CS237320B2 - Processing of racemic or opticaly active 5-substituted oxazolidine-2,4-dione - Google Patents

Abstract

A compound of the formula <IMAGE> wherein R<4> is hydrogen, lower alkanoyl or benzoyl and R<1> is <IMAGE> wherein R' is (C1-C4)alkyl or phenyl, R'' is hydrogen, (C1-C4)alkyl or phenyl and X is halo; <IMAGE> wherein Y is hydrogen or (C1-C3)alkoxy, Y' is hydrogen or (C1-C3)alkyl and Y'' is hydrogen or halo; <IMAGE> wherein Z' is hydrogen, halo or (C1-C3)alkoxy and Z'' is hydrogen or halo; <IMAGE> wherein W is hydrogen or halo, and n is 1 or 2; <IMAGE> wherein Q is sulfur or oxygen and V is hydrogen or (C1-C3)alkyl; <IMAGE> wherein Q is sulfur or oxygen; and V is hydrogen or (C1-C3)alkyl; or <IMAGE> wherein Y is sulfur or oxygen; X is hydrogen, halogen, methyl, phenyl, benzoyl or (C1-C3)alkoxy; X<1> is hydrogen or methyl; and X<2> is hydrogen or halo. The compounds are intermediates for certain hypoglycemic compounds.

Description

The invention relates to a process for the manufacture of certain

5-furyl-, 5-thienyl-, 5-chromanyl-, 2,3-dihydrobenzo [b] furanyl-, and 5-isoxazolyl derivatives of oxazolidine-2,4-dione, which are 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 in 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 measurement of sugar, urine or blood content. Administration of too high a dose of insulin leads to hypoglycaemia, which may result in mild abnormalities in blood glucose levels or 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 one of these agents fails in an individual case, the other agent may succeed in that case. From the foregoing, it is apparent that there is a continuing need for hypoglycaemic agents that are less toxic or successful if other agents fail.

In addition to the aforementioned hypoglycaemic agents, a number of other compounds having this type of activity have been described, as Blank recently summarized [See Burger‘s Medicinal Chemistry,

4th Edition, Part II, John Wiley and Sons, N.Y. (1979), pp. 1057-1080].

The oxazolidine-2,4-diones of the present invention are novel compounds, notwithstanding the fact that oxazolidine-2,4-diones are widely known as a group of compounds [for an extensive 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 β-lactam-type antibacterial agents (see U.S. Patent No. 2,721,197), as an antidepressant agent (see U.S. Patent No. 5,702,249). No. 3,699,229) and as an anticonvulsant agent [see Brink and Freeman, J. Neuro, Chem. 19 (7), pp. 1783-1788 (1972)] and further includes a series of phenyl-substituted 5-phenyloxazolidine-2,4-dione such as 5- (4-methoxyphenyl) oxazolidine-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 1 5- (2-pyrryl) oxazolidine-2,4-dione [see Ciamacian and Silber, Gazz, chim. 16: 357 (1886); Ber 19: 1708-1714 (1886)] The latter compound, for which no use is known so far, shows only relatively poor hypoglycemic activity (see Table I below).

Oxazolidine-2,4-dione and substituted oxazolidine-2,4-diones (specifically 5-methyl- and 5,5-dimethyl derivative) have already been described as acidic residues suitable for the addition of acid addition salts of hypoglycemically active basic biguanides with acids [see] U.S. Pat. 2,961,377]. It has now been found that neither oxazolidine-2,4-dione alone nor 5,5-dimethyloxazolidine-2,4-dione have the hypoglycemic activity of the compounds of the invention.

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

The invention provides compounds of formula I

(I) in which

R is hydrogen, C1-C4 alkanoyl (e.g., formyl, acetyl or isobutyryl), C2-C4alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl or isopropoxycarbonyl) or C1-C3 alkylcarbamoyl alkyl moieties (e.g., N-methylcarbamoyl or N-propylcarbamoyl)

R ¹ represents a 3-alkyl-5-isoxazolyl group having 1 to 3 carbon atoms in the alkyl moiety,

3- or 7-benzo [b] thienyl, a radical of formula

where

Z is halogen and n is 1 or 2, or a radical of formula

where either Y is an oxygen atom,

X ¹ represents a hydrogen atom, a halogen atom, a methyl group or a methoxy group;

X ² represents a hydrogen atom or an alkyl group, or

Y is a sulfur atom,

X ¹ represents a hydrogen atom, a halogen atom, a phenyl group, an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms, and

X ² represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.

Also included within the scope of the invention are 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 potency 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 the so-called precursors of these drugs. wherein the carboxyl 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 salts such as alkali metal salts (e.g., sodium and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), aluminum salts, ammonium salts, and salts with organic amines such as with benzathine (N, N'-dibenzylethylenediamine), choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), benethamine (N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2-hydroxyanediol-1,3) ), procaine, etc.

The term "pharmaceutically acceptable acid addition salts" refers to salts such as hydrochlorides, hydrobromides, hydroiodides, nitrates, hydrogen sulfates, 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. Among the compounds of formula I in which R is hydrogen, the following are the most preferred because of their excellent hypoglycemic activity:

5- (6-chloro-8-chromanyl) oxazolidine-2,4-dione,

5- (6-fluoro-8-chromanyl) oxazolidine-2,4-dione;

5- (5-chloro-2,3-dihydro-7-benzofuranyl) oxazolidin-2,4-dione;

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

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

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

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

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

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

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

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

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

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

5- (5-chloro-2-furyl) oxazolidin-2,4-dione;

5- (7-Benzo [b] thienyl] oxazolidin-2,4-dione a

5- (5-chloro-7-benzo [b] furanyl) oxazolidin-2,4-dione.

The compounds of the invention can be prepared by reacting phosgene with an inert solvent in an inert solvent

... (Π) in which

· R ¹ has the abovementioned meaning and

R ² represents a C 1 -C 3 alkyl group to form the compound of formula III

(III) wherein

R 1 and R 2 are as defined above, hydrolyzed to form a compound of formula (I) wherein R 1 is as defined above and R is hydrogen, followed by an optionally formed racemic compound of formula (I) wherein R 1 is as defined above and R represents a hydrogen atom, resolved into the optically active enantiomers by separating the diastereomeric salts prepared with an optically active amine and regenerating the above-defined optically active compounds of formula I by acidification, and / or obtaining a compound of formula I wherein R 1 is as defined above; R represents a hydrogen atom, acylated by reaction with an appropriate acid chloride, anhydride or isocyanate to give a compound of formula I wherein R 1 and R 2 are as defined above except for the hydrogen atoms R and the resulting product is isolated as · such or in the form of a pharmaceutically acceptable salt from the group I include alkali metal salts and acid addition salts, in the form of a racemate or an optically active enantiomer.

The above reaction scheme is illustrated by the following reaction scheme:

In accordance with the invention, the carboximidate of formula (II) is reacted with a phosphogen in an inert solvent such as tetrahydrofuran in the presence of 2 to 2.3 equivalents of a tertiary amine (e.g. triethylamine or N-methylmorpholine). Another equivalent of a tertiary amine is used when the carboximidate is reacted in the form of its acid addition salt (e.g., the hydrochloride). The reaction temperature is not critical, but lower temperatures (e.g., -10 to 10 ° C) are preferred in the initial stage of the reaction, especially if the intermediate 4-alkoxyoxazol-2-one (III) is to be isolated. Isolation of this intermediate is accomplished by simply adding the reaction mixture to dryness.

(II)

Subsequent reaction at a higher temperature (for example 20 to 150 ° C) or treatment in the presence of water converts intermediate (III) to the desired oxazolidine-2,4-dione. If the final product is to contain a primary or secondary amine function, this function is introduced to the primary or secondary amine function via the corresponding oxazolidine-2,4-done containing group selectively reducible (for example, by catalytic hydrogenation or metal in the presence of an acid). As the precursor of the indole derivative, for example, N-benzylindole can be used.

The carboximidate (II) is conveniently prepared from the corresponding aldehyde according to the scheme:

ie

OSi (CH3) ₃

The aldehyde (11) is converted to cyanohydrin (13) by standard procedures (for example, via a bisulfite adduct which is then reacted with cyanide in a two-phase water-organic solvent system). Alternatively, the aldehyde can be converted to trimethylsilyl-cyanohydrin by reaction with trimethylsilylcarbonitrile in the presence of a catalytic amount of a Lewis acid such as zinc iodide. If the aldehyde is solid, it is used. a generally inert organic solvent (e.g., methylene chloride or ether), in the case of a liquid aldehyde, may optionally also be used. The reaction temperature is not critical. The reaction is conveniently initiated at a reduced temperature (e.g. 0 to 5 ° C) and then allowed to proceed at room temperature for 30 min. a period of 'several hours or days' as needed to 'complete' the reaction. If desired, trimethylsilyl ether can be hydrolyzed to cyanohydrin, conveniently at a reduced temperature (e.g., -10 ° C) in a two-phase system consisting of a strong aqueous acid and an organic solvent.

Both cyanohydrin (13) and trimethylsilyl ether (12) are then converted to the carboximidate (II) by strong acid catalyzed alcoholysis (under strictly anhydrous conditions). Suitably, the nitrile is simply dissolved in an alcohol saturated with hydrogen chloride and the solution is allowed to stand until the carboximidate formation is complete. Temperature is not critical in this case, although lower temperatures (e.g., 0-25 ° C) generally lead to more darker yields.

The aldehydes required for the above syntheses are widely available either commercially or by literature procedures.

By way of example, Rosenmund hydrogenation of the corresponding acid chloride [e.g. 3-furaldehyde; see Hayes, J. Am. Chem. Soc. 71, 2581 (1949)], the preparation of the halomethyl derivatives by a S-mmell reaction [e.g. 3-thenaldehyde; Campaigne and LaSuer, J. Am. Oiem. Soc. 70, 1557 (1948)], formylation. [for example, 2-thenaldehyde, 3-methyl-2-thenaldehyde, 5-methyl-2-thenaldehyde; Watson and Michaels, J. Am. Chem. Soc. 72, 1422 (195-0), Organic Syntheses 31, 108 (1951); 3-Bromo-2-thienoldehyde; Elliot et al., J. Chem. Soc. (C), 2551 (1971)], reducing chloromethyl-substituted. aldehydes [e.g., 5-methyl-2-furaldehyde; Spence and Wild, J. Chem. 'Soc., 338' (193! 5)], oxidizing the corresponding alcohol [e.g., 2-thenaldehyde; Emerson and Patrick, J. Org. Chem., 14, 790 '(1949J), reacting Grignard reagents with formic acid orthoesters [e.g., 2-thenaldehyde; Cagniant, Bull, soc. Chim. France 16, 849 (194 * 9)], decarboxylation of α-keto acids [e.g., 2-thenaldehyde; Barger and Easson, J. Ohem. Soc., 2100 (1938)] and halogenation [e.g. A wide variety of the aldehydes required above are further available by hydrolysis of geminal dihalides, oxidation of primary alcohols, reaction of Grignard reagents with formic acid orthoesters, and other methods known in the art.

Pharmaceutically usable cationic salts of the compounds of the invention which 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 cases, the desired salts can be prepared by mixing the acid solution with a solution of a cationic salt of another acid, such as sodium ethylhexanoic acid or magnesium oleic acid, using a solvent from which the desired cationic salt precipitates, and the salt can of course be isolated by other means. 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 and the like. Those salts that do not precipitate directly are isolated by concentrating the reaction mixture to dryness or adding a non-solvent. .

The 3-acylated derivatives of the invention are readily prepared using standard acylation conditions, for example, by reaction of the oxazol-2,4-dione salt (as such or conveniently prepared in situ by adding one equivalent of a tertiary amine such as triethylamine, or N-). methylmolpholine, to the equivalent of the chloride or anhydride of the appropriate acid) or oxazolidin-2,4-dione, with the appropriate organic isocyanate, optionally in the presence of a catalytic amount of a tertiary amine base. In each case, 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 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.

The reactions used to prepare the compounds of the present invention can 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 can be used to distinguish 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 also help in the selection of optimal procedures.

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

Intact male white rats are used as test animals. The animals are fasted for about 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 orally, either water (control) or test compound 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 hour, 1 hour, 2 hours and 3 hours is calculated according to the following formula:

("glucose" content (content, glucose in control, treatment ^group) , _bh ------ X100%.

(glucose content in control, group)

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 glucose reduction in% after 0.5 hour and 1 hour. A glucose reduction of 0.9% or more generally represents a statistically significant hypoglycemic efficacy in this assay. For those compounds which show significant activity after, 2 or 3 hours, this activity is indicated in the notes.

.................... Ί hypoglycaemic activity of oxazolidine-2,4-dione in glucose tolerance test (rat)

Table I

Ar Dose (mg kg ^of] reduction 0.5 hours glucose content 1 hour 2-thienyl 10 11 8 5-benzoyl- 25 10 7 3-bromo- 10 8 6 ^a 5-bromo- 100 ALIGN! 36 19 Dec 5-chloro- 100 ALIGN! 26 17 3-methoxy- 5 13 16 5-methoxy- 25 9 7 3-methyl- 100 ALIGN! 30 17 10 14 12 5-methyl- 50 18 10 5-phenyl- 50 1 5 ^b) 3-thienyl 10 23 20 May 5 20 May 17 4-bromo- 100 ALIGN! 31 25 10 14 9 4-methoxy- 5 11 8 4-Methoxy-2-methoxy- thyl- 5 16 14 4-ethoxy- 5 19 Dec 19 Dec 4-ethoxy- 5 19 Dec 19 Dec 4-ethoxy-2-methyl- 5 7 12 4-propoxy- 5 11 6 2-furyl 100 ALIGN! 27 Mar: 23 10 11 7 3-bromo- 25 18 10 5 11 11 5-bromo- 50 19 Dec 20 May 10 2 11 5-chloro- 25 21 20 May 3-methoxy- 25 10 10 5-methyl- 100 ALIGN! 27 Mar: 19 Dec 5-phenyl 25 6 4 ^c) 3-furyl 10 17 13 5 14 8 2,5-dimethyl- 100 ALIGN! 33 ^e) 16 ^f) 4-iodine- 25 19 ^e) 0 ^f) 3-Benzo [b] thienyl 100 ALIGN! 11 5 7-Benzo [b] thienyl 100 ALIGN! -4 12 ^d) 7-Benzo [b] furanyl - - - 5-chloro- 10 23 ^e) 10 ^ř > 8-chromanyl - - - 6-chloro- 10 - 11 6-fluoro- 10 - 9 2,3-dihydrobenzo- furanyl - - - 5-chloro- 25 - 23 ^й ' 5-isoxazolyl- - - - 3-methyl- 100 ALIGN! 4 7 h)

Legend:

^(a) 11 after 2 hours ^(b) 9 after 2 hours

(c) after 3 hours, 10

d) 16 after 2 hours, 10 after 3 hours · 10

c) for 0.75 hours

f) for 1.5 hours

g) for 0.75 hours

(h) 24 hours after 2 hours, 14 hours after 3 hours.

The oxazolidine-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 does not cause any pain or irritation that may occur by injection. In cases where the patient cannot swallow the drug or when absorption after oral administration is impaired (whether due to disease or other effects), it is of course necessary to administer the drug parenterally. In both of the above modes of administration, the dosage ranges from about 0.10 to 50 mg / kg of patient body weight per day, preferably from about 0.20 to about 20 mg / kg of patient body weight per day, with the active ingredient being administered either in single or multiple doses. Although the optimum dosage in individual cases is determined by the attending physician, it is generally practiced that initially lower doses are administered, which are then gradually increased to determine the most appropriate. 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 described above. Thus, for oral administration, the active compounds of the present invention may be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions, and the like. auxiliary substances, etc.

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 invention may be used. Injectable solutions prepared in this manner may be administered intravenously, intraperitoneally, subcutaneously or intramuscularly, with intramuscular administration being preferred in humans.

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

Example 1

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

370 mg (1.66 mmol) of 5- [1-butyl) -2-furyl] oxazolidin-2,4-dione 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.

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 2

2- (6-chloro-8-chloro) -2-trimethylsiloxyethanenitrile

A solution of 7 g (0.036 mol) of 6-chlorochroman-8-carbaldehyde in 70 ml of methylene chloride is cooled to 0-5 ° C, 100 mg of zinc iodide are added, and 4.26 g (0.043 mol) of trimethylsilyl carbonitrile are added dropwise. . The reaction mixture was stirred at room temperature for 64 hours, then washed successively with saturated sodium bicarbonate solution (3 times) and once with brine, dried over anhydrous magnesium sulfate, and concentrated by filtration. 9.5 g of the title compound are obtained, which are obtained in the form of an oil.

IR (dichloromethane):

857, 1,479, 1,215, 1,190, 1,060 етЧ

Example 3

Ethyl 1- (6-chloro-8-chroman 1) -1-hydroxymothanecarboxamide amide hydrochloride

A solution of 9.29 g of the product of the preceding example in 15 ml of ethanol is added dropwise to 250 ml of saturated ethanolic hydrogen chloride solution cooled to 0 to 5 ° C, maintaining the temperature at 10 ° C. The reaction mixture was stirred at 0-5 ° C for 35 min. The oily residue was evaporated, which crystallized from ethanol / ether to give 5.7 g of the title compound, melting at 125-127 ° C with decomposition.

Mass spectrum: m / e = 271/269.

He attaches

5- (6-chloro-8-chromanyl) oxazolidine-2,4-dione

5.4 g (18.6 mmol) of the product of the preceding example are suspended in 250 ml of tetrahydrofuran, the suspension is cooled in ice-water and 6.01 g (0.06 mol) of triethylamine are added thereto. The reaction mixture was stirred at room temperature for 1 hour, then poured onto 1 ml of crushed ice and extracted three times with methylene chloride. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate and evaporated to a solid which recrystallized from toluene gave 3.28 g of the purified title compound, melting at 170-172 degrees Celsius.

Mass spectrum: m / e = 269/267.

Analysis for C12H10O4NCI:

calculated:

% H, 3.77;% N, 5.23.

found:

% C, 53.73;% H, 3.83;% 5.48.

Example 1 a d 5

5- (6-fluoro-8-chromanyl) oxazolidine-2,4-dione

3.9 g (0.0134 mol) of ethyl 1- (6-fluoro-8-chromanyl) -1-hydroxymethanecarboximidate hydrochloride were converted to the crude title compound by the procedure of Example 4. The crude solid product was taken up in 1 N sodium hydroxide solution. The product was precipitated twice with ether and the product was precipitated by slowly introducing an alkaline aqueous layer into an excess of 3 N hydrochloric acid, and recrystallized from toluene to give 2.73 g of the purified title compound, m.p. 174-176 ° C.

Mass spectrum: m / e = 251.

Analysis for C12H10O4NF:

calculated:

% C, 57.37;% H, 4.01;% N, 5.58%.

H, 3.91%; H, 5.40;

Example 6

5- (5-chloro-2,3-dihydro-7-benzo [b] furanyl) oxazolidin-2,4-dione

Using the procedure described in Example 4, 1.1 g of ethyl 1- (5-chloro-2,3-dihydro-7-benzo [b] furanyl] -1-hydroxymethanecarboximide hydrochloride was converted to 630 mg of the title product m.p. 197-199 ° C.

Mass spectrum: m / e = 255/253.

IC (KBr technology):

3084, 1833, 1810, 1746 cm -1

Example 7

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

Using the procedure described in Example 4, 2.2 g of ethyl-l-hydroxy-l- (3-methyl-5-isoxazolyl) -methankarbox midáthydrochloridu ⁷ was converted to the title product. After pouring the reaction mixture onto crushed ice, the product was extracted with ether, the combined extracts were dried and evaporated to an oily residue (1.4 g). Further extraction with ethyl acetate and evaporation gave an additional 0.4 g of oily material. The above oily fractions were combined and partitioned between 25 mL of 1 N sodium hydroxide and 25 mL of ether. The basic aqueous phase was separated, acidified with concentrated hydrochloric acid and extracted with 25 ml of ethyl acetate. The ethyl acetate extract was washed with water, evaporated to dryness and the residue triturated with ether. 146 mg of the product with a melting point of 173-175 ° C are obtained. The trituraco ether was evaporated to dryness and the residue was triturated with fresh ether to give an additional 238 mg of product, m.p. 175-177 ° C.

Example 8

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

Ethyl 1-hydroxy-1- (3-furyl) methanecarboximidate hydrochloride (1.5 g, 7.5 mmol) was treated with tetrahydrofuran (50 ml) and triethylamine (2.21 g, 21.9 mmol), cooled to 10 ° C and cooled to 10 ° C. Phosgene gas was added to the reaction mixture for 20 minutes, the reaction mixture was stirred for 30 minutes, nitrogen was added for 10 minutes, the mixture was poured slowly onto 100 g of crushed ice and extracted twice with ether. The crude aqueous phase was acidified and extracted with fresh ether. Evaporation of this last ether extract gave 600 mg of the product as a gummy solid which, after trituration with chloroform gave 109 mg of purified 5- (3-furyl) oxazolidine-2,4-dione, m.p. 86-88 ° C.

Mass spectrum: m / e = 167.

Addition of hexane to chloroform from trituration gave a second crop of 66 mg, mp 86-88 ° C.

Mass spectrum: m / e = 167.

Analysis for CzHsOéN:

calculated:

% C, 50.31;% H, 3.01;% N, 8.38.

H, 3.13; N, 8.37.

Example 9

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

Ethyl 1- (5-chloro-2-uryl) -1-hydroxymethanecarboximidate hydrochloride (1.2 g, 5 mmol) was suspended in tetrahydrofuran (50 ml), cooled in ice and 2.1 ml (15 mmol) added. The triethylamine is added to the phosgene gas for 20 minutes while maintaining the temperature at 10-20 ° C. The reaction mixture was purged with nitrogen and poured slowly into 100 ml of crushed ice. The aqueous mixture was extracted with ether (100 mL), washed with brine and concentrated. The oily residue is taken up in 15 ml of fresh ether, the solution is clarified and extracted with 10 ml of 1 N sodium hydroxide. The basic extract was acidified with concentrated hydrochloric acid and the product was extracted with ethyl acetate. The organic layer was washed with water and then concentrated to an oily residue (550 mg); 500 mg of this oil are chromatographed on about 50 ml of silica gel, eluting with hexane / ethyl acetate / 5% acetic acid (5: 1). The progress of column chromatography was monitored by thin layer chromatography using the same solvent mixture. The later eluted fractions containing the product were combined, evaporated to dryness and the residue triturated. with hexane. 177 mg of 5- (5-chloro-2-furyl) oxazolidine-2,4-dione, m.p. 112 DEG-114 DEG C., is obtained.

Mass spectrum: m / e = 201.

Rf = 0.25 (hexane-ethyl acetate with 5% acetic acid 5: 1).

Analysis for C7H4O4NCI:

calculated:

% H, 2.00%;% N, 6.95%.

H, 2.21; N, 6.77.

Example 10

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

982 mg (3,4 mmol) of ethyl 1- (5-bromo-2-furyl) -1-hydroxymethanecarboximidate hydrochloride were converted to 126 mg of 5- (5-bromo-2-furyl) oxazolidin-2 by the procedure of Example 8. 126 DEG-129 DEG.

Mass Spectrum: - in / u = 245, 247.

Rf = 0.2 (hexane-ethyl acetate with 5% acetic acid 5: 1). ·

Example 11

5- (3-bromo-2-uryl) oxazolidin-2,4-dione

The procedure is analogous to Example 9 except that the phosgene is introduced into the reaction mixture at 0-10 ° C. 4.4 g of ethyl 1- (3-bromo-2-furyl) -1-hydroxymethanecarboximidate hydrochloride are thus obtained. converted to 5- (3-bromo-2-furyl) oxazolidine-2,4-dione. 847 mg of purified product are obtained, m.p. 128-130 ° C.

R t = 0.20 (hexane-ethyl acetate with 5% acetic acid 5: 1).

Analysis for C7H4O4NBr:

calculated:

% C, 34.16;% H, 1.63;% N, 5.69.

H, 1.88; N, 5.67.

Example 12

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

10.5 g (6.2 mmol) of ethyl l- (2-furyl) ^{-1-hydroxymethankarbox:} midátu dissolved with stirring in 125 ml of tetrahydrofuran, cooled to 0 -to 5 ° C, treated with 12 Triethylamine (5 g, 0.124 mol) was added and phosgene gas was introduced into the cold solution for 35 minutes. The reaction mixture was warmed to room temperature, stirred for an additional 16 hours, then poured slowly into 1 liter of water with ice. The product is extracted with three portions of ethyl acetate. The extracts were combined and the product was extracted with four portions of 1 N sodium hydroxide. The combined aqueous extracts were acidified with 6 N hydrochloric acid and the product was extracted with 4 portions of chloroform. The combined chloroform extracts were dried over anhydrous magnesium sulfate, clarified with charcoal and evaporated after filtration. 2.1 g of crude product are obtained in the form of an oil which is chromatographed on 100 g of silica gel, eluting with chloroform / ethyl acetate (2: 1). Fractions of 10 ml are collected and the progress of column chromatography is monitored by thin layer chromatography. Evaporation of fractions 36 to 48 yielded 281 mg of purified 5- (2-furyl) oxazolidin-2,4-dione, m.p. 99-102 ° C.

Mass spectrum: m / e = 167.

Recrystallization from toluene yielded 235 mg of an even more pure product, melting at 101-103 ° C.

Analysis for C7H5O4N:

calculated:

% C, 50.31;% H, 3.02;% N, 8.38.

П A 1Р7РП O *

H, 3.25; N, 8.28.

Example 13

5- (5-Phenyl-2-thienyl) oxazoline-2,4-dione

790 mg (2.6 mmol) of ethyl 1-hydroxy-1- (4-phenyl-2-thienyl) methanecarboximidate hydride chloride and 1.4 ml (10 mmol) of triethylamine are treated with phosgene. After usual isolation and chromatography using a 2: 1 mixture of ethyl acetate and hexane as the eluent, 172 mg of 5- (5-phenyl-2-thienyl) -oxazolidine-2,4-diene is obtained, m.p. 233-235 ° C.

Analysis for C13H9O3NS:

calculated:

% C, 60.23;% H, 3.50;% N, 554.0%.

% C, 59.94;% H, 3.65;% 5.38.

Example 14

5- (2-thienyl) oxazolidine-2,4-dione g (5.4 mmol) of ethyl 1-hydroxy-1- (2-thienyl) methanecarboximidate and 15.1 ml (10.8 mmol) of triethylamine are dissolved in 100 ml of tetrahydrofuran The solution is cooled to 0-5 ° C and phosgene gas is introduced for 45 minutes · The reaction mixture is stirred at 0-5 ° C for 5 hours, then poured slowly into 150 do ml of crushed ice and the product extracts with 1.1 L of ethyl acetate in 3 portions The combined ethyl acetate extracts are washed twice with saturated sodium bicarbonate solution and once with a mixture of equal parts of water and saturated sodium carbonate solution. The product was extracted with several portions of ether and the combined ethereal extracts were washed with brine, dried over anhydrous magnesium sulfate, treated with charcoal and evaporated. 3.0 g of product are obtained which, after recrystallization from toluene, yields 1.8 g of 5- (2-thienyl-oxazolidin-4-one), m.p. 138-140 ° C.

Mass spectrum: m / e = 183.

Analysis for C7H5NO3S:

calculated:

15.89 ° ° C, 2.75% H, 7.65% N, found:

45.99% C, 2.87% H, 7.62% N.

Example 15

5- [3-methyl-2-thienyl) oxazolidine-2,4-dione

6.0 g (0.03 mol) of ethyl 4-methyl-oxytlt (3-methyl-2-thienyl) methanecarb (omidate) is dissolved in 75 ml of tetrahydrofuran, the solution is cooled to 0 to 5 ° C and treated with 6 ml. Triethylamine (07 g, 8.37 ml, 0.06 mol) was added and phosgene was added for 35 minutes The reaction mixture was slowly poured into 1 liter of ice-water and the product was extracted with three portions of ethyl acetate. The combined aqueous extracts were acidified with 6 N hydrochloric acid, and the product was extracted with three portions of fresh ethyl acetate, and these last organic extracts were dried over anhydrous magnesium sulfate and evaporated to give 2. 4 g (41%) of an oily product which crystallizes after scratching the sides of the vessel with a glass rod and recrystallized from toluene to give 1.83 g (total yield · 31%) of the purified 5- (3-methyl-1-2). --H Heny 1) oxazo mp 119-121 [deg.] C. Mass spectrum: m / e = 197.

Analysis for · C8H7O3NS:

calculated:

48.72 0/0 С »3.58 _0/0 N · 7.10% Found:

H, 3.58; N, 7.01.

A second crop of 0.63 g was obtained by extracting the initial ethyl acetate extracts with three portions of 1 N sodium hydroxide and further isolating as above.

Example 16

5- (5-methyl-2-hienyl) oxazolidine-2,4-dione

10 g (0.042 mol) of ethyl 1-hydroxy-1- (5-methyl-2-furyl) methanecarboximidate hydrochloride are mixed with 14.1 g (0.14 mol) of triethylamine in 250 ml of tetrahydrofuran and the solution is cooled to 0 to 0. 5 DEG C., cold phosgene gas is introduced for 30 minutes, then the mixture is warmed to room temperature and poured in portions to about 275 ml of crushed ice. The product is extracted twice with 200 ml of ethyl acetate each time, the ethyl acetate extracts are combined and extracted twice with 150 ml of 1N sodium hydroxide each. The combined aqueous extracts were acidified with hydrochloric acid and extracted twice with 250 ml of fresh ethyl acetate. The last organic extracts were combined, dried over anhydrous magnesium sulphate and evaporated. 7.2 g of 5- (5-methyl-2-thienyl) (xaz, olidin-254-dione) are obtained, which after recrystallization from chloroform-hexane yields 910 mg of purified product, m.p. 108-109 ° C.

Mass spectrum: m / e = 197.

Example 17

5- (5-chloro-2-thienyl) oxazolidin-2,4-dione

3.0 g (12 mmol) of ethyl 1- (5-chloro-2-thienyl) -1-hydroxymethanecarboximidate hydrochloride and 4.0 g (39 mmol) of triethylamine are mixed in 90 ml of tetrahydrofuran, the suspension is cooled to 0 ° C, Phosgene gas was introduced over 30 minutes, the reaction mixture was warmed to room temperature, stirred for 16 hours, then poured slowly onto 100 ml of crushed ice and the product was extracted twice with 100 ml of ethyl acetate. The combined ethyl acetate extracts were washed twice with 50 ml of water and once with 50 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulfate and, after filtration, evaporated to a semi-solid residue of 2.5 g. Recrystallization of this product from toluene yielded 0.6 g of purified 5- (5-chloro-2-henyl) oxazolidine-2,4-dione, m.p. 126-130 ° C.

Analysis for C7H4O3NCIS:

calculated:

% C, 38.64;% H, 1.84;% N, 4%;

% C, 38.17;% H, 2.07;% N, 6.91.

Example 18

5- (4-bromo-3-thienyl) oxazolidine-2,4-thione

6.0 g (23 mmol) of ethyl 1- (4-bromo-3-thicryl) -1-hydroxymethylcarbonyl) ximidate are treated with 5.15 g (51 mmol) of triethylamine in 250 ml of tetrahydrofuran, cooled in ice-water. and phosgene gas is introduced for 35 minutes. The reaction mixture was warmed to room temperature, stirred for 1.5 hours, then slowly poured onto 1 liter of crushed ice and the product was extracted with 3 portions of methylene chloride. The combined methylene chloride extracts were evaporated to an oily residue which crystallized upon addition of a small amount of ether and hexane. Trituration with about 40 ml of ether gave 3.4 g (56%) of 5- (4-bromo-3-thietyloxy-oxazolidine-4-dione), m.p. 158-161 ° C, which was recrystallized from 40 ml of toluene. 164 DEG-166 DEG C., 2.51 g of purified product.

Mass spectrum: m / e = 263/261.

Example 19

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

12.5 g (0.067 mol) of ethyl 1-hydroxy-1- (3-thienyl) metharkarboximidate and 16.1 g (0.159 mol) of triethylamine are mixed in 600 ml of tetrahydrofuran, the mixture is cooled to 0 ° C, over a period of Phosgene gas is introduced for 30 minutes; The reaction mixture was warmed to room temperature, allowed to stand for 16 hours, then poured slowly into 600 ml of ice-water (foaming releases excess phosgene) and extracted twice with 600 ml of ethyl acetate each time. The combined extracts were washed twice with 300 ml of 1 N sodium hydroxide each. The combined basic aqueous extracts were acidified with hydrochloric acid and the product was extracted twice with 300 ml of fresh ethyl acetate. The extracts are combined, dried over anhydrous magnesium sulphate and evaporated to a solid residue of 8.0 g which, after recrystallization from hot toluene, yields 5.5 g of purified 5- (3-thienyl) oxazolidin-2,4-dione mp 133-136 ° C; A second recrystallization from ethyl acetate / hexane yields an even further purified product. As a first crop of this crystallization, 2.352 g of product are obtained, m.p. 136-138 ° C.

Mass spectrum: m / e = 183.

IC (KBr): 5.5, 5.8 μη.

Example 20

Sodium-5- (oxazoline-2,4-dione)

3.0 g (16.4 mmol) of 5- (3-thienyl) oxazolidine-2,4-dione are dissolved in 60 ml of ethyl acetate, 300 mg of activated carbon are added, the mixture is stirred at 20 DEG C. for 10 minutes and filtered. and the residue on the filter was washed with ethyl acetate, 4.2 ml of a 3.78 N ethereal solution of sodium hydroxide were added to the filtrate, and the sodium salt crystallized from the mixture, after about 30 minutes 0.3 ml of water was added, the suspension was granulated for 30 minutes. at room temperature, then cooled to 5 ° C and granulated for an additional 30 minutes to give 3.37 g (95%) of sodium 5- (3-thienyl) oxazolidine-2,4-dione monohydrate at a temperature of mp 208-210 ° C.

Analysis for C7H4O3NSNa. H2O:

calculated:

% C, 37.67;% H, 2.71;% N, 6.28;

14.37% S, 10.30% Na, 8.07% H2O, found:

37.35% C, 3.03% H, 6.24% N, 27.83% O,

14.33% S, 10.76% Na, 8.30% H2O.

If sodium hydroxide is replaced with equivalent amounts of potassium hydroxide, diethanolamine, meglumine or piperazine, the corresponding salts are obtained. To facilitate precipitation of the product, the reaction solvent is evaporated as necessary or a non-solvent such as ether or hexane is added.

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

Example 21

5- (3-bromo-2-thienyl) -1H-azododirine-2-one

In 250 ml of tetrahydrofuran, 6.8 g (23 mmol) of ethyl 11 (2-bromo-2-thienyl) -1-hydroxy-4-methoxymethanecarbonyl oxidate hydrochloride and 7.6 g (10.5 ml; 76 mmol) of triethylamine are mixed, cooled to 0-5. The reaction mixture is warmed to room temperature, stirred for 16 hours, then poured slowly into 300 ml of crushed ice and extracted twice with 200 ml of chloroform. The combined chloroform extracts were washed with brine (60 ml), dried over anhydrous magnesium sulfate and, after filtration, evaporated to an oily residue which, upon addition of hexane and ether, precipitated a crystalline product. Recrystallization from toluene gave 2.25 g of 5- (3-bromo-2-thCenyl) zxazolidine-2,4-dicon, m.p. 138-139 ° C.

Analysis for C7H4O3NSB1 ':

calculated:

H, 1.59; N, 5.34; S, 12.21. Found:

% C, 32.41;% H, 1.75;% N, 5.49;

Example 2 2

5- (3-benzo [b] thienyl) oxazole-C 1 -C 12 1,2,4-dione

2.36 g (8.7 mmol) of ethyl 1- (3-benzo [b] thienyl) -1-hydroxymethoxybenzimidazole hydrochloride and 2.64 g (26 mmol) of triethylamine are combined in 50 ml of tetrahydrofuran, cooled to 10 [deg.] C and cooled to 10 [deg.] C. The reaction mixture was purged with nitrogen for 10 minutes, then slowly poured into 100 ml of ice and extracted twice with ether, and the combined ether extracts were washed with water and brine, dried over anhydrous sodium sulfate and dried. The crude product was dissolved in 1 N sodium hydroxide, washed twice with ether and acidified with 6 N hydrochloric acid to give 950 mg of purified 5- (3-benzo [ b] thienyl) dioxazole-2,4-dione, m.p. 202-205 ° C.

Mass spectrum: m / e = 233.

Analysis for C11H7O3NS:

calculated:

% C, 56.64;% H, 3.02;% N, 6.00.

H, 3.18; N, 5.69.

Example 23

5- (7-benzo [b] thienyl) oxazondine-2'-dione

Using the procedure described in Example 22, 1.1 g (4 mmol) of ethyl 1- (7-benzz [b] thienyl) -1-hydroxymethoxycarbodioxidate hydride and 1.7 ml (12 mmol) of triethylamine were reacted with phosgene. The crude product, isolated as an oil, was dissolved in 25 mL of ether and extracted with 50 mL of 1 N sodium hydroxide. The aqueous extract was acidified with concentrated hydrochloric acid. The product was extracted with fresh ether, the extract was washed with water and evaporated in vacuo to 670 mg of a solid residue, which recrystallized to give 0.45 g of 5- (7-benzd [b] thienyl) oxazoline. M.p. 130 DEG-132 DEG C .;

Analysis for C11H7O3NS:

calculated:

% C, 56.64;% H, 3.02;% N, 6.00.

H, 3.18; N, 5.91.

Example 24

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

The trium-o- (3-thienyl) zxazole-2,4-dione was dehydrated by drying in vacuo at 50 DEG-70 DEG C. 2.05 g (10 mmol) of the anhydrous salt was 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. There was obtained e-ethoxycarbonyl-5- (3-thienyl) oxazolidin-2,4-dione.

Example 25

3-acelyl-5- (3-thienyl) ox-3 -olidin-2,4-dione

Procedure

1.83 g (10 mmol) of 5- (3-thienyl) ox3zolidine-2,4-dione and 0.14 ml (10 mmol) of triethylamine are treated with 25 ml of 1,2-dib at room temperature in a few minutes 0.73 ml (10 mmol) of acetyl chloride are added dropwise, 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, filtered and evaporated. 3-Acyl-5- (S-thienyl) azolidin-P-di-one is obtained.

3 7'320

Procedure Β

1.83 g (10 mmol) of 5- (3-thienyl) oxazolidine-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. and the resulting 3-acetyl-5- (3-thienyl) oxalidin-2,4-dione is further isolated as in Procedure A.

Example 26

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

To 1.35 g of 1,2-dichloroethane is added 1.83 g (10 mmol) of 5- (3-thienyl) oxazolidine-2,4-dione and 1 drop of triethylamine, 0.58 ml (10 mmol) of methyl isocyanate are added and the mixture was stirred at room temperature for 4 hours. The reaction mixture is 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. 3- (N-methylcarbamoyl) -5- (3-thienyl) oxazolidin-2,4-dione is obtained.

Example 27

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

Using the procedure described in Example 8, 1.3 g (5.5 mmol) of the product of the previous example and 1.7 g (17 mmol) of triethylamine in 50 ml of tetrahydrofuran were reacted with phosgene at 0-5 ° C for 30 minutes. . The reaction mixture is stirred overnight at room temperature, then poured slowly onto 500 ml of crushed ice and extracted three times with 50 ml of chloroform each. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, and concentrated to a solid after filtration which, after recrystallization from toluene, yielded 510 mg of the purified title product, melting at 120-122 ° C.

IC (KBr - technology): 1377, 1732, 1767,

808 cm ^1st

Analysis for C8H7O4NS;

calculated:

45.06% C, 3.31 ·% H, 6.57% N, found:

% C, 45.31;% H, 3.41;% 6.85.

Example 28

5- (4-ethoxy-2-thienyl) oxazolidin-2,4-dione

Phosgene was added to a solution of 9.2 g of ethyl 1-hydroxy-1- (4-ethoxy-3-thienyl) methanecarboximidate hydrochloride at 0-5 ° C for 1 hour, and the reaction mixture was then allowed to react at room temperature for 1 hour. to give the title compound. To isolate the product, the reaction mixture is poured onto 1.5 liters of crushed ice and extracted three times with 200 ml of chloroform each. The organic layers were combined and extracted three times with 150 ml of 1 N sodium hydroxide each time, the basic extracts were combined, washed with 200 ml of fresh chloroform, acidified again with 3 N hydrochloric acid and extracted three times with 200 ml of chloroform each. The last three organic extracts were combined, washed with brine, dried (MgSO 4), and evaporated to a solid residue which was crystallized from toluene to give 4.06 g of the title compound, m.p. 146 ° C.

Mass spectrum: m / e = 227.

IR (KBr): 1,822, 1,737, 1,568 · cm ¹ ·

Analysis for C9H9O4NS:

calculated:

% C, 47.57;% H, 3.99;% N, 6.17.

H, 4.04; N, 6.06.

The chloroform from the washings of the basic extracts is extracted three times with 150 ml of fresh 1N sodium hydroxide each, these basic extracts are combined and, in a similar manner as above, a further 980 mg of product is obtained, m.p. 144-146 ° C.

Example 1 9

5- (4- (n-propoxy) -3- (4-hydroxyphenyl) oxazolidine) 2,4-dione

Using the procedure described in Example 27, 2.8 g (0.01 mol) of ethyl 1-hydroxy-1- (4- (n-propoxy) -3-thienyl) methanecarboximidate hydrochloride was converted to 5- [4- (n- propoxy) -3-thienyl] oxazolidin-2,4-dione. Recrystallization from toluene gave 1.63 g of product, m.p. 134-136 ° C.

Mass spectrum: m / e = 241.

IR (KBr): · 1,827, 1,747, 1,564 cm ^-1 .

Example · 3 0

5- (4-methoxy-2-methyl-1H-phenyl) -oxazolidine-2,4-dione

The procedure is as described in the Example, except that the reaction is carried out

3.5 hours at room temperature. In this way, 2.0 g (7.5 mmol) of ethyl-1-hydroxy-1- (4-methoxy-2-methyl-3-thienyl) methanecarboximidate hydrochloride was converted to the title compound. Recrystallization from toluene gave 0.52 g of the desired product, melting at 179-181 ° C.

Mass Spectrum: m / e = 227.

IC (KBr - technology): 1,820, 1,750, 1,727,

583 cm “!

Example 31

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

Using the procedure described in the previous example. 1.9 g of ethyl 1-hydroxy-1- (4-ethoxy-2-methyl-3-thienyl) methanecarboximidate hydrochloride was converted to 245 mg of the title compound, m.p. 136-138 ° C.

Mass spectrum: m / e = 241.

IR (KBr): 1824, 1743 cm @ -1.

Example 32

5- (5-chloro-7-benzo [b) furanyl) oxazolidin-2,4-dione

100 mg (0.39 mmol) of the title compound of Example 6 are suspended in 6 ml of chloroform and 100 mg (0.104 ml; 0.39 mmol) of bis- (trimethylsilyl) trifluoroacttamide are added in a single portion. After stirring for one minute, 69 mg (0.39 mmol) of N-succinimide was added along with a trace amount (single crystal) of benzoyl peroxide. The reaction mixture was warmed to room temperature for 2 hours, the insoluble material was filtered off, and the filtrate was evaporated under a stream of nitrogen to a semi-solid residue which was partitioned between 1 N sodium hydroxide and ethyl acetate. The aqueous layer was separated, washed with fresh ethyl acetate, acidified with 1 N hydrochloric acid and extracted three times with chloroform. The chloroform extracts were combined, dried over anhydrous magnesium sulfate and concentrated to an oily residue after filtration. 44 mg of the title compound crystallized from toluene, m.p. 154-157 ° C.

Mass Spectrum: m / e = 251, 253;

The following compounds can also be prepared as described above:

5- (3-methoxy-2-furanyl) oxazolidin-2,4-dione, m.p. 102-104 ° C; Rf = 0.6 (hexane-ethyl acetate 1: 1 with 5% acetic acid),

5- (5-phenyl-2-furyl) oxazolidin-2,4-dione, m.p. 216-218 ° C; R f = 0.6 (hexane-ethyl acetate 1: 1 with 5% acetic acid),

5- () oxazolidine-2,4-dione, m.p. 136.5-137.5 ° C,

144 DEG-145 DEG C., 5- (2,5-dimethoxy-1-3-trifluoromethyl) oxazolidine-2,4-dione, mass spectrum: m / e = 195,

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

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

P r a t a 1

6- cblorchroman

A mixture of 75 g of granulated zinc, 7.5 g of mercuric chloride, 125 ml of water and 4 ml of concentrated hydrochloric acid is shaken for 5 minutes, then allowed to settle and the liquid fraction is decanted off from the formed amalgam zinc. To the metal amalgam was first added a mixture of 100 ml of water and 126 ml of concentrated hydrochloric acid, then 15 g of 6-chloro-4-chromanone, and the mixture was

The mixture was heated at reflux for 1.5 hours. After cooling to room temperature, the liquid was decanted from zinc and extracted three times with ether. The combined extracts were dried over anhydrous magnesium sulphate and, after filtration, concentrated to an oily residue (14 g). This oil was chromatographed on 400 g of silica gel using hexane / ether (9: 1) as eluent. The progress of column chromatography was monitored by thin layer chromatography. Fractions of 15 ml were collected. Fractions containing pure product were combined and evaporated to give 8.72 g of the oily title compound.

NMR (CDCl3, δ ppm):

2.0 (multiplet, 2H), 3.7 (triplet, 2H),

4.1 (triplet, 2H), 6.9 (multiplet, 3H).

Mass spectrum: m / e = 170/168.

Rf 0.88 (2: 1 hexane-ether).

Preparation 2

C-chlorochroman-to-carbatdedyd

A mixture of 8.6 g (0.051 mol) of the product from the previous preparation and 75 ml of methylene chloride was cooled in ice water, 19.34 g (11.2 ml; 0.102 mol) of titanium tetrachloride was added, and then dropwise 6.2. g (0.054 mol) of 1,1-dichloromethyl methyl ether The reaction mixture was stirred at 0 ° C for 30 min and then poured slowly into 400 ml of saturated sodium bicarbonate solution. The aqueous phase was extracted three times with methylene chloride and the combined organic layers were washed sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated to give 7.9 g of the title compound, melting at 83-86 ° C.

NMR (deuterochloroform, δ in ppm):

2.0 (multiplet, 2H), 2.8 (triplet, 2H),

4.2 (triplet, 2H), 7.1 to 7.5 (multiplet, 2H),

10.2 (singlet, 1H).

Mass spectrum: m / e = 198/196.

Preparation 3

6-Fluorochroman

Using the procedure described in the preparation, 15 g of 6-fluoro-4-chromanone is converted to the title compound. . After chromatography, 5.7 g of 6-fluorochroman is obtained as an oil.

NMR · (deuterochlhrofhrm, δ in ppm):

2.0 '(multiplet, 2H), 3.8 (triplet, 2H),

4.1 '(triplet, 2H); 6.8 (multiplet, 3H).

Rf = 0.68 (2: 1 hexane-ether).

Mass Spectrum: m / e = 152.

Preparation 4

6-Fluorocorom8-8-carbaldehyde

Using the procedure described in the preparation, 5.5 g (0.036 mol) of the product of the preceding preparation were converted to the title compound which was first isolated as a viscous oil which crystallized from hexane. 3.4 g of the expected product are obtained, m.p. 54-57 ° C.

Mass spectrum: m / e = 180.

Preparation 5

3-Methyl-5-isoxazole-carboxamide 3-Methyl-5-isoxazolecarboxylic acid (g) was heated at reflux in 350 ml of thionyl chloride for 10 hours, then the mixture was stirred at room temperature for 16 hours. It is clarified by filtration and evaporated to an oily residue which is triturated several times with hot hexane. The liquids from these triturations were combined and evaporated to give a solid acid chloride (16.2-21 g).

g of the acid chloride prepared in this way,. is added portionwise to 300 ml of concentrated ammonium hydroxide at room temperature. After 1 hour granulation, 24.2 g of the title compound melting at 180-182 ° C is obtained by filtration.

Preparation · 6

The 3-methyl-5-isoxazolecarbonitrile product from the previous preparation was thoroughly mixed with 10 g of phosphorus pentoxide and the reaction flask was placed in an oil bath preheated to 140 ° C. The bath temperature was raised to 200 ° C and 2.9 g of the title compound was isolated by vacuum distillation. Spectrum of the product 16 · '(film), a nitrile band at 2220 cm ^_ 1 and no band in the amide I region of 1700 cm -1.

Preparation 7

3-Methyl-1- (5-a) -cyclo-2-ol-2-ol-2-ol;

1.08 g (0.01 mol) of the product from the previous preparation is dissolved in 25 ml of ether, the solution is cooled to -40 ° C and added thereto at this temperature. ml (0.012 mol) of 1 M diisobutylaluminum hydride in hexane. The mixture was stirred at -30 to -35 ° C for 10 minutes, while maintaining the temperature at -20 ° C, 60 ml of ethyl acetate were added thereto, then 15 ml were added thereto while maintaining the temperature at -25 ° C. ethanol and finally 3 ml of 6 N hydrochloric acid are added thereto while maintaining the temperature below -20 ° C. The reaction mixture · · · to · warmed to 5 ° C, the organic phase is washed · 25 ml of water and '· evaporated to an oil · --zbytek which is chromatographed on ⁵⁰ ml of silica gel using a mixture of · · · same parts of ether and hexane as eluent. The product-containing fractions were combined and evaporated to give 0.42 g of the desired compound, m.p. Deň: 32 ° C. A small sample of product melts at 43-45 ° C after further purification by sublimation.

Preparation 8

5-chlorobenzo [b] furan-2-carboxylic acid

31.3 g · (0.2 ·· mol) · 5-chlorosalicylaldehyde · dissolve in 200 · ml 2-butanone · add 82.9 g (0.6 mol) · potassium carbonate first and then 95.6 G (0.4 mol) of diethyl 2-bromomalonate and the mixture was heated under reflux for 5 hours. After cooling, the reaction mixture was freed from the salts by filtration and concentrated to an oily residue which was shaken between 500 ml of 10% sulfuric acid and 500 ml of ether. The aqueous layer was extracted twice more with 250 ml of fresh ether. The combined organic layers were washed with sodium chloride solution, dried over anhydrous magnesium sulfate and, after filtration, concentrated to a second oily residue. The second oily residue is dissolved in 400 ml of a 10% ethanolic potassium hydroxide solution, heated at reflux for 1 hour, and then evaporated to a solid residue. Dissolve in 1500 ml of water, filter to remove traces of insoluble matter, acidify with 6 N hydrochloric acid and filter off the precipitated solid.

Stirring this crude product in 1 liter of water yields 19 g of the purified title compound, melting at 259-262 degrees Celsius.

Mass spectrum: m / e = 198/196.

In an analogous manner, 5-fluorosalicylaldehyde and 6-chlorosalicylaldehyde are converted to 5-fluorobenzo [b] furan-2-carboxylic acid. and 6-chlorobenzo [b] furan-2-carboxylic acid, respectively.

Preparation 9

5- chlorobenzoobnuran

7.8 g of the title compound are mixed with 700 mg of copper powder and 50 ml of quinoline, heated at reflux for 5 minutes, then cooled to room temperature and diluted with 500 ml of ether. The insoluble material is filtered off, the filtrate is washed successively with 200 ml of 2 N hydrochloric acid and once with brine, dried over anhydrous magnesium sulphate and concentrated to an oily residue (6.2 g) which is chromatographed on 200 g of silica gel using of ether as eluent. Fractions of 300 ml are collected. Fractions 1 and 2 were combined and evaporated to give 6.1 g of the oily title compound.

In an analogous manner, other benzofurancarboxylic acids from the previous preparation are also converted to 5-fluorobenzoofuranofuran and

6-chlorobenzo [b] furan.

Preparation 10

3-Furaldehyde

To a suspension of 64.5 g (0.3 mol) pyridinium chlorochromate in 450 ml methylene chloride was added dropwise 19.6 g [0.2 mol) 3-furylmethanol in 50 ml methylene chloride. The exothermic reaction, which leads to a boiling reflux, is controlled by occasional cooling in ice. At the end of the 60 minute reaction time, the resin product began to precipitate. The reaction mixture was diluted with 600 milliliters of ether and the supernatant was added. decanting and filtering. The filtrate was passed through a short column of synthetic magnesium silicate using ether as the eluent. The collected fractions were combined and evaporated to an oily residue which, by distillation, gave 7.6 g of 3-furaldehyde, b.p. 68-72 ° C.

Alternatively, this aldehyde is prepared by Rosenmund reduction of 3-furoic acid chloride [Hayes, J. Am. Chem. Soc. 71, 2581 [1949]].

Fříprava 11

2- (2-furyl) -1,3-dioxolane

42 ml (0.5 mol) of 2-furaldehyde, 50 ml (0.9 mol) of ethylene glycol and about 200 mg of p-toluenesulfonic acid are mixed in 150 ml of toluene, and the mixture is heated under reflux for 6 hours to collect the resulting reactions. water in Dean-Stark's sump. The reaction mixture was cooled, diluted with 500 mL of ether and clarified by filtration. The filtrate is washed with 200 ml of saturated sodium bicarbonate solution and the organic phase is again clarified by filtration. The second filtrate was washed with 200 ml of water and the organic layer was concentrated to dryness to give 45 g of oily 2- (2-furyl .beta.-dioxolane).

Preparation 12

Dissolve 2- (5-chloro-2-yl) -1,3-dioxolane [0.1 mol] 2- (2-furyl) -1,3-dioxolane in 100 ml of tetrahydrofuran, The mixture was cooled to -25 to -20 ° C and treated with 45 ml (0.1 mol) of 2.2 M butyllithium in hexane over 10 minutes while maintaining this temperature. The mixture is allowed to warm to 0 ° C over 25 minutes, then recooled to -30 ° C and, while maintaining the temperature in the range of -30 to -25 ° C, 23.7 g [0.1 mol. of hexachloromethane in 50 ml of tetrahydrofuran. The reaction mixture is warmed to room temperature,

Stir 1.5 hours. it is then recooled to 5 ° C and slowly diluted with 500 ml of water. The product is extracted twice with 500 ml of ether each time and the extract is evaporated to dryness as an oily residue (15.8 g). This oil is chromatographed on 200 ml of silica gel with hexane / ethyl acetate [8: 1]. The progress of column chromatography was monitored by thin layer chromatography on silica gel using the same solvent mixture. The initial product-containing fractions were combined and evaporated to give 5 g of purified 2- [5-chloro-2-furyl) -1,3-dioxolane as an oil.

Rf = -0.6 (hexane-ethyl acetate 8: 1).

Fříprava 13

5-chloro-2-furaldehyde

Dissolve 4.8 g of 2- (5-chloro-2-furyl) -1,3-dioxolane in 20 ml of ether, add 10 ml of 6 N hydrochloric acid and stir the biphasic mixture at room temperature for 1 hour. The ether phase was separated, washed with water and evaporated to give 2.8 g of 5-chloro-2-furaldehyde as an oil.

Example 14

5-Bromo-2-fluoro-carboxamide 5-bromo-2-furoic acid was refluxed with 60 ml of thionyl chloride for 3 hours and the corresponding acid chloride was isolated by evaporation in oily form. This acid chloride was added dropwise with stirring to 150 ml of concentrated ammonium hydroxide. Filtration gave 5-bromo-2-furylcarboxamide (17.0 g), m.p. 140-143 ° C.

Preparation 15

5-Bromo-2-furylcarbonitrile 5-bromo-2-furylcarboxamide (g) was treated with 50 ml of phosphorus oxychloride, refluxed for 24 hours, then poured onto ice and the product was extracted with ether. Evaporation gave 6.4 g of oily 5-bromo-2-furyl carbonitrile.

Preparation 16

5-bromo-2-furaldehyde

Dissolve 2,3 g [13 mmol] of 5-bromo-2-furylcarbomtrifulum in 50 ml of ether, cool the solution to -10 ° C under nitrogen and, while maintaining the temperature at about -10 ° C, add dropwise 1, 9 g (13 mmol) of diisobutylaluminum hydride in toluene (25% solution). The reaction mixture was allowed to warm to room temperature, stirred for about 16 hours, then cooled to 0-5 ° C, diluted with 1 mL of methanol, acidified with 3 N hydrochloric acid and evaporated after washing with water. There was obtained 1.2 g of 5-bromo-2-furaldehyde, m.p. 74-76 ° C.

Preparation 17

3-Bromo-2-furldehyde

To 5.4 g (70 mmol) of dimethylformamide is added at 0-10 ° C 6.5 g (70 mmol) of phosphorus oxychloride, the resulting suspension is diluted with 10 ml of ethylene dichloride and added while maintaining the temperature at about 10 ° C. 9.2 g (63 mmol) of 3-bromofuran. 'The reaction mixture was heated for 1 hour at 58-60 ° ^C then cooled to 10 ° C with vigorous stirring and maintaining the temperature at 10-30 ° C was added slowly' 15 g of sodium acetate trihydrate dissolved in 25 ml water . The resulting mixture was heated at 68-72 ° C for 20 minutes, then cooled to room temperature and diluted with 20 mL of water. The product is extracted with 75 ml of ether, the ether extract is washed with water and concentrated. 0.9 g of oily 3-bromo-2-furaldehyde is obtained.

Rf = 0.65 (hexane-ethyl acetate) 3: 1.

Preparation 18

3-iodofuran

14.7 g (0.1 mol) of 3-biofluoromethane in 100 ml of ether are cooled. to -70 ° C and 42 ml (0.1 mol) of 2.4 M butyllithium in hexane was added dropwise over 0.5 hour while maintaining the temperature from -70 to -65 ° C. While maintaining the above temperature, 25 g (0.1 mol) of iodine in 200 ml of ether are added over 1 hour, the reaction mixture is warmed to room temperature, then recooled to 2 ° C and 100 ml of water are added dropwise. The ether layer was separated, washed. with an aqueous solution of thiosulphate and water, dried over anhydrous sodium sulphate and evaporated to an oily residue which, by distillation gives

15.7 g З’-осИ ^ гапи at boiling point. 48 ° C / 3.733 Pa.

Preparation 19

3fmethoxyfura'n

Dissolve 5.6 g (0.24 mol) of sodium metal in 150 ml of dry methanol, add 15.7 g (0.08 mol) of 3-iodofuran and 8 g (0.1 mol) of cuprous oxide, and with vigorous stirring for 42 hours under reflux. The reaction mixture was cooled to room temperature, diluted with 200 mL of water and the product was extracted with 100 mL of ether. The ethereal extract was washed with 15 ml of water, dried over anhydrous sodium sulfate and evaporated to give crude 3-methoxyfuran suitable for further work-up. The yield of this product, which is about 50% pure, is about 3-4 g.

Preparation 20

5-phenyl-2-henaldehyde

1.6 g (0.01 mol) of T-phenylthiophene [prepared according to J. Am. Chem. Soc. 46, 2339 (1924)] are dissolved in 20 ml of tetrahydrofuran, cooled to -40 ° C and cooled to -40 ° C. maintaining the temperature at -40 to -30 ° C, 4.5 mL of 2.2 M butyllithium in hexane was added over 3 minutes, warmed to 0 ° C, then cooled to -40 ° C while maintaining the temperature at -40 ° C. To -40 ° C to -30 ° C was added 1.2 mL (15 mmol) of dimethylformamide and the resulting mixture was warmed to room temperature for 0.5 hours then cooled to 0 ° C. 6 ml of 6 N hydrochloric acid, diluted with 10 ml of water and extracted with 20 ml of ether, evaporated to dryness to give 1.9 g of a crude product which, after recrystallization from about 35 ml of hexane, yields 0.9 g. 90 DEG-92 DEG C., purified 5-phenyl-4- (4-methylene) aldehyde.

Preparation 21

4-bromo-3-thenaldehyde g (0.062 mol) 3,4-dibromothiophene [J.

Org. Chem. 36, 2690 (1971)] in 20 mL of ether was cooled to -70 ° C and 34.8 mL (0.073 mol) of 2.1 M butyllithium in hexane was added dropwise over 5 minutes. After stirring at -70 ° C for 5 minutes, the solution was transferred to a solution of 6.8 g (0.093 mol) of dimethylformamide in 35 ml of ether using a nylon tube under nitrogen under pressure. The resulting mixture was heated at reflux for 2 hours, then cooled to room temperature, washed successively twice with 1N hydrochloric acid twice, then once with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to an oily residue after filtration, which is subjected to double distillation. 5.7 g of 4-bromo-3-thenaldehyde having a boiling point of 81 to 84 DEG C./0.7 mbar are obtained.

Mass spectrum: m / e = 192/190.

Preparation 22

2-phenylfuran

46.5 g (0.5 mol) of aniline are mixed with 500 ml of water and 100 ml of concentrated hydrochloric acid, cooled to -5 ° C and maintained at a temperature of -3 to -5 ° C over 45 minutes. a solution of 36.2 g (0.525 mol) of sodium nitrite in 100 ml of water is added dropwise.

After the addition was complete, the mixture was stirred at -35 ° C for 30 minutes, then 68 g of zinc chloride was added. Maximum precipitation of the d'azonium salt is achieved by adding 100 grams of sodium chloride. The reaction mixture was removed from the cooling bath, stirred for 5 minutes, carefully filtered and air dried without washing for 2 hours (premature vacuum drying of the product results in an explosive decomposition). The intermediate diazonium salt was suspended in 750 ml of furan at 0 ° C and 5 g of powdered sodium hydroxide was added to the suspension with vigorous stirring, followed by 10 g of anhydrous sodium acetate. The reaction mixture was stirred at 0 ° C for 5 hours and then at room temperature for 16 hours, the solids were filtered off and the filtrate was evaporated. 25 ml of crude product are obtained in the form of an oil which, by distillation, yields 9.2 to 9.6 g of 1-phenylfuran having a boiling point of 87 to 95 ° C / 2000 Pa (50 ° C / 133 Pa).

Preparation 23 ....... .............. ......

2-phenyl-2- (2-thienyl) -1,3-dioxolane

A mixture of 19 g (0.1 mol) of 2-benzoylthiophene, 11 ml (0.2 mol) of ethylene glycol, 150 ml of toluene and about 0.2 g of p-toluenesulfonic acid is heated under reflux for 6 hours, the water formed as · Secondary. the product is collected in a Dean-Stark well. Thin layer chromatography (ethyl acetate-hexane 1: 8) indicated that the reaction was about 40%. An additional 30 ml of ethylene glycol is added and refluxing is continued for 35 hours, after which time the reaction is still not complete. The reaction mixture is diluted with 200 ml of ether, washed twice with 150 ml of water and concentrated to dryness. The residue is chromatographed on about 500 ml of silica gel with ethyl acetate / hexane (1: 8) as eluent. The course of column chromatography is monitored by thin layer chromatography. The faster fractions containing the product were combined and evaporated to give 8 g of oily 2-phenyl-2- (2-thienyl) 11,3-diGoxolan.

Rf = 0.6 (ethyl acetate-hexane 1: 8).

Preparation 24

Methyl 4-methoxy-3-thenoate g of methyl 4-acetoxy-34henoate (U.S. Pat. No. 3,144,235) is dissolved in 20 ml of methanol and this solution is added to 100 ml of methanol containing 0.31 ml of concentrated The mixture was heated at reflux for 4 days, then neutralized with 0.6 g of sodium acetate and the solvent was evaporated, the residue was taken up in ether (200 ml), washed successively with water (2 x 50 ml) and water (2 x 50 ml). 1 N sodium hydroxide and twice with 50 ml each of sodium chloride, dried over anhydrous magnesium sulphate and, after filtration, evaporated to an oily residue which crystallized on standing to give 4.35 g of product, m.p. 64-66 ° C.

If the reaction described above was allowed to proceed for only one day, the desired product was isolated in low yield (2.2 g) after working up the reaction mixture. The two extracts in 1 N sodium hydroxide were combined and acidified to precipitate 5.13 g of methyl 4-hydroxy-3-thenolate.

If it dissolves. The alcohol is dissolved in 100 ml of methanol containing 0.3 ml of concentrated sulfuric acid and heated to reflux for 3 days. After treatment as described above, 2.10 g of the title compound is obtained. at 64-66 ° C.

Preparation 25

1- (4-Methoxy-3-thienyl) methanol

3.9 g (23 mmol) of methyl 4-methoxy-3-thenoate (U.S. Pat. No. 4,144,235) is dissolved in 50 ml of toluene, cooled in a solid carbon dioxide-acetone cooling bath and stirred for 30 minutes. 46 ml (46 mmol) of 1 H diisobutylaluminum hydride in hexane were added dropwise. The mixture was stirred for 2 hours with cooling in the above bath, then allowed to warm to room temperature and 14.7 g (18.6 mL; 0.46 mol) of methanol was slowly added thereto while maintaining the temperature below 30 ° C. The reaction mixture was stirred at room temperature for 16 hours, whereupon a granulated precipitate formed. The resulting mixture was filtered through a pad of diatomaceous earth, which was washed with methanol. The filtrate is combined with the washings and concentrated to give

2.8 g of the title compound as an oil.

Mass spectrum: m / e = 144.

Preparation 26

4-Methoxy-3-thienoldehyde

6.4 g (29.7 mmol) of pyridinium chlorochromate are dissolved in 100 ml of methylene chloride and this solution is added in one portion to a solution of 2.8 g (19.8 mmol) of the product of the preceding preparation also in 100 ml of methylene chloride. The mixture was stirred at room temperature for 3 hours, then diluted with 200 ml of ether and the precipitated black precipitate was separated by decanting from it, washed twice with 100 ml of ether each time, the decanted liquid phase was combined with the washings, successively. The residue was washed twice with 1 N hydrochloric acid, once with water, twice with 1 N sodium hydroxide and once with brine, dried over anhydrous magnesium sulfate and concentrated by filtration to give 2.6 g of the title compound as an oil.

Mass spectrum: m / e = 142.

IR (a! Chlrrmetean):

1688, 1544 cm ^-1 .

Preparation 27

Ethyl 4-ethoxy-3-thienoate

The procedure is similar to that described in U.S. Patent No. 4,144,235; Dissolve 20 g of methyl 4-acetoxy-3-thienoate in 240 ml of ethanol and add 0.62 ml of concentrated sulfuric acid. The reaction mixture is gently refluxed for 79 hours, then neutralized by the addition of 1.2 g of sodium acetate and evaporated to an oily residue. The mixture was partitioned between 400 ml of ether and 50 ml of water. The organic layer was separated, washed successively with 75 ml of water, 3 times with 50 ml of 1 N sodium hydroxide each time and twice with 75 ml of brine each time, dried over anhydrous magnesium sulphate and evaporated after filtration. 14.9 g of the title compound are obtained as an oil.

According to NMR spectroscopy, the product consists exclusively of ethyl ester and contains no methyl ester.

Preparation 28

1- (4-chloro-C-thienyl) methanol

Using the procedure of Preparation 25, 14 g of the product from the previous preparation were converted to

9.15 g of the title compound as an oil.

Preparation 29

4-tetrloxy-3-thenatdehyde

Using the procedure described in the preparation, 9.15 g of the product from the previous preparation was converted to the title compound, which was primarily isolated as an oil which rapidly crystallized upon cooling. 8.18 g of product are obtained, m.p. 42-45 ° C.

Mass spectrum: m / e = 156.

IR (KBrr-echnika):

3090, 2977, 1688 ст

Preparation 30 n-propyl 1-4- (n-propoxy) -3-thenoate

The reaction is carried out as described in the preparation, except that the reaction mixture is refluxed for 10 days. In this way, 6 g of ethyl 4-acetrxy-ε-thenoate in 750 ml of propane containing 0.109 ml of concentrated sulfuric acid was converted to 5.4 g of the title compound as an oil.

Mass spectrum: m / e = 228.

Preparation 31

1- (4- (n-propoxy) -3-thienyl) methanol

Using the procedure described in Preparation 25, 5.4 g of the product from the previous preparation was reduced to the title compound which was isolated as an oil-yellow. substance. Yield 3.44 g.

Mass Spectrum: m / e = 172.

Preparation 32

4- (4-proporyl) -C3: hennldahed

Using the procedure described in Preparation 26, 3.34 g of the product from the previous preparation was converted to 3.19 g of the title compound.

Mass spectrum: m / e = 170.

IR (aichlrrmetean):

1689, 1539 cm ^-1 .

Preparation 33

Ether-4-methoxy-2-methyl-3-chenoate

7.8 g of ethyl 4-hydroxy-2-methyl-3-thenoate [Chem. Ber. 48, p. 593 (1915)] is mixed with p

600 ml of methanol and 0.25 ml of concentrated sulfuric acid are added and the mixture is heated under reflux for 21 hours. The reaction mixture was evaporated to an oily residue which was taken up

500 ml of ether, the solution is washed twice with 50 ml of 1 N sodium hydroxide each time and once with brine, dried over anhydrous magnesium sulfate and evaporated. 7.8 g of the oily title compound are obtained.

I-NMR: m / e = 200.

The NMR spectrum of the product, measured in deuterochloroform, contains a singlet for methoxy protons, at 3.9 ppm.

The product is contaminated with a small amount of the corresponding methyl ester.

Preparation 34 (4-Methoxy-2-methyl-3-thienyl) methanol

7.8 g (0.039 mol) of the product from the previous preparation are dissolved in 100 ml of hexane and 75 ml of toluene, cooled to -78 ° C and 78 ml (0.078 mol) of 1 M diisobutylaluminum hydride in hexane are added dropwise over 40 minutes. . The mixture was stirred at -78 ° C for 2 hours, then warmed to room temperature and stirred for an additional 16 hours. While maintaining the temperature below 30 ° C, 25.0 g (31.6 ml; 0.78 mol) of methanol are added dropwise, the resulting mixture is stirred at room temperature for 1.5 hours and then clarified by filtration through a pad of diatomaceous earth. The filter cake is stirred with methanol and washed thoroughly with methanol and finally washed with methylene chloride. The filtrate was combined with the washings, dried over anhydrous magnesium sulfate, and evaporated after filtration. This afforded 5.56 g of the title compound as an oil.

Mass spectrum: m / e = 158.

IR (dichloromethane):

3598, 1582, 1708 cm ^-1 .

Preparation 35

4-Methoxy-2-methyl-3-thenaldehyde

Using the procedure described in Preparation 26, 5.4 g of the product from the previous preparation (0.034 mol) was converted to 5.23 g of the title compound isolated as an oil.

Claims (4)

A process for the preparation of racemic or optically active 5-substituted oxazolidine-2,4-diones of the general formula I (I) in which: R is hydrogen, C1 -C4 alkanoyl, C2 -C4 alkoxycarbonyl or C1 -C3 alkylcarbamoyl, and R ¹ represents a 3-alkyl-5-isoxazolyl group having 1 to 3 carbon atoms in the alkyl moiety, 3 or 7-benzo [b] thienyl group, a residue of the formula wherein either Y is an oxygen atom, X ¹ represents a hydrogen atom, a halogen atom, a methyl group or a methoxy group; X ² represents a hydrogen atom or a methyl group, or Y represents a sulfur atom, X ¹ represents a hydrogen atom, a halogen atom, a phenyl group, an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms, and X ² represents a hydrogen atom or a C 1 -C 3 alkyl group, and pharmaceutically acceptable salts thereof, including alkali metal salts and acid addition salts, in the form of a racemate or an optically active enantiomer, characterized in that the phosgene is left in an inert solvent to react with a compound of formula II wherein Z represents a halogen atom and n is 1 or 2, or a radical of formula (II) in which R ¹ has the abovementioned meaning and · R ² represents a C 1 -C 3 alkyl group to form the compound of formula III 2. A process according to claim 1, wherein the corresponding starting materials are used to form compounds of formula (I) in which: R is as in 1 a R ¹ represents 3- or 7-benzo [b] thienyl, a radical of formula or a radical of formula wherein Y is an oxygen or sulfur atom, X ¹ is methyl and X ² represents a hydrogen atom, and pharmaceutically acceptable salts thereof, including alkali metal salts and acid addition salts, in the form of the racemate or ¹ optically active enantiomers. 3. A process according to claim 1, wherein the corresponding starting materials are used to form compounds of formula (I) in which: R is as in 1 a R ¹ represents a radical of formula R ¹ R ² O in which R ¹ and R ² are as defined above, hydrolyzed to form a compound of formula I wherein R ¹ is as defined above and R is hydrogen, followed by an optionally formed racemic compound of formula I wherein R ¹ has and R is hydrogen, resolved into the optically active enantiomers by separating diastereomeric salts prepared with an optically active amine and regenerating the above defined optically active compounds of formula I by acidification, and / or obtaining a compound of formula I wherein R ¹ has and R is hydrogen, acylated by treatment with an appropriate acid chloride, anhydride or isocyanate to form a compound of formula I wherein R ¹ and R are as defined above except for R, and the resulting product is treated as a hydrogen atom. isolated as such or in the form of a pharmaceutically acceptable salt from the group consisting of alkali metal salts and acid addition salts, in the form of a racemate or an optically active enantiomer. 4. A process according to claim 1, wherein the corresponding starting materials are used to form compounds of formula (I) in which: R is as in 1 a R ¹ represents a 3-alkyl-5-isoxazolyl group having 1 to 3 carbon atoms in the alkyl moiety, 3- or 7-benzo [b] thienyl group, where: Z represents a halogen atom or a radical of formula wherein either Y represents an oxygen atom, X ¹ represents a hydrogen atom, a halogen atom, a methyl group or a methoxy group; X ² is a hydrogen atom or a methyl group, provided that when X ¹ is a hydrogen atom or a methyl group, X ² is not a hydrogen atom, or Y is a sulfur atom, X ¹ represents a hydrogen atom, a halogen atom, a phenyl group, an alkyl or alkoxy group. C 1 -C 3; and X ² represents a hydrogen atom or a C 1 -C 3 alkyl group, and pharmaceutically acceptable salts thereof, including alkali metal salts and acid addition salts, in the form of a racemate or optically active enantiomers. where Y is an oxygen or sulfur atom, and pharmaceutically acceptable salts thereof, including alkali metal salts and acid addition salts, in the form of a racemate or optically active enantiomers.