CS237347B2 - Processing of racemic or optically active 5-substituted oxazolidine-2,4-dione - Google Patents

Description

The invention relates to a process for the preparation of novel oxazolidine-2,4-dione derivatives; in particular, a process for preparing certain 5-furyl-, 5-thienyl-, 5-pyrrolyl-, 5-indolyl-, 5-thiazolyl- and 5-benzothiazolyl derivatives of oxazolidine-2,4-dione useful as hypoglycemic agents.

Despite the earlier discovery of insulin and its subsequent extensive use in the treatment of diabetes and the more recent discovery and use of sulfonylureas (e.g. chlorpropamide, tolbutamide, acetohexamide and tolazamide) and biguanides (e.g. phenformin) as orally administrable hypoglycemic agents . The use of insulin, required for a high percentage of diabetics in whom existing synthetic hypoglycaemic agents are not effective, requires multiple daily injections, which are usually performed by the patient himself. Determination of the appropriate insulin dosage requires frequent determination of the sugar content in urine or blood. Administration of too high a dose of insulin leads to hypoglycaemia, which may result in mild abnormalities in blood glucose levels, but also coma or even death. In cases where they are effective, synthetic hypoglycaemic agents are preferable to insulin, which are easier to administer and less likely to cause severe hypoglycaemic reactions. Unfortunately, clinically useful hypoglycaemic agents exhibit other manifestations of toxicity that limit their use. In general, however, if any of these agents fail in an individual case, the other agent may be successful in that case. From the above, it is apparent that there is a continuing need for hypoglycemic agents that are less toxic or successful if other agents fail.

In addition to the aforementioned hypoglycemic agents, a number of other compounds exhibiting this type of activity have been described, as Blank recently summarized [See Burger's Medicinal Chemistry, 4th Edition, Part II, John Wiley and Sons, NY (1979), p. 1057 to 1080].

The oxazolidine-2,4-diones of the present invention are novel compounds, despite the fact that o) xazolidine-2,4-diones are widely known as a group of compounds [for a comprehensive review of these compounds, see Clark-Lewis, Chem. Roar. 58, pp. 63-99 (1958)]. Known compounds belonging to this group include 5-phenyloxazolidine-2,4-dione, variously described as an intermediate for the manufacture of certain antibacterial / β-lactam type agents (see U.S. Patent No. 2,721,197), as an antidepressant agent (see U.S. Patent No. 5,950,167). No. 3,699,229) and as an anticonvulsant agent [see Brink and Freeman, J. Neuro. Chem. 19 (7), 1783-1788 (1972)], and a series of 5-phenyloxazolidine-2,4-dione substituted on the phenyl ring, such as 5- (4-methoxyphenyl) oixazolidine-2,4-dione [see King and Clark-Lewis, J. Chem. Soc., Pp. 3077-3079 (1961)], 5- (4-chlorophenyl) oxazolidine-2,4-dione [see Najer et al., Bull. soc. chim. France, pp. 1226-1230 (1961)], 5- (4-methylphenyl) oxazolidine-2,4-dione [see Reibsomer et al., J. Am. Chem. Soc. 61, pp. 3491-34 (1939)] and 5- (4-aminophenyl) oxazolidine-2,4-dione (see German Patent No. 108,026), as well as 5- (2-pyrryl) oxazolidine-2,4 -dione [see Ciamacian and Silber, Gazz. chim. Italian. 16, 357 (1886); Ber. 19, 1708-1714 (1886)]. The latter compound, for which no use is known so far, exhibits only relatively poor hypoglycemic activity (see Table I below).

Oxazolidine-2,4-dione and substituted oxazolidine-2,4-diones (specifically 5-methyl-a

5,5-dimethyl derivative) have already been described as acidic residues suitable for the preparation of acid addition salts of hypoglycemically active basic biguanides [see U.S. Patent No. 2,961,377]. It has now been found that neither oxazolidine-2,4-dione nor 5,5-dimethyloxazolidine-2,4-dione alone has the hypoglycemic activity of the compounds of the invention.

Recently, a group of spirooxazolidine-2,4-dione derivatives have been described which act as aldose reductase inhibitors and are thus useful in the treatment of certain complications of diabetes (see U.S. Patent No. 4,200,642).

A process for the synthesis of 3-aryloxyzolidine-2,4-diones (wherein the aryl group contains 6 to 12 carbon atoms and is optionally substituted with one or more halogen atoms, methyl or methoxy groups) is the subject of another recent patent (see U.S. Patent No. 4). 220,787). The utility of these compounds is not specified.

The present invention provides a process for the preparation of racemic or optically active 5-substituted oxazolidine-2,4-dione derivatives of the general formula I

in which

R is hydrogen, C1 -C4 alkanoyl (e.g. formyl, acetyl or isobutyryl), benzoyl, C2 -C4 alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl or isopropoxycarbonyl), C1 -C3 alkylcarbamoyl carbon atoms in the alkyl moiety (e.g., N-methylcarbamoyl or N-propylcarbamoyl), cycloalkylcarbamoyl of 5 to 7 carbon atoms in the cycloalkyl moiety (e.g., N-cyclohexylcarbamoyl), or a dialkyl237347 carbamoyl group containing 1 to 3 carbon atoms in each alkyl moiety (e.g., Ν, Ν-dimethylcarbamoyl), and

R 1 is either a radical of formula (i)

a) hydrolyzes the compound of formula 11

where

R‘ represents an alkyl group having 1 to 4 carbon atoms or a phenyl group,

R 1 represents a hydrogen atom, a C 1 -C 4 alkyl group or a phenyl group;

X represents a halogen atom, or R 1 represents a radical of formula (ii)

where

Q represents a hydrogen atom or a C 1 -C 3 alkyl group, or R 1 represents a radical of formula (iii)

'Ъ

OF/

O (II) in which

R1 is as defined above and

R 4 represents a hydrogen atom, a lower alkanoyl group or a benzoyl group to give a compound of formula '111'

in which

R1 is as defined above, whereupon optionally

b) resolving the racemic compound of formula (111) above into the optically active enantiomers by separating the diastereomeric salts prepared with the optically active amine and regenerating the optically active compounds of formula (111) by acidification, and / or

c) acylating the resulting compound of the above formula 111 with an acid chloride of the formula

R ² -Cl in which

R ² represents an alkanoyl group having 1 to 4 carbon atoms, a benzoyl group, an alkoxycarbonyl group having 2 to 4 carbon atoms, an alkylcarbamoyl group having 1-3 carbon atoms in the alkyl moiety, cykloalkylkarbamoylovou group having 5-7 carbon atoms in the cycloalkyl part or dialkylcarbamoyl each having 1 to 3 carbon atoms in each alkyl moiety, or a corresponding anhydride or isocyanate, to form a compound of formula 1V in which:

where

Y is sulfur or oxygen,

X is hydrogen, halogen, methyl, phenyl, benzoyl or C 1 -C 3 alkoxy; and

^X 'is hydrogen or methyl, and pharmaceutically acceptable cationic salts of those compounds in which R is hydrogen and pharmaceutically acceptable acid addition salts of those compounds in which R 1 contains a basic nitrogen function, wherein

R 1 and R ² are as defined above, and / or se

d) converting the resulting compound of formula III into its pharmaceutically acceptable cationic salt, and / or

e) converting the resulting compound of formula I containing a basic nitrogen in the residue R1 into its acid addition salt.

Compounds produced by the process of the invention when R 1 is as defined in (i) above include the corresponding 2 or 3-pyrrolyl and indolyl derivatives; when R 1 is as above in (ii), the corresponding thiazolyl and benzothiazolyl derivatives and those in which R 1 is the radical mentioned in (iii) above, when X 1 is hydrogen, include the entire set of 5- (2-furyl), 5- (3-furyl) -, 5- (2-thienyl) - and 5- (3-thienyl) oxazolidine-2,4-dione derivatives, wherein substituent X may be attached at any unoccupied carbon atom of the thiophene ring, i.e. a compound of formula ox wherein:

X and Y are as defined above and

Ox represents an oxazolidine-4-dione ring bonded at the 5-position, and when X and X1 are other than hydrogen, the second substituent may be bonded at any free position of any of the six residues.

The invention also includes pharmaceutically acceptable cationic salts of those compounds of formula I wherein R is hydrogen, and pharmaceutically acceptable acid addition salts of those compounds wherein R 1 contains a basic nitrogen group.

It is believed that the high activity characteristic of these substances is primarily due to those compounds in which R represents a hydrogen atom, and that those compounds in which R represents any of the series of carbonyl derivative residues defined above are so-called precursors. of these drugs from which the carbonyl side chain is cleaved by hydrolysis under physiological conditions to give the corresponding fully active compounds wherein R is hydrogen.

The term "pharmaceutically acceptable cationic salts" refers to such salts as the alkali metal salts (e.g. salts

sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts), aluminum salts, ammonium salts and organic salts. amines such as benzathine (N, N'-dibenzylethylenediamine), choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), benethamine (N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethylamine) -propanediol), procaine and the like.

The term "pharmaceutically acceptable acid addition salts" refers to such salts as hydrochlorides, hydrobromides, hydroiodides, nitrates, hydrogen sulphates, dihydrogen phosphates, mesylates, maleates, succinates and the like.

The compounds of the invention exhibit hypoglycaemic activity which allows them to be used clinically to lower blood glucose levels of hyperglycemic mammals, including humans, to normal levels. A particular advantage of the disclosed compounds is that they lower blood glucose levels to normal without causing hypoglycaemia. The compounds of the invention were tested for hypoglycemic (antihyperglycemic) activity in rats using the so-called glucose tolerance test, described in more detail below.

Because of their higher hypoglycaemic activity, those compounds in which R is hydrogen and pharmaceutically acceptable salts thereof are preferred. OF . of the compounds of formula I in which R is hydrogen, the following compounds are most preferred because of their excellent hypoglycemic activity:

5- [1-Methyl-2-pyrrole-1-yl] -ocyanate-2,4-dimethyl,

5- [1-ethyl-2-pyrrolidinyl] oxazolidin-2,4-dione;

5- (i-phenyl-2-pyrrolinyl) oxazolidin-2,4-dione,

5- (4-Benzothiazolyl) oxazolidin-2,4-dione;

5- (2-thiazolyl) oaazolidine-2,4-dione,

5- (3-thienyl) oxxzondine-2,4-dione,

5- (4-bromo-3-thienyl) oaazolidine-2,4-dione;

5- (4-thoay-3-thienyl) oaazolidin-2,4-dione;

5- (4-ethoay-2-methyl-3-phenyl) oxazolidin-4-one,

5- (4-methoxy-2-methyl-2-methyl-iodo-2,4-dione),

5- (3-methyl-2-thienyl) oxazolidin-2,4-dione,

5- (3-Methoxy-2-thienyl) oxazolidine-2,4-dione;

5- (3-furyl) oxazolidine-2,4-dione,

5- (2-furyl) o-azolidin-2,4-dione,

5- (3-bromo-2-furyl) oxazolidin-2,4-dione;

5- (5-chloro-2-furyl) oxazolidine-2,4-dione.

In accordance with the invention, the dialuric acid or acyidiauric acid of formula II is readily converted under the slightly basic conditions to the desired oxazolidine-2,4-dione of formula I.

Methods suitable for preparing the starting dialuric acids (II) are shown in the following reaction scheme, wherein R ¹ , R ² and R ⁴ are as defined above and M is lithium, MgCl, MgBr, Mgl or other suitable metal.

GOOR ²

J и <--- R. Or - RM * ₁

COOR (VI)

COOR ^Z

R <CH ¹ λ

COOR ² (A)

The general process for the preparation of the dialuric acids of formula (II) suitable as precursors of the o-xazo-lidine-2,4-dione of the invention is based on malonic acid esters (V) and comprises two. base-catalyzed condensation with urea. If the first reaction step is an oxidation, then the intermediate is a so-called tartronic acid derivative of the formula VI, while the first step of the condensation is a so-called barbituric acid of the formula VII . If R 1 contains an amine function (for example a 2-aminophenyl residue), it is preferred to carry out the oxidation in the first step, avoiding possible complications of nitrogen oxidation. If the condensation is carried out as a second step, then the dialuric acid is usually not isolated, at least not in pure form, and is directly converted further. basic condensation reaction conditions for oxazolidin-2,4-diolium.

Esters of substituted malonic acids,. Needed for top. the syntheses described, are either commercially available or are prepared by procedures described in the literature, such as by alcoholysis of the α-k-anesther [see Steele, J. Am. Chem. Soc. 53, 286 (1993)], alkoxycarbonylation of esters [see Hornlng and Finelli, Org. Syntheses 30, 43 (1950)] and the decarbonylation of α-keto esters obtained by condensation of dlalkyloxalate with carboxylic acid esters [Reichstein and Morsman, Helv. Chim. Acta. 17, 1123 (1934); Blicke and Zienty, J. Am. Chem. Soc. 63.2946. (1941)].

A somewhat less general method of preparing the corresponding intermediate dialuric acid is by reacting electron-rich heteroaryl or aryl compounds, for example according to the schemes:

At present, there is yet another method of preparing certain intermediate dialuric acids. This method, which is advantageous when the starting materials are readily available, consists in reacting the alloxane (preferably in the anhydrous state) with an appropriate organometallic derivative (e.g. organolithium or Grignard reagent). As an example is. the following reaction can be mentioned:

If this procedure is used to prepare oxazolidine-2,4-dio (s) in which R 1 carries a substituent entering into reaction with organometallic reagents, appropriate protection is required, for example, the acyl group is protected in the form of an ethylene ketal moiety. in other cases, such as when R 1 carries, for example, nitro or amino, this method is not applicable at all.

It will be understood that the advantage of any process for preparing the oxazolidine-2,4-diones according to the invention depends on the particular R 1 moieties as well as other factors such as the availability of the starting materials, the yields achieved, end products, the chemical nature of the substituents contained in the end products, and the like.

The pharmaceutically acceptable cationic salts of the compounds of the invention that form these salts are readily prepared by reacting the acid form of the compound with the appropriate base, usually one equivalent of the base, in a co-solvent. Typical bases include sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium methoxide, magnesium hydroxide, calcium hydroxide, benzathine, choline, diethanolamine, ethylenediamine, meglumine, benethamine, diethylamine, piperazine and tromethamine. Those salts that do not precipitate directly are isolated by concentrating the reaction mixture to dryness or by adding a non-solvent. In some instances, the desired salts may be prepared by mixing the acid solution with a solution of a cationic salt of another acid (e.g., sodium ethylhexanoic acid or magnesium oleic acid) using a solvent from which the desired cationic salt precipitates, resulting in a salt. of course, it can also be isolated by other means, such as by concentrating the reaction mixture and adding a non-solvent.

The pharmaceutically acceptable acid addition salts of those compounds of the invention which form such salts are readily prepared by reacting the corresponding compound in base form with the appropriate acid, usually one equivalent of the acid, in a co-solvent. Typical acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, maleic acid, succinic acid, etc. Those salts that do not precipitate directly are isolated by concentration, the reaction mixture to the or by adding a non-solvent.

The 3-acylated derivatives of the invention are readily prepared using standard acylation conditions, for example by reaction of the oxazolidine-2,4-dione salt [as such or conveniently prepared in situ by adding one equivalent of a tertiary amine such as triethylamine or N-methylmorpholine to the equivalent of chloride or the anhydride of the appropriate acid) or oxazolidine-2,4-dione with the appropriate organic isocyanate, optionally in the presence of a catalytic amount of a tertiary amine base. In each of these cases, the reaction is carried out in an inert solvent such as toluene, tetrahydrofuran or methylene chloride. Temperature is not critical and can be varied within wide limits (e.g., from 0 to 150 ° C). It is understood that this acylation may be complicated by competitive or even selective acylation of the side chain (R1) if the side chain contains a primary or secondary amine function.

It will be appreciated that the compounds of the invention are asymmetric and may therefore exist in two optically active enantiomeric forms. Those racemic compounds of the invention that are acidic (R-hydrogen) form salts with organic amines. Thus, such racemic forms can generally be resolved into the optically active forms by the classical method of preparing diastereomeric salts with optically active amines, which salts can be separated by selective crystallization. Alternatively, compounds containing a basic amine function can be resolved by converting such a compound to an optically active acid salt, preferably (glucose content of the control group) - (glucose content of the

Clinically useful hypoglycaemic agents are effective in this test. The hypoglycaemic activity values measured for the compounds of the invention are summarized in the following Table I. This table shows the percent glucose reduction after 0.5 hours and 1 hour. By a strong organic acid such as sulfonic acid. In general, one of the enantiomeric forms always has a higher potency than the other.

The reactions used to prepare the compounds of the invention can generally be monitored by standard thin layer chromatography methods using commercially available plates. Suitable eluents include conventional solvents, such as chloroform, ethyl acetate or hexane, or combinations thereof, which distinguish between starting materials, products, by-products and in some cases intermediates. The application of these methods, which are all well known, will allow further improvements in the methodology of the specific examples below, such as the selection of more optimal reaction times and temperatures, and will help in the selection of optimal procedures.

The oxazolidine-2,4-diones of the invention may be used clinically as antidiabetic agents. The glucose tolerance test described below demonstrates the hypoglycaemic efficacy required for this clinical use.

Intact male white rats are used as test animals. The test animals are fasted for approximately 18 to 24 hours, then weighed, numbered and divided into groups of 5 or 6 animals, as appropriate. Glucose (1 g / kg) is then administered intraperitoneally to each group of animals, and either water (control) or test compound is administered orally at a dose ranging from 0.1 to 100 mg / kg orally. Blood samples are taken from the tails of both control and treated animals for 3 hours to determine the glucose content (mg / 100 ml). At time 0 the blood glucose content of the control and treated animals is the same. The% glucose reduction after 0.5 hours, 1 hour, 2 hours and 3 hours is calculated according to the following formula:

glucose content in the treated group)

In general, a 100% glucose content of 9% or more generally represents a statistically significant hypoglycemic efficacy in this test. For those compounds which show significant activity after · 2 · or 3 hours, this activity is indicated in the notes.

control groups)

Hypoglycemic efficacy of oixazolidine-2,4-dione in glucose tolerance test (rat)

Tab u lk a 'l

Ar dose (mg / kg) reduction of blood glucose (%) o, 5 hours and an hour 2-thienyl i0 ii 8 5-benzoyl · 25 io 7 3-bromo- io 8 6 ^{a |} 5-bromo- ioo 36 i9 5-chloro- ioo 26 i7 3-methoxy- 5 i3 i6 5-Methoxy- 25 9 7 3-methyl- ioo 3o i7 io i4 i2 5-methyl- 5o i8 io 5-phenyl- 5o and 5 ^b > 3-thienyl io 23 2o 5 2o i7 4-bromo- ioo 3i 25 io i4 9 4-methoxy- 5 ii 8 4-Methoxy-2-methyl- 5 i6 i4 4-ethoxy- 5 i9 i9 4-Ethoxy-2-methyl- 5 7 i2 4-propoxy- 5 ii 6 2-furyl ioo 27 Mar: 23 io ii 7 3-bromo- 25 i8 io 5 ii ii 5-bromo- 5o i9 2o io 2 ii 5-chloro- 25 2i 2o 3-methoxy- 25 io io 5-methyl- ioo 27 Mar: i9 5-phenyl- 25 6. 4 ^c > 3-furyl io i7 i3 5 i4 8 2,5-dimethyl- ioo 33d> i6 ^e) 4-iodine- 25 i9d) oe) 2-pyrrolyl ioo ii 8 1-methyl- ioo i8 i7 i-ethyl- ioo i4 i6 1- (1-Butyl) - ioo 4 i3 i-phenyl- ioo 3o 32 B-indol - - - 5-bromo- ioo 9 io i-methyl- ioo ii 8 2-thiazolyl 75 ii io 2-benzthiiazolyl 5o 8 io 5-isoxazolyl - - - 3-methyl- ioo 4 7 ^f > Legend: d) after about 74 hours (a) after 2 hours, the value of ii ^e ) for 1.5 hours (b) 9 hours after 2 hours  24 hours after 2 hours, c - after 3 hours i0 i4 after 3 hours,

The 0xazolidine-2,4-diones of the invention are clinically administered to mammals, including humans, orally or parenterally. Oral administration is preferred because it is more comfortable, and - avoiding any pain or irritation that may occur by injection. In cases where the patient cannot swallow the drug or when absorption is impaired after oral depression (whether due to disease or other effects), it is of course necessary to administer the drug parenterally. In the aforementioned routes of administration, the dosage ranges from about 0.10 to 50 milligrams per kilogram of body weight of the patient per day, preferably from about 0.20 to 20 mg / kg of patient weight per day, wherein the active ingredient is administered either as a single dose or in divided doses. While the optimum dosage in individual cases will be determined by the attending physician, it is generally practiced by initially administering lower doses which are then gradually increased to determine the most appropriate dosage. The dosage varies depending on the compound used and the patient being treated.

The compounds of the invention may be used in the form of pharmaceutical compositions comprising the active ingredient, or a pharmaceutically acceptable acid addition salt thereof, in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include aqueous or organic solutions. The active ingredient is contained in such pharmaceutical compositions in amounts sufficient to achieve the desired dosage as described above. Thus, for oral administration, the active compounds of the invention may be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions, and the like. as flavoring agents, sweeteners, excipients and the like.

For parenteral administration, the compounds described herein may be combined with a sterile aqueous or organic medium to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol, and the like, as well as aqueous solutions of water-soluble pharmaceutically acceptable acid addition salts of the compounds of the present invention may be used. Injectable solutions prepared - in this manner - may be administered intravenously, intraperitoneally, subcutaneously or intramuscularly, with in-tramuscular administration being preferred for humans.

The invention is illustrated by the following non-limiting examples.

He did

a) - Methyl 2,3-epoxy-5,5-dimethoxy-3-methylvalerate

A solution of -132 g of acetyl acetaldehyde dimethylacetal and 174 g of chloroacetate; methylene chloride in 800 ml of ether is cooled to 0 DEG C. under nitrogen and 86 DEG C. of sodium methoxide are added in portions over 2 hours while maintaining the temperature at 0 DEG to -5 DEG. The reaction mixture was stirred at 0-6 for 2 hours, then at 25 ° C for 16 hours, re-cooled to 0 ° C and diluted with a solution of acetic acid (10 ml) in water (150 ml). The ether phase is decanted off, the residue is stirred with 100 ml of fresh ether and decanted again. The decanted ether fractions were combined, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate and concentrated. 240 g of the title compound is obtained in the form of an oil which is used directly in the next step (b).

b) - Methyl 3-methylfuran-2-carboxylate

240 g of the title compound of the preceding reaction step are distilled using a Vigreux column having a length of 50 cm, equipped with a distillation head to adjust the different rellux ratio. Using a heating bath of - 180 DEG C., distillation is continued until no more methanol (no more than 66 g of distillate is collected). The residue is cooled and distilled in a water pump vacuum. 117 g of the title compound are obtained, boiling at 130 to 134 ° C / 2 kPa, which crystallizes on standing.

c) -3-methylfuran-2-carboxylic acid

A mixture of 117 g of the title compound preceded by (1 H) - (steps) -. 275 ml ^; --20This caustic soda - - se - 2 - hours - - heats - to - boiling under. reflux condenser, then. is acidified. 170 ml of concentrated - hydrochloric acid to pH-1 and cooled to room temperature. 92.5 g of the title compound are isolated by filtration, m.p. - 133-135 ^° C.

d) 3-methylfuran g of the title compound of the preceding step, 4.5 g of copper powder and 50 g of quinoline from a 250 ° C oil bath distilled using two Vigreux columns -Length 15 cm. After 1 hour 10 g of the title compound was collected as distillate. This material is stabilized by the addition of 50 mg hydroquinone and stored in a refrigerator until use.

e) 5- (3-Methyl-a-4-methyl-2-furyl) -

-5-hydroxy-2,4,6 (1H, 3H, 5H) pyrimidine trione

To 18.3 ml (1.1 equivalents) -2,2-M n-butyllithium in hexane, 3 g of the title compound in 50 ml of ether was added under nitrogen at -40 ° C. The reaction mixture was heated at 25 ^° C for 1 hour, then cooled to -50 ^° C and a solution of 6.23 g of anhydrous alloxane in 20 ml dry tetrahydrofuran was added dropwise while maintaining the temperature at -40 to -50 ° C. The reaction mixture was again warmed to 25 ° C over 30 minutes and quenched slowly. by adding 100 ml of -1 N hydrochloric acid. The aqueous layer was separated and extracted once with ~ 50 mL of ethyl acetate. The organic phases are combined and, after drying over sodium sulfate, concentrated. 3.3 g of the title compound are obtained in the form of a resinous material which is used immediately in the next step.

f) (3 ' -ethyl-2-furyl) oxazolidin-2,4-dione and (4-methyl-2-furyl) oxazlididine-2,4-dione

Dissolve 3.3 g of the freshly prepared title compound in 25 ml of 1N sodium hydroxide solution, stir for 15 minutes, then extract with 20 ml of ethyl acetate (discard the extract) and acidify with glacial acetic acid. to pH 4 and extracted twice with 35 ml each of ethyl acetate. The acidic - organic - layers - are combined and dried over sulfate. . the sodium was evaporated to give 700 mg of an oily mixture of the title compounds.

These isomeric products were purified by repeated column chromatography on silica gel using hexane / ethyl acetate mixtures first in a ratio of 4: 1, then 5: 1 and finally 9: 1 as eluents. In this way, a mixture of equal parts of the title compound is obtained, both of which have Rf -? - 0.2 - 0.25 - - - (hexane-ethyl acetate 5: 1).

260 mg of a mixture of isomeric compounds was separated by medium pressure liquid chromatography using a silica gel column (30 cm x -X 25 mm) and a hexane / ethyl acetate (4: 4) mixture. As eluent, 5 fractions were collected. Crystallization of the evaporation residue of the first (fastest running) fraction from a mixture of 1 ml of ether and 3 ml of hexane gave 15 mg of pure 4-methyl-isomer, m.p. 96.5-98 ° C. Crystallization of the fifth (slowest-running) fraction from a mixture of 1 ml of ether and 3 ml of hexane gave 12 mg of pure 3-methylisomer, m.p. 124.5-126 ° C.

Example 1 a d 2

(a) 3-chlorofuran

A solution of 30 g of 3-61-41111111111 in 150 ml of dry ether is cooled to -70 ° C under nitrogen and 111 ml of 2.2 M n-butyllithium ( 1.2 equivalents) in hexane. The mixture was stirred at -70 ° C for 30 minutes, then 48.3 g of hexahloroethane in 150 ml of ether was added dropwise while maintaining the temperature below -60 ° C. The reaction mixture was stirred at -70 ° C for 1 hour, then warmed to 25 ° C over 30 minutes, and ice water was added. The organic layer was separated, washed once with 50 ml of water and, after drying over sodium sulfate, distilled. Fractions boiling at 60-85 ° C (42.5 g) gave the title compound along with a portion of hexane. This mixture is directly used in the next step.

b) 5- (3-chloro- and 4-chloro-2-furyl) -

-5-hydroxy-2,4,6 (1H, 3H, 5H) pyrimidinetrione

To a solution of 6.3 mL of diisopropylamine in 25 mL of dry tetrahydrofuran at -70 ° C under nitrogen was added 20.5 mL of 2.2 M n-butyllithium in hexane. The mixture was stirred at -70 ° C for 15 minutes, then 4.61 g of the title compound of the preceding step together with hexane was added thereto while maintaining the temperature at -65 to -70 ^° C. The resulting mixture was stirred at -70 ° C for a further 2.5 hours, then 7.03 g of anhydrous alloxane in 25 mL of tetrahydrofuran was added while maintaining the temperature below -65 ° C. The reaction mixture is stirred for a further 15 minutes at -70 [deg.] C., then - heated to 25 [deg.] C. over 30 minutes, - 60 ml of water is added thereto, the aqueous layer is separated, - acidified with -6 N acid hydrochloric acid to pH 1 and extracted twice with 50 ml of ethyl acetate each time. The ethyl acetate extracts were combined with the original organic layer, decolorized with activated carbon and dried over sodium sulfate and concentrated. It is obtained

2.8 g of an oily title compound which is used immediately in the next step.

c) 5- (3-chloro-2-uryl) oxazplidine-

-2,4-dipne and 5- (4-chloro-2-furyl) oxazolidin-2,4-dione

The 2.8 g freshly prepared mixture of the title compounds was stirred in 25 ml of 1 N sodium hydroxide solution for 15 minutes, then extracted with 25 ml of ethyl acetate (the extracts were discarded), acidified with glacial acetic acid to pH 4 and extracted twice with 40 ml of ethyl acetate each time. The acidic ethyl acetate extracts were combined and dried over sodium sulfate. 480 mg of an oily residue are obtained, which is chromatographed on 40 ml of silica gel, collecting 8 ml fractions. Fractions 1 to 60 are eluted with hexane / ethyl acetate 9: 1, fractions 61- to 119 with hexane / ethyl acetate 7: 1 and fractions 121 to 180 with 5: 1 hexane / ethyl acetate. The combined organic layers were combined and evaporated to give 4 mg of crude 4-chloroisomer. From the combined fractions 116-210, after evaporation, 110 mg of crude 3-chloroisomer is obtained which, after purification by crystallization from a mixture of ether and hexane, is filtered off.

yields 55 mg of pure material melting at up to 98 ° C.

Roughly 25 mg of crude 4-chloroisomer, prepared several times from above. of the procedure described above, is rechromatographed on 10 ml of silica gel which is chromatographed on silica gel. sequentially eluting first with 4: 1, 2: 1 and 1: 1 hexane · ethyl acetate: 1: 1, and then · ethyl acetate / methanol · 1: 2: 1 · and 1 ·: 1 The fractions were combined and evaporated to give 23 mg of an oily material which, upon crystallization with dichloromethane, melted at 119-120 ° C. According to microanalysis, this is the desired product contaminated with about 5% of dichloro and bromo chloro analogues.

Changed to 3

a) 3'-bromofuran-1-carbaldehyde

To 7.6 ml of dimethylformamide at 10 ° C under nitrogen is added 21.2 ml of phosphorus oxychloride at a rate such that the temperature is kept below 20 ° C. After the addition of 33 ml of 1,2-dichloroethane, the mixture is cooled to 0 DEG C. and 28 g of 3-bromo-uranium are added in a slow stream (there is no exothermic reaction). The resulting mixture was heated at 60 ° C for 1.5 hours, then cooled to 10 ° C and added (first slowly) to 50 g of sodium acetate trihydrate in 100 mL of water, maintaining the temperature below 30 ° C. The aqueous mixture is cooled to 25 ° C, diluted with 50 ml of water and extracted once with 250 ml of ether. The organic layer was washed first with 50 ml of water (2 x 50 ml) and then with saturated sodium bicarbonate solution (4 x 50 ml each) (first carefully as carbon dioxide evolved), dried over sodium sulfate and decolorizing with charcoal, and concentrated by filtration. 24.2 g of the title compound are obtained.

b) 3-Bromo-2 ^and -methylfuran

12.3 g of hydrazine are added in portions to a solution of 17 g of the title compound in 25 ml of ethylene glycol in portions, followed by cautious addition of 12.1 g of potassium hydroxide in small portions, the mixture being the exothermic reaction is heated to reflux. After the reflux has subsided, the mixture is heated in a bath at 140 ° C for 1.75 hours, then cooled slightly and distilled under reduced pressure (about 6.7 kPa). Collect the biphasic fraction boiling at about 85 ° C and dilute with 75 ml of hexane. The lower hydrazine layer was separated, cooled to 0 ° C and, after acidification with 3N hydrochloric acid, extracted with hexane. The original organic layer was combined with hexane extract and evaporated after drying with sodium sulfate. 9 g of an oily title compound are obtained, containing 20% hexane,

o) 3-hydroxy-3- (2-methyl-3 ^: -furyl-2,4,6 · (1H, 3H; 5H) pyrimidinetrione

10.7 ml of 2.3 M n-butyllithium in hexane was added dropwise to 75 ml of isopropyl ether cooled to -70 ° C under nitrogen, maintaining the temperature below -60 ° C. While maintaining the temperature below -65 ° C, 3.6 g of the title compound of the preceding reaction step (i.e. 4.5 g of an 80% solution of this material in hexane) is then added dropwise. The mixture was stirred at -70 ° C for 0.5 hour, and 3.81 g of anhydrous alloxane in 35 ml of tetrahydrophthirane was added dropwise over 0.5 hours while maintaining the temperature below -60 ° C. The reaction mixture was warmed to 0 ° C over 15 minutes and treated with 65 mL of 1 N hydrochloric acid. The aqueous layer was separated and extracted once with 75 mL of ethyl acetate. The two organic layers were combined and evaporated to dryness with sodium sulfate to give 1.6 g of a foamed title compound which was used immediately for the next reaction.

d) 5- (2-methyl-3-furyl) oxazolidine-

-2,4-dione

1.6 g of the title compound are stirred with 15 ml of 1 N sodium hydroxide solution for 15 minutes at room temperature, then the mixture is extracted with 20 ml of ethyl acetate (the extract is discarded). The aqueous layer was acidified to pH 4 with glacial acetic acid and extracted twice with 50 ml of ethyl acetate each time. The acidic extracts were combined, dried over sodium sulfate and the solvent was evaporated in vacuo. The residue is chromatographed on 75 ml of silica gel using a mixture of equal parts of hexane and ethyl acetate as eluent to collect 8 ml of fractions. Fractions 70 to 20 are combined and concentrated to a solid which, after recrystallization from a mixture of 20 ml of ether and 60 ml of hexane, yields 290 mg of the purified title compound, m.p. 138 ° C.

Analysis · for CsHyNOí:

calculated

% H, 3.83;% N, 7.73%

% C, 53.03;% H, 3.93;

Example 4

a) 5-llydroxy-5- (1-methyl-2-pyrrolyl) -2,4,6 (1H, 3H, 5H) pyrimidinetrione

3.2 g (0 ', 02' mol) of alloxan hydrate are dissolved in 5'0'ml of ethanol with heating, 1.6 g (0.02 mol) of 1-methylpyrrole are added and the mixture is heated to steam bath, in which hydrogen chloride gas is introduced. The reaction mixture was allowed to stand for 0.5 hour at room temperature, then evaporated to dryness and residue

2 '3 7 3 ‘4 Ϋ is triturated with water to form. 2.9 g of the title compound is obtained as a solid.

Mass spectrum:

m / e = 223.

Rf = 0.5 (ethyl acetate-hexane with 5% acetic acid 1: 1).

b) 5- (1-methyl-2-pyrrolyl) oxazolidine-2,4-dione

2.8 g of the product of the previous step are mixed with 25 ml of 1 N sodium hydroxide and the mixture is heated on a steam bath for 30 minutes, whereupon all solids are completely dissolved. Upon acidification, a gum product precipitates and solidifies upon trituration with water. 1.2 g of crude product are obtained, which, after recrystallization from methanol / ether, yields 0.70 g of the title compound, melting at 108 DEG-114 DEG C. with decomposition.

I - p

Mass spectrum:

m / e = 180.

Analysis for CeHeOsN2:

calculated

% C, 53.33;% H, 4.48;% N, 15.55

% H, 4.72;% N, 15.28.

Example 5

a) 5-hydroxy-5- (1-ethyl-2-pyrrolyl) -2,4,6 (1H, 3H, 5H) pyrimidine trione g (0.01 mol) potassium pyrrole [J. Chem. Soc., p. 52 ( 1931)] is suspended in 5 ml of tetrahydrofuran and 1 ml (0.012 mol) of ethyl iodide is added with slight heat evolution, and the reaction mixture is stirred for 0.5 hours, then heated at reflux for 0.5 hours. The mixture is cooled to room temperature, diluted with 15 ml of water and extracted with 10 ml of ether, washed with 5 ml of water and then treated with 1.6 g of alloxane hydrate dissolved in 25 ml of ethanol under heating. The residue is refluxed for 0.5 h, evaporated to a water-soluble gum residue, taken up in 25 ml of ethyl acetate, washed twice with 10 ml of water each time, and evaporated to give 0% of the title compound. 6 g of the title compound in the form of a resinous material.

Mass spectrum:

m / e = 237.

b) 5- (1-ethyl-2-pyrrolyl) oxazolidine-2,4-dione

The procedure described in the preceding step is repeated on a three times larger scale. The primarily isolated resin product (0.03 mol of pyrimidine trione) was stirred with 60 ml of 1 N sodium hydroxide for 0.5 hour, then the mixture was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The extract was freed from insoluble impurities by filtration and concentrated to a 2.2 g resin residue. This resin material was chromatographed on 100 ml of silica gel using a mixture of equal parts of ethyl acetate and hexane as eluent and monitoring the progress of thin layer chromatography. The initial fractions containing the desired product were combined and evaporated to an oily residue which crystallized on standing. Trituration with water gave 170 mg of the purified title compound, melting at 90-93 ° C.

Mass spectrum:

m / e = 194.

For C9H10O3N2 = 0.25 H2O: calculated

% C, 54.40;% H, 5.32;% N, 14.10

% H, 5.16;% N, 13.76.

Example 6

a] S-hydroxy-S-III-1-butyl) -

-2-pyrrolyl] -2,4,6 (1H, 3H, 5H) pyrimidinetrione

A mixture of 3.0 g (0.03 mol) of potassiumpyrrole, 9.2 g (0.05 mol) of 1-iodobutane and 10 ml of tetrahydrofuran was heated at reflux for 1.5 hours while turning to a thick mass. The reaction mixture was diluted with 30 mL of water and extracted with 35 mL of ether. The ethereal extract was washed with water and added to a solution of 4.8 g (0.03 mol) of anhydrous alloxane in 50 ml of ethanol prepared under heating. The ether was distilled off, 5 ml (0.03 mol) of 6N hydrochloric acid was added to the residue, the mixture was heated under reflux for 3 minutes, cooled, evaporated and the gummy residue triturated with water. 5.1 g of the title compound melting with decomposition at 135 ° C is obtained.

Mass spectrum:

m / e = 265.

b) 5- [1- (1-Bu-yl-2-furyl) oxazolidine-

-2,4-dione

5.1 g (0.019 mol) of the product from previous 233434 was treated with 38 ml (0.038 mol) of 1N sodium hydroxide, stirred at room temperature for 10 minutes, filtered, washed with ether, cooled in water and The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and evaporated to a gummy material which was chromatographed on silica gel using ethyl acetate as eluent. Chromatography was followed by thin layer chromatography to give 950 mg of partially purified product as an oil, which gave after rechromatography using a mixture of equal parts of ethyl acetate and hexane as eluent, 0.59 g of the purified title compound as an oil.

Mass spectrum:

m / e = 222.

Rf = 0.72 (ethyl acetate).

Analysis for C 11 H 14 O 3 N 2. 0.5 H2O: calculated

Found: C, 57.38; H, 6.57; N, 12.17

H, 6.35; N, 12.15.

Example 7

Sodium 5- [1- (1-butyl) -2-furyl] oxazolidin-2,4-dione

370 mg (1.66 mmol) of the product of the previous example are dissolved in 5 ml of methanol and 90 mg (1.66 mmol) of sodium bicarbonate are added. The resulting solution was evaporated to dryness and the solid residue was triturated with ether to give 300 mg of the title compound, melting at 123-126 ° C with decomposition. ‘

Thin layer chromatography using a mixture of equal parts of ethyl acetate and hexane with 5% acetic acid as solvent system moves the product as fast as the corresponding free base.

Example 8

a) 5-Hydroxy-5- (1-phenyl-2-pyrrolyl) -2,4,6 (1H, 3H, 5H] pyrimidinetrione

A mixture of 1.4 g (0.1 mol). 1-phenylpyrrole, 1.6 g. Alloxanhydrate (0.01 mol) and ethanol (50 ml) were heated under reflux for 16 minutes. Thin layer chromatography showed no reaction. 10 ml (0.01 mol) of 1 N hydrochloric acid are added and the acidified mixture is stirred for 15 min. The mixture was heated at reflux for 10 minutes. TLC indicated incomplete reaction. An additional 1.6 g (0.01 mol) of alloxane hydrate was added, the mixture was heated under reflux for a further 15 minutes, then cooled and evaporated to dryness. Trituration of the residue with water gave 2.3 g of the title compound, melting at 232-234 ° C with decomposition.

Mass spectrum:

m / e = 285.

Rf = 0.3 (ethyl acetate-hexane 1: 1).

Analysis for C 11 H 11 O 4 N 3. 0.25 H2O: calculated

% H, 4.00;% N, 14.50

% H, 4.05;% N, 14.56.

b) 5- (1-Phenyl-2-pyrrolyl) ox-azolidine-2,4-dione g of the product of step a) was heated on a steam bath for 20 minutes with 20 ml of 1 N sodium hydroxide. The mixture was cooled in ice water, acidified with concentrated hydrochloric acid, and the liquid over the precipitated gum precipitate was decanted off. The resinous material was taken up in ethyl acetate, the solution was washed with water and evaporated to an oily residue (0.47 g). The decanted aqueous phase was also extracted with ethyl acetate. The extract was washed with water and evaporated to a second crop of oily material (0.28 g). The two oily fractions were combined and chromatographed on 150 ml of silica gel using a mixture of equal parts of ethyl acetate and hexane as eluent. The initial fractions containing the desired product were combined and evaporated. The oily residue, 410 mg, crystallized from ether / hexane gave 280 mg of the purified title compound, melting at 130-132 ^° C.

Mass spectrum:

m / e = 242.

Rf = 0.47 (ethyl acetate / hexane 1: 1).

Analysis for C 3 H 10 O 3 N 2:

calculated

% C, 64.46;% H, 4.16;% N, 11.57

% C, 64.40;% H, 4.35;% N, 11.56.

Example 9

a) 5-Hydroxy-5- (1-methyl-3-indolyl) -2,4,6 (1H, 3H, 5H) pyrimidinetrione

23! 73''417 ^f

No.

Mixture 1.6 g. (0.01 mol) of alloxan hydrate, 1.3 g (0.01 mol) of 1-methylindole and 50 ml of ethanol are heated at reflux for 0.5 hour, then concentrated to half the volume, The resulting product was filtered to give 2.7 g of the title compound, Rf = 0.5 (ethyl acetate-hexane with 5% acetic acid 1: 1).

b) The 5- [1-methyl-3-indolyl] oxazolidine-2,4-dione g of the product from previous step a) was heated for 15 minutes. on . steam bath with 35 ml of 1 N sodium hydroxide. The reaction mixture was cooled to room temperature, acidified to pH 1 with concentrated hydrochloric acid, and the liquid was decanted from a small amount (130 mg) of the resinous material. The decanted liquid was clarified by filtration, cooled in ice water and the precipitated solid, 330 mg, was filtered off. The filtrate was extracted with ethyl acetate, the extract was washed with water and evaporated to a solid. residue of · weight · 0,61 grams. The two solids were combined and recrystallized from ethyl acetate / hexane to give the title compound (0.33 g), temperature. Mp 152-153.5 ° C.

Analysis for C 12 H 10 O 3 N 2. 0.125 HžO:

calculated

% C, 61.99;% H, 4.45;% N, 12.05

% C, 61.99;% H, 4.45;

P-said ad · 10

(a) 5-hydroxy-5- (5-bromo-3-indolyl)

-2,4,6, (1 H, 3H, 5H) pyrimidinetrione

1.6 g (0.01 mol) of alloxan hydrate are dissolved in 40 ml of ethanol under heating. 1.96 g (0.01 mol) of 5-bromoindole are added and heating to near reflux is continued for 15 minutes. Thin layer chromatography showed no reaction. While maintaining the reaction mixture almost at reflux, 10 ml of 1 N hydrochloric acid are added and after 10 minutes the reaction mixture is concentrated to a wet solid residue. Trituration of this wet solid with water gave 3.17 g of the title compound, m.p. 250 ° C.

R _f = 0.45 (ethyl acetate - hexane with 5% acetic acid 1: 1).

Rf = 0.3 (ethyl acetate-hexane with 5% acetic acid 1: 5).

b) 5- (5-bromo-3-indolyl) oxazolidine-

-2,4-dione

3.1 g of the product of the preceding step

(a) is heated on a steam bath with 50 ml of 1 N sodium hydroxide for 15 minutes, then the mixture is cooled and 1.25 g of crude product is precipitated by the addition of concentrated hydrochloric acid. Chromatography on; Silica gel, eluting with ethyl acetate / hexane (column chromatography was monitored by thin layer chromatography) gave 0.41 g of the title compound, m.p. 185-189 ° C.

Rf = 0.55 (ethyl acetate-hexane with 5% acetic acid 1: 5).

Analysis for C.uH7O3N2Br:

calculated

H, 9.49%; N, found

% C, 45.10;% H, 2.68;

Example 11

(a) 5-hydroxy-5- (2-thiazolyl) -

-2,4,6- (1H, 3H, 5H) pyrimidinetrione

Dissolve 1.7 g (00) of 2 mol of thiazole in 35 ml of tetrahydrofuran, cool to -60 ° C and add 9 ml (0,0216 mol) of 2,4 M butyllithium dropwise over 20 minutes. in hexane and the reaction mixture was stirred at -60 ° C for an additional 30 minutes. In this way 2-thiazclyl lithium is formed. 3 g (0.021 mol) of anhydrous alloxane are dissolved in 20 ml of tetrahydrofuran and the solution is added dropwise to the mixture obtained above while maintaining the temperature at -60 ° C. The reaction mixture is allowed to warm to room temperature with stirring for 30 minutes, then recooled to 0 ° C, 25 ml of 1N hydrochloric acid are added in portions and the mixture is extracted. ml of ethyl acetate. The ethyl acetate extract is washed with 15 ml of water, dried over anhydrous sodium sulfate and, after filtration, evaporated. 1.9 g of the title compound is obtained.

Mass spectrum:

m / e = 227.

Rf = 0.4 (ethyl acetate · hexane · p. 5% acetic acid 1: 1).

In an analogous manner, the oxazole is converted to 54-dihydro-η 5 - (20-oxazolyl) -2,4,6- (1 H, 3 H, 5 H) pyrimidinetrione.

b) 5- (2-thiazolyl) oxazolidin-2,4-dione

1.37 g of the title compound of the preceding step (a) is stirred at room temperature with 24 ml of 1 N sodium hydroxide.

The reaction mixture was allowed to stand for 25 minutes, then acidified with 3 ml of glacial acetic acid and extracted twice with 50 ml of ethyl acetate. The extracts were dried (Na2SO4), filtered and evaporated to a solid residue. The weight of the first residue was 184 milligrams and the second residue was 85 mg. The solids were combined and chromatographed on 50 mL silica gel eluting with ethyl acetate / hexane (5% acetic acid). The course of column chromatography is monitored by thin layer chromatography. Fractions containing pure product were combined. Evaporate to dryness and triturate with hexane. 155 mg of purified title compound melting at 150-152 ° C is obtained.

Analysis for C.H..O5N2S:

calculated

% C, 39.13;% H, 2.19;% N, 15.21

% C, 39.53;% H, 2.52;

In an analogous manner, the further product from step a) is converted to 5- (2-otxazolyl) oxazolidine-2,4-dione.

Example 12

(a) 5-hydroxy-5- (2-benzthlazolyl) -2,4,6- (1H, 3H, 5H) pyrimidin trione

Using the procedure described in Example 11a), 2.7 g (0.02 mol) of benzthiazole was converted to the corresponding 2-lithium derivative, which, by treatment with anhydrous alloxane, gave the title compound. The product is first isolated in oily form and then crystallized from a mixture of ether and hexane. 2.2 g of the desired product, R _f = 0.55 (ethyl acetate - hexane with 5% acetic acid 1: 1-b ... .7.

b] 5- (2-Benzothiazolyl) oxazoline;

-2,4-dione

2.15 g of the product from previous step a) were added. Stir with 30 ml of 1 N sodium hydroxide for 30 minutes. The reaction mixture was extracted with ether and 0.46 g of product was precipitated from the aqueous layer by acidification with 6 N hydrochloric acid. Chromatography on 50 ml of silica gel using a mixture of equal parts of ethyl acetate and hexane with 5% acetic acid as eluent and monitoring the progress of column chromatography by thin layer chromatography followed by recrystallization from acetone / isopropyl ether gave 110 mg of the purified title compound. , melting at 214-216 ^° C.

Analysis for C10H6O3N2S:

calculated

% C, 51.29;% H, 2.58;% N, 11.96

% C, 51.51;% H, 2.99;% N, 12.21.

Example 13

(a) 5-hydroxy-5- (3-methoxy-2-thienyl) -

-2,4,6 (1H, 3H, 5H) pyrimidinetrione

2.5 g of 3-methoxythiophene [raw material prepared according to Arkiv. Kemi. 12, 239-246 (1958); Chem. Abstr. 52, 20115d] and 3.2 g of alloxane hydrate are dissolved in 25 ml of ethanol under heating, 3 ml (3 mmol) of 1N hydrochloric acid are added and the mixture is heated under reflux for 3 minutes. The reaction mixture was cooled to room temperature and diluted with 15 mL of water to induce further crystallization of the product. After filtering off and washing first with a mixture of equal parts of ethanol and water and then with water, 1.5 g of 5-hydroxy-5- (3-methoxy-2-thienyl) -2,4,6 (1H, 3H, 5H) pyrimidinetrione is obtained, m.p. with decomposition at 190-210 ° C.

R _; = 0.3 (hexane-ethyl acetate with 5% acetic acid 1: 1).

Mass spectrum:

m / e 256.

b) 5- (3-methoxy-2-thienyl) oxazolklin-2,4-dione g 5-hydroxy-5- (3-methoxy-2-thienyl) -2,4,6 (1H, 3H, 5H) pyriidinidine trione The reaction mixture was acidified, clarified and extracted twice with 50 ml of ethyl acetate each time, the combined ethyl acetate extracts were washed with water and evaporated to dryness to give 0.5 g of ethyl acetate. g of a solid residue, which is chromatographed on about 85 ml of silica gel, is monitored by thin layer chromatography to give 300 mg of 5- (3-methoxy-2-thienyl) oxazolidin-2,4-dione at a temperature of 60 DEG C. mp 156-158 ° C.

Analysis for CaH / OiNS:

calculated

% C, 45.08;% H, 3.31;% N, 6.57

H, 3.39; N, 6.47.

Example 14

a) 5-hydroxy-5- (5-phenyl-2-furyl) -2,4,6 (1H, 3H, 5H) pyrimidin trione

5.76 g (40 mmol) of 2-phenylfuran are treated with 100 ml of tetrahydrofuran, cooled to -30 ° C and added dropwise over 5 minutes while maintaining the temperature at -20 to -30 ° C.

19.1 ml of 2.3 M butyllithium in hexane. Reaction

The mixture is allowed to warm to room temperature, then recooled to: -30 ° C and 5.96 g (42 g) is added over 5 minutes while maintaining the temperature of -20 to -30 ° C. Mmol) of sublimed alloxane in 40 ml of tetrahydrofuran. The reaction mixture was again warmed to room temperature, cooled again to 0 ° C, 50 mL of 1 N hydrochloric acid was added in portions over 2-3 minutes, and the resulting mixture was extracted with 100 mL of ethyl acetate. The extract was filtered through a pad of anhydrous magnesium sulfate and evaporated. 9.4 g of 5-hydroxy-5- (5-Tenyl-2-furyl) -2,4,6 (1H, 3H, 5H) pyrimidine trione are obtained as a gummy solid having an Rf = 0 , 75 (hexane-ethyl acetate with 5% acetic acid 1: 1) contaminated with Rf -

- 0,45.

b) 5- (5-phenyl-2-furyl) oxazolidin-2,4-dione

Dissolve 0.7 g of 5-hydroxy-5- (5-phenyl-2-furyl) -2,4,6 (1H, 3H, 5H) pyrimidinetrione in 15 ml of 1 N sodium hydroxide, stir the solution for 15 minutes at a temperature of The mixture was extracted with ethyl acetate, slightly acidified with about 1 ml of glacial acetic acid and extracted with 25 ml of ethyl acetate. The latter ethyl acetate extract is washed with about 6.5 ml of water, filtered through a pad of anhydrous magnesium sulfate and evaporated. There was obtained 100 mg of solid 5- (5-phenyl-2-furyl) oixazolidine-2,4-dione, m.p. 216 DEG-218 DEG C. and Rf = 0.6 (hexane-ethyl acetate with 5% acetic acid 1: 1). ).

Example 15

(a) 5-hydroxy-5- (5-methyl-2-uryl) -2,4,6 (1H, 3H, 5H) pyrimidinetrione

3.28 · g (3.58 ml; 40 mmol) of 2-methylfuranate ··· · mix with 100 ml of tetrahydrofuran, flush with nitrogen, cool to -30 ° C and maintain the temperature - 20 to -30 [deg.] C, 19.1 ml

2.3 M butyllithium in hexane. The reaction mixture was warmed to room temperature, re-cooled to -30 ° C, and 5.96 g of sublimed alloxane in 40 ml of tetrahydrofuran was added dropwise over 10 minutes while maintaining the temperature between -20 to -30 ° C. The reaction mixture was warmed to room temperature, cooled to 0 ° C, and 50 mL of 1 N hydrochloric acid was added portionwise while maintaining the temperature at 0-5 ° C. The resulting mixture was extracted with 100 mL of ethyl acetate, washed with 25 mL of water, filtered through a pad of anhydrous magnesium sulfate, and evaporated. 6.3 g of solid 5-hydroxy-5- (5-methyl-2-furyl) -2,4,6 (1H, 3H, 5H) pyrimidinedione are obtained.

Mass spectrum:

m / e · 224.

b) 5- (S-methyl-4-cyclopropyl) -azolidin-2,4-dione

6.3 g of 5-hydroxy-5- (5-methanol ---- furyl-2,4,6 (1H, 3H, 5H) of pyrimidine trione are dissolved in 50 ml of 1 N sodium hydroxide and the solution is stirred for 15 minutes at The reaction mixture is extracted with 50 ml of ethyl acetate, acidified with glacial acetic acid and the product is extracted three times with 30 ml of fresh ethyl acetate each time. The combined ethyl acetate extracts are filtered through a pad of anhydrous magnesium sulfate and evaporated to an oily residue. Chromatograph on 50 ml of silica gel using hexane / ethyl acetate / 5% acetic acid as the eluent and the column chromatography was monitored by thin layer chromatography using the same solvent mixture to combine fractions containing pure product and evaporate to dryness. and the residue was triturated with hexane to give 311 mg of product, m.p. 135-138 ° C, which after recrystallization from a methanol mixture; Water yields 142 mg of purified 5- (5-methyl-2-furyl) oxazolidine-2,4-dione, m.p. 136.5-137.5 ° C.

Analysis for C3H7NO1:

calculated

% C, 53.01;% H, 3.90;% N, 7.73

% H, 4.03;% N, 7.65.

Example 16

a) 5-hydroxy-5- (3-thienyl) -2,4,6 (1H, 3H, 5H) -pyrimidinetrione ml of isopropyl ether cooled to -70 · ° C and keeping the temperature -70 to ^-60,? To this was added C, 10 ml (24 mmol) of 2.4 M butyllithium in hexane over 10 minutes. 1.9 ml [20 mmol] of 3-bromothiophene is added over 20 minutes while maintaining a temperature of -72 to -68 ° C, and the mixture is stirred for a further 30 minutes at -72 to -70 °. A solution of 3 g (21 mmol) of sublimed alloxane in 25 ml of tetrahydrofuran was added over 40 minutes while maintaining a temperature of -70 to -65 ° C. The reaction mixture is stirred for 15 minutes at the above temperature, then the cooling bath is removed, the reaction mixture is stirred for 1 hour at room temperature, then cooled to 5 ° C, 40 ml of 1 N acid are slowly added. and the organic phase is separated. The aqueous phase is extracted with 35 ml of ethyl acetate, the extract is combined with the organic phase, washed with 10 ml of water and, after drying with anhydrous sodium sulfate, concentrated. 1.41 g (31%) of solid 5-hydroxy-5- (3-thienyl) -2,4,6 (1H, 3H, 5H) pyrimidinetrione were obtained.

3 7 33 7

Mass spectrum:

m / e - 226.

b] 5- [3-thienyl) oxazolidine-2,4-dione

Dissolve 1.16 g (5.1 mmol) of 5-hydroxy-5- (3-thienyl) -2,4,6 (1H, 3H, 5H) pyrimidinetrione in 11 ml (11 mmol) of 1 N sodium hydroxide solution The mixture was allowed to stand at room temperature for 15 minutes, then acidified with acetic acid and the product crystallized over 35 minutes. Filtration afforded 480 mg (51%) of 5- (3-thienyl) oxazolidine-2,4-dione, m.p. 133-135 ° C.

Additional product was obtained by extracting the mother liquor with ethyl acetate, washing the extract with water and evaporating to dryness. 80 mg of the desired product is obtained, contaminated with the starting material.

Example 17

(a) 5- (3-Furyl-5-hydroxy) -

-2.4.6 (1H, 3H, 5H) pyrimidinetrione

The procedure of Example 16a) was repeated except that 2.94 g (1.8 mL; 20 mmol) of 3-bromofuran was used in place of 3-bromothiophene. 1.62 g of oily 5- (3-furyl) -5-hydroxy-2,4,6 (1H, 3H, 5H) pyrimidinetrione are obtained.

Mass spectrum:

m / e = 210.

b) 5- (3-furyl) oxazolidine-2,4-dione

1.62 g of 5- (3-furyl) -5-hydroxy-2,4,6 (1H, 3H, 5H) -pyrimidine trione are dissolved in 15 ml of 1 N sodium hydroxide and the solution is allowed to stand at room temperature for 15 minutes, and then extracted with 5 ml of ethyl acetate. The aqueous layer was acidified with ca. 1.5 ml glacial acetic acid and the product was extracted with 25 ml ethyl acetate. The extract was washed with 5 ml of water, filtered through a pad of anhydrous sodium sulfate and evaporated. 470 mg of crude product is obtained.

Mass spectrum:

m / e = 167.

Crystallization of this crude product from chloroform gave 129 g of purified 5- (3-furyl) oxazolidine-2,4-dione, m.p. 88-90 ° C (m / e = 167). A second crop of lower melting point product is obtained from the mother liquor.

Example 18

5- (3-thienyl) oxazolidine-2,4-dione

0.46 g (20 mmol) of sodium is dissolved in 50 ml of absolute ethanol, and to the resulting warm sodium ethoxide solution (about 60 ° C) is first added 7 g (about 20 µmol) of the crude 2-benzoyloxy-2- ether mixture. (3-thienyl) malonic acid; and then 1.2 g (20 mmol) of urea dissolved in 20 mL of hot ethanol. The reaction mixture was heated in an oil bath at 105-110 ° C for 4.5 hours, then cooled, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The extract is washed with water and concentrated to an oily residue which, by trituration with 20 ml of a mixture of equal parts of ether and hexane, affords a mixture of 5- (3-thienyl) oxazolidine-2,4-dione and intermediate 5-benzoyloxy-5- (3). (thienyl) -2,4,6 (1H, 3H, 5H) pyrimidinetrione (0.8 g). 0.3 g of this mixture was dissolved in 1 N sodium hydroxide (5 ml) and the solution was allowed to stand at room temperature for 20 minutes. The reaction mixture is clarified by filtration and acidified with acetic acid to precipitate 100 mg of 5- (3-thienyl) oxazolidine-2,4-dione, m.p. 136-138 ° C.

Example 19

(a) 5-hydroxy-5- (5-methoxy-2-thienyl) -

-2,4,6 (1H-1,3H, 5H) pyrimidine trione

2.3 g (20 mmol) of 2-methoxythiophene are dissolved in 35 ml of ether, and 9 ml [21.6 mmol] of 2.4 M butyllithium in hexane are added dropwise with cooling over 15 minutes. The temperature is raised to 35 ^DEG C. during the addition. The reaction mixture is stirred at room temperature for 1 hour, and a solution of 3 g (21 mm @ 2) of sublimed alloxane in 20 ml is added over 10 minutes while maintaining a temperature of -20 DEG to -15 DEG. tetrahydrofuran.

The mixture was warmed to room temperature, stirred for 0.5 h, cooled to 5 ° C and 35 mL of 1 N hydrochloric acid was added portionwise. The organic phase is separated and the aqueous phase is extracted with 25 ml of ethyl acetate. The extract was combined with the organic phase, washed with water, concentrated to dryness and the residue triturated with hexane. 1.4 g of solid 5-hydroxy-5- (5-methoxy-2-thienyl) -2,4,6 (1H, 3H, 5H) pyrimidinetrione are obtained.

Mass spectrum:

m / e = 256.

b) 5- (5-methoxy-2-thienyl) oxazolidine-2,4-dione

Dissolve 1.1 g of 5-hydroxy-5- (5-methoxy-2-thienyl) -2,4,6 (1H-1H-pyrimidin-trione) in 10 ml of 1 N sodium hydroxide, leave the solution for 1.5 hours The mixture was allowed to stand at room temperature, then extracted with ether, acidified with acetic acid, diluted with 15 ml of water, and the precipitated product was collected by filtration to give 567 mg of the product melting at 144-146 ° C with decrystallization from acetone / hexane. 487 mg of purified 5- (5-methoxy-2-thienyl) oxazolidine-2,4-dione melting at 147-148 ° C in two portions.

Analysis for C8H7O4NS;

calculated

45,08%,, 3,31% Η, 6,57% Ν, τίλΙρ'ζρτίο

45.08% С, 3.41% Η, 6.39% Ν.

Example 20

(a) 5-hydroxy-5- [5- (2-phenyl-1,3-dioxolane);

-2-yl) -2-thienyl] -2,4,6 (1H, 3H, 5H) pyrimidinetrioin

3.26 g (14 mmol) of 2-phenyl-2-thienyl-1,3-dioxolane are dissolved in 35 ml of ether at room temperature and 6.25 ml (15 mmol) of 2,4 M butyllithium are added dropwise over 15 minutes. The mixture was stirred at room temperature for 75 minutes, then cooled, maintaining 2.15 g (15 mmol) of sublimed solution dropwise over 10 minutes while maintaining a temperature of -15 to -20 ° C. The reaction mixture was stirred at room temperature for 30 minutes, then cooled to 5 ° C, treated with 35 mL of 1 N hydrochloric acid in small portions, and the resulting layer was washed with 15 mL of water, filtered through a pad. anhydrous sodium sulfate and evaporated to give an oily 5-hydroxy-5- [5- (2-phenyl-1,3-dioxolan-2-yl) thienyl] 2,4,6 (1H, 3H, 5H) pyrimidinetrione of Rf = 0.25 (hexane-ethyl acetate with 5% acetic acid 1: 1), contaminated with starting material Rf = 0.8.

b) 5- (5- (2-Phenyl-1,3-dioxolan-2-yl) -

-2-thienyl] oxazolidine-2,4-dione

All of the crude product prepared in step (a) above is taken up in 35 ml of 1 N sodium hydroxide and the solution is allowed to stand for 30 minutes. After acidification, the product is extracted with isopropyl ether, the extract is washed with water and evaporated. 0.40 g of 5- [5- (2-phenyl-1,3-dioxolan-2-yl) -2-thienyl] oxazolidin-2,4-dlone is obtained.

Rf = 0.65 (ethyl acetate-hexane with 5% acetic acid 1: 1).

Example 21

5- (5-Benzoyl-2-thienyl) oxazolidine-2,4-dione

0.40 g of 5- [5- (2-phenyl-1,3-dioxolan-2-yl) -2-thienyl] oxazolidin-2,4-dione is dissolved in 30 ml of ether and the solution is stirred at a temperature of 1 hour with 10 ml of 6 N hydrochloric acid. Ethyl acetate (10 ml) was added, the organic layer was separated and evaporated to dryness in vacuo. 0.388 g of a residue is obtained which is chromatographed on 50 ml of silica gel, eluting with hexane / ethyl acetate / 5% acetic acid (1: 1). The progress of column chromatography is monitored by thin layer chromatography. 0.22 g of purified 5 is obtained from the initial fractions

- (5-Benzoyl-2-thienyl) oxazolidin-2,4-dione, m.p. 153-155 ° C.

Mass spectrum:

m / e = 287.

Analysis for C14H9O1NS:

calculated

% C, 58.52;% H, 3.16;% N, 4.87.

% C, 58.69;% H, 3.50%;

Example 22

Capsules containing 5- (3-thienyl) oxazolidin-2,4-dione

The following ingredients were mixed and stirred for 30 minutes:

sodium 5- (3-thienyl) oxazolidine-2,4-dione monohydrate 30.46 g ^x) lactose anhydrous (USP) 14.05 g dried corn starch (US P) 5.00 g ⁴ Matches 25 g of the active substance (unsolvated) free acids).

The mixture is ground between the rollers with a slot of about 1 mm and stirred for a further 30 minutes, then 1.00 g of a magnesium stearate / sodium lauryl sulfate (90:10) mixture is added, the resulting mixture is stirred for 20 minutes and then filled. to No. 0 gelatin capsules such that each capsule contains 505 mg of the mixture corresponding to 250 mg of the active ingredient.

For the preparation of capsules with a higher content of active ingredient, larger capsules filled with a larger amount of the mixture are used.

The same procedure is used to prepare capsules containing 100 mg of the active ingredient, using the following ingredients:

sodium 5- (3-thienyl) oxazolidine-2,4-dione monohydrate 12.18 g ^x) anhydrous lactose (US P) 32.32 g dried corn starch (USP) 5.00 g mixture of magnesium stearate and lauryl sulfate (90:10 ) 0.50 g ^x) corresponds to 10 g of active substance (unsolvated free acid).

The lower dose of the active ingredient in the composition is used to prepare capsules containing less active ingredient.

Example 25

Tablets

By mixing the following ingredients in the indicated weight ratios, a tablet base is prepared:

sucrose (U. S. P.) 80.3 tapioca starch 13.2 magnesium stearate 6.5

An appropriate amount of sodium 5- (3-thienyl) oxazolidine-2,4-dione monohydrate is mixed into this tablet base to obtain tablets containing 50 mg, 100 mg, and 100 mg, respectively. 250 mg of active substance (weight corresponds to · free acid) The ratio of the mixture to the active substance ranges from 1: 0.167 to 1: 1, which in extreme cases means 60.2 mg of sodium salt monohydrate and 300 mg of the mixture in a tablet containing 50 mg of active ingredient, and .304.6 mg of sodium salt monohydrate and 250 mg of a mixture in a tablet containing 250 mg of active ingredient.

Example 26

Injectable preparation

The vials are dry-filled with sterile sodium 5- (3-thienyl) oxazolidine-2,4-dione such that each vial contains 670.1 mg of sodium salt monohydrate, equivalent to 550 mg of free acid. Before use, 11 ml of water for injection is added to the contents of the ampoule and mixed. agitation to give a solution containing 50 mg / ml of the active ingredient. This solution is suitable for intravenous, intramuscular or subcutaneous injection.

Alternatively, the ampoules are filled by the lyophilization method. To this end, 2 ml of a sterile aqueous solution containing 335 mg / ml of sodium salt monohydrate is introduced into each ampoule. The ampoules are then lyophilized.

Example 27

3-ethoxycarbonyl-5- (3-thienyl) oxazolidin-2,4-dione

The sodium 5- (3-thienyl) oxazolidine-2,4-dione monohydrate is dehydrated by drying under vacuum at 50-70 ° C; 2.05 g (10 millimoles) of the anhydrous salt is suspended in. 35 ml of 1,2-dichloroethane, 1.41 g (10 mmol) of ethyl chloroformate are added, the reaction mixture is heated under reflux for about 2 hours, then cooled to room temperature, the by-product sodium chloride is filtered off. and the filtrate is concentrated to dryness. 3-Ethoxycarbonyl-5- (3-thienyl) oxazolidin-2,4-dione is obtained.

Replacing ethyl chloroformate with an equivalent amount of acetyl chloride, isobutyrylride, Ν, Ν-dimethylcarbamoyl chloride or benzoyl chloride yields:

3-acetyl-5- (3-thienyl) oxazolidin-2,4-dione;

3-isobutyryl-5- (3-thienyl) oxazolldine-2,4-dione,

3- (Ν, Ν-dimethylcarbamoyl) -5- (3-thienyl) oxazolidin-2,4-dione, respectively;

3-Benzoyl-5- (3-thienyl) oxazolldine-2,4-dione.

Example 28

3-acetyl-5- (3-thienyl) oxazolidin-2,4-dione

Procedure

1.83 g (10 mmol) of 5- [3-thienyl) oxazolidin-2,4-dione and 0.14 ml (10 mmol) of triethylamine. The reaction mixture is treated with 25 ml of 1,2-dichloroethane at room temperature, 0.73 ml (10 mmol) of acetyl chloride are added dropwise over a few minutes, the reaction mixture is stirred for 3 hours and then evaporated to dryness. The residue was partitioned between saturated sodium bicarbonate solution and chloroform, the chloroform layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated after filtration. 3-Acetyl-5- (3-thienyl) oxazolidin-2,4-dione is obtained.

Procedure B

1.83 g (10 mmol) of 5- (3-thienyl) oxazolidium-2,4-dione and 1.14 ml (12 mmol) of acetic anhydride are mixed with 20 ml of tetrahydrofuran, the reaction mixture is stirred for 40 hours, then evaporated to dryness. The resulting 3-acetyl-5- (3-thienyl) oxazolidine-2,4-dione is further isolated as in Procedure A.

Using the same procedure, replacing acetic anhydride with a solution of mixed acetic anhydride and acid. formic acid in acetic acid [see Blackwood et al., J. Am. Chem. Soc., 82, 5192 (1960)], propionic anhydride or benzoic anhydride can be prepared by:

3-formyl-5- (3-thienyl) oxazolidin-2,4-dione, 3-propionyl-5- (3-thienyl) oxazolidin-2,4-dione, respectively

3-Benzoyl-5- (3-thienyl) oxazolidin-2,4-dione.

Example d 29

3- (N-methylcarbamoyl) -5- (3-thienyl) oxazolidin-2,4-dione

To 1.35 g (10 mmol) of 5- (3-thienyl) oxazolidine-2,4-dione and 1 drop of triethylamine are added to 35 ml of 1,2-dichloroethane, 0.58 ml (10 mmol) of methyl isocyanate are added and the mixture is stirred for 4 hours. The reaction mixture was diluted with 35 mL of 1,2-dichloroethane, washed with saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated by filtration to give 3- (N-methylcarbamoyl) - 5- (3-thienyl) oxazolidin-2,4-diPn.

Example 30

(a) 5-hydroxy- (2,5-dimethyl-3-furyl) -2,4,6 (1H, 3H, 5H nyrimidinetrione) ml of isopropyl ether is cooled to -68 degrees Celsius and 5 ml (10,5) is added to the solution. mmol] 2.1 M butyllithium in hexane while allowing the temperature to rise to -60 ° C. While maintaining the temperature at -65 to -68 ° C, 1.2 ml (9 mmol) of 1,5-dimethyl-3- is then added dropwise. iodofuran [J. Am. Chem. Soc. 70, page 739 (1948)] The mixture was stirred at -68 degrees Celsius for 0.5 hour and then added dropwise over 30 minutes while maintaining a temperature of -65 to -60 ° C. A solution of 1.5 g (10.6 mmol) of anhydrous alloxane in 15 ml of tetrahydrofuran was allowed to warm to 0 ° C with stirring over 15 minutes, 25 ml of 1 N hydrochloric acid was added thereto, and the organic phase was separated. The combined organic layers were washed with 10 mL of water and evaporated to give 1 g of the title compound.

Rf = 0.05 (ethyl acetate-hexane with 5% acetic acid 1: 5).

b) 5- (2,5-dimethyl-3-furyl) oxazolidine-2,4-dione g of the product from step a) is taken up in 10 ml of 1 N sodium hydroxide, allowed to stand for 15 minutes, then extracted with 5 ml of sodium hydroxide. ml of ethyl acetate, acidified with acetic acid and extracted with 25 ml of ethyl acetate. The acidic extract was washed with 5 ml of water and evaporated to a solid residue of 340 mg which was chromatographed on 50 ml of silica gel using a mixture of equal parts of ethyl acetate and hexane as eluent.

The progress of column chromatography is monitored by thin layer chromatography. Fractions containing pure product were combined, evaporated to dryness and the residue was recrystallized from ether / hexane. 170 mg of the title compound melting at 144-145 ° C is obtained.

Mass spectrum:

m / e - 195.

Rf = 0.3 (ethyl acetate-hexane with 5: 1 acetic acid 1: 5),

R f = 0.55 (ethyl acetate-hexane 1: 1).

Analysis for C9H90dN:

calculated

% H, 4.65;% N, 7.18

H, 4.76; N, 7.04.

Example 31

(a) 5-hydroxy-5- (4-iodo-3-furyl) -2,4,6 (1H, 3H, 5H) pyrimidinetrione

To 2 ml (4.6 mmol) of 2,3 M butyllithium in hexane, dissolved in 15 ml of ether, slowly add 0.96 (3 mmol) of 3,4-diiodofuran in 5 ml of ether at -65 ° C. The mixture was stirred at -65 ° C for 20 minutes and then a solution of 0.57 g (4 mmol) of anhydrous alloxane in 10 mL of tetrahydrofuran was slowly added to this solution of 4-iodo-3-furyllithium at -65 ° C. After 10 minutes of reaction at the above temperature, the reaction mixture was warmed to 15 ° C, acidified with 15 mL of 1 N hydrochloric acid and extracted with ether. The ethereal extract was washed with 10 ml of water, concentrated to dryness and the residue triturated with 2 ml of hexane. 108 mg of the title compound are obtained,

Mass spectrum:

m / e = 336.

Rf = 0.5 (ethyl acetate-hexane with 5% acetic acid 1: 1).

b] 5- (4-iodo-3-furyl) oxazolidin-2,4-dione

100 mg of the product of step (a) is left to stand at room temperature for 15 minutes with 1 ml of 1 N sodium hydroxide. The reaction mixture was acidified with acetic acid and extracted with 3 mL of ethyl acetate. The organic extract was washed with 1 ml of water and evaporated to a gum residue of 63 mg.

120 mg of the crude product prepared as described above are chromatographed on 50 ml of silica gel using a mixture of equal parts of ethyl acetate and hexane as the eluent, the progress of column chromatography being monitored by thin layer chromatography. The first fraction eluted from the column was combined and evaporated to a 78 mg gum residue which, after crystallization from chloroform, afforded 45 mg of the purified title compound, melting at 140-144 ° C.

Analysis for C7H1O4NI:

calculated

% C, 28.69;% H, 1.38;% N, 4.78

% C, 28.37;% H, 1.62;% N, 4.74.

The following compounds of the general formula are prepared in an analogous manner

R ¹ physicochemical data

R ¹ physicochemical data

3-pyridyl

2-methoxy, m.p. 183-186 ° C;

R _f 0.32 (ethyl acetate-chloroform 1: 2)

2-ethoxy

5-chloro-2-methoxy

5-chloro-2-ethoxy, mp 140-143 ° C, mass spectrum: m / e 272 mp 212-214 ° C, mass spectrum m / e 244/242, IC (KBr): 3174, 3074, 2980, 1830, 1752 ^cm-1 mp 145-147 ° C, MS: m / e 256, _Rf 0.56 (ethyl acetate-chloroform 1: 1)

3-methoxy m.p. 147-148 ° C (dec.)

M.p. 126-130 ° C

3-bromo, m.p. 139 [deg.] C

M.p. 108-109 ° C, mass spectrum: m / e 197

5-bromo, mp 139-139.5 ° C mass spectrum: m / e 263 (261)

8-quinolyl mass spectrum: m / e 228

5-phenyl, mp 233-235 ° C

3-thienyl

4-bromo, mp 164-166 ° C, mass spectrum: m / e 263 (261)

6-chloro, mp 207-210 ° C,

IC (KBr): 1839, 1825, 1740 cm ^-1

4-ethoxy

202 DEG-204 DEG C., mass spectrum: m / e 246, IR (KBr): 1819, 1743, 1363 cm @ -1, m.p. 144 DEG -146 DEG C., mass spectrum: m / e 227, IR (m.p. KBr): 1822, 1737, 1568 cm ^-1

7-methoxy

5-quinolyl

6-methoxy, mp 207-208 ° C, mp 144-146 ° C

4-n-propoxy, mp 134-136 ° C, mass spectrum: m / e 241, IR (KBr): 1827, 1747, 1564 cm ^-1

2-furyl, m.p. 101-103 ° C

3-methoxy mp 102-104 ° C,

R _f 0.6 (hexane-ethyl acetate with 5% acetic acid 1: 1)

4-methoxy-2- m.p. 179-181 ° C; methyl mass spectrum: m / e 227

IR (KBr): 1820, 1750, 1727, 1583 cm ^-1

4-ethoxy-2-methyl, m.p. 136-138 ° C, mass spectrum: m / e 241, IR (KBr): 1824, 1743 cm ^-1

3-bromo, m.p. 128-130 ° C,

RI 0.20 (hexane-ethyl acetate with 5% acetic acid 5: 1)

6-chloro-8-chromanyl, m.p. 170-172 ° C, mass spectrum: m / e 269 / (267)

5-chloro melting point 112-114 ° C, mass spectrum: m / e 201, Rf 0.25 (hexane-ethyl acetate with 5% acetic acid 5: 1)

6-fluoro-8-chromanyl m.p. 174-176 ° C, mass spectrum: m / e 251

5-bromo

3-furyl

2,5dimethyl

Ж

5-iodo, mp 126-129 ° C, mass spectrum: m / e 245 247,

R _f 0.2 (hexane-ethyl acetate with 5% acetic acid 5: 1), mp 144-145 ° C, MS: m / e 195, Rf 0.3 (ethyl acetate-hexane with 5% acetic acid 1: 5 )

Rf 0.55 (ethyl acetate-hexane 1: 1) mp 140-144 ° C

3-methylisoxazolyl 5-chloro-7-benzo (b) furanyl melting point 173-175 ° C melting point 154-157 ° C, mass spectrum: m / e 261, 253

5-chloro-2,3- m.p. 197-199 ° C, -dihydroben mass spectrum: 255/253 from [b] furanyl (KBr): 3084, 1833, 1810, 1746 cm ^-1

3-benzo [b] - mp 202-205 ° C, thienyl mass spectrum: m / e 233

7-benzo [b] m.p. 130-132 ° C thienyl

2-thienyl

3-methyl melting point 138-140 ° C, mass spectrum: m / e 183 melting point 119-121 ° C, mass spectrum: m / e 197

Claims (3)

SUBJECT A process for the preparation of racemic or optically active 5-substituted oxazolidine-2,4-diones of formula I wherein: R 1 represents a 3-pyridyl radical substituted at the 2-position by methoxy or ethoxy or further substituted by a chlorine at the 5-position, an 8-quinolyl radical, optionally substituted at the 7-position by chlorine, fluorine or methoxy, a 6-methoxy-5-quinolyl radical, a 2-pyrrolyl radical substituted at the 1-position with methyl, ethyl or phenyl, a 2-furyl residue, optionally substituted at the 3-position with bromine or methoxy, at the 5-position with chlorine, bromine, methyl or phenyl, or at the 1-position with 1-butyl, 3-furyl optionally substituted in positions 2 and 5 with two methyl groups or in position 5 with iodine, a 2-thienyl radical optionally substituted in position 3 with methyl, bromine or methoxy, or in position 5 with methyl, chlorine, bromine, methoxy, phenyl, benzyl or 2-phenyl-1,3-dioxolan-2-yl; the 4-position with bromine, methoxy, ethoxy or n-propoxy and, if the 4 'position is a methoxy or ethoxy substituent, also the methyl group at the 2,5-position, a 5-bromo-3-indolyl radical, 1-methyl-3-indolyl residue, 2-thiazolyl residue, 2-benzothiazolyl residue, 6-chloro-8-chromanyl residue, 6-fluoro-8-chromanyl residue, 3-methylisoxazolyl residue, 5-chloro-7-benzo [b] furanyl residue, 5-chloro-2,3-dihydrobenzo [b] furanyl, 3-benzo [b] thienyl, or 7-benzo [b] thienyl, and the pharmaceutically acceptable acid addition salts of the above compounds wherein the R1 moiety contains basic nitrogen, with acids characterized by: The method of claim 1 wherein the compound of formula (II) O OF THE INVENTION in which R1 is as defined above, reacted with an aqueous base, and then the optionally formed compound of formula I containing a basic nitrogen in the residue R1 is converted to its acid addition salt. 2. The method of claim 1, wherein the method is used. the corresponding starting materials, to give compounds of general formula. of formula I wherein R 1 represents a 2-furyl radical, optionally substituted at the 3-position with bromine or methoxy, or at the 5-position with chlorine, bromine, methyl or phenyl, or in the 1-position with 1-butyl, a 3-furyl radical optionally substituted in positions 2 and 5 methyl groups or in the 5-position iodine, 2-thienyl radical, optionally. substituted. v. position 3 with methyl, bromine or methoxy, or position 5 with methyl, chlorine, bromine, methoxy, phenyl, benzyl or 2-phenyl-1,3-dioxolan-2-yl, 3-thienyl, optionally substituted at the 4-position with bromine, methoxy, ethoxy or n-propoxy and, if a 4-methoxy or ethoxy substituent is present at the 4-position, also a methyl group at the 2,5-chloro-7-benzo [b] furanyl radical, 5-chloro A -2,3-dihydrobenzo [b] furanyl residue, a 3-benzo [b] thienyl residue or a 7-benzo [b] thienyl residue. 3. A process according to claim 1, wherein the corresponding starting materials are used to form compounds of formula (I) in which: R 1 represents a 3-pyridyl radical substituted at the 2-position by methoxy or ethoxy or further substituted by a chlorine at the 5-position, an 8-quinolyl radical, optionally substituted at the 7-position by chlorine, fluorine or methoxy, a 6-methoxy-5-quinolyl radical, a 2-pyrrolyl radical substituted with 1-methyl, ethyl or phenyl, 5-bromo-3-indolyl, 1-methyl-3-indolyl, 2-thiazolyl, 2-benzothiazolyl, 6-chloro-c-chromanol, 6 a fluoro-8-chromanyl radical or a 3-methylsoxazolyl radical and pharmaceutically acceptable acid addition salts of the above compounds wherein the R1 radical contains nitrogen.