>

  
  <EMI ID = 41.1>

  
  <EMI ID = 42.1>

  

  <EMI ID = 43.1>


  
  <EMI ID = 44.1>

  
inserted in any vacant position in any one of these six variants: the second formula includes

  
  <EMI ID = 45.1>

  

  <EMI ID = 46.1>
 

  
The invention also relates to cationic salts, acceptable from the pharmaceutical point of view,

  
of compounds of formula (1), when R is hydrogen,

  
as well as the pharmaceutically acceptable acid addition salts of these compounds when R contains a basic nitrogen function.

  
We consider that the great inherent activity

  
to these compounds mainly resides in the compounds

  
in which R is hydrogen, and the compounds in which R is one of various carbonyl derivatives defined above represent so-called pro-

  
  <EMI ID = 47.1>

  
lique is eliminated by hydrolysis under physiological conditions giving the fully active compounds in which R is hydrogen.

  
The term "pharmaceutically acceptable cationic salts" means salts such as alkali metal salts (e.g. sodium and potassium), alkaline earth metal salts (e.g. calcium and magnesium), salts aluminum, ammonium salts and organic amine salts such as

  
  <EMI ID = 48.1>

  
etc.

  
The term "pharmaceutically acceptable acid addition salts" covers salts

  
such as hydrochloride, hydrobromide, hydroiodide,

  
Nitrate, hydrogen sulfate, dihydrogen phosphate,

  
Mesylate, maleate, succinate, etc.

  
The compounds of the present invention possess hypoglycemic activity, reflecting their clinical utility in lowering the blood glucose level of hyperglycemic mammals, including humans, by bringing it back to normal values. They offer the special advantage of lowering blood sugar within a normal range without the risk of causing hypoglycemia. The compounds of the present invention were tested for

  
  <EMI ID = 49.1>

  
glucose as described in more detail below.

  
The preferred compounds because of their better hypoglycemic activity are those in which R is hydrogen, or their salts acceptable from the point of view

  
  <EMI ID = 50.1>

  
which R is hydrogen, those which are most appreciated because of their excellent hypoglycemic activity are the following:

  
  <EMI ID = 51.1>

  
5- (5-chloro-2-methoxy-3-pyridyl) oxazolidine-2,4dione;

  
  <EMI ID = 52.1>

  
  <EMI ID = 53.1>

  
dione.

  
The compounds of the present invention are prepared by various methods which are illustrated by the

  
  <EMI ID = 54.1>

  
DIAGRAM 1

  
  <EMI ID = 55.1>
  <EMI ID = 56.1>
 On this diagram:

  
  <EMI ID = 57.1>

  
R <2> is a lower alkyl radical (for example methyl or ethyl);

  
  <EMI ID = 58.1>

  
or phenyl; and

  
  <EMI ID = 59.1>

  
than acetyl or benzoyl.

  
A particularly advantageous synthesis for obtaining compounds of the present invention consists

  
  <EMI ID = 60.1>

  
last compound with phosgene in an inert solvent

  
  <EMI ID = 61.1>

  
equivalents of a tertiary amine (e.g. triethylamine, N-methylmorpholine). Another equivalent of tertiary amine is used if the carboximidate is introduced in the form of the acid addition salt (for example hydrochloride-

  
  <EMI ID = 62.1> reaction, in particular if it is desired to isolate the intermediate 4-alkoxyoxazole-2-one (4). Isolation of this intermediate compound is carried out by simple evaporation to dryness of the reaction mixture. In a subsequent reaction at higher temperatures (e.g. 20 to
150 [deg.] C) or during an aqueous treatment, the compound

  
  <EMI ID = 63.1>

  
dione desired. When you want a primary amino function

  
  <EMI ID = 64.1>

  
selectively reducible group (for example by catalytic hydrogenation or by an acid / metal pair) into primary or secondary amine. For example, an N-benzylindole can be used as a precursor for an indole derivative.

  
The carboximidate (3) is advantageously prepared from the corresponding aldehyde according to the sequence:

  

  <EMI ID = 65.1>


  
The aldehyde (11) is converted to cyanohydrin

  
  <EMI ID = 66.1>

  
by the bisulfite adduct which is reacted with a cyanide in a two-phase solvent

  
  <EMI ID = 67.1>

  
tick of a Lewis acid such as zinc iodide. An inert solvent (e.g. methylene chloride, ether) is generally used when the aldehyde is a solid, but its use is optional when the aldehyde is a liquid. The temperature of the

  
  <EMI ID = 68.1>

  
ment the reaction at reduced temperature (for example 0-5 [deg.] C) by allowing it to develop at room temperature for a few hours or a few days, whichever is suitable for obtaining a complete reaction.

  
If necessary, the trimethylsilyl ether can be hydrolyzed to cyanohydrin, advantageously at temperature

  
  <EMI ID = 69.1>

  
comprising a strong acid in aqueous solution and an organic solvent.

  
Cyanohydrin (13) or trimethylsilyl ether

  
(12) is converted to the carboximidate (3) by alcoholysis, catalyzed by a strong acid (under very anhydrous conditions). A practical method is to simply dissolve the nitrile in the alcohol that has been saturated

  
hydrogen chloride and let the solution stand

  
  <EMI ID = 70.1>

  
The temperature is not decisive, although fairly low temperatures (for example 0 to 25 [deg.] C) generally lead to optimal yields.

  
Aldehydes. necessary in the above syntheses are very easy to obtain, either commercially or by methods described in the literature. For example, N-alkylpyrrole-2carbaldehydes are obtained by alkylation of pyrrole-2-carbaldehyde
(Weygand, Organic Preparations, Interscience, New York
1945, page 403) using conditions specially illustrated in the following about preparation

  
N-alkylpyrroles, or by Reimer-Tieman formylation of an N-alkylpyrrole (see Weygand loc. cit.); of 3 are obtained. similarly from

  
  <EMI ID = 71.1>

  
by interaction of Grignard reagents with esters <EMI ID = 72.1>

  
Rence can also be obtained by hydrolysis of twin dihalides, by oxidation of primary alcohols, by interaction of Grignard reagents with orthoformic esters and other methods known in the art. Other methods will be indicated in the Preparations described in detail below.

  
Another suitable precursor for the 2, 4-diones oxazolidine of the present invention which have no. no primary or secondary amino function is alphahydroxyamide (5). The latter compound is converted to

  
  <EMI ID = 73.1>

  
chloroformate. alkyl in the presence of a basic catalyst such as potassium carbonate, either by

  
  <EMI ID = 74.1>

  
generally suitable as a solvent for the latter

  
  <EMI ID = 75.1>

  
  <EMI ID = 76.1>

  
each. When it is desired that the final product has a primary or secondary amino function, this function

  
  <EMI ID = 77.1>

  
containing a suitable precursor group, as described above.,

  
  <EMI ID = 78.1>

  

  <EMI ID = 79.1>


  
Suitable conditions for the hydrolysis of cyanohydrin (13) are to treat 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 amide

  
  <EMI ID = 80.1>

  
intermediate form of compound (5) can be isolated under these conditions. Overhydrolysis to the acid can be avoided by monitoring the reaction by thin layer chromatography, as detailed below. Advantageous conditions for the aminolysis of the ester (6) consist in simply heating the ester in hot concentrated ammonium hydroxide.

  
The alpha hydroxy ester (6) itself can also be used as an immediate precursor to the desired oxazolidine-2,4-dione. The ester is reacted with urea (or one of certain substituted ureas such as

  
  <EMI ID = 81.1>

  
a basic catalyst such as sodium ethylate (preferably an equivalent) in alcohol at a temperature

  
  <EMI ID = 82.1>

  
is by no means limited to a single lower alkyl ester but can be any one of a wide variety of esters, e.g. phenyl ester, benzyl ester, etc. In addition, the ester can be replaced by a 1,3-dioxolane4-one, an alpha-acyloxy-ester or a thioester, for example
  <EMI ID = 83.1>
 and the urea can be replaced by a urethane.

  
Two other precursors which are suitable for

  
  <EMI ID = 84.1>

  
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, of a metaperiodate or of peroxide of aqueous hydrogen, usually in excess and in the presence of a cosolvent such as a lower alcohol. The reaction temperature is not critical, temperatures in the range of 25 to

  
  <EMI ID = 85.1>

  
  <EMI ID = 86.1>

  
amino, whereas a competing oxidation at the level

  
nitrogen tends to reduce yields and complicate the isolation of the desired product; however, it has been found that when the product contains a tertiary amine

  
(eg pyridine, quinoline), a periodate or bromine constitute a reagent well suited for this purpose. Oxazolidine-2,4-diones are obtained from alkylthio (8) compounds by simple hydrolysis catalyzed by an acid or a base. Preferable conditions lie in the use of aqueous hydrochloric acid in a temperature range of 0 to 50 [deg.] C.

  
The precursor compound 2-thioxo (7) is prepared from the corresponding aldehyde (11), which is generally carried out in an aqueous acid medium by the action of a thiocyanate (1-1.1 equivalent) and a cyanide
(1 to 1.2 equivalent) at 0-70 [deg.] C, according to the method of Lindberg and Pederson by which the preparation of 5- (2-thienyl) -2-thiooxazolidine-4-one was reported

  
  <EMI ID = 87.1>

  
can be prepared by alkylation of 2-thioxo compounds

  
(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 a lower alcoholate in <EMI ID = 88.1>

  
product of this reaction.

  
Another suitable precursor is the derivative

  
  <EMI ID = 89.1>

  
oxazolidine-2,4-dione, preferably under aqueous acidic conditions. The desired 2-iminooxazolidine-4-one is obtained by condensation of the alpha-hydroxyester (6) with guanidine or with thiourea in the presence of an equivalent of a strong base such as

  
  <EMI ID = 90.1>

  
(isomer of compound 4) or of 2-thioalkylated compound (8), by cyclization, induced by an alkaline base,

  
  <EMI ID = 91.1>

  
4-imino derivatives (isomer of derivatives 9). These latter compounds are also readily hydrolyzed to oxazolidine-

  
  <EMI ID = 92.1>

  
also prepared from the silver salt of the desired oxazolidine-2,4-dione.

  
Dialuric acids and dialuric acyl acids (10) are also very useful as precursors of the oxazolidine-2,4-diones of the present invention. They are easily transformed under moderately basic conditions into the desired oxazolidine-2,4-diones. Methods suitable for the preparation of precursor dialuric acids (10) are illustrated in

  
  <EMI ID = 93.1>

  
Scheme II, in which substituents R, R and R have the definitions given above and M represents Li, MgCl, MgBr, Mgl or another suitable metal:

  
  <EMI ID = 94.1>

  

  <EMI ID = 95.1>


  
A general process for the preparation of dialuric acids which are suitable as precursors of the oxazolidine-2,4-diones of the present invention consists in starting from malonic esters (14), this process involving the two stages of condensation with urea, catalyzed by a base, and oxidation to the hydroxylated or acyloxylated compound. When the first step is oxidation,

  
the intermediate compound is a derivative of tartronic acid

  
(15) while when the first step is condensation, the intermediate compound is called barbituric acid (16). When R carries an amino function
(e.g. 2-aminophenyl), it is best to conduct oxidation as the first step to prevent possible complications of nitrogen oxidation. When a condensation constitutes the second stage, the dialuric acid is usually not isolated, at least in the pure form, and it is then converted under basic conditions of condensation into oxazolidine2,4-dione.

  
When the substituted malonic esters necessary for the above syntheses are not commercially available, they are obtained by methods described in the literature, for example by alcoholysis

  
  <EMI ID = 96.1>

  
  <EMI ID = 97.1>

  
Zienty, J. Am. Chem. Soc. 63; 2946 (1 94 It ?.

  
A less general process for preparing suitable intermediate dialuric acid is to react a rich heteroaryl / aryl compound

  
  <EMI ID = 98.1>

  

  <EMI ID = 99.1>
 

  
There is now another process for the preparation of certain intermediate dialuric acids. This process, preferred when suitable starting materials are readily available, involves the reaction of the alloxane (preferably in anhydrous form) with the suitable organometallic derivative
(such as an organolithium, a Grignard reagent). For example :

  

  <EMI ID = 100.1>


  
Protective measures are necessary when using this process to prepare certain oxazoli-

  
  <EMI ID = 101.1>

  
who. is not compatible with organometallic reactions; for example one. acyl group is protected under

  
  <EMI ID = 102.1>

  
for example when R carries a group such as nitro or amino, this process generally lacks interest.

  
It is obvious to those skilled in the art that the most advantageous process for obtaining the oxazolidine2,4-diones of the present invention varies by a value

  
  <EMI ID = 103.1>

  
availability of starting materials, yields,

  
  <EMI ID = 104.1>

  
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 which form such salts are readily prepared by reacting the acid forms with a suitable base, usually an equivalent, in a cosolvent. Representative bases are sodium hydroxide, sodium methylate, sodium ethylate, sodium hydride, potassium methylate, magnesium hydroxide, calcium hydroxide, benzathine, la.

  
  <EMI ID = 105.1>

  
not directly are 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 be otherwise isolated by concentration and addition of a non-solvent.

  
The pharmaceutically acceptable acid addition salts of the compounds of the present invention which form such salts are readily prepared by reaction of the basic forms with a suitable acid, usually an equivalent, in a co-solvent. The

  
  <EMI ID = 106.1>

  
hydrobromic, nitric, sulfuric, phosphoric; methane-

  
  <EMI ID = 107.1>

  
not directly precipitated are isolated by dry concentration or by addition of a non-solvent.

  
3-acylated derivatives of the present invention are easily prepared under conventional acylation conditions, for example by reaction of the oxazolidine salt.

  
  <EMI ID = 108.1>

  
are suitable chloride or acid anhydride) or by reaction of oxazolidine-2,4-dione with suitable organic isocyanate, optionally in the presence of a catalytic amount of a tertiary amino base. In both cases, the reaction is carried out in an inert solvent such as toluene, tetrahydrofuran or <EMI ID = 109.1>

  
and can vary within a wide range (e.g.

  
  <EMI ID = 110.1>

  
concurrent or even selective of the side chain

  
  <EMI ID = 111.1>

  
primary or secondary.

  
It is obvious to those skilled in the art that the compounds of the present invention are asymmetric and

  
  <EMI ID = 112.1>

  
optically active. The racemic compounds of the present invention, which are acids when R is hydrogen, form salts with organic amines. These racemic forms are therefore generally capable

  
of a resolution in optically active forms, by

  
the conventional process of forming diastereoisomeric salts with optically active amines, now

  
  <EMI ID = 113.1>

  
alternatively, the compounds which carry a basic amino function can be split by formation of a salt with an optically active acid, preferably a strong organic acid such as a sulfonic acid. Usually,

  
  <EMI ID = 114.1>

  
activity than the other.

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

  
  <EMI ID = 115.1>

  
such as chloroform, ethyl acetate or hexane or suitable mixtures of these solvents which differentiate the starting materials, the products, the sub-. products and in some cases intermediate products .. The application of these methods which are well known in

  
practice improves methodology further

  
  <EMI ID = 116.1>

  
which follows, for example the choice of the optimal 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 anti-diabetic agents. The hypoglycemic activity necessary for this clinical use is defined by the glucose tolerance test method given below.

  
Uncastrated male albino rats constitute the laboratory animals used for these purposes. Test animals are fasted for about 18-24 hours. The rats are weighed, numbered and divided into groups of five or six as required. We then administer

  
to each group of animals intraperitoneally glucose (1 g per kg) and, orally, water (controls) or the compound (at a dose usually chosen in the range 0.1 to 100 mg / kg). Blood levels are measured

  
glucose (mg / 100 ml) on tail blood samples over a period of

  
3 hours both in the control groups and in the treated groups. With equivalent blood glucose levels at time zero in the control group and in the treated groups, the percentage of blood glucose lowering is calculated at 0.5 hours, 1 hour, 2 hours and 3 hours according to the following formula:

  
  <EMI ID = 117.1>

  
  <EMI ID = 118.1>

  
/ Blood glucose "witness" /

  
Hypoglycemic agents of clinical interest show activity in this test. Hypoglycemic activities determined for the compounds

  
  <EMI ID = 119.1>

  
This table shows the percentage of reduction

  
the blood glucose level after 0.5 hours and after 1 hour. A decrease in blood sugar of 9% or more generally reflects hypoglycemic activity of statistical significance in this test. Compounds that only show significant activity after 2 hours or

  
  <EMI ID = 120.1>

  
  <EMI ID = 121.1>

  

  <EMI ID = 122.1>
 

  
Table 1 (continued)
  <EMI ID = 123.1>
   <EMI ID = 124.1>
  <EMI ID = 125.1>
 The oxazolidine-2,4-diones of the present invention are administered clinically to mammals,

  
including humans, orally or parenterally.

  
Oral administration is preferred because it is more convenient and because it avoids possible pain and irritation from the injection. However, in case

  
where the patient cannot swallow the medicine, or if absorption is disturbed after oral administration, for example in case of illness or abnormality, it is essential that the medicine is administered parenterally.

  
Whatever the route of administration, the dosage

  
is in the range of about 0.10 to about 50 mg /

  
kg of patient's body weight per day, preferably in the range of about 0.20 to about 20 mg / kg of body weight per day, which is administered at one time or in multiple doses. However, the optimal dosage for the individual patient being treated is determined

  
by the doctor responsible for treatment, enough doses

  
  <EMI ID = 126.1>

  
additions being made to determine the most suitable dosage. This dosage varies depending on the particular compound being used and the patient being treated. ''

  
The compounds can be used in pharmaceutical preparations containing the compound or a pharmaceutically acceptable acid salt of the compound, in combination with a pharmaceutically acceptable carrier or diluent. Advantageous examples of pharmaceutically acceptable carriers or carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The active compound is present in these pharmaceutical compositions in amounts sufficient to provide the desired dosage amount within the range defined above. Thus, for oral administration, the compounds can be combined with a solid support or diluent

  
or liquid suitable for forming capsules, tablets, <EMI ID = 127.1>

  
etc. The pharmaceutical compositions can optionally contain other components such as perfumes, sweeteners, excipients, etc. For parenteral administration, the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions may be used in sesame oil or peanut oil, in aqueous propylene glycol, etc.

  
as well as aqueous solutions of water soluble salts of pharmaceutically acceptable acid addition of the compounds. The injectable solutions prepared in this way can then be administered by the

  
  <EMI ID = 128.1>

  
muscle, intramuscular administration being preferable in humans.

  
The present invention is illustrated by the following examples, given without limitation.

  
  <EMI ID = 129.1>

  
carbon tetrachloride and the mixture is refluxed for 2 hours. The reaction mixture is cooled, evaporated to dryness and taken up with multiple portions of fresh carbon tetrachloride. The acid chloride hydrochloride obtained is dissolved in 50 ml of methanol

  
  <EMI ID = 130.1>

  
room temperature, then it is evaporated giving an oil which is taken up in chloroform. The chloroform solution is washed with two portions of saturated sodium bicarbonate and then a portion of brine, dehydrated over anhydrous magnesium sulfate, filtered and evaporated to give the product indicated in the title,

  
  <EMI ID = 131.1>

  
. Following the same procedure, we trans- <EMI ID = 132.1>

  
methyl pyridine-3-carboxylate.

  
EXAMPLE 2

  
  <EMI ID = 133.1>

  
2.69 g of a 50% dispersion of sodium hydride in oil (0.056 mol) is washed three times with petroleum ether. After the third decantation, the traces of petroleum ether are removed by evaporation under vacuum. 30 ml of dimethyl sulfoxide are added and the mixture is heated

  
  <EMI ID = 134.1>

  
of at the end of which the evolution of hydrogen has ceased.

  
The mixture is cooled in an ice and water bath and

  
dilute it with 30 ml of anhydrous tetrahydrofuran. The compound. indicated in the title of the previous example (4.63 g,

  
  <EMI ID = 135.1>

  
added drop by drop in 5 minutes. The reaction mixture is heated and stirred at room temperature for

  
  <EMI ID = 136.1>

  
  <EMI ID = 137.1>

  
chloroform. The combined organic phases are dried over magnesium sulfate, filtered and concentrated, giving the product indicated in the title,

  
  <EMI ID = 138.1>

  
Following the same procedure, we trans-

  
  <EMI ID = 139.1>

  
  <EMI ID = 140.1>

  
The compound indicated in the title of

  
  <EMI ID = 141.1>

  
and acetic anhydride (40 ml) in 80 ml of toluene and the mixture is heated to 115 [deg.] for 16 hours. The mixture is cooled and evaporated to dryness under vacuum to obtain the crude product. We chromatograph the latter <EMI ID = 142.1>

  
mixture of chloroform and ethyl acetate at 2: 1, -controlling by chromatography- on a thin layer and

  
  <EMI ID = 143.1>

  
clearly containing the product are collected and

  
concentrated giving an oil. To eliminate

  
  <EMI ID = 144.1>

  
in moist ethanol, the mixture is kept for 15 minutes, it is re-evaporated, it is continued with toluene, it is taken up in chloroform, it is dried over anhydrous magnesium sulphate, filtered and re-evaporated to obtain the product indicated in the title under the form of an oil / 3.16 g; Rf 0.60 (ethyl acetate: methanol 3: 1); me
255; infrared spectrum (CH2C12) 1748, 1686, 1582, 1460,

  
  <EMI ID = 145.1>

  
Following the same procedure, we trans-. forms the methylated compound of the preceding example in 2-

  
  <EMI ID = 146.1>

  
sodium in 50 ml of absolute ethanol and the solution is cooled in an ice-water bath. 234 mg (3.9

  
  <EMI ID = 147.1>

  
in the title of the previous example in 5 ml of ethanol.

  
The mixture is heated at reflux for 16 hours then

  
  <EMI ID = 148.1>

  
  <EMI ID = 149.1>

  
toluene. The gum is chromatographed on 40 g of silica gel using an acetate mixture as eluent

  
  <EMI ID = 150.1>

  
thin layer matography and 10 ml fractions are collected. Fractions 6-15 containing the product are

  
  <EMI ID = 151.1>

  
By the same procedure, we convert

  
  <EMI ID = 152.1>

  
3-pyridyl) oxazolidine-2,4-dione.

  
EXAMPLE 5

  
  <EMI ID = 153.1>

  
4 g of 2-ethoxypyridine-3carboxylic acid is converted to its acid chloride hydrochloride by heating under reflux with 8.6 ml of thionyl chloride for 60 minutes. The reaction mixture is evaporated

  
dry with toluene recovery to remove excess thionyl chloride. We take the residue in

  
  <EMI ID = 154.1>

  
  <EMI ID = 155.1>

  
  <EMI ID = 156.1>

  
extract the aqueous phase with fresh toluene and combine the two organic phases, wash with

  
water then with brine, they are dried over anhydrous magnesium sulphate, filtered and evaporated to obtain the product indicated in the title under

  
  <EMI ID = 157.1>

  
protons / CDC13 / delta (ppm) 1,6 (2s, 6H), 4,4-5,0 (2q, 4H),

  
  <EMI ID = 158.1>. EXAMPLE 6 <EMI ID = 159.1>

  
Using methylene chloride instead of chloroform for isolation, the procedure of Example 2 is used to convert the product of the previous example (3.0 g) to the product indicated in the title / 2 , 63 g; melting point 89-91 [deg.] C; proton magnetic resonance / CDC13 / delta (ppm), 1.5 (t, 3H), 2.8 (s, 3H), 4.2-4.8 (s and q, 4H), 6.8-7 , 1 and 8.0-8.4
(3H) 7.

  
EXAMPLE 7

  
  <EMI ID = 160.1>

  
Using a reaction time of 4 hours at 100 [deg.] C and then 48 hours at room temperature, the procedure of Example 3 is followed to convert the product of the previous example (2.5 g) into the crude product which is isolated in the form of an oil by evaporation of the reaction mixture. The oil is taken up in ethyl acetate, washed successively with three

  
  <EMI ID = 161.1>

  
a portion of brine, it is dried over anhydrous magnesium sulfate and evaporated to obtain the product indicated in the title in the form of an oil / 2.96 g; Rf 0.78 (ethyl acetate: methanol 10: 1); m / e 2697.

  
  <EMI ID = 162.1>

  
  <EMI ID = 163.1>

  
The product of the previous example (2.9 g) is

  
  <EMI ID = 164.1>

  
concentrated nium, the mixture is stirred at room temperature for 3 hours, then it is evaporated, giving the crude product in the form of an oil (2.7 g). The oil is chromatographed on 170 g of silica gel, with elution with ethyl acetate and control by thin layer chromatography. The fractions containing the product are combined and evaporated, giving the product indicated in the title in the form of an oil.

  
  <EMI ID = 165.1>

  
proton magnetic resonance / CDC13 / delta (ppm) 1.4

  
  <EMI ID = 166.1>

  
EXAMPLE 9

  
  <EMI ID = 167.1>

  
We mix the product of the previous example
(900 mg, 4.6 mmol) with 25 ml of tert-butanol. 1.08 g (9.2 mmol) of dimethyl carbonate are added, followed by 1.03 g (9.2 mmol) of potassium tert-butoxide and the reaction mixture is refluxed for 3.5 hours. The reaction mixture is cooled, poured into

  
  <EMI ID = 168.1>

  
and extracted with two portions of ethyl acetate. The aqueous phase is saturated and extracted with an additional amount of ethyl acetate. The three organic phases are combined, rinsed with a small portion of water and then brine, dehydrated on

  
  <EMI ID = 169.1>

  
crude product in the form of a viscous oil. The product indicated in the title is purified by crystalli-

  
  <EMI ID = 170.1>

  
  <EMI ID = 171.1>

  

  <EMI ID = 172.1>


  
EXAMPLE 10

  
  <EMI ID = 173.1>

  
add in a single portion to 150 ml of methanol (slightly exothermic reaction) and which is then made basic with triethylamine (approximately 1.1 equivalent). The reaction mixture is evaporated to dryness and the residue is distributed between ethyl acetate and water. The ethyl acetate phase is washed with fresh water and then with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give the product indicated in the

  
  <EMI ID = 174.1>

  
  <EMI ID = 175.1>

  
EXAMPLE

  
  <EMI ID = 176.1>

  
Following the procedure of the example. 2, the product of the previous example (9.7 g, 0.045 mole) is transformed into the product indicated in the title which is isolated in the form of a viscous oil (10.3 g, m / e
249/247).

  
EXAMPLE 12

  
  <EMI ID = 177.1> <EMI ID = 178.1>

  
at 100 [deg.] C, the procedure of Example 3 and the separation process of Example 7 are followed to convert the product of the previous example (10.3 g) to the product indicated in the title in the form of a viscous oil

  
  <EMI ID = 179.1>

  
125 ml of anhydrous ammonia methanol are saturated at 0-5 [deg.] C. We add the product of the previous example
(8.8 g) in 25 ml of methanol and the mixture is stirred

  
  <EMI ID = 180.1>

  
then it is concentrated in a viscous oil (7.3 g).

  
The oil is chromatographed on 400 g of silica gel using a 1: 1 mixture of chloroform and ethyl acetate as eluent, checking by thin layer chromatography and collecting 10 ml fractions. The proper fractions 190-270

  
containing the product are collected and evaporated giving <EMI ID = 181.1>

  
Using a reflux period of 15 hours, the procedure of Example 9 is followed to convert the product of the previous example (1.25 g, 5.8 mmol) to the product indicated in the title. To isolate the

  
  <EMI ID = 182.1>

  
room temperature and the pH is adjusted to 3 with

  
  <EMI ID = 183.1>

  
under vacuum to obtain a slightly gummy solid which gives the crude product which can be filtered, by stirring with 25 ml of water (1.09 g, melting point
199-204 [deg.] C). By recrystallization from 15 ml of ethanol, the purified product indicated in the title is obtained

  
  <EMI ID = 184.1>

  
infrared spectrum (KBr) 3174, 3074, 2980, 1830, 1752

  
  <EMI ID = 185.1>

  
1.6 g of ethyl 2- (6-chloro-8quinoleyl) -2-hydroxyacetate in 300 ml of concentrated ammonium hydroxide are heated to reflux. Since there is no complete dissolution, the reaction mixture is cooled, diluted with 50 ml of ethanol and again heated to

  
reflux for 0.5 hour. The reaction mixture is concentrated to a volume of 100 ml, cooled slowly and

  
320 mg of the product indicated in the title are collected by filtration (melting point 195-198 [deg.] C). An additional quantity (145 mg) of product is collected by concentration of the mother liquor to 50 ml and extraction in three portions of ethyl acetate. The organic phases bring together

  
  <EMI ID = 186.1>

  
dehydrated over anhydrous magnesium sulfate, filtered and evaporated to dryness.

  
By following the same operating mode, we transform

  
  <EMI ID = 187.1>

  
indicated in the title of the previous example (300 mg,

  
  <EMI ID = 188.1>

  
for 18 hours, then it is allowed to cool to room temperature, its pH is adjusted to 3 with acid: IN hydrochloric acid and it is diluted with hydrochloric acid.

  
  <EMI ID = 189.1>

  
Washed with two additional portions of ethyl acetate.

  
The organic phases are combined, washed with

  
  <EMI ID = 190.1>

  
brine, dehydrated over anhydrous magnesium sulfate, filtered and evaporated to give an oil
(130 mg). By crystallization of the oil in isopropyl ether, the purified product indicated in

  
  <EMI ID = 191.1>

  
Following the same procedure, the benzofuran analog of the preceding example is transformed.

  
  <EMI ID = 192.1>

  
2,4-dione.

  
EXAMPLE 17

  
  <EMI ID = 193.1>

  
300 ml of concentrated ammonium hydroxide. The reaction mixture is slowly cooled, clarified by filtration and evaporated to dryness. By crushing the

  
  <EMI ID = 194.1>

  
qué in the.title (860 mg, melting point 169-171 [deg.] C).

  
  <EMI ID = 195.1>

  
Using a reflux period of 3.5 hours,

  
  <EMI ID = 196.1>

  
3.8 mmol) into the product indicated in the title by following the procedure of Example 16. In this case, a pH equal to 2 is used to carry out the separation without the addition of excess IN hydrochloric acid and the recrystalli-

  
  <EMI ID = 197.1>

  
484 mg (4.9 mmol) of potassium thiocyanate and 370 mg (5.7 mmol) of potassium cyanide are mixed.

  
  <EMI ID = 198.1>

  
  <EMI ID = 199.1>

  
  <EMI ID = 200.1>

  
  <EMI ID = 201.1>

  
reaction at 90-100 [deg.] C for 25 minutes, it is cooled, it is deactivated in crushed ice, its pH is adjusted

  
  <EMI ID = 202.1>

  
chloroform. The organic phase is dried over anhydrous magnesium sulfate, filtered and evaporated to dryness (163 mg). It is divided between hydroxide

  
  <EMI ID = 203.1>

  
basic and extracted with fresh ethyl acetate. We

  
  <EMI ID = 204.1>

  
dehydrates, they are filtered and evaporated to obtain the product indicated in the title / 72 mg; Rf 0.65

  
  <EMI ID = 205.1>

  
equal to 8 is added with salt and extracted with ethyl acetate giving an additional harvest (114 mg). The last aqueous phase is acidified and extracted with ethyl acetate giving a third harvest
(115 mg).

  
In. following the same operating mode, we transform

  
  <EMI ID = 206.1>

  
EXAMPLE 20

  
  <EMI ID = 207.1>

  
The compound indicated in the title of the previous example (230 mg, 0.94 mmol) is taken up in 6 ml of

  
  <EMI ID = 208.1>

  
Bromine (0.07 ml, 21.7 mg, 2.7 moles) is added and the reaction mixture is allowed to warm slowly to room temperature and then stirred for one hour. The reaction mixture is evaporated to dryness and

  
  <EMI ID = 209.1>

  
ethyl acetate. The aqueous phase is separated, acidified and extracted with two portions of fresh ethyl acetate. We collect the acid extracts, we <EMI ID = 210.1>

  
oil. By crystallization from a mixture of toluene and chloroform and recrystallization from toluene,

  
we obtain the purified product indicated in the title

  
  <EMI ID = 211.1>

  

  <EMI ID = 212.1>


  
Following the same procedure, the chlorine compound of the previous example is converted into 5- (7-chloro -; -,

  
8-quinoleyl) -oxazolidine-2,4-dione.

  
EXAMPLE 21

  
  <EMI ID = 213.1>

  
in the product indicated in the title. After deactivation in ice, a first crop is isolated (190 mg)

  
  <EMI ID = 214.1>

  
  <EMI ID = 215.1>

  
A second crop (176 mg) is isolated in the same way by adjusting the pH of the aqueous phase to 8 with bicarbonate and extracting it with additional ethyl acetate. The two crops have a m / e value of 274. The second crop also has a m / e value of 258, which

  
which indicates contamination by the product of the next step.

  
-EXAMPLE- 22 <EMI ID = 216.1>

  
above (0.36 g, 1.31 mmol) are taken up in 15 ml of methanol. 0.56 g (2.62 mmol) of sodium metaperodate in 7.2 ml of 5% sodium bicarbonate is added dropwise. After stirring for 3 hours at room temperature, the reaction mixture is quenched with water, acidified and extracted with two portions of ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness
(110 mg). The pH of the aqueous phase is adjusted to 7 and an additional quantity of crude product is obtained
(100 mg) by extraction with ethyl acetate. Raw crops are collected, taken up in hydroxide

  
  <EMI ID = 217.1>

  
acetic acid and extracted with fresh ethyl acetate. The last organic extracts are combined and evaporated to dryness. By trituration of the residue with ether, leaving the mixture to stand until crystallization is complete, the product indicated in the title is obtained (34 mg, melting point 144-146 [deg.] C).

  
  <EMI ID = 218.1>

  
  <EMI ID = 219.1>

  
Following the procedure of Example 19, but adjusting the pH to 7 with bicarbonate after deactivation and adding ethyl acetate to

  
  <EMI ID = 220.1>

  
carbaldehyde (2.0 g, 10.7 mmol) in the indicated product

  
  <EMI ID = 221.1>

  
chloroform 2: 1) 7. This product is not divided between an aqueous base and ethyl acetate, and a second crop is not isolated by adding salt to the aqueous phase and subsequent extraction.

  
  <EMI ID = 222.1>

  
  <EMI ID = 223.1>

  
We mix the product of the previous example
(0.74 g, 2.7 mmol) with 30 ml of methanol and 15 ml of 5% sodium bicarbonate. 1.15 g (5.4 mol) of sodium metaperiodate in 15 ml are added dropwise. 3 'water. After stirring for 3 hours at room temperature, the reaction mixture is quenched with water, acidified to pH 2-3 and extracted with two portions of ethyl acetate. We collect the extracts,

  
  <EMI ID = 224.1>

  
  <EMI ID = 225.1> purifies indicated in the title (100 mg; melting point
207-208 [deg.] C).

  

  <EMI ID = 226.1>


  
EXAMPLE 25

  
  <EMI ID = 227.1>

  
trione

  
Dissolved by heating 3.2 g (0.02 mole) of hydrated alloxane in 50 ml of ethanol. 1.6 g are added

  
  <EMI ID = 228.1>

  
  <EMI ID = 229.1>

  
passing hydrochloric gas. After standing at room temperature for 0.5 hour, the reaction mixture is evaporated to dryness and the residue is triturated with water to obtain the product indicated in the title, under

  
  <EMI ID = 230.1>

  
(ethyl acetate: hexane 1: 1/5%. acetic acid) _ /.

  
EXAMPLE 26

  
  <EMI ID = 231.1>

  
We mix the product of the previous example
(2.8 g) with 25 ml of IN sodium hydroxide and the mixture is heated in a boiling water bath for 30 minutes, during which time the total dissolution takes place. By acidification, a gum precipitate is obtained which solidifies by trituration with water (1.2 g). By recrystallization from a mixture of methanol and ether, the

  
  <EMI ID = 232.1>

  
  <EMI ID = 233.1>

  

  <EMI ID = 234.1>


  
EXAMPLE 27

  
  <EMI ID = 235.1>

  
trione

  
1 g (0.01 mole) of potassium salt is suspended.

  
  <EMI ID = 236.1> of tetrahydrofuran. 1 ml (0.012 mole) of ethyl iodide is added and a slight exothermic reaction is observed.

  
The mixture is stirred for 0.5 hour, heated at reflux for 0.5 hour, allowed to cool to room temperature, diluted with 15 ml of water and extracted with 10 ml of ether . The ether extraction phase is washed with 5 ml of water, then alloxane hydrate (1.6 g) which has been dissolved in 25 ml of ethanol is added by heating. The ether is boiled off and

  
reflows the ethanolic residue for 0.5 hour

  
then it is evaporated to obtain a gum soluble in

  
  <EMI ID = 237.1>

  
the solution is washed with 10 ml portions of water and re-evaporated to obtain the product indicated in the title, in the form of a gum (0.6 g, m / e 237).

  
EXAMPLE 28

  
  <EMI ID = 238.1>

  
The procedure of the previous example is repeated on a triple scale. The gum product initially isolated (0.03 mole of pyrimidinetrione) is stirred with
60 ml of IN sodium hydroxide for 0.5 hour then acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The extract is separated by filtration from insoluble impurities and concentrated to give a gum (2.2 g). The gum is chromatographed on 100 ml of silica gel with elution using a mixture of acetate.

  
  <EMI ID = 239.1>

  
written on a thin layer. The first fractions contain the desired product. They are collected and evaporated to obtain an oil which crystallizes at rest. By trituration with water, the purified product indicated in the title is obtained (170 mg; melting point 90-93 [deg.] C; m / e 194).

  

  <EMI ID = 240.1>
 

  
EXAMPLE 29

  
  <EMI ID = 241.1>

  
pyrimidinetrione

  
Mix 3.0 g (0.03 mole) of potassium salt of the pyrrole, 9.2? (0.05 mole) of 1-iodobutane and 10 ml of tetrahydrofuran and the mixture is heated at reflux for 1.5 hours, during which time the reaction mixture takes on the consistency of a thick mass. The reaction mixture is diluted with 30 ml of water and extracted with 35 ml of ether. The ether is rinsed with water and then added to a solution of anhydrous alloxane
(4.8 g, 0.03 mole) obtained by heating in 50 ml <EMI ID = 242.1> 5 ml of 6N hydrochloric acid (0.03 mole) and the mixture is refluxed for 3 minutes, then cooled, it is evaporated to a gummy consistency and the gum is triturated water to obtain the product indicated in

  
  <EMI ID = 243.1>

  
2657.

  
EXAMPLE 30

  
  <EMI ID = 244.1>

  
The product of the preceding example (5.1 g, 0.019 mol) is stirred at ambient temperature for 10 minutes in mixture with 38 ml (0.038 mol) of hydroxide.

  
  <EMI ID = 245.1>

  
with ether, it is cooled in an ice-water bath, it is acidified with concentrated hydrochloric acid and it is extracted with three portions of ethyl acetate. The organic extracts are combined, washed with brine, dried over anhydrous sodium sulfate and evaporated to a gummy solid. This material is chromatographed on silica gel with elution with ethyl acetate and control by thin layer chromatography, and the partially purified product is obtained which is isolated in the form of an oil (950 mg). This product is rechromatographed using a 1: 1 mixture of ethyl acetate and hexane as eluent and the purified product indicated in the title is obtained, in the form

  
  <EMI ID = 246.1>

  

  <EMI ID = 247.1>


  
EXAMPLE 31

  
  <EMI ID = 248.1>

  
dione

  
We dissolve the product of the previous example
(370 mg, 1.66 mmol) in 5 ml of methanol. We add
90 mg (1.66 mmol) of sodium bicarbonate. The resulting solution is evaporated to dryness and the solid residue is triturated with ether to obtain the indicated product

  
  <EMI ID = 249.1>

  
(decomposition) ; mobility in thin layer chromatography, with a mixture of ethyl acetate: hexane 1: 1/5% acetic acid, identical to that of the free base form / 7.

  
  <EMI ID = 250.1>

  
pyrimidinetrione

  
Mix and reflux for 15 minutes

  
  <EMI ID = 251.1>

  
hydrated allcxane and 50 ml ethanol. No reaction was observed by thin layer chromatography. 10 ml (0.01 mole) of IN hydrochloric acid are added and the acidified mixture is refluxed for 15 minutes. An incomplete reaction is observed by chromatography

  
  <EMI ID = 252.1>

  
of alloxane (1.6 g, 0.01 mole) and the mixture is refluxed for a further 15 minutes, cooled and

  
it is evaporated to dryness. By trituration of the residue with water, we obtain

  
  <EMI ID = 253.1>

  
232-234cC (decomposition); Rf 0.3 (ethyl acetate: hexane 1: 1) 7.

  

  <EMI ID = 254.1>
 

  
EXAMPLE 33

  
  <EMI ID = 255.1>

  
The product of the previous example (1 g) is heated in a boiling water bath for 20 minutes with

  
  <EMI ID = 256.1>

  
cooled in a water and ice bath, acidified with concentrated hydrochloric acid and the supernatant liquor is separated by decantation from the resulting gummy precipitate.

  
The gum is taken up in ethyl acetate, the solution is washed with water and it is evaporated to an oily consistency (0.47 g). The aqueous solution separated by decantation is also extracted with ethyl acetate, the extract is rinsed with water and it is evaporated to give a second oil (0.28 g). The two oils are combined; chromatographed on 150 ml of silica gel, eluting with a mixture of ethyl acetate: hexane at 1: 1 and checking by thin layer chromatography.

  
The first product fractions are combined, evaporated to give an oil (410 mer) and the oil is crystallized from a mixture of ether and hexane, giving the purified product indicated in the title / 280 mg; melting point 130-132 [deg.] C; m / e 242; Rf 0.4.7 (ethyl acetate:
hexane 1: 117,

  

  <EMI ID = 257.1>


  
EXAMPLE 34

  
  <EMI ID = 258.1>

  
and the mixture is refluxed for 0.5 hour, then concentrated to half its volume, diluted with water and the resulting product is collected by filtration

  
  <EMI ID = 259.1>

  
acetic) 7 ..

  
EXAMPLE 35

  
  <EMI ID = 260.1>

  
The product of the previous example (2 g) is heated in a boiling water bath for 15 minutes with 35 ml

  
  <EMI ID = 261.1>

  
reaction at room temperature, it is acidified to pH1 with concentrated hydrochloric acid and separated by decantation of a small amount of gum
(130 mg). The decanted liquid is clarified by filtration, cooled in an ice and water bath and the resulting solid material (330 mg) is collected by filtration. The filtrate is extracted with ethyl acetate; the extract is rinsed with water and evaporated to dryness (0.61 g). The solid products are collected and recrystallized in a mixture <EMI ID = 262.1>

  

  <EMI ID = 263.1>


  
EXAMPLE 36

  
  <EMI ID = 264.1>

  
trione

  
1.6 g (0.01 mole) of allo hydrate are dissolved in 40 ml of ethanol while heating. Ci: added 1.96 g
(0.01 mole) of 5-bromindole and heating is continued

  
  <EMI ID = 265.1>

  
thin-film writing indicates no reaction. 10 ml of IN hydrochloric acid are then added while

  
  <EMI ID = 266.1>

  
after 10 minutes, the reaction mixture is concentrated until wet solid material is obtained. By trituration of this solid material with water,

  
  <EMI ID = 267.1>

  
  <EMI ID = 268.1>

  
  <EMI ID = 269.1>

  
1: 5/5% acetic acid) 7 ..

  
EXAMPLE 37

  
  <EMI ID = 270.1>

  
The product of the above example is heated
(3.1 g) in a boiling water bath with 50 ml of IN sodium hydroxide for 15 minutes, then the mixture is cooled and the crude product is precipitated (1.25 g) by acidification with concentrated hydrochloric acid .

  
By chromatography on silica gel, with a 1: 1 mixture of ethyl acetate: hexane as eluent and by checking by thin layer chromatography, we obtain

  
  <EMI ID = 271.1>

  
185-189 [deg.] C; Rf 0.55 (ethyl acetate:
hexane 1: 5/5% acetic acid! 7.

  

  <EMI ID = 272.1>


  
EXAMPLE 38

  
  <EMI ID = 273.1>

  
35 ml tetrahydrofuran and the solution is cooled

  
at -60 [deg.] C. 9 ml of 2.4M butyllithium in hexane (0.0216 mol) are added dropwise over 20 minutes and the reaction mixture is stirred for a further 30 minutes

  
at -60 [deg.] C. 2-thiazolyllithium is formed in this way. Anhydrous alloxane (3 g, 0.021 mole) is dissolved in
20 ml of tetrahydrofuran and the solution is added dropwise over 20 minutes while maintaining the temperature at -60 [deg.] C. The reaction mixture is allowed to stir

  
  <EMI ID = 274.1>

  
  <EMI ID = 275.1>

  
25 ml of concentrated hydrochloric acid and the deactivated reaction mixture is extracted with 50 ml of ethyl acetate. The ethyl acetate extraction phase is rinsed with 15 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated to give the

  
  <EMI ID = 276.1>

  
(ethyl acetate: hexane 1: 1/5% acetic acid) 7.

  
Following the same procedure, we convert

  
  <EMI ID = 277.1>

  
pyrimidinetricne.

  
EXAMPLE 39

  
  <EMI ID = 278.1>

  
The product indicated in the title of the preceding example (1.37 g) is stirred at room temperature

  
with 24 ml IN sodium hydroxide. The reaction mixture is left to stand for 25 minutes, it is acidified

  
with 3 ml of glacial acetic acid and extracted with two 50 ml portions of ethyl acetate. Do we dehydrate them? separately on sodium sulfate, they are filtered and evaporated to dryness, the first giving 184 mg, the second 85 mg of solid material. These solid materials

  
  <EMI ID = 279.1>

  
  <EMI ID = 280.1>

  
hexane 1: 1/5 5 acetic acid and checking by thin layer chromatography. The clean fractions containing the product are combined, evaporated to dryness and the residue is triturated with hexane, giving the purified product indicated in the title (155 mg .; melting point 150-152 [deg.] C).

  

  <EMI ID = 281.1>


  
Following the same procedure, we convert

  
  <EMI ID = 282.1>

  
oxazolidine-2,4-dione.

  
  <EMI ID = 283.1>

  
  <EMI ID = 284.1>

  
trione

  
Following the procedure of Example 38, 2.7 g (0.02 mole) of benzthiazole are transformed into its 2-lithio derivative, then the latter is reacted with anhydrous alloxane to obtain the indicated product. in the title, originally isolated as an oil. This oil is crystallized from a mixture of ether and hexane / 2.2 g; Rf. 0.55 (ethyl acetate: hexane 1: 1 /

  
  <EMI ID = 285.1>

  
EXAMPLE 41

  
  <EMI ID = 286.1>

  
The product of the previous example is stirred

  
  <EMI ID = 287.1>

  
30 minutes. The reaction mixture is extracted with ether and the product is precipitated (0.46 g) by acidification of the aqueous phase with 6N hydrochloric acid. By chromatography on 50 ml of silica gel with an ethyl acetate: hexane mixture at 1: 1/5% acid

  
  <EMI ID = 288.1>

  
  <EMI ID = 289.1>

  

  <EMI ID = 290.1>


  
EXAMPLE 42

  
  <EMI ID = 291.1>

  
Cooled to 0-5 [deg.] C 7 g (0.036 mole) of 6chlorochromane-8-carbaldehyde in 70 ml of methylene chloride. 100 mg of zinc iodide are added and then drop

  
4.26 g (0.043 mole) of trimethylsilylcarbonitrile. The reaction mixture is stirred at room temperature for 64 hours; then we wash it successively with

  
three portions of saturated sodium bicarbonate and one portion of brine, it is dried over sulfate

  
magnesium anhydrous, filtered and evaporated to obtain the product indicated in the title, in the form of a

  
  <EMI ID = 292.1>

  
ethyl carboximidate 9.29 g of the product are added dropwise

  
  <EMI ID = 293.1>

  
saturated ethanolic hydrogen chloride (250 ml) cold

  
  <EMI ID = 294.1>

  
The mixture is stirred at 0-5 [deg.] C for 35 minutes, then evaporated to obtain an oil. By crystallization in

  
  <EMI ID = 295.1>

  
(decomposition) ; m / e 271/2697.

  
EXAMPLE 44

  
  <EMI ID = 296.1>

  
product of the previous example in 250 ml of tetrahydrofuran, the suspension is cooled in an ice-water bath and 6.01 g (0.06 mole) of triethylamine are added. Passing phosgene through the cold mixture
30 minutes while stirring at room temperature for 1 hour, then pour the mixture into 1 liter of crushed ice. The cooled reaction mixture is extracted with three portions of methylene chloride. The combined extracts are washed with brine, dried over magnesium sulfate and evaporated to dryness. The residue is recrystallized from toluene to give the purified product indicated in the title (3.28 g, melting point
170-172 [deg.] C, m / e 269/267).

  

  <EMI ID = 297.1>


  
  <EMI ID = 298.1>

  
  <EMI ID = 299.1>

  
Following the procedure of Example 42, 3.2 g (0.0178 mole) of 6-fluorochroman-8carbaldehyde is converted into the product indicated in the title, under

  
  <EMI ID = 300.1>

  
  <EMI ID = 301.1>

  
Using a reaction time of one hour at 0-5 [deg.] C, the procedure of Example 43 is used.

  
  <EMI ID = 302.1>

  
  <EMI ID = 303.1>

  
  <EMI ID = 304.1>

  
  <EMI ID = 305.1>

  
  <EMI ID = 306.1>

  
The crude solid is taken up in hydroxide

  
  <EMI ID = 307.1>

  
  <EMI ID = 308.1>

  
slowly from the basic aqueous phase to excess 3N hydrochloric acid. By recrystallization from toluene, the purified product indicated in the title is obtained

  
  <EMI ID = 309.1>

  

  <EMI ID = 310.1>


  
EXAMPLE 48

  
  <EMI ID = 311.1>

  
20 mg of zinc iodide and then 970 mg (9.8 mmol) of trimethylsilylcarbonitrile are added and the mixture is stirred for 16 hours at room temperature, then it is diluted with 50 ml of ether and washed with three portions saturated sodium bicarbonate and a portion of brine,

  
it is dried over anhydrous magnesium sulfate, filtered and evaporated to obtain the product indicated in the title in the form of an oil II, 4 g; m / e 283 /
281; infrared spectrum (CHC12) 1479, 1457, 1435, -1180,

  
  <EMI ID = 312.1>

  
  <EMI ID = 313.1>

  
siloxyethanenitrile.

  
EXAMPLE 49

  
  <EMI ID = 314.1>

  
Following the procedure of Example 43, the compound indicated in the title of the preceding example (1.37 g) is converted into the product indicated in the title.

  
of this example. The initially isolated solid is resuspended twice in ether to

  
  <EMI ID = 315.1>

  
149-152 "C (decomposition); m / e 257/255; infrared spectrum

  
  <EMI ID = 316.1>

  
Following the same procedure, the fluorinated compound of the previous example is converted into the hydrochloride.

  
  <EMI ID = 317.1>

  
2,4-dione

  
  <EMI ID = 318.1>

  
the compound indicated in the title of the example is converted

  
  <EMI ID = 319.1>

  
  <EMI ID = 320.1>

  
  <EMI ID = 321.1>

  
Following the same procedure, we

  
  <EMI ID = 322.1>

  
  <EMI ID = 323.1>

  
carbaldehyde to the product shown in the title, which is isolated in the form of an oil (6.5 g, no aldehyde proton according to nuclear magnetic resonance).

  
Following the same procedure, we convert

  
  <EMI ID = 324.1>

  
ethyl carboximidate

  
The product indicated in the title of the example

  
  <EMI ID = 325.1>

  
cold saturated ethanolic hydrogen and the solution is

  
  <EMI ID = 326.1>

  
the title is collected by filtration (3.3 g, point of fu-

  
  <EMI ID = 327.1>

  
By the same procedure, the other products of the previous example are converted into hydrochloride.

  
  <EMI ID = 328.1>

  
ethyl methanecarboximidate.

  
EXAMPLE 53

  
  <EMI ID = 329.1>

  
Following the procedure of Example 44, the product indicated in the title of the preceding example (2.2 g) is converted into the product indicated in, the title of

  
  <EMI ID = 330.1> of oil (0.4 g). The oils are combined and distributed between 25 ml of IN sodium hydroxide and 25 ml of ether. The basic aqueous phase is separated, acidified with concentrated hydrochloric acid and extracted with 25 ml of ethyl acetate. The ethyl acetate extraction phase is rinsed with water, evaporated to dryness, the <EMI ID = 331.1>

  
merger 173-175 [deg.] C).

  
The ether trituration product is evaporated to dryness and the residue is triturated with fresh ether.
(238 mg, melting point 175-177 [deg.] C).

  
Following the same procedure, the other products of the preceding example are converted into 5- (5-isothia-

  
  <EMI ID = 332.1>

  
oxazolidine-2,4-dione.

  
EXAMPLE 54

  
  <EMI ID = 333.1>

  
125 mg of 5- (2-ethoxy3-pyridyl) oxazolidine-2,4-dione are suspended in 100 ml of water and the mixture is dissolved by heating to 56 ° C. Chlorine is bubbled through the hot solution for 30 minutes, during which time the temperature slowly drops to 34 [deg.] C and a precipitate is formed. The reaction mixture is purged with nitrogen for 30 minutes and the product is collected.

  
  <EMI ID = 334.1>

  
Following the same procedure and using 10% fluorine in nitrogen, the

  
  <EMI ID = 335.1>

  
16 hours at room temperature. The reaction mixture is washed successively with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate, filtered and evaporated <EMI ID = 336.1>

  
  <EMI ID = 337.1>

  
the reaction mixture to about half its volume and diluted with ether. By filtration with

  
  <EMI ID = 338.1>

  
  <EMI ID = 339.1>

  
phosgene in the reaction mixture cooled for
20 minutes. After stirring the mixture for another

  
  <EMI ID = 340.1>

  
  <EMI ID = 341.1> acidifies the basic aqueous phase and extracts the fresh ether. We isolate the product in the form of a substance

  
  <EMI ID = 342.1>

  
By adding hexane to the chloroform trituration product, a second crop of product is obtained
(66 mg; melting point 86-88 [deg.] C, m / e 167).

  

  <EMI ID = 343.1>


  
EXAMPLE 58

  
  <EMI ID = 344.1>

  
2.7 g (21 mmol) of 5-chloro-2- are dissolved

  
  <EMI ID = 345.1>

  
at room temperature, thin layer chromatography (hexane: ethyl acetate 8: 1) then indicating that the reaction is complete. By dry concentration, we obtain

  
  <EMI ID = 346.1>

  
in the form of an oil ^ proton magnetic resonance / CDCl3 / delta: 0.3 (s, 9H); 5.4 (s, 1H); 6.1
(d, 1H); 6, 5 (d, lE).:.!.

EXAMPLE 59

  
  <EMI ID = 347.1>

  
ethyl carboximidate

  
2.3 g of 2- (5-chlorb-2-furyl) -2- are dissolved

  
  <EMI ID = 348.1>

  
  <EMI ID = 349.1>

  
  <EMI ID = 350.1>

  
merger 112-114 [deg.] C: m / e 203).

  
  <EMI ID = 351.1>

  
  <EMI ID = 352.1>

  
3'ethyl in 50 ml of tetrahydrofuran and cooled with healthy ice. After the addition of 2.1 ml (15 mmol) of

  
  <EMI ID = 353.1> reaction for 20 minutes while maintaining the temperature at 10-20 [deg.] C. Nitrogen is passed through the mixture and it is poured slowly into 100 ml of crushed ice. The cooled reaction mixture is extracted with
100 ml of ether and the ether is re-extracted with brine and concentrated in an oil. The oil is taken up in 15 ml of fresh ether, the solution is clarified and extracted with 10 ml of IN sodium hydroxide. The basic extract is acidified with concentrated hydrochloric acid and the product is extracted into ethyl acetate. After re-extraction with water, the ethyl acetate phase is concentrated in an oil (550 mg) - A portion of this

  
  <EMI ID = 354.1>

  
silica gel, the eluent used consisting of a 5: 1 hexane: ethyl acetate mixture containing 5% acetic acid. The column is concentrated by chromatography on a thin layer (even eluent). The last

  
  <EMI ID = 355.1>

  
112-114 [deg.] C; m / e 201; Rf 0.25 (hexane: ethyl acetate 5: 1 with 5% acetic acid).

  

  <EMI ID = 356.1>


  
  <EMI ID = 357.1>

  
  <EMI ID = 358.1>

  
1.1 g (6 mmol) of 5-bromo-2furaldehyde are dissolved in 50 ml of ether. A catalytic amount (about 50 mg) of zinc iodide is added, then 746 mg (1.2 equivalents) of trimethylsilylcarbonitrile is added dropwise. The reaction is monitored by infrared spectroscopy (disappearance of a characteristic carbonyl absorption) and by magnetic resonance of the protons (disappearance of a characteristic peak of the aldehyde protons). After 60 minutes &#65533; at room temperature, the reaction mixture is washed with saturated sodium bicarbonate, twice with water and finally with brine, it is dried over anhydrous sodium sulfate and evaporated to obtain

  
  <EMI ID = 359.1>

  
6.4 (d, 1H); 6.6 (d, 1H) 7.

  
  <EMI ID = 360.1>

  
  <EMI ID = 361.1>

  
ethyl carboxylic midate

  
Following the procedure of the example

  
  <EMI ID = 362.1>

  
evaporation of the mother liquor and trituration of the residue with ether.

  
'EXAMPLE- '63

  
  <EMI ID = 363.1>

  
ethyl 5- (5-bromo-2-furyl) oxazolidine-2,4-dione

  
  <EMI ID = 364.1>

  
(hexane: ethyl acetate 5: 1 with 5% acetic acid) _ / by the procedure of Example 57.

  
  <EMI ID = 365.1>

  
  <EMI ID = 366.1>

  
Following the procedure of Example 55, 1.75 g (10 mmol) of 3-bromo-2furaldehyde in 50 ml of ether are reacted with 8.8 ml (70 mmol) of trimethylsilylcarbonitrile in the presence of approximately
100 mg zinc iodide. At the end of the 16 hour reaction period, the supernatant ether is separated by <EMI ID = 367.1>

  
carboxi mid ethyl date

  
6.8 g of 2- (3-bromo-2-furyl) -2trimethoxysilylethanenitrile are dissolved in 70 ml of chloride

  
  <EMI ID = 368.1>

  
solution at around 5 [deg.] C for 2 hours. By dry concentration and trituration with acetone, we obtain

  
  <EMI ID = 369.1>

  
  <EMI ID = 370.1>

  
(decomposition) ^.

  
  <EMI ID = 371.1>

  
  <EMI ID = 372.1>

  
Following the procedure of Example 60, with the difference that phosgene is bubbled through the

  
  <EMI ID = 373.1>

  
ethyl carboximidate in 847 mg of 5- (3-bromo-2-furyl-

  
  <EMI ID = 374.1>

  
  <EMI ID = 375.1>

  
acetic acid)% ..

  

  <EMI ID = 376.1>


  
  <EMI ID = 377.1>

  
  <EMI ID = 378.1>

  
furaldehyde, 500 mg of zinc iodide are added and the mixture is stirred. 30 ml of

  
  <EMI ID = 379.1>

  
warm to room temperature and stir for about 64 hours at room temperature. We dilute

  
the reaction mixture with methylene chloride, it is extracted twice with saturated sodium bicarbonate, it is dried over anhydrous magnesium sulfate ,. we treat it with activated carbon, we filter it and

  
  <EMI ID = 380.1>

  
ethanenitrile with ethanolic hydrogen chloride

  
  <EMI ID = 381.1>

  
reaction of approximately 2 hours. The crude product is isolated by evaporation of the reaction mixture until an oil is obtained. The oil is partitioned between 400 ml of chloroform and saturated sodium bicarbonate. The chloroform is washed twice with sodium bicarbonate

  
  <EMI ID = 382.1>

  
of an oil - [magnetic resonance of protons / CDCl- /

  
  <EMI ID = 383.1>

  
tetrahydrofuran with stirring and the

  
  <EMI ID = 384.1>

  
triethylamine and phosgene is passed for 35 minutes through the cold solution, allowed to warm to room temperature and stirred for further
16 hours. The reaction mixture is poured slowly into 1 liter of water and ice. The product is extracted into three portions of ethyl acetate. The extracts are combined and the product is extracted into four portions of IN sodium hydroxide. The combined aqueous extracts are acidified with 6N hydrochloric acid and the product is extracted into four portions of chloroform.

  
The combined chloroform extracts are dried over anhydrous magnesium sulfate, treated with activated carbon, filtered and evaporated to give the crude product as an oil (2.1 g). By chromatography on a column of 100 g of silica gel with as eluent

  
a 2: 1 mixture of chloroform and ethyl acetate,

  
in fractions of 10 ml controlled by thin layer chromatography, the fractions are obtained by evaporation,
36-48, purified 5- (2-furyl) oxazolidine-2,4-dione

  
  <EMI ID = 385.1>

  

  <EMI ID = 386.1>


  
EXAMPLE 70

  
  <EMI ID = 387.1>

  
trione

  
  <EMI ID = 388.1>

  
pyrimidinetrione7et 75 ml of ethanol and the mixture is heated to reflux for one hour. The reaction mixture is allowed to cool to room temperature and

  
  <EMI ID = 389.1>

  
  <EMI ID = 390.1>

  
EXAMPLE 71

  
  <EMI ID = 391.1>

  
  <EMI ID = 392.1> acidifies the reaction mixture with acetic acid and the product is extracted into ethyl acetate, then it is isolated in the crude form by evaporation until an oil is obtained . By chromatography on approximately
100 ml of silica gel, which is checked by thin layer chromatography, 470 mg of 5- (3-

  
  <EMI ID = 393.1>

  
5% acetic acid).

  
EXAMPLE 72

  
  <EMI ID = 394.1>

  
in the presence of approximately 50 mg of zinc iodide. After shaking

  
  <EMI ID = 395.1>

  
thin layer chromatography indicates that the reaction is complete. By dry evaporation, 1.65 g of

  
  <EMI ID = 396.1>

  
trimethylsiloxyethanenitrile in 30 ml of cold saturated ethanolic hydrogen chloride and the

  
  <EMI ID = 397.1>

  
EXAMPLE 74

  
  <EMI ID = 398.1> amine with phosgene and the conforming product is isolated

  
  <EMI ID = 399.1>

  

  <EMI ID = 400.1>


  
EXAMPLE 75

  
  <EMI ID = 401.1>

  
Following the procedure of Example 67,

  
  <EMI ID = 402.1>

  
dehyde for 16 hours with 60 ml of trimethylsilylcarbonitrile in the presence of zinc iodide (approximately 0.5 g) to obtain in the form of an oil 92 g of 2- (2-thienyl) -

  
  <EMI ID = 403.1>

  
siloxyethanenitrile in 450 ml of absolute ethanol. We

  
  <EMI ID = 404.1>

  
hydrogen chloride for 40 minutes. We maintain the

  
  <EMI ID = 405.1>

  
dry- Triturated -the residue with 4 portions of 200 ml of ether, then. it is distributed between 400 ml of chloride

  
  <EMI ID = 406.1>

  
the organic phase twice with saturated sodium bicarbonate, it is treated with activated carbon, it is filtered and it is concentrated to obtain 1-hydroxy-1

  
  <EMI ID = 407.1>

  
  <EMI ID = 408.1>

  
EXAMPLE 77

  
  <EMI ID = 409.1>

  
hydrofuran. The solution is cooled to 0-5 [deg.] C and phosgene is passed through it for 45 minutes. We continue

  
  <EMI ID = 410.1>

  
reaction mixture slowly over 1500 ml of crushed ice.

  
The product is extracted into 1.1 liters of ethyl acetate in three portions. After gathering the phases

  
  <EMI ID = 411.1>

  
times with saturated sodium bicarbonate and once

  
  <EMI ID = 412.1>

  
of water at 1: 1. After gathering the leaguers. of washing with bicarbonate and carbonate, they are acidified to pH 1-2 with 6N hydrochloric acid and the product is extracted into several portions of ether. After having

  
  <EMI ID = 413.1>

  
with brine, they are dried over anhydrous magnesium sulfate, treated with activated charcoal, filtered and evaporated to obtain the product
(3.0 g). By recrystallization from toluene, we obtain

  
  <EMI ID = 414.1>

  
fusion 138-l40 [deg.] C, m / e 183).

  

  <EMI ID = 415.1>


  
. EXAMPLE '78 <EMI ID = 416.1>

  
Following the procedure of Example 67, 31.6 g (0.25 mole) of 3-methyl-2-thenaldehyde are reacted with 30 ml of trimethylsilylcarbonitrile for
16 hours in the presence of 500 mg of zinc iodide. We

  
  <EMI ID = 417.1>

  
thylènet then it is isolated as indicated in example 13,

  
  <EMI ID = 418.1> <EMI ID = 419.1>

  
ethyl

  
13 g of 2- (3-methyl-

  
  <EMI ID = 420.1>

  
cold ethanol, saturated with hydrogen chloride while maintaining the temperature at 0-4 [deg.] C. After one hour at 0-4 [deg.] C, the reaction mixture is evaporated to dryness. We grind it up

  
  <EMI ID = 421.1>

  
then it is distributed between 300 ml of methylene chloride and bicarbonate of: saturated sodium. The separate chloromethylenic phase is washed with two additional portions of saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and evaporated,

  
  <EMI ID = 422.1>

  
ethyl carboximidate (8.0 g, 69%; melting point
73-76 [deg.] C; m / e 199).

  
EXAMPLE 80

  
  <EMI ID = 423.1>

  
75 ml of tetrahydrofuran and the solution is cooled

  
  <EMI ID = 424.1>

  
triethylamine, phosgene is passed through the solution for 35 minutes and poured slowly into

  
a liter of ice and water. The product is extracted into three portions of ethyl acetate. The extraction phases are combined with ethyl acetate and the product is extracted into four portions of saturated sodium bicarbonate. The combined aqueous extracts are acidified with 6N hydrochloric acid and the product is reextracted in three portions of fresh ethyl acetate. The combined fresh organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated <EMI ID = 425.1>

  
  <EMI ID = 426.1>

  
  <EMI ID = 427.1>

  

  <EMI ID = 428.1>


  
We get a second crop of product
(0.63 g) by extraction of the initial phases of extraction with ethyl acetate with three portions of hydroxide

  
  <EMI ID = 429.1>

  
above.

  
EXAMPLE 81

  
  <EMI ID = 430.1>

  
thenaldehyde, 266 mg zinc iodide and 100 ml ether

  
and the mixture is stirred at room temperature. 23.5 g (0.24 mole) of trimethylsilylcarbonitrile are added dropwise and the reaction mixture is stirred for a further 2 hours. It is diluted with 100 ml of ether, washed with two 50 ml portions of bicarbonate of

  
sodium at 5%, then with two 25 ml portions of brine, it is dried over anhydrous magnesium sulfate,

  
  <EMI ID = 431.1>

  
ethyl carboximidate

  
  <EMI ID = 432.1>

  
nitrile and the solution is kept at 0 [deg.] C for 2.5 hours. The reaction mixture is evaporated to dryness and the residue is triturated with diethyl ether to

  
  <EMI ID = 433.1>

  
  <EMI ID = 434.1>

  
cold reaction mixture, let it warm up

  
at room temperature and pour it in portions

  
on about 275 ml of crushed ice. The product is extracted into two 200 ml portions of ethyl acetate. The extraction phases are combined with ethyl acetate

  
and extracted with two 150 ml portions of hydroxide

  
  <EMI ID = 435.1>

  
with hydrochloric acid and then extracted with two 250 ml portions of fresh ethyl acetate. The last combined organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated to give 7.2 g

  
  <EMI ID = 436.1>

  
recrystallization from a mixture of chloroform and hexane, the purified product is obtained (910 mg; point

  
  <EMI ID = 437.1>

  
EXAMPLE 84

  
  <EMI ID = 438.1>

  
5 g (34 mmol) of 5-chlorothenaldehyde are mixed with 50 mg of zinc iodide and 30 ml of diethyl ether and the mixture is cooled to 0 ° C. 4.04 g (40 mmol) of trimethylsilylcarbonitrile are added dropwise and the reaction mixture is allowed to warm to ambient temperature, then it is stirred for 4 hours. Additional equal portions of trimethylsilyl-carbonitrile and zinc iodide are added and the reaction mixture is stirred for an additional 16 hours. Diluted with ether, washed with two 30 ml portions of 5% sodium bicarbonate, washed once with

  
30. ml of brine, it is dried over anhydrous magnesium sulphate and 1 <1> evaporates to obtain 4.0 g of

  
  <EMI ID = 439.1>

  
(100 ml). The solution is cooled to 0-5 [deg.] C and saturated with hydrogen chloride. We maintain the mixture

  
  <EMI ID = 440.1>

  
and grind it with ether to get the chlorhy-

  
  <EMI ID = 441.1>

  
Following the same procedure, the other nitriles of the previous example are converted into the hydrochloride.

  
  <EMI ID = 442.1>

  
ethyl and 4.0 g (39 mmol) triethylamine in 90 ml

  
  <EMI ID = 443.1>

  
  <EMI ID = 444.1>

  
  <EMI ID = 445.1>

  
ambient and stirred for 16 hours. The reaction mixture is poured slowly into 100 ml of crushed ice and the product is extracted into two 100 ml portions of ethyl acetate. After having combined the extraction phases with ethyl acetate, they are rinsed with two 50 ml portions of water and a 50 ml portion of saturated sodium chloride, they are dried over anhydrous magnesium sulfate, we filter them and we

  
  <EMI ID = 446.1>

  
(0.6 g, melting point 126-1300C).

  

  <EMI ID = 447.1>


  
Following the same procedure, we

  
  <EMI ID = 448.1> <EMI ID = 449.1>

  
dione.

  
EXAMPLE 87

  
  <EMI ID = 450.1>

  
We cool! 0-5 [deg.] C 5.5 g (29 mmol) of 4-bromo-3-thenaldehyde in 75 ml of methylene chloride. 50 mg of zinc iodide are added, then 3.47 g (35 mmol) of trimethylsilylcarbonitrile are added dropwise over a period of 3 minutes. The mixture is allowed to warm to ambient temperature, it is stirred for 16 hours, it is washed twice with saturated sodium bicarbonate, it is washed with brine, it is dried over anhydrous magnesium sulfate, in the filter and we evaporated it to get the

  
  <EMI ID = 451.1>

  
in the form of an oil (7.6 g, 90%, m / e 291/289).

  
EXAMPLE 88

  
  <EMI ID = 452.1>

  
ethyl

  
Hydrogen chloride is passed through.

  
  <EMI ID = 453.1>

  
trimethylsiloxyethanenitrile in 200 ml of ethanol, cooled in an ice bath. After another 20 minutes at

  
  <EMI ID = 454.1>

  
grind with ether to obtain the hydrochloride of the product under the ferras of a hygroscopic solid. The salt is taken up in a mixture of methylene chloride and saturated sodium bicarbonate. The separate chloromethyl phase is washed twice with saturated sodium bicarbonate, washed with brine, dried over. anhydrous magnesium sulfate, filtered and evaporated

  
  <EMI ID = 455.1> <EMI ID = 456.1>

  
(m / e 265/263).

  
EXAMPLE 89

  
  <EMI ID = 457.1>

  
tetrahydrofuran, the mixture is cooled in an ice and water bath and phosgene is passed through it for 35 minutes. The reaction mixture is allowed to warm to room temperature, stirred for 1.5 hours, poured slowly over one liter of crushed ice and the product is extracted into three portions of

  
  <EMI ID = 458.1>

  
are evaporated to give an oil which crystallizes on adding a small amount of ether and hexane and which is triturated in approximately 40 ml of ether to give 3.4 g

  
  <EMI ID = 459.1>

  
Alternatively, the solution of the lithium derivative of 3,4-dibromothiophene in ether is reacted with 1.05 equivalent of alloxane, in accordance with the procedure of Example 54, which gives the 5 -

  
  <EMI ID = 460.1>

  
dinetrione. Following the procedure of Example 55, the latter compound is converted into 5- (4-bromo-3-thienyl)

  
  <EMI ID = 461.1>

  
10.6 g (0.107 mole) of trimethylsilylcarbonitrile are added dropwise over 10 minutes and the reaction mixture is stirred. For 16 hours, dilute with 60 ml of ether, wash with two 30 ml portions of bicar - <EMI ID = 462.1>

  
it is dried over anhydrous magnesium sulfate, filtered and evaporated to obtain 14.3 g of 2- (3-

  
  <EMI ID = 463.1>

  
hours and the product is isolated in the form of the hydrochloride by evaporation of the reaction mixture to dryness and trituration of the residue with ether. The salt is taken up in 400 ml of chloroform and 100 ml of saturated sodium bicarbonate. The separated chloroform phase is washed with an additional 100 ml of saturated sodium bicarbonate, washed with brine, dried over magnesium sulfate, filtered and

  
  <EMI ID = 464.1>

  
ethyl methanecarboximidate / magnetic resonance of

  
  <EMI ID = 465.1>

  
mole) of triethylamine in 600 ml of tetrahydrofuran

  
  <EMI ID = 466.1>

  
phosgene in the mixture for 30 minutes, we leave

  
the mixture warm to room temperature and allowed to stand for 16 hours. It is then poured slowly into 600 ml of ice and water (foaming of excess phosgene) and it is extracted twice with 600 ml portions of ethyl acetate. The combined extracts are washed with two 300 ml portions of IN sodium hydroxide. The combined basic extracts are acidified with hydrochloric acid and the product is reextracted in two fresh 300 ml portions of ethyl acetate. The combined fresh extracts are dried over anhydrous magnesium sulfate, filtered and evaporated to give 8.0 g of solid material. By recrystallization from hot toluene, the 5- (3-thienyl) oxazolidine-2,4-dione is obtained (5.5 g, melting point
133-136 [deg.] C).

   A second recrystallization from a mixture of ethyl acetate and hexane improves the purification
(first harvest: 2.352 g; melting point 136-138 [deg.] C,

  
  <EMI ID = 467.1>

  
  <EMI ID = 468.1>

  
3-thenaldehyde and 13.8 g (0.133 mole) of bisulfite

  
sodium in 152 ml of water for 2 hours to form

  
the bisulfite adduct in situ. We cool

  
the reaction mixture at 5 [deg.] C and 200 ml are added thereto

  
ethyl acetate. We add drop by drop in 30

  
minutes in two-phase system with stirring, 17.4 g
(0.267 mole) of potassium cyanide in 75 ml of water.

  
The reaction mixture is warmed to 20 [deg.] C and held there for one hour. We add potassium cyanide again
(5.7 g, 0.088 mole) and the mixture is stirred for a further

  
10 minutes at 20 [deg.] C. The phases are separated and the

  
aqueous phase with 50 ml of ethyl acetate. The combined ethyl acetate phases are washed with

  
saturated sodium chloride, which gives a solution

  
clean of 3-thenaldehyde cyanohydrin in ethyl acetate.

  
The solution of ethyl acetate 3thenaldehyde in acetate is stirred at room temperature and 41.6 g (52.7 ml, 10 equivalents) of ethanol and 15.2 ml (0.182 mole) are added thereto. hydrochloric acid, and the mixture is refluxed for 17

  
die. The reaction mixture is cooled to 25 [deg.] C, washed with 100 ml of water and then with bicarbonate of

  
  <EMI ID = 469.1>

  
anhydrous magnesium sulfate, it is treated with

  
  <EMI ID = 470.1>

  
obtaining an oil (about 11.5 g) which, by adding 46 ml of mixture of toluene and isooctane

  
  <EMI ID = 471.1>

  
crystalline ethyl acetate melting at 55-57 [deg.] C.

  
EXAMPLE 94

  
  <EMI ID = 472.1>

  
(6.3 moles) of 15N ammonium hydroxide and the suspension is heated to reflux for 2.5 hours. The solution

  
  <EMI ID = 473.1>

  
toluene. The reaction mixture is allowed to cool

  
  <EMI ID = 474.1>

  
tion with washing with toluene, 105.9 g (75%) are obtained

  
  <EMI ID = 475.1>

  
A second harvest is obtained (10.3 g, point of

  
fusion 114-120 [deg.] C) evaporating the aqueous phase of the filtrate to 50 ml and granulating with 100 ml of toluene. By recrystallization of the first and second harvests from ethyl acetate, 77-79% of product is recovered.

  
  <EMI ID = 476.1>

  
sodium methylate (10 g, 0.185 mole) and diethyl carbonate (22.0 ml, 0.182 mole) in 200 ml of ethanol. The reaction mixture is heated at reflux for 3 hours, cooled to 20 ° C. and diluted slowly with 100 ml of water. The ethanol is removed by evaporation and the aqueous residue is treated with activated carbon and then filtered. A layer of ethyl acetate is deposited on the filtrate and the pH is adjusted to 1.0 with <EMI ID = 477.1>

  
aqueous and washed with 100 ml of ethyl acetate.

  
After bringing the ethyl acetate extraction phases together, they are dried over anhydrous magnesium sulfate. The ethyl acetate is removed by vacuum distillation with displacement with toluene to a final volume of 150 ml. The resulting suspension is

  
  <EMI ID = 478.1>

  
  <EMI ID = 479.1>

  
oxazolidine-2,4-dione in 60 ml of ethyl acetate and

  
the solution is treated with 300 mg of activated carbon. After

  
  <EMI ID = 480.1>

  
washing with ethyl acetate. Methanolic sodium hydroxide (3.78 N, 4.2 ml) is added and the sodium salt is allowed to crystallize. After about 30 minutes, 0.3 ml of water is added. The suspension is granulated for
30 minutes at room temperature, then cool

  
  <EMI ID = 481.1>

  
  <EMI ID = 482.1>

  
5- (3-thienyl) oxazolidine-2,4-dione in the form of the nonohydrate (melting point 208-210 [deg.] C).

  
  <EMI ID = 483.1>

  
: calculated for

  

  <EMI ID = 484.1>


  
Sodium hydroxide is replaced by an equivalent of potassium hydroxide, diethanolamine, meglumine or piperazine to obtain the corresponding salts. The solvent is removed by evaporation or a non-solvent such as ether or hexane is added, in an amount necessary to facilitate the precipitation of the product.

  
- The same procedures are used to produce the pharmaceutically acceptable salts of the other oxazolidine-2,4-diones of the present invention.

  
EXAMPLE 97

  
  <EMI ID = 485.1>

  
  <EMI ID = 486.1>

  
dehyde and 50 mg of zinc iodide with 180 ml of methylene chloride. 4.0 g (5.2 ml,

  
  <EMI ID = 487.1>

  
reaction mixture for 24 hours at room temperature, diluted with 50 ml of methylene chloride, washed with 60 ml of 5% sodium bicarbonate and then with 50 ml of brine, dried over anhydrous magnesium sulfate , we filter it and we evaporate it to

  
  <EMI ID = 488.1>

  
ethanenitrile in the form of an oil (m / e 291/289).

  
  <EMI ID = 489.1>

  
  <EMI ID = 490.1>

  
stirring for 30 minutes at the same temperature, the reaction mixture is evaporated to dryness. By trituration of the solid residue with ether, 7.0 g of

  
  <EMI ID = 491.1>

  
6.8 g (23 mmol) of 1- (2-bromo-2--) hydrochloride are mixed in 250 ml of tetrahydrofuran

  
  <EMI ID = 492.1>

  
  <EMI ID = 493.1>

  
  <EMI ID = 494.1>

  
ambient, stir for 16 hours and pour <EMI ID = 495.1>

  
nel disabled is extracted twice with portions of
200 ml of chloroform. Chloroform extracts

  
  <EMI ID = 496.1>

  
over anhydrous magnesium sulfate, filtered and. evaporated giving an oil. Addition of hexane and ether

  
gives a crystalline product. By recrystallization in

  
toluene, 5- (3-bromo-2-thienyl) oxazolidine2,4-dione (2.25 g, melting point 138-139 [deg.] C) is obtained.

  

  <EMI ID = 497.1>


  
  <EMI ID = 498.1>

  
  <EMI ID = 499.1>

  
7.9 g (0.123 mole) of potassium cyanide and 10 g (0.104 mole) of thiocyanate are mixed. potassium

  
  <EMI ID = 500.1>

  
  <EMI ID = 501.1>

  
30%, which gives an oil. The reaction mixture is diluted with 104 ml of water and stirred for 48 hours, during which time a granular solid substance forms. The solid is collected by filtration and distributed between chloroform and 5% sodium bicarbonate. The mixture is filtered and the aqueous phase is separated, acidified and the precipitated product is collected by filtration. By recrystallization in the

  
  <EMI ID = 502.1>

  
120 [deg.] C, m / e 279-277).

  

  <EMI ID = 503.1>


  
  <EMI ID = 504.1>

  
  <EMI ID = 505.1> <EMI ID = 506.1>

  
becomes slightly cloudy. The turbidity is reduced by the addition of 1 ml of ethanol. The mixture is heated to

  
  <EMI ID = 507.1>

  
diluted with 100 ml of water and extracted with chloroform.

  
The chloroform extract is washed with two portions of

  
  <EMI ID = 508.1>

  
  <EMI ID = 509.1>

  

  <EMI ID = 510.1>


  
  <EMI ID = 511.1>

  
  <EMI ID = 512.1>

  
trione

  
Dissolve by heating in 25 ml of ethanol

  
  <EMI ID = 513.1>

  
  <EMI ID = 514.1>

  
add 3 ml (3 mmol) of IN hydrochloric acid and the mixture is refluxed for 3 minutes. It is allowed to cool to room temperature and diluted with
15 ml of water to crystallize more product.

  
  <EMI ID = 515.1>

  
Rf 0.3 (hexane: ethyl acetate 1: 1 with 5% acetic acid) m / e 2567.

  
- EXAMPLE 103 <EMI ID = 516.1> one hour. The mixture is acidified, clarified ^ '

  
  <EMI ID = 517.1>

  
ethyl. After having combined the extraction phases with ethyl acetate, they are rinsed with water and they are evaporated to dryness. (0.5 g solid). By chromatography on approximately 85 ml of silica gel, which is checked by thin layer chromatography, we obtain

  
  <EMI ID = 518.1>

  
melting point 156-158 [deg.] C).

  

  <EMI ID = 519.1>


  
  <EMI ID = 520.1>

  
  <EMI ID = 521.1>

  
trione

  
5.76 g (40 mmol) of 2-phenylfuran is mixed with 100 ml of tetrahydrofuran and the mixture is cooled

  
  <EMI ID = 522.1>

  
  <EMI ID = 523.1>

  
the temperature between -20 and -30 * 0. We leave the mixture

  
  <EMI ID = 524.1>

  
  <EMI ID = 525.1>

  
  <EMI ID = 526.1>

  
  <EMI ID = 527.1>

  
3 'ethyl 1: 1/5% acetic acid) / contaminated with the starting material (Rf 0.45):

  
  <EMI ID = 528.1>

  
  <EMI ID = 529.1> <EMI ID = 530.1>

  
  <EMI ID = 531.1>

  
for 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 extraction phase is rinsed with approximately 6.5 ml of water, filtered through a layer of anhydrous magnesium sulfate and evaporated.

  
  <EMI ID = 532.1>

  
  <EMI ID = 533.1>

  
  <EMI ID = 534.1>

  
  <EMI ID = 535.1>

  
  <EMI ID = 536.1>

  
trione

  
  <EMI ID = 537.1>

  
2-methylfuran with 100 ml of tetrahydrofuran. The reaction mixture, purged with nitrogen, is cooled to
-30 [deg.] C and butyllithium (19.1 ml, 2.3M in hexane) is added over a period of 10 minutes, the temperature being maintained between -20 and -30 [deg.] C. The reaction mixture is allowed to warm to ambient temperature, then it is brought to -30 [deg.] C. Sublimated alloxane (5.96 g) is added dropwise over 10 minutes to 40 ml of tetrahydrofuran, while maintaining the temperature.

  
  <EMI ID = 538.1>

  
  <EMI ID = 539.1>

  
  <EMI ID = 540.1>

  
hydrochloric acid IN while maintaining the temperature: between 0 and 5 [deg.] C. The reaction mixture is extracted with .00 ml of ethyl acetate. The extract is rinsed with 25 ml of water, filtered through a layer of anhydrous magnesium sulfate and evaporated to obtain 6.3 g of <EMI ID = 541.1> <EMI ID = 542.1>. EXAMPLE 107 <EMI ID = 543.1>

  
6.3 g of 5-hydroxy-5- (5-methyl-2- are dissolved

  
  <EMI ID = 544.1>

  
  <EMI ID = 545.1>

  
room for 15 minutes. The reaction mixture is extracted with 50 ml of ethyl acetate and it is acidified with glacial acetic acid. The product is then extracted into fresh ethyl acetate (three 30 ml portions). After having combined the ethyl acetate extraction phases, they are filtered through a layer of anhydrous magnesium sulfate and evaporated until an oil is obtained. The oil is chromatographed on 50 ml of silica gel using a hexane: ethyl acetate mixture 1: 1/5% acetic acid as eluent. The column is checked by thin layer chromatography using the same eluent. The clean fractions containing the product are combined, evaporated to dryness and triturated with hexane (311 mg, point of

  
  <EMI ID = 546.1>

  
purified oxazolidine-2,4-dione (melting point 136.5-
13?, 5 [deg.] C).

  

  <EMI ID = 547.1>


  
  <EMI ID = 548.1>

  
  <EMI ID = 549.1>

  
40 ml of isopropyl ether are cooled to -70 [deg.] C. Butyllithium in hexane is added in 10 minutes
(2.4M, 10 ml, 24 mmol) keeping the temperature between -70 and -60 [deg.] C. 1.9 ml are added in 20 minutes

  
(20 nmoles) of 3-bromothiophene while maintaining the temperature

  
  <EMI ID = 550.1>

  
30 minutes between -72 and -70 [deg.] C. 3 g (21 mmol) of sublimed alloxane in 25 ml of tetrahydrofuran are added over 40 minutes, keeping the temperature between -70 and
-65 [deg.] C. We continue to stir at this temperature for
15 minutes. The cooling bath is removed and the reaction mixture is stirred for one hour at room temperature, then cooled to 5 [deg.] C. 40 ml of IN hydrochloric acid are added slowly and the organic phase is separated. The aqueous phase is extracted with 35 ml of ethyl acetate. After gathering the

  
  <EMI ID = 551.1>

  
of water, they are dried over anhydrous sulfate of

  
  <EMI ID = 552.1>

  
  <EMI ID = 553.1>

  
solid trione (m / e 226).

  
When this reaction is combined in tetrahydrofuran with reverse addition of 3-bromothiophene to butyllithium, immediately adding 0.5 equivalent of alloxane hydrate instead of one equivalent of anhydrous alloxane. the product obtained consists of a

  
  <EMI ID = 554.1>

  
oxazolidine-2,4-dione by the method of Example 55.

  
  <EMI ID = 555.1>

  
  <EMI ID = 556.1>

  
  <EMI ID = 557.1>

  
at room temperature for 15 minutes. The solution is acidified with acetic acid and the product is allowed to crystallize in 35 minutes. Filtration is obtained

  
  <EMI ID = 558.1>

  
melting at 133-135 [deg.] C. Another crop of product is obtained by extracting the mother liquor with ethyl acetate. The extract is rinsed with water and evaporated to dryness

  
(80 mg, contaminated with starting material).

  
EXAMPLE 110

  
  <EMI ID = 559.1>

  
We repeat the detailed procedure of the example
108 but by replacing 3-bromothiophene with 3-bromo- <EMI ID = 560.1>

  
  <EMI ID = 561.1>

  
  <EMI ID = 562.1>

  
EXAMPLE 111

  
5- (3-furyl) oxazolidine-2,4-dione

  
1.62 g of 5- (3-furyl) -5-hydroxy-2,4,6 are dissolved
(1H, 3H, 5H) pyrimidinetrione in 15 ml of hydroxide

  
  <EMI ID = 563.1>

  
minutes at room temperature, then it is extracted with 5 ml of ethyl acetate. The aqueous phase is acidified with glacial acetic acid (about 1.5 ml) and

  
  <EMI ID = 564.1>

  
the extract with 5 ml of water, it is filtered on a layer of anhydrous sodium sulphate and .on the evaporated to obtain the crude product in the form of an oil (470 mg, m / e 167).

  
  <EMI ID = 565.1>

  
  <EMI ID = 566.1>

  
  <EMI ID = 567.1>

  
lower melting point from the mother liquor.

  
'EXAMPLE 112

  
  <EMI ID = 568.1>

  
30.2 g (0.29 mol) of sodium bisulfite are dissolved in 190 ml of water and the mixture is heated to 50 ° C. We add

  
  <EMI ID = 569.1>

  
  <EMI ID = 570.1>

  
period during which everything goes into solution, except a small amount of gummy solid. We cool

  
  <EMI ID = 571.1>

  
isopropyl ether. While stirring, sodium cyanide (24.8, g, 0.25 mole) in 190 ml of water is added dropwise over 20 minutes, maintaining the temperature

  
  <EMI ID = 572.1>

  
room for 1 hour. The organic phase is separated

  
  <EMI ID = 573.1>

  
fresh propyl. The combined organic extracts are washed with brine, dried over anhydrous magnesium sulphate, filtered and concentrated to give 3-thenaldehyde cyanohydrin in the form of an oil
(28.3 g, 92%).

  
  <EMI ID = 574.1>

  
  <EMI ID = 575.1>

  
  <EMI ID = 576.1>

  
  <EMI ID = 577.1>

  
of 3-thenaldehyde then 0.5 ml of concentrated hydrochloric acid. The reaction mixture is stirred at room temperature for one hour, poured onto crushed ice and extracted with three portions of ethyl acetate. The combined extracts are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil which partially crystallizes by scraping. By recrystalli-

  
  <EMI ID = 578.1>

  
  <EMI ID = 579.1>

  
Mixed esters of commercial 2- (3-thienyl) malonic acid (47% ester of

  
  <EMI ID = 580.1>

  
dimethyl; 11.4 g) to a dispersion of sodium hydride in oil (50%, 2.4 g) suspended in 70 ml of toluene. There is an exothermic reaction, the

  
  <EMI ID = 581.1>

  
stirred for 3 hours at room temperature, then cooled in an ice and water bath. 8 g of benzoyl peroxide in 100 ml of toluene are added in one period

  
  <EMI ID = 582.1>

  
the mixture is stirred for 30 minutes at room temperature, diluted by adding 50 ml dropwise: water (initial foaming is observed) and finally,

  
  <EMI ID = 583.1>

  
  <EMI ID = 584.1> evaporated to obtain the methyl / ethyl esters

  
  <EMI ID = 585.1>

  
as an oil (15.5 g containing about 1.2 g of oil from the sodium hydride dispersion).

  
EXAMPLE 115

  
  <EMI ID = 586.1>

  
0.46 g (20 mmol) of sodium is dissolved in
50 ml of absolute ethanol. Crude mixed esters of 2-benzoyloxy-2- (3-thienyl) malonic acid (7 g, approximately 20 mmol, as prepared in Example 60), then urea (1.2 g, 20 mmol) in

  
  <EMI ID = 587.1>

  
The reaction mixture is cooled, acidified with concentrated hydrochloric acid and extracted! acetate

  
  <EMI ID = 588.1>

  
until an oil is obtained. By crushing with

  
  <EMI ID = 589.1>

  
  <EMI ID = 590.1>

  
intermediate trione. A portion of this mixture (0.3 g)

  
  <EMI ID = 591.1>

  
solution is left standing for 20 minutes at room temperature. The reaction mixture is clarified by filtration and acidified with acetic acid to

  
  <EMI ID = 592.1>

  
melting at 136-138 [deg.] C).

  
EXAMPLE 116

  
  <EMI ID = 593.1>

  
  <EMI ID = 594.1>

  
3'ether. 1.98 g (20 mmol) are added dropwise

  
  <EMI ID = 595.1> the reaction mixture is washed successively with saturated sodium bicarbonate, water and brine, it is dried over anhydrous sodium sulfate, it is

  
  <EMI ID = 596.1>

  
siloxyethanenitrile in 10 ml of saturated ethanolic hydrogen chloride and the solution is kept for
4 p.m. at around 5 [deg.] C. The reaction mixture is evaporated to dryness and triturated with ether to obtain

  
  <EMI ID = 597.1>

  
ethyl methanecarboximidate (2.2 g, melting point
128-131 [deg.] C, m / e 235).

  
EXAMPLE 118

  
  <EMI ID = 598.1>

  
ethyl and 2.64 g (26 mmol) of triethylamine in

  
50 ml of tetrahydrofuran and the mixture is cooled to

  
  <EMI ID = 599.1>

  
tional cooled for 30 minutes, then purged with nitrogen for 10 minutes. The reaction mixture is poured slowly into 100 ml of ice and extracted twice with ether. After having combined the extraction phases with ether, they are rinsed with water and then with brine, they are dried over anhydrous sodium sulfate, they are filtered and they are evaporated to obtain 1.7 g of a gummy solid. We dissolve this

  
  <EMI ID = 600.1>

  
  <EMI ID = 601.1>

  
  <EMI ID = 602.1>

  
  <EMI ID = 603.1> <EMI ID = 604.1>

  

  <EMI ID = 605.1>


  
  <EMI ID = 606.1>

  
  <EMI ID = 607.1>

  
carbonitrile and about 50 mg of zinc iodide and the mixture is stirred for one hour at room temperature, and at this time, thin layer chromatography indicates that the transformation is complete. The reaction mixture is evaporated to dryness, which gives 2.2 g

  
  <EMI ID = 608.1>

  
  <EMI ID = 609.1>

  
  <EMI ID = 610.1>

  
tallization in acetone.

  
EXAMPLE 121

  
  <EMI ID = 611.1>

  
Following the procedure of Example 118, 1.1 g (4 mmol) of phosgene is reacted.

  
  <EMI ID = 612.1>

  
amine. The crude product, isolated in the form of an oil, is dissolved in 25 ml of ether and the product is extracted

  
  <EMI ID = 613.1>

  
  <EMI ID = 614.1> is extracted into fresh ether which is rinsed with water and evaporated in vacuo giving a solid residue
(670 mg). This residue is recrystallized to give 0.45 g

  
  <EMI ID = 615.1>

  
at 130-132 [deg.] C.

  

  <EMI ID = 616.1>


  
EXAMPLE 122

  
  <EMI ID = 617.1>

  
in 35 ml of ether. While cooling, butyllithium in hexane (2.4M, 9 ml, 21.6 mmol) is added dropwise over 15 minutes, the temperature reaching 35 ° C. during this addition. The reaction mixture is stirred for one hour at room temperature. While maintaining the temperature between -20 and -15 [deg.] C, we add

  
in 10 minutes 3 g (21 nnnoles) of alloxane sublimed in

  
20 ml of tetrahydrofuran. The mixture is allowed to warm to room temperature, it is stirred for half an hour, it is cooled to 5 [deg.] C and it is deactivated by adding 35 ml of IN hydrochloric acid to it, in portions. The organic phase is separated and the aqueous phase is extracted with 25 ml of ethyl acetate. After having combined the organic phase and extract, they are rinsed with water, they are concentrated to dryness and they are triturated with hexane.

  
  <EMI ID = 618.1>

  
  <EMI ID = 619.1>

  
for 1.5 hours at room temperature, it is extracted with ether, it is acidified with acetic acid, it is diluted with 15 ml of water and filtered to obtain the product sa

  
/ 567 mg, melting point 144-146 [deg.] C (decomposition) 7.

  
By recrystallization from a mixture of acetone and

  
  <EMI ID = 620.1>

  
  <EMI ID = 621.1>

  
fusion 147-148 [deg.] C (decomposition! / *

  

  <EMI ID = 622.1>


  
  <EMI ID = 623.1>

  
  <EMI ID = 624.1>

  
35 ml of ether. Butyllithium in hexane (2.4M, 6.25 ml, 15 mmol) is added dropwise over 15 minutes, the temperature rising to 33 [deg.] C. The mixture is stirred for 75 minutes at room temperature and then cooled. Keeping the temperature between -15 and <EMI ID = 625.1>
(15 mmol) of sublimed alloxane, in 20 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature for 30 minutes, cooled to 5 [deg.] C,

  
  <EMI ID = 626.1>

  
in small portions, and extracted with 25 ml of ethyl acetate. The organic phase is rinsed with 15 ml of water, filtered on a layer of anhydrous sodium sulfate

  
  <EMI ID = 627.1>

  
/ oil, Rf 0.25 (hexane: ethyl acetate 1: 1/5% acetic acid ^ contaminated with starting material (Rf 0.8).

  
EXAMPLE 125

  
  <EMI ID = 628.1>

  
2,4-dione

  
The whole crude product from the previous example is taken up in 35 ml of IN sodium hydroxide and the solution is left to stand for 30 minutes. After acidification, the product is extracted into isopropyl ether. The extract is rinsed with water and

  
  <EMI ID = 629.1>

  
and the solution is stirred with 10 ml of hydrochloric acid

  
6N at room temperature for one hour. We add

  
10 ml of ethyl acetate, and the organic phase is separated 1 [deg.] Evaporating to dryness under vacuum (0.388 g). By chromatography

  
  <EMI ID = 630.1>

  
  <EMI ID = 631.1>

  
we check by thin layer chromatography, we

  
  <EMI ID = 632.1>

  
  <EMI ID = 633.1>

  
(melting point 153-155 [deg.] C, m / e 287).

  

  <EMI ID = 634.1>


  
  <EMI ID = 635.1>

  
  <EMI ID = 636.1>

  
The following ingredients are mixed by shaking for 30 minutes:

  
Sodium salt monohydrate

  
5- (3-thienyl) oxazolidine-2,4-dione 30.46 * Lactose, anhydrous, U.S.P. 14.05 g Corn starch, dried, U.S.P. 5.00 g

  
  <EMI ID = 637.1>

  
not solvated).

  
The mixture is ground (1 plateau 016 mm tray) and stirred for another 30 minutes. Magnesium stearate and sodium lauryl sulphate are added in a mixture of 90/10 (1.00 g) and the mixture is stirred for
20 minutes. The mixture obtained is loaded into gelatin capsules n [deg.] 0 (load weight of 505 mg) of <EMI ID = 638.1>

  
Larger capsules are used to prepare more powerful capsules.

  
The same procedure is used to prepare 5 100 mg capsules from the following ingredients:

  

  <EMI ID = 639.1>


  
  <EMI ID = 640.1>

  
not solvated) ..

  
A lower amount of active ingredient is used in the mixture to prepare lower potency capsules.

EXAMPLE 128

TABLETS

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

  

  <EMI ID = 641.1>


  
One incorporates in this base for tablets a

  
  <EMI ID = 642.1>

  
  <EMI ID = 643.1>

  
holding 50 mg, 100 mg or 250 mg of active ingredient

  
(weight equivalent to free acid). The ratio of the mixture to the active substance is within the limits of 10.167 to 1-1, for example at the extremes, 60.2 mg of salt

  
sodium monohydrate and 300 mg of mixture in a 50 mg or 304.6 mg tablet of sodium salt monohydrate and
250 mg of mixture in a 250 mg tablet.

  
"EXAMPLE 129

INJECTABLE PREPARATION

  
The sterile 5- (3-thienyl) oxazolidine-2,4-dione sodium salt of <EMI ID = 644.1>

  
sodium monohydrate (equivalent to 550 mg of free acid).

  
Before use, sterile water for injectables (11 ml) is added and the mixture is shaken to form a solution containing 50 mg / ml of active drug, which is suitable for intravenous, intramuscular or sub-injection. cutaneous.

  
Alternatively, ampoules are loaded by a lyophilization process. 2 ml of a sterile aqueous solution containing 335 mg / ml of sodium salt monohydrate are introduced into each ampoule. The bulbs are freeze-dried on trays.

  
EXAMPLE 130

  
  <EMI ID = 645.1>

  
The sodium salt monohydrate of 5- (3-thienyl) oxazolidine-2,4-dione is removed from its water by dehydra-

  
  <EMI ID = 646.1>

  
for about 2 hours. The mixture is allowed to cool to ambient temperature, the sodium chloride formed as a by-product is filtered off and

  
  <EMI ID = 647.1>

  
Method A <EMI ID = 648.1>

  
oxazolidine-2,4-dione and 0.14 ml (10 mmol) of triethyl-

  
  <EMI ID = 649.1>

  
ambient. 0.72 ml (10 mmol) of acetyl chloride is added dropwise over a few minutes and the reaction mixture is stirred for 3 hours. The reaction mixture is evaporated to dryness and the residue is distributed between saturated sodium bicarbonate and chloroform. The chloroform phase is washed with water, then with brine, dehydrated over anhydrous magnesium sulfate, filtered

  
  <EMI ID = 650.1>

  
dine-2,4-dione.

  
Method B

  
  <EMI ID = 651.1>

  
acetic with 20 ml of tetrahydrofuran and stirred for 40 hours. The mixture is evaporated. reactive to

  
  <EMI ID = 652.1>

  
The same procedure, but with replacement of acetic anhydride by an equivalent of reagent consisting of. acetoformic acid / acetic formic anhydride solution in acetic acid; see Blackwood

  
  <EMI ID = 653.1>

  
  <EMI ID = 654.1>

  
  <EMI ID = 655.1>

  
  <EMI ID = 656.1>

  
(10 mmol) of methyl isocyanate and the reaction mixture is stirred for 4 hours at room temperature.

  
The reaction mixture is diluted with 35 ml of 1,2-dichloroethane, washed with saturated sodium bicarbonate, then brine, dried over anhydrous magnesium sulfate, filtered and stored.

  
  <EMI ID = 657.1>

  
oxazolidine-2,4-dione.

  
EXAMPLE 133

  
  <EMI ID = 658.1>

  
Following the procedure of Example 55, 2.6 g (18.3 mmol) of 4-methoxy-3thenaldehyde and 2.15 g (21.7 mmol) of trimethylsilylcarbonitrile are transformed into 250 ml of ether in the presence 50 mg

  
  <EMI ID = 659.1>

  
in the form of an oil (3.9 g, m / e 241).

EXAMPLE 134

  
  <EMI ID = 660.1>

  
  <EMI ID = 661.1>

  
in 20 ml of methanol is added dropwise and the

  
  <EMI ID = 662.1>

  
reaction mixture is concentrated to. dry and the residue

  
  <EMI ID = 663.1>

  
  <EMI ID = 664.1>

  
position) ^ * By recrystallization from a mixture of methanol and ether, the indicated purified product is obtained

  
  <EMI ID = 665.1>

  
Following the procedure of Example 57,

  
  <EMI ID = 666.1>

  
5.5 mmol) and 1.7 g (17 mmol) of triethylamine in

  
  <EMI ID = 667.1>

  
minutes at 0-5 [deg.] C. The reaction mixture is stirred for about 16 hours at room temperature. The reaction mixture is poured slowly into 500 ml of ice

  
  <EMI ID = 668.1>

  
chloroform. The combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. By recrystallization from toluene, the product is obtained; .

  
  <EMI ID = 669.1>

  
  <EMI ID = 670.1>

  
  <EMI ID = 671.1>

  

  <EMI ID = 672.1>


  
  <EMI ID = 673.1>

  
  <EMI ID = 674.1>

  
nitrile in 300 ml of ether in the presence of 50 mg of zinc iodide in 13 g of product indicated in the title, under

  
  <EMI ID = 675.1>

  
of protons reveals the absence of the aldehyde proton.

  
  <EMI ID = 676.1>

  
  <EMI ID = 677.1>

  
but also following the procedure of Example 134, the product of the previous example (13 g) is converted into the compound indicated in the title.

  
  <EMI ID = 678.1>

  
Using a phosgene duration of one hour at 0-5 "C, then a reaction time of one hour at room temperature, the product is converted

  
from the previous example (9.2 g) in the product indicates in

  
  <EMI ID = 679.1>

  
tional in 1.5 liters of crushed ice and extracted with three 200 ml portions of chloroform. The organic phases are combined and extracted with three

  
  <EMI ID = 680.1>

  
basic extracts are combined, rinsed with 200 μl of fresh chloroform, re-acidified with 3N hydrochloric acid and extracted with three 200 ml portions

  
chloroform. The last three organic extracts are combined, washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness and the residue is crystallized from toluene to give the compound indicated in the title / 4.06 g, point of fusion

  
  <EMI ID = 681.1>

  
  <EMI ID = 682.1>

  

  <EMI ID = 683.1>


  
The chloroform rinse aid is reextracted with three 150 ml portions of hydroxide

  
  <EMI ID = 684.1>

  
and an additional amount of product (980 mg, melting point 144-146 [deg.] C) is collected in the same manner.

  
  <EMI ID = 685.1>

  
  <EMI ID = 686.1>

  
thenaldehyde and 2.28 g (2.9 ml, 23 mmol) of trimethylsilylcarbonitrile in 250 ml of ether, in the presence of
50 mg of zinc iodide, in the product indicated in the

  
  <EMI ID = 687.1>

  
  <EMI ID = 688.1>

  
  <EMI ID = 689.1>

  
  <EMI ID = 690.1>

  
Using a reaction time of 20 minutes after the end of the addition, the procedure of Example 137 is used to convert the product of the previous example (4.5 g) to the product indicated in the title of the <EMI ID = 691.1>

  
(decomposition)/.

  
EXAMPLE 141

  
  <EMI ID = 692.1>

  
Following the procedure of Example 135,

  
  <EMI ID = 693.1>

  
  <EMI ID = 694.1>

  
2,4-dione recrystallized from toluene / T, 63 g;

  
  <EMI ID = 695.1>

  
  <EMI ID = 696.1>

  
EXAMPLE 142

  
  <EMI ID = 697.1>

  
nitrile

  
Following the procedure of Example 55, 5.2 g (33.3 mmol) of 4-methoxy-2-methyl-

  
  <EMI ID = 698.1>

  
carbonitrile in 350 ml of ether, in the presence of 50 mg of zinc iodide, in the product indicated in the title

  
  <EMI ID = 699.1>

  
  <EMI ID = 700.1>

  
EXAMPLE 143

  
  <EMI ID = 701.1>

  
The procedure of Example 137 is applied to the product of the previous example (7.2 g) to form

  
5.8 g of a mixture of the title compound and

  
corresponding ethoxyether (consisting of approximately 40% methyl ether and 60% ethyl ether based on the proton magnetic resonance; having the two m / e values of 243 and 229).

  
We take a portion of this mixture (2.5 g)

  
  <EMI ID = 702.1>

  
spend hydrogen chloride for one hour. After stirring for another hour at 0 [deg.] C, the reaction mixture is evaporated to obtain a viscous oil. By crystallization from ether, the product indicated in the title / 2.1 g is obtained; melting point 123-125 [deg.] C (decomposition); m / e 2297.

  
The corresponding methyl imidate of the product indicated in the title is obtained by direct reaction

  
of the product of the previous example with methanolic hydrogen chloride, in accordance with the procedure of Example 134,

EXAMPLE 144

  
  <EMI ID = 703.1>

  
ethyl methanecarboximidate

  
A portion (2.5 g) of the mixed methyl and ethyl ethers of the preceding examples is taken up in 100 ml of ethanol and the mixture is cooled to 0 [deg.] C. Hydrogen chloride is passed for one hour through the cold solution, stirred for another hour at 0 ° C. and evaporated until an oil is obtained. The oil is crystallized by trituration with ether. By resuspension in ether, 2.07 g of the product indicated in the title is obtained, melting at 105-107 [deg.] C while decomposing

  
  <EMI ID = 704.1>

  
EXAMPLE 145

  
  <EMI ID = 705.1>

  
Using a reaction time of 3.5 hours. at room temperature, but also following

  
the procedure of Example 57, the product of Example 143 (2.0 g, 7.5 mmol) is converted into the indicated product

  
  <EMI ID = 706.1>

  
melting point 179-181 [deg.] C; m / e 227; infrared spectrum

  
  <EMI ID = 707.1>

  
  <EMI ID = 708.1>

  
  <EMI ID = 709.1>

  
Following the procedure of the previous example, the product of Example 144 (J., 9 g) is converted into the product indicated in the title / 245 mg, melting point 136-138 [deg.] C; m / e 241; infrared spectrum (KBr)

  
  <EMI ID = 710.1>

  
EXAMPLE 147

  
  <EMI ID = 711.1>

  
trione 35 ml of isopropyl ether is cooled to <EMI ID = 712.1> hexane, 10.5 mmol) while allowing the temperature to rise to -60 [deg.] C. 1.2 ml are then added dropwise

  
  <EMI ID = 713.1>

  
70, page 739 (19481 / keeping the temperature between
-65 and -68 [deg.] Co After stirring for half an hour at
-68 [deg.] C, anhydrous alloxane (1.5 g, 10.6 mmol) dissolved in 15 ml of tetrahydrofuran is added dropwise over 30 minutes, maintaining the temperature between
-65 and -60 [deg.] C. The reaction mixture is left under stirring to warm to O [deg.] C in 15 minutes, to which it is added. <EMI ID = 714.1>

  
organic. The aqueous phase is extracted with 20 ml of ethyl acetate. The combined organic phases are washed

  
  <EMI ID = 715.1>

  
indicated in the title (Rf 0.05, ethyl acetate: hexane

  
  <EMI ID = 716.1>

  
EXAMPLE 148

  
  <EMI ID = 717.1>

  
We use the product of the previous example

  
  <EMI ID = 718.1>

  
stand for 15 minutes. The solution is extracted with 5 ml of ethyl acetate, it is acidified with acetic acid and it is extracted with 25 ml of ethyl acetate. The acid extract is rinsed with 5 ml of water and evaporated to dryness

  
(340 mg); the solid material is chromatographed on 50 ml of silica gel, eluting with a mixture

  
  <EMI ID = 719.1>

  
by thin layer chromatography. The clean fractions are combined, evaporated to dryness and the residue is recrystallized from a mixture of ether and hexane, giving the purified product indicated in the title / 170 mg; melting point 144-145 [deg.]; m / e 195; Rf 0.3 (ethyl acetate: hexane 1: 5/5% acetic acid); Rf 0.55

  
  <EMI ID = 720.1>

  

  <EMI ID = 721.1>


  
EXAMPLE 149

  
  <EMI ID = 722.1>

  
trione

  
0.96 g (3 mmol) of 3,4diiodofuran in 5 ml of ether is slowly added to a cold solution (-65 [deg.] C) of butyllithium (2 ml, 2.3M in hexane, 4, 6 mmol) in 15 ml of ether. The reaction mixture is stirred

  
  <EMI ID = 723.1>

  
anhydrous alloxane in 10 ml of tetrahydrofuran and the solution obtained is slowly added to the solution of 4-iodo-3-furyl-lithium at -65 "C. After 10 minutes at the same temperature, the reaction mixture is allowed to warm up at 15 [deg.] C, it is acidified with 15 ml of acid

  
  <EMI ID = 724.1>

  
extraction phase with ether with 10 ml of water, it is

  
  <EMI ID = 725.1>

  
of hexane to obtain 108 mg of the product indicated in the

  
  <EMI ID = 726.1>

  
5% acetic acid} / -

  
  <EMI ID = 727.1>

  
  <EMI ID = 728.1>

  
The product of the example is allowed to stand

  
  <EMI ID = 729.1>

  
for 15 minutes at room temperature. We acidify

  
  <EMI ID = 730.1>

  
with 3 ml of ethyl acetate. The organic extract is rinsed with 1 ml of water and evaporated until a gum (63 mg) is obtained. The raw material (120 mg) prepared in this way is chromatographed on 50 ml of gel

  
silica, using an acetate mixture as eluent

  
  <EMI ID = 731.1>

  
thin-layer chromotography. The first fractions of the column are combined and evaporated to give a gum (78 mg) which crystallizes in chloroform giving the purified product indicated in the title (45 mg; melting point 140-144 [deg.] C).

  

  <EMI ID = 732.1>


  
EXAMPLE 151

  
  <EMI ID = 733.1>

  
100 mg (0.39 = mole) of the product indicated in the title of Example 50 is suspended in 6 ml of chloroform and 100 mg is added in a single portion.

  
  <EMI ID = 734.1>

  
acetamide. After stirring for one minute, add

  
69 mg (0.39 mmol) of N-bromosuccinimide together with traces (a single crystal) of benzoyl peroxide.

  
The mixture is heated to reflux for 2 hours, allowed to cool to room temperature, it is freed from insoluble materials by filtration and evaporated until semi-solid materials are obtained, under a stream of nitrogen. The residue is partitioned between

  
  <EMI ID = 735.1>

  
aqueous, washed with fresh ethyl acetate,

  
  <EMI ID = 736.1>

  
three servings of chloroform. The chloroform extracts are combined, they are dried over sulfate, anhydrous magnesium, they are filtered, they are concentrated until an oil is obtained and the product indicated in the title is obtained, by crystallization from toluene ( 44 mg;

  
  <EMI ID = 737.1>

  
By the same procedure, the fluorinated analog of Example 50 is converted into 5- (5-fluoro-7-

  
  <EMI ID = 738.1>

  
Sodium ethylate is prepared by adding 1.4 g (0.06 mole) of sodium in portions to 50 ml of anhydrous ethanol. The solution is diluted with 20 ml of ethanol and 4.5 g of 2-chloropyridine-3carboxylic acid are added. The reaction mixture is heated in a pressure-resistant steel container at 170 ° C for 6 hours. The container is cooled and its contents are evaporated to dryness under vacuum. The residue is taken up in 150 ml of water and acidified to a constant pH of 4.5. The aqueous solution is saturated with salt and extracted with four portions of ethyl acetate.

  
After having combined the ethyl acetate extraction phases, they are rinsed with brine, they are dried over anhydrous magnesium sulphate, they are filtered and evaporated to obtain 4.33 g of the product indicated in the title, melting at 85-88 [deg.] C. ,

PREPARATION 2

  
  <EMI ID = 739.1>

  
2.8 liters of methanol are successively loaded into a stainless steel autoclave with stirring.
259 g of sodium methylate (in portions, keeping the temperature below 35 ° C) and 190 g of 2chloro-3-pyridinecarboxylic acid. We close the autoclave and

  
the reaction mixture is heated to 110 [deg.] C (gauge pressure of 0.35 MPa) for 48 hours. The reaction mixture is cooled to 25 [deg.] C and discharged from the autoclave. Solids are collected by filtration. By concentrating the filtrate, a second harvest is obtained. These process steps are repeated until almost all of the methanol has been removed.

  
We collect the various solid matter crops,

  
they are taken up in 2.5 liters of water and the solution of concentrated hydrochloric acid is acidified to. pH 2.7 by keeping the temperature below 20 [deg.] C. The product

  
  <EMI ID = 740.1>

  
collected by filtration (141 g). The purified product indicated in the title is obtained by recrystallization from a mixture of ethyl acetate and hexane (120.5 g,

  
  <EMI ID = 741.1>

  
PREPARATION 3

  
2- (6-chloro-8-quinolyl) -2-ethyl oxoacetate

  
We add drop by drop in =: 10 minutes 6 g

  
  <EMI ID = 742.1>

  
  <EMI ID = 743.1>

  
  <EMI ID = 744.1>

  
  <EMI ID = 745.1>
-70 "C. The mixture is still kept for 30 minutes at this temperature and a cold solution (OOC) of diethyl oxalate (14.6 g, 0.10 mole) in 50 ml of tetrahydrofuran is added dropwise We maintain <EMI ID = 746.1>

  
0-5 [deg.] C with 17 ml of acetic acid crystallizable in

  
50 ml of tetrahydrofuran. After warming up to room temperature, the deactivated mixture is poured

  
in 500 ml of water, then diluted with 500 ml of ethyl acetate and 500 ml of saturated sodium bicarbonate. The organic phase is separated, washed with 500 ml of fresh bicarbonate, dried over anhydrous magnesium sulfate, filtered and evaporated until an oil is obtained. By crushing with two portions of
100 ml of hexane, the product indicated in the title is obtained (2.3 g, melting point 107-110 [deg.] C: m / e 265/263).

  
  <EMI ID = 747.1>

  
  <EMI ID = 748.1>

  
  <EMI ID = 749.1>

  
ethanol. After a few minutes, the reaction mixture is diluted with 750 ml of ethyl acetate and

  
750 ml of water. The aqueous phase is extracted with 250 ml of fresh ethyl acetate. The organic phases are combined, they are washed with three 250 ml portions of brine, they are dried over anhydrous magnesium sulfate,

  
they are filtered and evaporated to obtain the product indicated in the title, initially an oil which <EMI ID = 750.1>

  
m / e 267/265).

  
'PREPARATION 5

  
  <EMI ID = 751.1>

  
  <EMI ID = 752.1>

  
product indicated in the titx, triturated in hexane
(1.6 g; melting point 114-117 [deg.] C).

  
PREPARATION 6

  
  <EMI ID = 753.1>

  
Following the procedure of Preparation 4, the product of the previous Preparation is transformed
(1.5 g, 6.1 mmol) in the product indicated in the title. The product initially obtained in the form of a cloudy oil is taken up in ethyl acetate, washed with brine, dehydrated, filtered and evaporated into an oil which rapidly crystallizes (1.23 g, melting point 84 -87 [deg.] C) ..

  
PREPARATION 7

  
  <EMI ID = 754.1>

  
25 g of sodium hydroxide are dissolved in

  
35 ml of water while cooling, 5 g of 6-hydroxyquinoline in 15 ml of chloroform are added and: the reaction mixture is heated to reflux (approximately 90 ° C.) for 12 hours, period during which two more are added 15 ml portions of chloroform - one after two hours and the other after 6 hours. The reaction mixture is cooled and the crude product is collected by filtration. The crude product is dissolved in 125 ml of hot water, the solution is treated with activated carbon, it is filtered hot, it is cooled

  
and acidified with acetic acid, then filtered to obtain the product indicated in the title / 2.5 g; melting point 136-137 [deg.] C; m / e 173; proton / CDCl- magnetic resonance: an aldehyde proton at 10.5 ppm and aromatic protons &#65533; 7.2-9.4 ppm /.

  
PREPARATION 3

  
  <EMI ID = 755.1>

  
The product of the pre-preparation is mixed

  
  <EMI ID = 756.1>

  
  <EMI ID = 757.1>

  
0.83 ml (8.8 mmol) of dimethyl sulfate and the mixture is stirred at room temperature for 16 hours.

  
  <EMI ID = 758.1>

  
  <EMI ID = 759.1>

  
and the mixture is stirred for a further 4 hours at room temperature and then for 3 hours at 60 [deg.] C. We

  
  <EMI ID = 760.1>

  
ambient, the salts are filtered off and the filtrate is evaporated to dryness. The residue is taken up in ethyl acetate, washed successively with two portions

  
  <EMI ID = 761.1>

  
portion of brine, it is dried over anhydrous magnesium sulfate, filtered and evaporated.

  
  <EMI ID = 762.1>

  
(ethyl acetate: chloroform 2: 1); proton / CDC13 / delta magnetic resonance (ppm): 4.2 (s, 3H), 7.4-9.1

  
  <EMI ID = 763.1>

  
'PREPARATION 9

  
  <EMI ID = 764.1>

  
Following the procedure of Preparation 7, 5 g of 7-hydroxyquinoline is transformed into the product indicated in the title (3.3 g, melting point 127-130 [deg.] C;

  
  <EMI ID = 765.1>

  
aldehyde at 10.8 ppm, aromatic protons at 7.0-8.9 ppm.

  
  <EMI ID = 766.1>

  
  <EMI ID = 767.1>

  
Following the procedure of preparation 8, the product of the previous preparation is transformed.
(3.3 g, 19 mmol) in the product indicated in the title

  
  <EMI ID = 768.1>

  
  <EMI ID = 769.1>

  
  <EMI ID = 770.1>

  
6-chlorochroman

  
75 g of zinc foam, 7.5 g of mercuric chloride, 125 ml of water and 4 ml of concentrated hydrochloric acid are mixed, the mixture is shaken for 5 minutes, it is allowed to sediment and the liquids by decantation of the resulting amalgamated zinc. A mixture of 100 ml of water and 126 ml of concentrated hydrochloric acid is added to the metal, then 15 g of S-chloro-4-chromanone and the mixture is refluxed

  
  <EMI ID = 771.1>

  
ambient, it is separated from the sine by decantation and the decanted liquor is extracted with three portions of ether.

  
The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated to an oil.
(14 g). The oil is chromatographed on 400 g of silica gel using a 9: 1 mixture of hexane and ether as eluent, checking by thin layer chromatography and collecting fractions of
15 ml. The clean fractions containing the product are combined and evaporated, giving the indicated product.

  
  <EMI ID = 772.1>

  
magnetic proton nance / CDC13 / delta (ppm) 2, 0 (m, 2H),

  
  <EMI ID = 773.1>

  
  <EMI ID = 774.1>

  
PREPARATION 12

  
  <EMI ID = 775.1>

  
The product of the previous preparation (8.6 g, 0.051 mol) is cooled in a water and ice bath.
75 ml of methylene chloride. Titanium tetrachloride (19.34 g, 11.2 ml, 0.102 mole) is added, followed by dropwise addition of 1,1-dichloromethyl methyl ether (6.2 g, 0.054 mole). The reaction mixture is stirred at 0 [deg.] For 30 minutes, then poured slowly into 400 ml of saturated sodium bicarbonate. The aqueous phase is extracted with three fresh portions of methylene chloride. The combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give the product.

  
  <EMI ID = 776.1>

  
  <EMI ID = 777.1>

  
PREPARATION 13 6-fluorochroman

  
Following the procedures of Preparation 11, 15 g of 6-fluoro-4-chromanone are transformed

  
  <EMI ID = 778.1>

  
  <EMI ID = 779.1>

  
PREPARATION 14

  
  <EMI ID = 780.1>

  
Following the procedures of Preparation 12, the product of the previous Preparation (5.5 g, 0.036 mole) is transformed into the product indicated in the title, initially isolated in the form of a viscous oil which is crystallized in l 'hexane
(3.4 g; melting point 54-57 [deg.] C m / e 180).

  
  <EMI ID = 781.1>

  
  <EMI ID = 782.1>

  
isoxazole-carboxylic for 10 hours in 350 ml of thionyl chloride, then the mixture is stirred at room temperature for 16 hours, clarified by filtration and evaporated to obtain an oil. Oil is repeatedly triturated with hexane

  
  <EMI ID = 783.1>

  
are evaporated to give the acid chloride (16.2 to

  
G) in the form of a solid material.

  
While stirring, the acid chloride prepared as indicated (35 g) is added in portions to 300 ml of hydroxide, of concentrated ammonium at room temperature.

  
.% near granulation for one hour, the product indicated in the title is collected by filtration (24.2 g,

  
  <EMI ID = 784.1>

  
The product of the preceding preparation (5 g) is intimately mixed with 10 g of phosphorus pentoxide and the mixture is introduced into a preheated oil bath.

  
  <EMI ID = 785.1>

  
collects the product indicated in the title by vacuum distillation / 2.9 g, infrared spectrum (film), strip

  
  <EMI ID = 786.1>

  
  <EMI ID = 787.1>

  
The product of the preceding preparation (1.08 g, 0/01 mole) is dissolved in 25 ml of ether and

  
  <EMI ID = 788.1>

  
15 ml of methanol are added dropwise and many

  
  <EMI ID = 789.1>

  
6N hydrochloric acid. We warm the mixture

  
  <EMI ID = 790.1>

  
25 ml of water, then evaporated to obtain an oil.

  
  <EMI ID = 791.1>

  
using a 1: 1 mixture of ether and hexane as eluent. The product fractions are combined and evaporated, giving the product indicated in the title

  
  <EMI ID = 792.1>

  
  <EMI ID = 793.1>

  
PREPARATION 18

  
  <EMI ID = 794.1> (0.6 mole) of potassium carbonate then 95.6 g (0.4

  
  <EMI ID = 795.1>

  
mixture at reflux for 5 hours, then cooled, freed from the salts by filtration and concentrated until an oil is obtained. The oil is distributed between 500 ml of 10% sulfuric acid and 500 ml of ether.

  
The aqueous phase is extracted with two 250 ml portions

  
  <EMI ID = 796.1>

  
combined, they are dried over anhydrous sulfate. magnesium, they are filtered and concentrated until a second oil is obtained. We dissolve this in
400 ml of 10% ethanolic potassium hydroxide, the solution is heated to reflux for one hour and concentrated to dryness. The solids are dissolved in
1500 ml of water, the solution is filtered to remove traces of insoluble matter, it is acidified with hydrochloric acid 68 and the precipitated solids are collected by filtration. The purified product Indicated in the. titer is obtained by resuspending the solid in a liter of water (19 g,.

  
  <EMI ID = 797.1>

  
powder and 50 ml of quinoline and the mixture is heated at reflux for 50 minutes, then cooled to room temperature.

  
  <EMI ID = 798.1>

  
insoluble matter is separated by filtration and the filtrate is washed successively with 5 portions of 200 ml of 2N hydrochloric acid and one portion of brine, dehydrated over anhydrous magnesium sulfate and concentrated

  
  <EMI ID = 799.1> 200 g of silica gel, the eluent used being ether

  
and the collected fractions having a volume of 300 ml.

  
Fractions 1 and 2 are combined and evaporated, giving the product indicated in the title, in the form of an oil (6.1 g).

  
Following the same procedure, the other benzofuran-carboxylic acids of the Preparation are converted

  
  <EMI ID = 800.1>

  
furan.

  
PREPARATION 20

  
  <EMI ID = 801.1>

  
Palladium fixed on carbon (5 12.2 g) in 400 ml of acetic acid is prehydrogenated with the press-

  
  <EMI ID = 802.1> .title of the previous preparation (6.1 g) in 100 ml of acetic acid is added and the hydrogenation is continued until a little more than one equivalent of hydrogen has been consumed . The catalyst is removed <EMI ID = 803.1>

  
is neutralized with saturated potassium carbonate and extracted with four 200 ml portions of ether. The combined extracts are washed with brine,

  
  <EMI ID = 804.1>

  
and evaporated to give an oil. The oil is chromatographed on 400 g of silica gel, 1 <1> eluent used being of, hexane supplemented with 3% ether. The fractions having a volume of 15 ml and the control being carried out by thin layer chromatography. Fractions 70-90 containing the pure product are combined and evaporated to obtain the product indicated in the title

  
  <EMI ID = 805.1>

  
Following the same procedure, we convert

  
  <EMI ID = 806.1>

  
Following the procedure of Preparation 12, the compound, indicated in the title of the previous Preparation (2.1 g), is converted into crude product. contaminated with an isomeric aldehyde. The product: purified indicated in the title is obtained by digestion of

  
  <EMI ID = 807.1>

  
  <EMI ID = 808.1>

  
  <EMI ID = 809.1>

  
Following the same operating mode, the 5-fluoro compound from the previous preparation is converted.

  
  <EMI ID = 810.1>

  
carbaldehyde.

  
By following the operating mode of the. Preparation

  
  <EMI ID = 811.1>

  
ethyl hydroxyacetate. -

  
PREPARATION 22

  
  <EMI ID = 812.1>

  
in 20 ml of benzene and bromination is carried out with

  
  <EMI ID = 813.1>

  
  <EMI ID = 814.1>

  
  <EMI ID = 815.1>

  
  <EMI ID = 816.1>

  
  <EMI ID = 817.1>

  
isolate the product, neutralize the reaction mixture with hydrochloric acid, separate the salts by filtration and evaporate the filtrate to dryness.

  
The alcohol (1 g) is dissolved in 10 ml of methylene chloride and the solution is added dropwise to a suspension of 1.5 equivalent of chloro-

  
  <EMI ID = 818.1> speed of addition using a reflux condenser and optionally cooling in an appropriate bath.

  
The reaction mixture is diluted with ether and the supernatant liquor is separated by decantation and filtration. The product is purified by filtration through a short column of magnesium silicate using ether as the eluent and is isolated by removing the solvent in vacuo.

  
PREPARATION 23

  
3-furaldehyde

  
19.6 g (0.2 mole) are added dropwise

  
  <EMI ID = 819.1>

  
to a suspension of 64.5 g (0.3 mole) of chlorochromate

  
of pyridinium in 450 ml of methylene chloride. The exothermic reaction - which causes a strong reflux, is controlled by possible cooling in an ice bath. After 60 minutes, a solid material

  
gummy precipitated. The reaction mixture is diluted

  
with 600 ml of ether and the supernatant liquor is separated

  
by a mixed decantation and filtration operation.

  
The filtrate is passed over "Florisil" (synthetic magnesium silicate) contained in a short column,

  
using ether as the eluent. The collected fractions are combined and evaporated to give an oil. By distillation of the oil, 3-furaldehyde is obtained (7.6 g; boiling point 68-72 [deg.] C / 40-45 mm).

  
Alternatively, this aldehyde is prepared

  
  <EMI ID = 820.1>

  
  <EMI ID = 821.1>

  
42 ml (0.5 mole) of 2-furaldehyde are mixed,
50 ml (0.9 mole) of ethylene glycol and approximately 200 mg

  
  <EMI ID = 822.1>

  
the mixture is refluxed for 6 hours, collecting the water formed as a by-product in a Dean-Stark separator. The mixture is cooled, diluted with
500 ml of ether and clarified by filtration. The filtrate is washed with 200 ml of saturated sodium bicarbonate and the organic phase is clarified again by filtration. This second filtrate is washed with 200 ml of water and the organic phase is concentrated to dryness, which gives 45 g of 2- (2-furyl) -1,3-dioxolane in the form of an oil.

  
PREPARATION 25

  
  <EMI ID = 823.1>

  
of temperature, butyllithium is added to the hexane
(45 ml, 2.2 M, 0.1 mole) in a 10 minute period.

  
  <EMI ID = 824.1>

  
  <EMI ID = 825.1>

  
hydrofuran. The reaction mixture is allowed to warm to ambient temperature, it is stirred for 1.5 hours,

  
  <EMI ID = 826.1>

  
with 500 ml of water. We extract the product in two times
500 ml of ether and it is collected in the form of an oil (15.8 g) by dry evaporation. The oil is chromatographed on a volume of 200 ml of silica gel using an 8: 1 mixture of hexane and ethyl acetate as eluent and checking by thin layer chromatography on silica gel with the same eluent. The first fractions containing the product

  
  <EMI ID = 827.1>

  
2-furyl) -1,3-dioxolane purified, in the form of an oil

  
  <EMI ID = 828.1>

  
  <EMI ID = 829.1>

  
5-chloro-2-furaldehyde

  
  <EMI ID = 830.1>

  
dioxolane in 20 ml of ether. 10 ml of 6N hydrochloric acid are added and the mixture of two phases is stirred for one hour at room temperature. The ether phase is separated, washed with water and evaporated to give 5-chloro-2-furaldehyde in the form of an oil (2.8 g).

  
PREPARATION 27

  
  <EMI ID = 831.1>

  
20 g of 5-bromo-2-furoic acid are refluxed for 3 hours with 60 ml of thionyl chloride and the corresponding acid chloride is isolated in the form of an oil by concentration. Acid chloride is added dropwise to 150 ml of hydroxide

  
  <EMI ID = 832.1>

  
filtration 17.0 g of 5-bromo-2-furylcarboxamide, flux

  
  <EMI ID = 833.1>

  
PREPARATION 28

  
  <EMI ID = 834.1>

  
10 g of 5-bromo-2-furylcarboxamide are mixed with 50 ml of phosphorus oxychloride and the mixture is heated at reflux for 24 hours. The mixture is poured onto ice, the product is extracted into ether and the 5-bromo-2-furyl- is thus obtained by evaporation.

  
  <EMI ID = 835.1>

  
PREPARATION 29 5-bromo-2-furaldëhyde

  
  <EMI ID = 836.1>

  
furylcarbonitrile in 50 ml of ether and the solution is cooled to -10 [deg.] C under a nitrogen atmosphere. 1.9 g (13 mmol) of diisobutyl aluminum hydride are added dropwise in the form of a 25% solution in

  
  <EMI ID = 837.1>

  
The reaction mixture is allowed to warm to room temperature and is stirred for about 6 hours. The reaction mixture is cooled.

  
  <EMI ID = 838.1>

  
acidifies it with 3N hydrochloric acid, it is washed

  
&#65533; water and evaporate to obtain 1.2 g of 5-bromo-

  
  <EMI ID = 839.1>

  
PREPARATION 30

  
  <EMI ID = 840.1>

  
  <EMI ID = 841.1>

  
phosphorus to 5.4 g (70 mmol) of dimethylformamide

  
  <EMI ID = 842.1>

  
with 10 ml of dichlorethylene. Maintaining the mixture

  
  <EMI ID = 843.1>

  
furan. The reaction mixture is then heated to
58-60 [deg.] C for one hour and then cooled again to 10 [deg.] C. 15 g of sodium acetate trihydrate dissolved in 25 ml of water are slowly added, with proper stirring and keeping the temperature between 10 and 30 [deg.] C.

  
The mixture is again heated to 68-72 [deg.] C for 20 minutes, allowed to cool to room temperature and diluted with 20 ml of water. We extract the product

  
  <EMI ID = 844.1>

  
then it is concentrated to obtain 3-bromo-2-furaldehyde

  
  <EMI ID = 845.1>

  
ethyl acetate 3: il.7.

  
PREPARATION 31

  
3-iodofuran

  
Cooled to -70 ° C. 14.7 g (0.1 mole) of 3bromofuran in 10 0 ml of ether. Butyllithium (42 ml, 2.4M, 0.1 mol) in hexane is added dropwise over 0.5 hour while maintaining the temperature between <EMI ID = 846.1>

  
mole) in 200 ml of ether in one hour, maintaining the same temperature range. The reaction mixture is allowed to warm to room temperature, then cooled again to 2 [deg.] C. 100 ml of water are added dropwise. The ether phase is separated, washed with aqueous thiosulfate and then with water,

  
it is dried over anhydrous sodium sulfate,

  
  <EMI ID = 847.1>

  
this oil to obtain 3-iodofuran (15.7 g, period

  
  <EMI ID = 848.1>

  
PREPARATION 32 3-Methoxyfuran

  
5.6 g (0.24 mol) of metallic sodium are dissolved in 150 ml of anhydrous methanol. 15.7 g (0.08 mole) of 3-iodofuran and 8 g (0.1 mole) of cuprous oxide are added and the mixture is refluxed with vigorous stirring for 42 hours. The reaction mixture is cooled

  
at room temperature, it is diluted with 200 ml of water and the product is extracted into 100 ml of ether. The sentence

  
  <EMI ID = 849.1>

  
drated on anhydrous sodium sulfate and evaporated in

  
  <EMI ID = 850.1>

  
  <EMI ID = 851.1>

  
subsequent.

  
PREPARATION 33

  
  <EMI ID = 852.1>

  
tion at -40 [deg.] C. Butyllithium in hexane (4.5 ml, 2.2 M) is added over 3 minutes while maintaining the temperature.

  
  <EMI ID = 853.1>

  
  <EMI ID = 854.1>

  
between -40 and -30 [deg.] C. The reaction mixture is allowed to warm to room temperature and is maintained there

  
  <EMI ID = 855.1>

  
deactivate it with 6 ml of 6N hydrochloric acid,

  
  <EMI ID = 856.1>

  
purified dehyde (0.9 g, melting point 90-92 [deg.] C) is obtained by recrystallization from about 35 ml of hexane.

  
PREPARATION 34

  
  <EMI ID = 857.1> <EMI ID = 858.1>

  
butyllithium in hexane (34.8 ml of 2.1M solution, 0.073 mole). After stirring for 5 minutes at -70 ° C., the solution is transferred, by means of a "Nylon" tube under nitrogen pressure, to a solution of

  
6.8 g (0.093 mole) of dimethylformamide in 35 ml of ether, The resulting mixture is heated under reflux for 2 hours, it is allowed to cool to room temperature, it is washed successively with two portions

  
  <EMI ID = 859.1>

  
saturated sodium and a portion of brine, it is dried over anhydrous magnesium sulphate, filtered and concentrated to obtain an oil. The oil is distilled twice to obtain 5.7 g of 4-bromo-

  
  <EMI ID = 860.1>

  
192/190).

  
PREPARATION 35

  
  <EMI ID = 861.1>

  
46.5 g (0.5 mole) of aniline are mixed with
500 ml of water and 100 ml of concentrated hydrochloric acid

  
  <EMI ID = 862.1>

  
(0.525 mole) of sodium nitrite in 100 ml of water drop by drop over 45 minutes, keeping the temperature

  
  <EMI ID = 863.1>

  
  <EMI ID = 864.1>

  
68 g of chlorinated zinc. The maximum precipitation of the diazonium salt is obtained by the addition of 100 g of sodium chloride. The mixture is stirred for 5 minutes, the cooling bath. having been removed, and it is carefully filtered, without washing, then air dried for 2 hours. (Prior drying of this product

  
under vacuum led to explosive decomposition). The

  
intermediate diazonium salt is suspended in

  
  <EMI ID = 865.1>

  
add 5 g of powdered sodium hydroxide, then 10 g of anhydrous sodium acetate. The reaction mixture is stirred

  
product is collected in a Dean and Stark separator. Thin layer chromatography (ethyl acetate: hexane 1: 8) indicates a degree of reaction

  
  <EMI ID = 866.1> room temperature. The solid material is collected by filtration and the filtrate is evaporated to obtain the crude product (25 ml of oil). 9.2-9.6 g of 1-phenylfuran are obtained by distillation (boiling point 87-95 [deg.] /
15 mm, boiling point 50 [deg.] / 1 mm).

  
PREPARATION 36

  
  <EMI ID = 867.1>

  
19 g (0.1 mole) of 2-benzoylthiophene, 11 ml are mixed and heated under reflux for 6 hours.

  
  <EMI ID = 868.1>

  
  <EMI ID = 869.1>

  
  <EMI ID = 870.1>

  
continues to heat at reflux for 35 hours. The reaction is still incomplete. The reaction mixture is diluted with 200 ml of ether, it is washed twice with

  
  <EMI ID = 871.1>

  
The residue is chromatographed on approximately 500 ml of silica gel using a 1: 8 mixture of ethyl acetate and hexane as eluent and a check is carried out by thin layer chromatography. Fractions containing

  
  <EMI ID = 872.1>

  
  <EMI ID = 873.1>

  
ethyl: hexane 1:87.

  
  <EMI ID = 874.1>

  
methyl (United States patent n [deg.] 3,144,235)

  
  <EMI ID = 875.1>

  
of methanol containing 0.31 ml of concentrated sulfuric acid. The mixture is refluxed for 4 days, then neutralized with 0.6 g of sodium acetate and the solvent is removed by evaporation. The residue is taken up in 200 ml

  
  <EMI ID = 876.1> <EMI ID = 877.1>

  
  <EMI ID = 878.1>

  
50 ml of brine, dehydrated over anhydrous magnesium sulphate, filtered and evaporated giving an oil which crystallizes on standing (4.35 g; melting point 64-66 "C).

  
When this reaction mixture is only treated after one day, only a low yield (2.2 g) of the desired product is obtained. The two extraction phases with sodium hydroxide IN are combined and acidified, which causes 5.13 g of 4-hydroxy to precipitate.

  
  <EMI ID = 879.1>

  
in 100 ml of methanol containing 0.3 ml of concentrated sulfuric acid and the solution is heated to reflux for 3 days, the above treatment gives 2.10 g of the product indicated in the title, melting at 64-66 [ deg.] C.

  
PREPARATION 38

  
  <EMI ID = 880.1>

  
methyl thenoate (patent of the United States of America

  
n [deg.] 4 144 235) in 5Q ml. of toluene and the solution is cooled in an acetone and dry ice bath. 46 ml of hydride are added dropwise over 30 minutes

  
  <EMI ID = 881.1>

  
stir the mixture for a further 2 hours at bath temperature, then allow it to warm to room temperature. Keeping the temperature below

  
  <EMI ID = 882.1>

  
methanol. The mixture is then stirred for 16

  
hours at temperature: room, period during which a granular precipitate is formed. The mixture

  
is filtered through diatomaceous earth and washed with methanol. The combined filtrate and washing liquors are concentrated, giving the product indicated in the title, in the form of an oil (2.8 g, m / e 144).

  
PREPARATTON 39

  
  <EMI ID = 883.1>

  
6.4 g (29.7 mmol) of pyridinium chlorochromate are dissolved in 100 ml of methylene chloride and the solution obtained is added in a single portion to

  
a solution of the product of the previous example (2.8 g,

  
19.8 mmol) also in 100 ml of methyl chloride

  
  <EMI ID = 884.1>

  
ambient for 3 hours, diluted with 200 ml of ether and separated from the black precipitate by decantation.

  
The precipitate is washed with two 100 ml portions of ether.

  
After having collected the decanted liquor and the washing liquors, the mixture is filtered and washed successively

  
  <EMI ID = 885.1>

  
of water, two portions of IN sodium hydroxide and one portion of brine, it is dried over anhydrous magnesium sulfate, filtered and concentrated to obtain the product indicated in the title, in the form of a

  
  <EMI ID = 886.1>

  
  <EMI ID = 887.1>

  
PREPARATION 40

  
  <EMI ID = 888.1>

  
Following approximately the procedure of US Patent No. 4,144,235, 20 g of methyl 4-acetoxy-3-thenoate are dissolved in

  
  <EMI ID = 889.1>

  
concentrated. The reaction mixture is refluxed moderately for 79 hours, then neutralized with 1.2 g of sodium acetate and evaporated to obtain an oil. The latter is distributed between 400 ml of ether

  
and 50 ml of water. We separate the organic phase and we

  
wash successively with 75 ml of water, three portions of

  
  <EMI ID = 890.1>

  
of brine, it is dried over anhydrous magnesium sulfate, filtered and evaporated to obtain the product indicated in the title in the form of an oil 14 14.9 g, the magnetic resonance spectrum of protons indicates that it is entirely the ethyl ester and not the methyl ester%.

  
PREPARATION 41

  
  <EMI ID = 891.1>

  
Following the procedure of the Preparation
38, the product from the previous Preparation is converted
(14 g) into the product indicated in the title, in the form of an oil (9.15 g).

  
PREPARATION 42

  
  <EMI ID = 892.1>

  
Following the procedure of the Preparation
39, the product of the previous Preparation is converted
(9.15 g) of the product indicated in the title, initially isolated in the form of an oil which rapidly crystallizes

  
  <EMI ID = 893.1>

  
  <EMI ID = 894.1>

  
  <EMI ID = 895.1>

  
  <EMI ID = 896.1>

  
Following the procedure of the Preparation
40, and using a reaction reflux time of
10 days, 6 g of methyl 4-acetoxy-3-thenoate in 750 ml of 1-propanol containing 0.19 ml of concentrated sulfuric acid are transformed into the product indicated in

  
  <EMI ID = 897.1>

  
  <EMI ID = 898.1>

  
Following the procedure of the Preparation
38, the product of the previous preparation is reduced
(5.4 g) to the title compound, which is isolated as an oil (3.44 g; m / e. 172).

  
  <EMI ID = 899.1>

  
  <EMI ID = 900.1>

  
Following the procedure of the Preparation
39, the product of the previous preparation is converted

  
  <EMI ID = 901.1>

  
  <EMI ID = 902.1>

  
  <EMI ID = 903.1>

  
  <EMI ID = 904.1> <EMI ID = 905.1>

  
concentrated and the mixture is refluxed for 21 hours.

  
The reaction mixture is evaporated until an oil is obtained which is taken up in 500 ml of ether, washed

  
  <EMI ID = 906.1>

  
  <EMI ID = 907.1>

  
anhydrous magnesium sulfate and evaporated to obtain the product indicated in the title in the form of an oil (7.8 g; m / e 200; magnetic resonance of the protons /

  
  <EMI ID = 908.1>

  
is contaminated with a small amount of the methyl ester <EMI ID = 909.1>

  
The product of the previous preparation (7.8 g,

  
  <EMI ID = 910.1>

  
of toluene and the solution is cooled to -78 [deg.] C. Diisobutyl hydride is added dropwise over 40 minutes.

  
  <EMI ID = 911.1>

  
  <EMI ID = 912.1>

  
warm to room temperature and stir for another 16 hours. 25.0 g (31.6 ml, 0.78 mole) of methanol are added dropwise to the reaction mixture while maintaining the temperature below 30 ° C. After stirring for 1.5 hours at room temperature,

  
the reaction mixture is clarified by filtration through

  
  <EMI ID = 913.1>

  
resuspension of the cake and finally washing with methylene chloride. After collecting the filtrate and the washing liquors, the mixture is dried over anhydrous magnesium sulfate, filtered and evaporated to obtain 5.56 g of the product indicated in the title,

  
  <EMI ID = 914.1>

  
  <EMI ID = 915.1>

  
PREPARATION 48

  
  <EMI ID = 916.1> Following the procedure of the Preparation

  
39 .. the product from the previous Preparation is converted

  
  <EMI ID = 917.1>

  
0.36 (chloroform) /.


    

Claims (1)

 <EMI ID = 918.1> 1. Racemic or optically active compound of formula  <EMI ID = 919.1> in which  <EMI ID = 920.1>  <EMI ID = 921.1> R represents (a) a group of formula  <EMI ID = 922.1>  <EMI ID = 923.1>  <EMI ID = 924.1>  <EMI ID = 925.1> (b) a remainder of formula:  <EMI ID = 926.1>  in which Y is hydrogen or an alkoxy radical  <EMI ID = 927.1>  <EMI ID = 928.1> (c) a remainder of formula:  <EMI ID = 929.1> in which Z 'is hydrogen, a halogen radical or  <EMI ID = 930.1> halogen? (d) a remainder of formula:  <EMI ID = 931.1>  <EMI ID = 932.1> (e) a remainder of formula:  <EMI ID = 933.1> where Q is sulfur- or oxygen and V is  <EMI ID = 934.1> (f) a remainder of formula:  <EMI ID = 935.1>  <EMI ID = 936.1>   <EMI ID = 937.1>  <EMI ID = 938.1> wherein Y is sulfur or oxygen; X is  <EMI ID = 939.1>  <EMI ID = 940.1> the methyl radical; and X is hydrogen or the halo radical;  <EMI ID = 941.1> ble of this compound when R is hydrogen? or a pharmaceutically acid addition salt  <EMI ID = 942.1> basic nitrogen. 2. Compound according to claim 1, in  <EMI ID = 943.1>  <EMI ID = 944.1>  <EMI ID = 945.1> or a chlorine or fluoro radical. 3. A compound according to claim 1, in which R corresponds to the formula:  <EMI ID = 946.1> where W is a chlorine or fluoro radical and n is equal to 1 or 2. '  <EMI ID = 947.1> which R is a remainder of formula:  <EMI ID = 948.1>  <EMI ID = 949.1>  <EMI ID = 950.1>  <EMI ID = 951.1>  <EMI ID = 952.1>  <EMI ID = 953.1>  <EMI ID = 954.1>  <EMI ID = 955.1>  <EMI ID = 956.1>  <EMI ID = 957.1>  <EMI ID = 958.1>  <EMI ID = 959.1> R represents: (a) a remainder of formula:  <EMI ID = 960.1>  <EMI ID = 961.1> phenyl; (b) a remainder of formula:  <EMI ID = 962.1> wherein W is hydrogen or a halogen radical and n is 1 or 2; (c) a remainder of formula:  <EMI ID = 963.1>  <EMI ID = 964.1>  <EMI ID = 965.1>  <EMI ID = 966.1>  <EMI ID = 967.1>  wherein Y is sulfur or oxygen; X is hydrogen, a halo, methyl, phenyl radical,  <EMI ID = 968.1>  <EMI ID = 969.1> halogëno. 8. Compound of formula:  <EMI ID = 970.1> in which R 9 and R6 have the definitions given above. 9. Compound of formula:  <EMI ID = 971.1>  <EMI ID = 972.1> 10. Compound of formula:  <EMI ID = 973.1>  <EMI ID = 974.1> or a benzoyl radical and R <1> has the definition given above. 11. Compound of formula:  <EMI ID = 975.1>  in which R is hydrogen, an alkyl radical  <EMI ID = 976.1> above. 12. Compound of formula:  <EMI ID = 977.1> in which R has the definition given above. 13. Compound of formula:  <EMI ID = 978.1> in which R <1> and R <2> have the definitions given above. 14. Compound of formula:  <EMI ID = 979.1>  <EMI ID = 980.1> above. 15. A method of lowering the blood glucose level in a hyperglycemic mammal, which comprises administering an amount, lowering blood glucose, of a racemic or optically active compound according to claim 1.