KR850000390B1 - Process for preparing 5-substituted oxazolidines-2,4-diones - Google Patents

Abstract

5-Substd. oxazolidine-2,4-diones of formula (I) or their pharmaceutically acceptable cationic salts are prepd. by oxidizing compds. of formula (II) at 25-100≰C in an inert solvent, with an excessive amt. of oxidizing agent. In the formulas, R1 is of formula (III); Z' is H or methoxy; Z" is H; Q is S; X≰is H or halo; and X1 is H. (I) are hypoglycaemic agent, used for reducing blood glucose levels in the control of diabetes. Doses are. e.g., 0.10-50, pref. 0.20-20 mg/kg/day.

Description

5-molded oxazolidine ｜ Method for preparing 2,4-dione

The present invention relates to a process for preparing a new racemic or optically active 5-substituted oxazolidine-2,4-dione of the following general formula (I) and pharmaceutically nontoxic salts thereof useful as hypoglycemic agents.

In the above formula

R is hydrogen, (C ₁ to C ₄ ) -alkanoyl (eg formyl, acetyl, isobutyryl), benzoyl, (C ₂ to C ₄ ) -carbalkoxy (eg carbomethoxy, carethoxy, Carboisopropoxy), (C ₁ to C ₃ ) -alkylcarbamoyl (eg N-methylcarbamoyl, N-propylcarbamoyl), (C ₅ to C ₇ ) -cycloalkylcarbamoyl (eg N- Cyclohexylcarbamoyl) or di- (C ₁ to C ₃ ) -dialkylcarbamoyl (eg, N, N-dimethylcarbamoyl);

R ¹ represents a group of the following general formulas (i) to (vii):

2- or 3-pyrrolyl and indolyl derivatives of,

7-halo-8-chromenyl or 5- or 6-halo-7-benzofuranyl derivatives,

의 3-, 4- 및 5-이소티아졸릴 및 이속사졸릴 유도체, 또는

3-, 4- and 5-isothiazolyl and isoxazolyl derivatives of, or

[From here

R 'is (C ₁ to C ₄ ) alkyl or phenyl,

R '' is hydrogen, (C ₁ to C ₄ ) alkyl or phenyl,

X is halo (fluoro, chloro, bromo or iodo),

Y is hydrogen or (C ₁ to C ₃ ) alkoxy,

Y 'is hydrogen or (C ₁ to C ₃ ) alkyl,

Y '' is hydrogen or halo,

Z 'is hydrogen, halo or (C ₁ to C ₃ ) alkoxy,

Z '' is hydrogen or halo,

W is hydrogen or halo,

n is 1 or 2,

Q is sulfur or oxygen,

V is hydrogen or (C ₁ to C ₃ ) alkyl,

X ¹ is hydrogen or methyl,

X ² is hydrogen, fluoro, chloro, bromo or iodo,

X ⁰ is hydrogen, fluoro, chloro, bromo, iodo, methyl, phenyl, benzoyl or (C ₁ to C ₃ ) alkoxy,

Provided that when X ¹ is hydrogen, the substituent X ⁰ in (a) of group (vii) may be attached at any of the empty carbon positions of the furan / thiophene ring, and thus the compound of general formula (I) may be oxazolidine- All of the 5- (2-furyl)-, 5- (3-furyl) -5- (2-thienyl)-and 5- (3-thienyl) -derivatives of 2,4-dione, ie

Wherein X ⁰ and Q are as defined above, and O _x means an oxazolidine-2,4-dione ring attached at the 5-position; If both X ⁰ and X ¹ are not hydrogen, the second substituent may be present at an empty position in any one of the six derivatives; In (b) of group (vii) oxazolidine may be substituted at the 2-, 3- or 7-position of the benzo [b] furan / benzo [b] thiophene ring system as follows.

Wherein Q and O _x are as defined above.

The present invention provides 5-furyl, 5-thienyl, 5-chromenyl, 2,3-dihydro benzo [b] furanyl, 5-pyridyl, 5 of oxazolidine-2,4-dione useful as a hypoglycemic agent. -Quinolyl, 5-pyrrolyl, 5-indolyl, 5-thiazolyl, 5-oxazolyl, 5-isothiazolyl and 5-isoxazolyl derivatives.

Initially, insulin was discovered and used extensively in the treatment of diabetes mellitus, and then sulfonylureas (e.g. chlorpropamide, tolbutamide, acetohexamide, tol azamide) and biguanides (e.g. Has developed and used phenformin, but the treatment of diabetes is not satisfactory. When insulin is used in severely diabetic patients who are not commercially available as synthetic hypoglycemic agents, they should generally be self-injected several times a day. To determine the proper dosage of insulin, it is often necessary to measure the equivalent in urine or blood.

In addition to the hypoglycemics mentioned above, several other compounds have recently been reported to have this type of action by blank. See Blank, Burger's Medicinal Chemistry, Foruth Edition, Part II, John Wiley and Sons, N.Y. (1979), pp. 1057-1080.

Although oxazolidine-2,4-dione is a widely known compound, see Clark-Lewis, Chem. Rev. 58, pp. 63-99 (1958)], oxazolidine-2,4-diones prepared according to the process of the present invention are novel compounds. Among these compounds, among the known compounds, as intermediates of certain β-lactam antimicrobial agents (see Sheehan, US Pat. No. 2,721,197), as antidepressants [Plotnikoff, US Pat. No. 3,699,229], as antispasmodic, see Brink and Freeman, J. Neuro. Chem. 19 (7), pp. 1783-1788 (1972); 5-phenyloxazolidine-2,4-dione, which has been variously reported; Several 5-phenyloxazolidine-2,4-diones substituted on a phenyl ring, for example 5- (4-methoxyphenyl) oxazolidine-2,4-dione [King and Clark-Lewis, J. .Chem. Soc., Pp. 3077-3079 (1961)], 5- (4-chlorophenyl) oxazolidine-2,4-dione [Najer et al., Bull. Soc. Chem. France, pp. 1226-1230 (1961)], 5- (4-methylphenyl) oxazolidine-2,4-dione [Reibsomer et al., J. Am. Chem. Soc. 61, pp. 3491-3493) and 5- (4-aminophenyl) oxazolidine-2,4-dione (see Federal Republic of Germany Patent No. 108,026); And 5- (2-pyryl) oxazolidine-2,4-dione [Ciamacian and Silber, Gazz, Chim. ital. 16,357 (1886); Ber. 19, 1708-1714 (1886).

The compounds mentioned at the end are not known for their use in the prior art and show only relatively mild hypoglycemic action (see Table I).

Oxazolidine-2,4-dione and substituted oxazolidine-2,4-dione (specifically 5-methyl and 5,5-dimethyl derivatives) are known to form acid addition salts with hypoglycemic, basic biguanides. It is reported as a residue of a suitable acid (Shapiro and Freedman, US Pat. No. 2,961,377). We have demonstrated that neither oxazolidine-2,4-dione itself or 5,5-dimethyl oxazolidine-2,4-dione has hypoglycemic action of the compounds of the present invention.

Recently, a group of spiro-oxazolidine-2,4-dione derivatives known as aldose reductase inhibitors has been found to be effective in treating complications of diabetes (Schnur, US Patent 4,200,642).

Methods of synthesizing 3-aryloxazolidine-2,4dione, wherein the aryl group contains 6 to 12 carbon atoms and is unsubstituted or substituted with one or more halogen atoms, methyl or methoxy, have recently been known. Is the subject of another US patent (Scholz, US Pat. No. 4,220,787). There is no mention of the use of these compounds.

The present invention also includes pharmaceutically harmless cationic salts of compounds of formula (I), wherein R is hydrogen, and pharmaceutically harmless acid salts of compounds of formula (I), wherein R 'contains basic nitrogen functionality.

The high functionality inherent in these compounds is predominantly present in compounds where R is hydrogen, and furthermore, compounds in which R is one of the various carbonyl derivatives described above represent so-called pro-drugs, e.g. It is removed by hydrolysis under chemical conditions to give an active compound wherein R is hydrogen.

"Pharmaceutically nontoxic cationic salts" means alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts), aluminum salts, salts such as ammonium salts and benzatin (N, N ' Dibenzyl ethylenediamine), choline, diethanol amine, ethylenediamine, meglumine (N-methylglucamine), bentamine (N-benzylphenethylamine), diethylamine, piperazine, tromethamine ( Salts with organic amines such as 2-amino-2-hydroxy methyl-1,3-propanediol) and procaine.

"Pharmaceutically nontoxic acid addition salts" include hydrochloride 'hydrobromide, hydroiodide, nitrate, hydrogen sulfate, dihydrogen phosphate, mesylate, maleate, succinate and the like.

The compounds of the present invention exhibit hypoglycemic action in clinical trials that lower blood sugar levels in hyperglycemic mammals, including humans. These compounds have the advantage of lowering blood sugar levels to normal, especially without the risk of causing hypoglycemia. Compounds of the invention were tested for hypoglycemic activity in rats using the glucose tolerance test as described below.

Preferred compounds are those wherein R is hydrogen or a pharmaceutically harmless salt thereof, since these compounds have excellent hypoglycemic activity. Among the compounds of formula (I) wherein R is hydrogen, the most preferred compounds having excellent hypoglycemic action are: 5- (1-methyl-2-pyrrolyl) oxazolidine-2,4-dione, 5- ( 1-ethyl-2-pyrrolyl) oxazolidine-2,4-dione, 5- (1-pentyl-2-pyrrolyl) oxazolidine-2,4-dione, 5- (2-methoxy-3 -Pyridyl) oxazolidine-2,4-dione, 5- (2-ethoxy-3-pyridyl) oxazolidine-2,4-dione, 5- (5-chloro-2-methoxy-3 -Pyridyl) oxazolidine-2,4-dione, 5- (5-chloro-2-ethoxy-3-pyridyl) oxazolidine-2,4-dione, 5- (8-quinolyl) oxa Zolidine-2,4-dione, 5- (7-methoxy-8-quinolyl) oxazolidine-2,4-dione, 5- (6-chloro-8-quinolyl) oxazolidine-2, 4-dione, 5- (6-fluoro-8-quinolyl) oxazolidine-2,4-dione, 5- (2-benzothiazolyl) oxazolidine-2,4-dione, 5- (2 -Thiazolyl) oxazolidine-2,4-dione, 5- (6-chloro-8-chromenyl) oxazolidine-2,4-dione, 5- (6-fluoro-8-chromenyl) oxa Zolidine-2,4-dione, 5- (5-chloro-2,3-di Idro-7-benzofuranyl) oxazolidine-2,4-dione, 5- (3-methyl-5-isoxazolyl) oxazolidine-2,4-dione, 5- (3-thienyl) oxa Zolidine-2,4-dione, 5- (4-bromo-3-thienyl) oxazolidine-2,4-dione, 5- (4-ethoxy-3-thienyl) oxazolidine-2 , 4-dione, 5- (4-ethoxy-2-methyl-3-thienyl) oxazolidine-2,4-dione, 5- (4-methoxy-2-methyl-3-thienyl) oxa Zolidine-2,4-dione, 5- (3-methyl-2-thienyl) oxazolidine-2,4-dione, 5- (3-methoxy-2-thienyl) oxazolidine-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) Oxazolidine-2,4-dione, 5- (7-benzo [b] thienyl) oxazolidine-2,4-dione, and

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

Compounds of the present invention are prepared according to Scheme I below.

In the following scheme

R ¹ is as defined above and R ² is lower alkyl (eg methyl or ethyl).

Reaction Scheme Ⅰ

Oxazolidine-2,4-dione precursor

Two other precursors suitable for the synthesis of the desired oxazolidine-2,4-dione are thio compounds (II) and (8). The desired oxa in the presence of a cosolvent, such as a lower alcohol, in general using an excess of 2-thioxo compound (II) under oxidizing conditions, for example mercury ions, aqueous bromine or chlorine, metaperiodate, or aqueous hydrogen peroxide. Convert to zolidine-2,4-dione. The reaction temperature is not critical but is generally in the range 25 to 100 ° C. Where R ¹ has an amine functionality, a competitive oxidation reaction occurs in nitrogen, which reduces yield and makes the separation of the desired product difficult, so other methods are generally preferred, but the product contains tertiary-amines (e.g. pyridine, quinoline). Reagents that are well suited for this purpose are periodate or bromine. The alkylthio compound (8) is simply acid or base catalyzed hydrolysis to afford oxazolidine-2,4-dione. It is preferable to use aqueous hydrochloric acid at the temperature of 0-50 degreeC as reaction conditions.

Precursor 2-thioxo compound (II) is reacted with the corresponding aldehyde, generally in an aqueous, acidic medium, with thiocyanate (1 to 1.1 equivalents) and cyanide (1 to 1.2 equivalents) at 0 to 70 ° C. Subsequently, the preparation of known 5- (2-thienyl) -2-thioxazolidin-4-one [See Acta. Pharm Suecica 5 (1), pp. 15-22 (1968); Chem. Abstr. 69,52050k] by Lindberg and pederson method. Precursor 2-alkylthio compound (8) is equivalent to 2-thioxo compound (II), preferably at least 2 equivalents of lower alkoxides.

Pharmaceutically nontoxic cationic salts of the compounds of the present invention which form such salts are readily prepared by reacting an acid with a suitable base, typically 1 equivalent, in a cosolvent. Representative bases include sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium methoxide, magnesium hydroxide, calcium hydroxide, benzatin, choline, diethanolamine, ethylenediamine, meglumine, benethanamine, diethylamine, Piperazine and tromethamine. These salts, which do not precipitate directly, are concentrated to dryness or separated by addition of a nonsolvent. In some cases, the acid solution is mixed with a solution of another salt of the cation (sodium ethyl nusanoate, magnesium oleate) using a solvent to precipitate the desired cationic salt to prepare the salt or to separate it by concentration and addition of a nonsolvent. can do.

Pharmaceutically unfavorable acid addition salts of the compounds of this invention which form such salts are readily prepared by reacting a base with a suitable acid, typically 1 equivalent, in a co-solvent. Representative acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, maleic acid, succinic acid and the like. Salts that do not precipitate directly are concentrated, dried or separated by addition of a nonsolvent.

The 3-acylated derivatives of the present invention may be prepared by reaction with standard acylation conditions, for example, with oxazolidine-2,4-dione salts (triethylamine or N-methyl moiety together with itself or with 1 equivalent of an appropriate acid chloride or acid anhydride). Conveniently in the same reaction system by addition of one equivalent of a tertiary amine such as poline) or optionally by reaction of oxazolidine-2,4-dione with an appropriate organic isocyanate in the presence of a catalytic amount of tertiary amine base. Are manufactured. In either case, the reaction was carried out in a reaction inert solvent such as toluene, tetrahydrofuran or methylenechloride.

Since the compounds of the present invention are asymmetric, there may be two optically active enantiomeric forms. The racemic compound of the invention, present as an acid where R is hydrogen, forms salts with organic amines. Thus, the racemic form can generally be isolated into the optically active form by conventional methods of forming diastereomer salts with the optically active amine and can be separated by selective crystallization. Compounds containing basic amine functional groups can also be isolated by forming salts with optically active acids, preferably strong organic acids such as sulfonic acids. In general, one of the enantiomeric forms has been shown to be more active than the other.

The reactions used in the preparation of the compounds of the present invention can generally be monitored by standard tlc methods using commercially available plates. Eluents are conventional solvents such as chloroform, ethyl acetate or hexane, or suitable mixed solvents thereof, and separate starting materials, products, by-products and even intermediates. By using such methods well known in the art, it is possible to improve the test methods of the specific examples described below and to select, for example, more suitable reaction times and temperatures and optimum processes.

Oxazolidine-2,4-dione of the present invention is easily adopted for clinical use as a therapeutic agent for diabetes. The hypoglycemic action required for these clinical uses is demonstrated by the following glucose tolerance test methods. Albino rats (males) are used as experimental test animals and glucose tolerance tests are performed. The test animals are starved for approximately 18 to 24 hours. Rats are weighed and numbered and grouped in groups of 5 or 6 as needed. Glucose (1 g per kg) was administered intraperitoneally to each group of animals and water (control) or compound (dose selected from 0.1 to 100 mg / kg)

Clinically useful hypoglycemic agents show activity in this test. The hypoglycemic activity measured for the compounds of the present invention is summarized in Table 1. This table records the blood glucose lowering rate at 0.5 hours and 1 hour. Blood glucose lower than 9% generally indicates a statistically significant hypoglycemic effect in this trial. Compounds that show significant action at only 2 or 3 hours have the action as reported in the footnote.

TABLE 1

Hypoglycemic Action of Oxazolidine-2,4-Dione in Glucose Tolerance in Rats

(a) 2 to 11

(b) 2 to 9

(c) three to ten

(d) 16 to 2 hours; 3 to 10

(e) at 0.75 hours

(f) at 1.5 hours

(g) at 0.75 hours

(h) 2 to 9

(i) 3 hours to 12

(j) 2 to 24 hours, 3 to 14 hours

Oxazolidine-2,4-dione of the present invention is administered orally or parenterally to mammals, including humans. Oral administration is preferred, more convenient and avoids pain and irritation upon injection. However, parenteral administration of the drug is necessary if the patient is unable to take the drug due to disease or other disorders or if absorption is poor due to oral administration. By any route, from about 0.10 to about 50 mg, preferably from about 0.20 to about 20 mg / kg, per kg body weight of the patient is administered in single or multiple doses daily. However, the optimal dose for each patient to be treated will be determined by the person in charge of treatment, generally at a lower dose initially and then weighed to determine the most suitable dose. This depends on the specific compound used and the patient to be treated.

These compounds can be used as pharmaceutical preparations containing the compound or a pharmaceutically toxic salt thereof and a pharmaceutically toxic carrier or diluent. Inert solid fillers or diluents and sterile aqueous or organic solutions are suitable as pharmaceutically nontoxic carriers. The active compound is contained in such a pharmaceutical composition in an amount sufficient to provide the desired dose within the aforementioned ranges. Thus, for oral administration, the compounds of the present invention may be mixed with suitable solid or liquid carriers or diluents to give capsules, tablets, powders, syrups, solutions, suspensions

The present invention is described in the following Examples, and the present invention is not limited to these Examples.

Example 1

5- (8-quinolyl) oxazolidin-4-one-2-thione

484 mg (4.9 mmol) of potassium thiocyanate and 370 mg (5.7 mmol) of potassium cyanide are combined in 5 ml of water and cooled to 0 ° C. Quinoline-8-carbaldehyde [J. Org. Chem. 41, p 957 (1976)] is then added dropwise to 1.9 ml of 30% hydrochloric acid. After stirring for 25 minutes at 0 C, the reaction mixture was heated to 90 to 100 ° C. for 25 minutes, cooled and treated with crushed ice, adjusted to pH 8 with sodium bicarbonate, and extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate, filtered, evaporated and dried (163 mg). The product obtained is partitioned between 1N sodium hydroxide and ethyl acetate. The bastosis is acidified and extracted with fresh ethyl acetate. The combined two layers of ethyl acetate were dried, filtered and evaporated to afford 72 mg of the title product [R _f : 0.65 (ethyl acetate)]. The original aqueous layer, pH 8, is chlorided and extracted with ethyl acetate to give 114 mg more product. The last aqueous phase is acidified and extracted with ethyl acetate to give 115 mg of the third product.

Example 2

5- (8-quinolyl) oxazolidine 2,4-dione

230 mg (0.94 mmol) of the title compound of Example 1 are dissolved in 6 ml of methanol: water (2: 1) and cooled to 0 ° C. 0.07 ml (21.7 mg, 2.7 mmol) bromine is added and the reaction mixture is slowly warmed to room temperature and stirred for 1 hour. The reaction mixture is evaporated, dried and the residue is partitioned between 1N sodium hydroxide and ethyl acetate. The aqueous layer is separated, acidified and extracted twice with fresh ethyl acetate. The combined acidic extracts are dried and evaporated to yield 144 mg of oil. Crystallization from toluene-chloroform followed by recrystallization from toluene yields 40 mg of the purified title product. m / e: 228

Elemental _{analysis: C 12 H 8 O 3 N} 2 · O.33H 2 O

Calculated Value: C61.54 H3.70 N11.96

Found: C61.50 H3.89 N11.52

According to the same method, the chloro compound of Example 1 is converted to 5- (7-chloro-8-quinolyl) -oxazolidine 2,4-dione.

Example 3

5- (6-methoxy-5-quinolyl) oxazolidin-4-one-2-thione

0.77 g of 6-methoxyquinoline-5-carbaldehyde is converted to the title product according to the method of Example 1. Treated with ice, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, evaporated and dried to separate 190 mg of the primary component. Bicarbonate was added to the aqueous phase, adjusted to pH 8, extracted with ethyl acetate, and 176 mg of the secondary product was isolated in the same manner. Both products are m / e 274. The secondary product is also m / e 258, which indicates that the next product is mixed.

Example 4

5- (6-methoxy-5-quinolyl) oxazolidine-2,4-dione

The products of Example 3 were combined (0.36 g, 1.31 mmol) and responded to 15 ml of methanol. 0.56 g (2.62 mmol) of sodium metaperiodate in 7.2 ml of 5% sodium bicarbonate is added dropwise. After stirring for 3 hours at room temperature the reaction mixture is treated with water, acidified and extracted twice with ethyl acetate. The organic extracts are combined and dried over anhydrous magnesium sulfate, filtered, evaporated and dried (110 mg). The aqueous phase is adjusted to pH 7 and extracted with ethyl acetate to give 100 mg more crude product. The crude products are combined, dissolved in 1N sodium hydroxide, acidified to pH 4 with acetic acid and extracted with fresh ethyl acetate. The latter organic extracts are combined, evaporated and dried. The residue is triturated with ether and the mixture is left to crystallize to give 34 mg of the title product. Melting Point: 144 to 146 ° C

Example 5

5- (7-methoxy-8-quinolyl) oxazolidin-4-one-2-thione

According to the method of Example 1, however, after treatment, the pH was adjusted to 7 using sodium bicarbonate and extracted with ethyl acetate to convert 2.0 g (10.7 mmol) of 7-methoxyquinoline-8-carbaldehyde to 1.17 g of the title product. Let; R _f : 0.7 [2: 1 ethyl acetate: chloroform] does not partition the product between the aqueous base and ethyl acetate and does not chloride and extract the aqueous phase to separate the secondary product.

Example 6

5- (7-methoxy-8-quinolyl) oxazolidine-2,4-dione

0.74 g (2.7 mmol) of the product of Example 5 are combined with 30 ml of methanol and 15 ml of 5% sodium bicarbonate. 1.15 g (5.4 mmol) of sodium metaperiodate in 15 ml of water is added dropwise. After stirring for 3 hours at room temperature the reaction mixture is treated with water, acidified to pH 2-3 and extracted twice with ethyl acetate. The combined extracts are dried and evaporated to dryness. (360 mg). Recrystallization from water gives 100 mg of the purified title product.

Melting Point: 207-208 ℃

Elemental _{analysis: C 13 H 9 N 2 O} 3 · 1.2H 2 O

Calculated Value: C59.40 H4.34 N10.66

Found: C59.33 H4.01 N10.66

Example 7

5- (5-Bromo-2-thienyl) -2-thioxooxazolidin-4-one

7.9 g (0.123 mol) of potassium cyanide and 10 g (0.104 mol) of potassium thiocyanate are combined in 8.5 ml of water and stirred at 0 ° C. 20 g (0.104 mol) of 5-bromo-2-tenaldehyde are added to form a slurry. 50.7 ml of 30% hydrochloric acid is added to produce an oil ball. The reaction mixture was diluted with 104 ml of water and stirred for 48 hours to form a granular solid. Filtration recovers the solid and partitions between chloroform and 5% sodium bicarbonate. The mixture is filtered, the aqueous layer is separated, acidified and filtered to recover the precipitated product. Recrystallization from toluene yields 2.08 g of purified 5- (5-bromo-: 2-thienyl) -2-thioxo oxazolidin-4-one.

Melting point: 119 to 120 ° C.: m / e: 279/277

Elemental Analysis: C ₇ H ₄ BrNO ₂ S ₂

Calculation: C30.23 H1.95 N5.04

Found: C30.54 H1.72 N5.26

Example 8

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

1.5 g of 5- (5-bromo-2-thienyl) -2-thioxooxazolidin-4-one 1 at 50 ° C .; 1 water: responds to 10 ml of ethanol. To the stirred solution was added 7.0 ml of 30% hydrogen peroxide, which became somewhat turbid. 1 ml of ethanol is added to reduce turbidity. The mixture is heated at 70 ° C. for 30 min, cooled slightly and diluted with 100 ml of water and extracted with chloroform. The chloroform extract is washed twice with 50 ml of sodium bicarbonate. The aqueous extracts were combined, filtered and clarified, acidified to pH 1.0 with hydrochloric acid and filtered to yield 0.51 g (36%) of 5- (5-bromo-2-thienyl) oxazolidine-2,4-dione. .

Melting point: 139 to 139.5 ° C; m / e: 263/261

Elemental Analysis: C ₇ H ₄ BrNO ₃ S

Calculation: C32.08 H1.54 N5.34

Found: C32.16 H1.69 N5.47

Preparation Example 1

6-hydroxyquinoline-5-carbaldehyde

25 g of sodium hydroxide was reacted with 35 ml of water, a solution of 5 g of 6-hydroxyquinoline in 15 ml of chloroform was added, and the reaction mixture was heated to reflux (about 90 ° C.) for 12 hours, during which 15 ml of chloroform was added once at a time. After an hour, another 6 hours later. The reaction mixture is cooled down and the crude product is recovered by filtration. The crude material is dissolved in 125 ml of hot water treated with activated charcoal, filtered while hot and cooled, acidified with acetic acid and filtered to give 2.5 g of the title product. Melting point: 136 to 137 ° C m / e: 173: pnmr / CDCl ₃ represents an aldehyde proton at 10.5 ppm and an aromatic proton at 7.2 to 9.4 ppm.

Production Example 2

6-methoxyquinoline-5-carbaldehyde

A solution of 1.7 g (9.8 mmol) of the product of Preparation Example 1 in 85 ml of acetone is combined with 1.21 g (8.8 mmol) of potassium carbonate. 0.83 ml (8.8 mmol) of dimethylsulfate are added and the mixture is stirred at rt for 16 h. Further 0.34 g (2.5 mmol) of potassium carbonate and 0.23 ml (2.5 mmol) of dimethylsulfate are added and the mixture is stirred at room temperature for at least 4 hours and then at 60 ° C. for 3 hours. The reaction mixture is cooled to room temperature, filtered to remove salts and the filtrate is evaporated to dryness. The residue was dissolved in ethyl acetate and in order with 1N ammonium hydroxide.

R _f : 0.35 (2: 1 ethyl acetate: chloroform); pnmr / CDCl ₃ / δ (ppm): 4.2 (S, 3H), 7.4 to 9.1 (m, 5H), 10.3 (S, 1H)

Preparation Example 3

7-hydroxyquinoline-8-carbaldehyde

According to the method of Preparation Example 1, 5 g of 7-hydroxy quinoline is converted to 3.3 g of the title product. Melting point: 127 to 130 ° C; m / e: 173; pnmr CDCl ₃ shows aldehyde protons at 10.8 ppm and aromatic protons at 7.0-8.9 ppm.

Production Example 4

7-methoxyquinoline-8-carbaldehyde

According to the method of Preparation Example 2, 3.3 g (19 mmol) of the product of Preparation Example 3 are converted to 2.1 g of the title product. pnmr / CDCl ₃ / δ (ppm): 4.1 (S, 3H), 7.5 to 9.0 (m, 5H) 11.2 (S, 1H)

Claims (1)

The tao compound of formula (II) is oxidized with an excess of an oxidizing agent in a reaction inert solvent at 25 to 100 ° C., so that 5-substituted oxazolidine, a racemate of formula (I-1)- A process for preparing a 2,4-dione compound or a pharmaceutically toxic cationic salt thereof.

In the formula, R ¹ represents a group of the following general formula.

[Wherein Z 'is hydrogen or methoxy, Z "is hydrogen, Q is sulfur, X ⁰ is hydrogen or halo, and X ¹ is hydrogen.