HU201939B - Process for producing spiro(quinazoline-4,4-imidazolidine) derivatives - Google Patents

Description

The present invention relates to a novel process for the preparation of quinazolinone derivatives. More particularly, the invention relates to a novel process for the preparation of quinazolinone derivatives of the formula I and their salts. In the general formula (I) 5

R ¹ is lower alkyl or hydrogen,

R ² , R ³ , R ⁴ and R ⁵ each independently represent 10 hydrogen or halogen, lower alkyl or lower alkoxy groups, or two adjacent groups of 15 R ² , R ³ , R ⁴ and R ⁵ together at their terminal ends are lower alkylene they form a -dioxy group and the other two groups represent a hydrogen atom.

Next the number became 204 534 and 269 378 European Published release file 25 to the spiro-1,2,3,4-tetrahydro-quinazolin-4,4'-imidazolidine] -2,2 ', ^5-trione, 3- (lower) alkyl spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-triones and derivatives substituted on the benzene ring are useful in the treatment of diabetic diseases such as for the prevention and treatment of diabetic neurosis.

We have done intensive research work above. a novel process for the preparation of said quinazolinone derivatives, and it has been discovered that these compounds can be prepared much more readily and in higher yields than a known preparation by using a 5-hydroxy-5- [2- (alkoxycarbonyl-40-amino) -phenyl] imidazolidine is reacted with a lower alkanol and then the corresponding 5-alkoxyimidazolidine derivative is reacted with a lower alkylamine or with ammonia. 45

Accordingly, it is an object of the present invention to provide a 5-hydroxy-5- [2- (alkoxycarbonylamino) phenyl] imidazolidine derivative of formula (II) wherein -COOR ⁶ is a protected carboxylic acid. 50, while R ² , R ³ , R ⁴ and R ⁵ are as defined above, reacted with a lower alkanol and then a 5-alkoxyimidazolidine derivative of formula (III) wherein R ⁷ is short alkyl, while R ² , R ³ , R ⁴ , R ⁵ and -COOR ⁶ are as defined above, is reacted with a lower alkylamine or ammonia when a desired compound of formula (I) or a compound of formula (IV) is used. The compound of Formula 60, wherein R 4, R ² , R ³ , R ⁴ , R ^5, and -COOR ⁶ are as previously defined, is obtained and, when obtained, is subjected to intramolecular cyclization and finally 65 case something The compound of formula (I) thus obtained is converted into a salt.

The reaction of the starting compounds of formula II with a lower alkanol is carried out in a conventional manner, for example in the presence or absence of an acid catalyst. The protected carboxyl group represented by the formula -COOR ^{6 may include} conventional protecting groups such as a lower alkyl group, a phenyl group or an aralkyl group such as benzyl or phenethyl. Examples of lower alkanol include methanol, ethanol, isopropanol or mixtures thereof. The 5-alkoxyimidazolidine compound (III) corresponding to the alkanol used is obtained. An acidic catalyst may be, for example, an organic acid (such as p-toluenesulfonic acid, methanesulfonic acid or camphorsulfonic acid), an inorganic acid (such as sulfuric acid or hydrochloric acid) or a strongly acidic ion exchange resin (e.g. Amberlite IR-120 ion exchange resin). The reaction may be carried out at temperatures of from 0 ° C to 80 ° C, preferably from 20 ° C to 60 ° C. This reaction does not require the use of a solvent as the lower alkanol serves as the solvent. The compounds of formula (III) thus obtained can be used in the next step without further treatment.

The reaction of the compounds of formula (III) with lower alkyl amines or ammonia is carried out in a solvent. If the reaction is carried out in the presence of an equimolar amount of a lower alkylamine or ammonia, an intermediate of formula (IV) is first obtained, which is then subjected to intramolecular cyclization by reaction with an additional amount of lower alkylamine or ammonia. Conversely, when the reaction is carried out in excess, such as 1-4 molar equivalents of lower alkylamine or ammonia, the desired compound of formula (I) is obtained directly from the corresponding 5-alkoxyimidazolidine derivative of formula (III). The reaction solvent may be, for example, methanol, ethanol, tetrahydrofuran, dioxane or aqueous mixtures thereof. The lower alkyl amines or ammonia may be used alone or in the form of solutions in water or in an organic solvent. Aqueous solutions are generally preferred. The reaction is carried out at a temperature of 0 ° C to 80 ° C, preferably 10 ° C to 60 ° C.

Compounds of formula (II) used as starting materials may be prepared by reacting an isatin derivative of formula (V) wherein R ² , R ³ , R ⁴ and

HU 201939 Β

^R5 is as defined above - or its salts, such as sodium or potassium salt of the formula wherein X is halogen with a compound of formula (VI) and - COOR ⁶ are as defined above - is reacted in a solvent such as tetrahydrofuran, optionally an amine, e.g. for example in the presence of triethylamine at a temperature of 0 ° C to 80 ° C, followed by the reaction of a compound of formula VII, wherein R ² , R ³ , R ⁴ , R ⁵ and -COOR ⁶ are as previously defined. and in a solvent such as tetrahydrofuran at a temperature between 50 ° C and 120 ° C. The starting compounds of formula (II) thus obtained can be used in the process of the invention without any isolation and purification step, obviously in a very advantageous manner.

In summary, it can be stated that the compounds of formula (I) can be readily prepared from the isatin derivatives of formula (V) by isolation of certain intermediates formed during synthesis, i.e., compounds of formulas (VII) (II), (III) and (IV). and without cleaning. In addition, commercially available aqueous solutions of such alkylamines or ammonia may be advantageously employed in the reaction of the compounds of formula III or IV with lower alkyl amines or ammonia, so that the process of the present invention is highly advantageous for industrial scale production, as there is no loss of intermediates during the isolation and purification steps, whereby the compounds of formula (I) can be prepared from said isatin derivatives of formula (V) in greater than 70%, i.e., high yields.

The invention is further illustrated by the following embodiments.

Example 1

A solution of 14.0 g of 5- [2- (ethoxycarbonylamino) phenyl] -5-hydroxyimidazolidine-2,4-dione and 0.7 g of concentrated sulfuric acid in 50 ml of methanol was added at 45 ± 5 ° C. After stirring for 1 hour, 24 g of a 40% aqueous solution of methylamine are added. The reaction mixture was stirred at the said temperature for 3 hours and then concentrated under reduced pressure. The residue was dissolved in 50 ml of water and the resulting aqueous solution was adjusted to pH 4 with concentrated hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and dried. Thus, 11.2 g (91%) of 3-methyl-epiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', m.p. We get a '-trion.

IR (cm ^-1 ): 3330, 3120, 3080,

1781, 1735, 1680,

1615

MS (m / s): 246 (M ^4).

Example 2

5- [2- (Benzyloxycarbonylamino) -phenyl] -5-hydroxy-imidazolidine-2,4-dione, 5-hydroxy-55- [2- (methoxycarbonyl-amino) -phenyl] - imidazolidine-2,4-dione and 5-hydroxy-5- [2- (isobutoxycarbonylamino) phenyl] imidazolidine-2,4-dione were treated as described in Example 1 when 89% Yield 3-methylspiro [10,3,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione.

This product has the same physico-chemical characteristics as the product of Example 1.

Example 3 (1) - (a) 27.9 g of 5- [2- (ethoxycarbonylamino) phenyl] -5-hydroxyimidazolidine-2,4-dione and 1.4 g of concentrated sulfuric acid in 100 ml ethanol solution was stirred at 45 ° C for 1 hour and then cooled, the precipitated crystals were collected by filtration, washed and dried to give 23.6 g (77%) of 5-ethoxy-5 (m.p. 177-179 ° C). [2- (Ethoxycarbonylamino) phenyl] imidazolidine-2,4-dione is obtained.

IR W ^ul (cm ' ¹ ):

3400,

3080,

1720,

3210, 3110, 1790, 1740, 1595

MS (m / s): 307 (M ^4). (l) - (b) 5.6 g

A mixture of 5- [2- (ethoxycarbonylamino) phenyl] -5-hydroxyimidazolidine-2,4-dione and 1.0 g. Of Amberliet IR-120 strongly acidic ion exchange resin in 20 ml of methanol. Stir at 45 ± 5 ° C for 3.5 hours and allow to stand overnight. The resin was filtered off and the filtrate was concentrated under reduced pressure. 5.8 g (99%) of 5- [2- (ethoxycarbonylamino) phenyl] -5-methoxyimidazolidine-2,4-dione are obtained as a viscous oil.

IR W '* ¹ (cm ^-1 ): 3390, 3250, 3100,

1790, 1740, 1590

MS (m / s): 261 (M -32 ^4).

(2) 15.4 g of 5-ethoxy-5- [2- (ethoxycarbonylamino) phenyl] imidazolidine-2,4-dione and 3.9 g of 40% (w / w) aqueous methylamine solution A solution of 100 ml of methanol was stirred at 25 ° C for 6 hours, then the reaction mixture was allowed to stand overnight and then concentrated under reduced pressure. A small amount of methanol was added to the residue, and the precipitated crystals were collected by filtration, washed and dried. Yield: 5- [2- (ethoxycarbonylamino) phenyl] -5- (methylamino) imidazolidine-2,4-dione (9.8 g, 67%), m.p.

IR V · »·» ** ¹ (cm ^-1 ): 3340, 3230, 3140,

3080, 1785, 1735,

1700, 1590.

(3) 2.9 g of the product obtained in Step (2) above are mixed with 30 ml of methanol and 3.0 g of 40% (w / w) aqueous methylamine solution.

HU 201939 Β was stirred at 45 ° C for 3 hours, then methanol was distilled off. The resulting residue was dissolved in water and the pH of the aqueous solution was adjusted to 4 with concentrated BOH. The precipitated crystals were collected by filtration, washed with water and dried. This gives 2.4 g of 3-methylspiro [1,2,3,4-tetrahydroquinazoline-4,4 '-imidazolidine] -2,2', 5 '-trione.

This product has the same physico-chemical characteristics as the product of Example 1.

Example 4 (1) The appropriate starting compounds of formula (II) were treated as described in Example 3, Steps (l) - (a) or (l) - (b), using the general formula (III) listed in Table 1 below. Compounds of formula (II) are obtained.

Table 1

Compound of Formula III (R ^{2 *} , R ⁴ and R '= H, R® = -CiH5) R3 R7 mp cl C2H5 164-167 ° C (dec.) cl CH3 169-171 ° C (dec.)

(2) The two products obtained in Step (1) above are then treated as described in Example 3, Step 2, m.p. 190-192 ° C (with decomposition) 5- [5-chloro-2- (ethoxycarbonyl). amino) -phenyl] -5- (methylamino) -imidazolidine-2,4-dione is obtained.

IR ax ¹ * ¹ (cm ^-1 ): 3330, 3140, 3090, 1790,

1740, 1705, 1590.

(3) The product obtained in Step (2) above is then treated as described in Example 3, Step 3, when 6-chloro-3-methyl-spiro [1,2,3,4] m.p. Tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione is obtained.

The corresponding sodium salt has the following IR spectrum:

(cm ^-1 ): 3330, 3180, 3090, 1703,

1648th

Example 5

To tetrahydrofuran (200 mL) was added isatin (29.4 g) followed by triethylamine (30.7 mL) and ethyl chloroformate (20.9 mL) with stirring. The resulting reaction mixture was stirred at room temperature for 5 minutes and the precipitated crystals were collected by filtration. To the filtrate was added 12 g of urea and the resulting mixture was refluxed for 15 hours and then the solvent was distilled off. Methanol (200 mL) was added followed by concentrated sulfuric acid (2.9 g). The resulting mixture was stirred at 45 ± 5 ° C for 1 hour and then treated with 96 g of 40% aqueous methylamine solution. The reaction mixture was stirred at the same temperature for 3 hours and then methanol was distilled off. The residue was dissolved in water and the resulting aqueous solution was adjusted to pH 4 with concentrated hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and dried. There was thus obtained 36.6 g (74X) of 3-methylspiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione.

This product has the same physico-chemical characteristics as the product of Example 1.

6-23. Examples

By proceeding as described in Example 5, the corresponding isatin derivatives can be prepared from the compounds of formula I listed in Table 2 below.

HU 201939 Β

Table 2 Compounds of formula (I)

Example number: Compounds of formula (I) wherein R ¹ = -CH 3, R ⁵ = H R ² R ³ R ⁴ op. 6th H F H > 280 ° C 7th cl H H > 280 ° C 8th H H cl > 280 ° C 9th H OCH 3 H 270-272 ° C 10th H CH3 H > 280 ° C 11th H - OCH2O- > 280 ° C 12th H cl -CHs > 280 ° C 13th H H -OCHs 270-272 ° C 14th H H -CHs > 280 ° C The example Compounds of formula (I), serial number: for which R ¹ = -CHs, R ² = H R ³ R ⁴ R ⁵ op. or IR spectrum 15th F F F mp> 280 ° C 16th H H F mp> 280 ° C 17th cl cl H IR "/" d ^{"1 (cm-1):} 3250, 1770, 1720, 1615, 1597 18th cl H cl mp> 280 ° C 19th cl OCH 3 cl mp> 280 ° C The example Compounds of formula (I), serial number: for which R ¹ = CH3; R ² = H R ² R ³ R ⁴ op. 20th H Br H > 280 ° C 21st CH3 H H > 280 ° C 22nd H cl -OCHs > 280 ° C The example Compounds of general formula (I), serial number: wherein R ^ R ⁵ = H R ¹ op. 23rd CH3 (CH) 3- 263-266 ° C

Reference Example 1 (1) To 150 ml of tetrahydrofuran is added 14.7 g of 50 isatine followed by 12.1 g of triethylamine, and thereto is added dropwise a solution of 20.5 g of benzyloxy in tetrahydrofuran under stirring. contains carbonyl chloride. The resulting mixture 55 was stirred at 0-10 ° C for 15 minutes, then the solvent was distilled off and water was added to the residue. The precipitated crystals were collected by filtration, washed and dried. Yield: 25.4 g (90%) of 1- (benzyloxycarbonyl) -isatin, m.p. 144-50-147 ° C.

(2) 25 g of the product obtained in step (1) above are added to 175 ml of tetrahydrofuran and 8.0 g of urea are added. The resulting mixture was refluxed for 24 hours, then washed, dried and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 9: 1). The fractions containing the desired product were collected and the eluent was distilled off and chloroform was added to the residue. The precipitated crystals were collected by filtration and dried to give 22.7 g (75%) of 5- (2- (benzyloxycarbonylamino) phenyl) -5-hydroxy, m.p. 185-186 ° C. -imidazolidine-2,4-dione is obtained.

HU 201939 Β

2-5. PREPARATION

From the appropriate starting materials, the following compounds were prepared as described in Reference Example 1: 5 (2) 5-hydroxy-5- [2- (isobutoxycarbonylamino) phenyl] imidazolidine-2,4-dione; op. 173-174 ° C (dec.);

(3) 5-Hydroxy-5- [2- (ethoxycarbonylamino) phenyl] imidazolidine-2,4-dione, m.p. 169-10-170 ° C (dec.);

(4) 5-hydroxy-5- [2- (ethoxycarbonylamino) phenyl] imidazolidine-2,4-dione, m.p. 189-190 ° C (dec.);

(5) 5-Hydroxy-5- [2- (methoxycarbonylamino) phenyl] imidazolidine-2,4-dione, m.p. 192 ° C (dec.).

Claims (4)

1. Process for the quinazoline derivatives of the formula I and their salts - for the formula I R ¹ is lower alkyl or hydrogen, R ² , R ³ , R ⁴ and R ⁵ each independently represent hydrogen, halogen, lower-alkyl or lower-alkoxy, or two adjacent ceoports 35 at their terminal ends together with R ² , R ³ , R ⁴ and R ⁵ to form a lower alkylenedioxy group and the other two groups for the preparation of hydrogen atoms, characterized in that a 5-alkoxyimidazolidine derivative of the formula (III) in which -COOR * is a protected carboxyl group and R ⁷ is a lower alkyl group, whereas R ^2, R ^3, R ⁴ and R ^s are as defined above - with a lower alkyl amine or ammonia and thereafter optionally to a product thus obtained was subjected to intramolecular cyclization, and if desired the product of formula (I) thus to salt. Process according to claim 1, characterized in that the starting 5-alkoxyimidazolidine derivative of formula (III) is a 5-hydroxy-5- [2- (alkoxycarbonylamino) phenyl] compound of formula (II) ] imidazolidine derivatives - are used and are obtained by reacting a lower alkyl alcohol compound - wherein R ^2, R ^3, R ^4, R ^s and -COOR® are as defined in claim 1. 3. The method of claim 1 or 2, characterized in that the starting compound (II) or (III) compound is used as a compound wherein R ^l is lower alkyl or hydrogen, R ² represents H, halogen, lower alkyl, R ³ and R ⁴ each independently represent hydrogen, halogen, lower alkyl or lower alkoxy, or R ³ and R ⁴ together at the terminal end form a lower alkylene dioxy, and R ⁵ is hydrogen or halogen. 4. A process according to claim 3 wherein R ¹ is hydrogen or methyl or n-butyl, R ² is hydrogen or chloro or methyl. , R ³ and R ⁴ each independently represent hydrogen, fluoro, chloro, bromo or methyl or methoxy, or R ³ and R ⁴ together form a methylenedioxy group at their terminal end, and R ⁵ is hydrogen, fluoro or chloro.