MXPA01009054A - Process for producing quinazoline derivative or salt thereof - Google Patents

Abstract

A process for producing a quinazoline derivative represented by general formula (I) which comprises reacting a compound represented by general formula (II) with a compound represented by R3-X (III) in an appropriate solvent in the presence of an alkali metal carbonate and optionally of a small amount of water. In the formulas, R1 represents hydrogen or halogeno;R2 represents protected carboxy;R3 represents ar(lower)alkyl optionally substituted by one or more appropriate substituents;Z represents lower alkylene;and X represents an acid residue.

Description

PROCESS FOR THE PREPARATION OF QUINAZOLINE DERIVATIVES OR SALTS FROM THEMSELVES FIELD OF THE INVENTION This invention relates to a novel process for the preparation of a quinazoline derivative (I), known, useful as an intermediate for the production of drugs for the treatment and prevention of diabetic complication and the like, for example.

BACKGROUND OF THE INVENTION A process for the preparation of the quinazoline derivative (I) by the use of a quinazoline derivative (II) as a material compound, has been specifically described in Japanese Patent Application Laid-open No. Sho 62-96476, more particularly in Example 4 thereof. However, this process for the preparation uses sodium hydride as a base and is not suitable for mass production for safety.

POSSIBILITY OF INDUSTRIAL APPLICATION This invention provides a novel industrial process for the preparation of the quinazoline derivative (I).

DESCRIPTION OF THE INVENTION This invention relates to a process for the preparation of the quinazoline derivative (I) represented by the following general formula: wherein R1 is hydrogen or halogen, R2 is protected carboxyl, R3 is ar (lower alkyl) which may have one or more suitable substituents, Z is lower alkylene, or a salt thereof.

The process for the preparation of the quinazoline derivative (I) or a salt thereof according to this invention will be described below.

Process (II) (I) or a salt thereof or a salt thereof wherein R1, R2, R3 and Z are as defined above, and X is an acidic residue. As a result of various studies in novel processes for the preparation of the quinazoline derivative (I), the inventors of this invention found that the quinazoline derivative (I) was obtained safely with high yields in an unexpectedly short reaction time without variations. in the reaction time by the addition of alkali metal carbonate to the compound (II) in a suitable solvent, by the reaction of the compound (III) with the mixture, and by the addition of a small amount of water as necessary, whereupon the inventors completed this invention suitable for mass synthesis. The salts of the quinazoline derivative (I) obtained by this invention can include, for example, an alkali metal salt, such as the lithium salt, the sodium salt, the potassium salt, etc., an alkaline earth metal salt , such as calcium salt, magnesium salt, etc .; a salt with a base, for example, a salt with an inorganic base, such as the ammonium salt, etc., a salt with an organic base, such as the triethylamine salt, the pyridine salt, the picoline salt, the ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, etc .; a salt with an acid, for example, a salt by the addition of inorganic acid, such as hydrochloride, hydrobromide, sulfate, phosphate, etc. and a salt by addition of organic acid, such as formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc. The quinazoline derivative (I) and a salt thereof obtained by this invention are useful as intermediates for the production of medicaments for the treatment of diabetic complication and the like.

For example, the quinazoline derivative (I) and a salt thereof are useful as intermediates for the production of a quinazoline derivative represented by the following general formula (A): wherein R1, R3 and Z are each as defined above. The quinazoline derivative (A) and a salt thereof have the inhibitory action of aldose redue, and are useful for the treatment and prevention of diabetic complication and the like, such as diabetic neuropathy [e.g., diabetic penoferal neuropathy ( for example, neuralgia, etc.), diabetic autonomic disorder (for example, impotence, etc.), etc.], diabetic nephropathy, diabetic retinopathy, diabetic keratopathy, diabetic cataracts, etc. The quinazoline derivative (A) and a salt thereof can be produced by processing the quinazoline derivative (I) or a salt thereof by using a conventional method (for example, hydrolysis). In the foregoing and subsequent descriptions in this specification, various suitable examples included in the scope of the definitions will be explained later in detail. The term "lower" in this specification means, unless otherwise indicated, 1 to 6 carbon atoms. Suitable "halogen" may include fluorine, chlorine, bromine and iodine. "Lower alkyl portion" suitable in "ar (lower alkyl) which may have one or more suitable substituents" may include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like. "Aryl portion" suitable in "ar (lower alkyl) which may have one or more suitable substituents" may include phenyl, naphthyl and the like. "Suitable substituents" on "ar (lower alkyl) which may have one or more suitable substituents" may include mono (or di or tri) halo (lower alkyl (e.g., chloromethyl, bromomethyl, chloropropyl, 1,2-dichloroethyl, 1,2-dibromoethyl, 2,2-dichloroethyl, trifluoromethyl, 1,2,2-ricloroethyl, etc.), lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, hexyloxy, etc.), halogen (eg, fluorine, chlorine, bromine, iodine, etc.), lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.) , etc. Suitable "protected carboxyls" may include esterified carboxyl, eg, lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, etc.), mono (or di or tri) phenyl (alkoxycarbonyl lower) that the nitro group can have (eg, benzyloxycarbonyl, 4- nitrobenzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, etc.), in which the most preferable example may be the alkoxycarbonyl of 1 to 4 carbon atoms and the most preferable may be ethoxycarbonyl. Suitable "lower alkylene" may include linear or branched, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, ethylmethylene, propylene and the like, in which the most preferable example may be alkylene of 1 to 4 carbon atoms. carbon and the most preferable may be methylene and methylmethylene.

Suitable "acid residue" may include halogen (eg, chlorine, bromine, iodine, fluorine, etc.), or acyloxy, such as lower alkanesulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, etc.), lower alkoxysulfonyloxy (eg, methoxysulfonyloxy, ethoxysulfonyloxy, etc.), arenesulfonyloxy (for example, benzenesulfonyloxy, toluenesulfonyloxy, etc.), etc.). The process for the preparation of the quinazoline derivative (I) of this invention will be described later in detail.

Process The quinazoline derivative (I) or a salt thereof can be prepared by the addition of alkali metal carbonate to the compound (II) or a salt thereof in a suitable solvent, by the reaction of the compound (III) or a salt of the same with the mixture, and by adding a small amount of water as necessary. Suitable salts the compound (II) can be referred to as the salts with acids exemplified for the compound (I). Suitable salts of the compound (III) can be referred to as the salts with bases exemplified for the compound (I). The alkali metal carbonate to be used may include potassium carbonate, sodium carbonate, etc. Preferably, powdered potassium carbonate is used. The reaction with the compound (II) or a salt thereof is carried out in the presence or absence of a conventional solvent which does not adversely influence the reaction, such as acetone, N, N-dimethylformamide, dichloromethane, methanol, ethanol, etc. The reaction temperature is not critical, and the reaction is usually carried out at room temperature or under heating. By adding a small amount of water (for example, 1 to 5% by weight, preferably 2 to 4% by weight, of the compound (II) or a salt thereof) as necessary, the reaction time can be shortened without variations in the reaction time. The process for the preparation of the quinazoline derivative (I) or a salt thereof from the compound (II) or a salt thereof, according to this invention, can be carried out continuously without being isolated and purified in the intermediate of the process.

It is found that the quinazoline derivative (A) and a salt thereof have aldose reductase inhibiting action, whereby the quinazoline derivative (A) and a salt thereof are valuable as medicaments for the treatment of diabetic complication. , such as dysraphy due to corneal damage, cataracts, neuropathy, retinopathy and nephropathy, more particularly, cataracts and neuropathy. This invention will be described below according to the following Examples.

Example 1 Ethyl 2- (7-chloro-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl) acetate (40 kg), 200 liters of acetone and 23.5 kg of powdered potassium carbonate were supplied inside a reaction vessel of 800 liters and suspended. 49.3 kg of 4-bromo-2-fluorobenzyl bromide were added to the mixture, and the mixture was reacted with the mixture for 5 hours under reflux. Then 20 kg of glacial acetic acid was added to the mixture and it was heated to reflux for 2 hours, 320 liters of methanol were added thereto under reflux, the mixture was cooled to 5 ° C or less, and crystals were obtained by filtration.

The crystals were washed with 80 liters of methanol and 400 liters of water successively, and dried under vacuum at 40 ° C to obtain 63.8 kg of the 2 - [3 - (- bromo-2-fluorobenzyl) -7-chloro-1, 2 , 3,4-tetrahydro-2,4-dioxoquinazolin-1-yl) ethyl acetate (96% yield).

Example 2 55 kg of 2- (7-chloro-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl) ethyl acetate, 385 liters of acetone and 29.6 kg of pulverized potassium carbonate were supplied into the a reaction vessel of 1500 liters and suspended. 54.7 kg of 4-bromo-2-fluorobenzyl bromide was added to the mixture and 1.65 kg of water was added, subsequently and then reacted with the mixture for 1 to 2 hours at an internal temperature of 48 to 53 ° C. After adding 29.2 kg of industrial 80% acetic acid to the mixture, and heating it for 1 to 2 hours at the same temperature, 440 liters of methanol were added to it under heating, and the crystals were precipitated. The crystals were then washed with 110 liters of methanol and 550 liters of water successively just as in the case of Example 1, to obtain 88.6 kg of 2- [3- (4-bromo-2-fluorobenzyl) -7-chloro-1 2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl] ethyl acetate (97% yield). Then, 88.6 kg of ethyl 2- [3- (4-bromo-2-fluorobenzyl) -7-chloro-l, 2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl] acetate were supplied. 550 liters of methanol and 275 liters of water, in a reaction vessel of 1500 liters and suspended. 27.5 liters of 24% aqueous sodium hydroxide solution was added to the mixture, and the reaction was carried out for about 1 hour at an internal temperature of 70 to 75 ° C. The insoluble materials in the reaction solution were removed by filtration and then washed with a mixed solution of 41 liters of methanol and 41 liters of water. After filtering and washing, they were transferred to a reaction vessel of 1500 liters, 23.1 kg of 35% industrial hydrochloric acid were dropwise added to it, in about 2 hours at an internal temperature of 68 to 73 ° C. The temperature was then lowered to 20-30 ° C, and crystals were obtained by filtration. The crystals were washed with 275 liters of water to obtain the acid 2- [3- (4-bromo-2-fluorobenzyl) -7-chloro-l, 2,3,4-tetrahydro-2,4-dioxoquinazolin- 1 - il] acetic in a wet state.

Then, the acid 2 - [3 - (- bromo-2-fluorobenzyl) -7-chloro-l, 2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl] acetic acid (wet state) obtained, 835 liters of 2-propanol and 66 liters of water, were supplied in a 1500-liter reaction vessel and suspended. After the mixture was dissolved at an internal temperature of 75 to 80 ° C, the mixture was clarified and filtered with a filter, and then washed with 55 liters of 2-propanol. After filtering and washing were transferred to a reaction vessel of 1500 liters, 127 liters of water were added drop by drop to it in about 30 minutes at an internal temperature of 75 to 80 ° C. The temperature was then lowered to 65-70 ° C, and the crystals were precipitated, and the stirring was carried out for approximately 30 minutes. After cooling to 0 ° C or less, the crystals were filtered. The crystals were washed with 165 liters of water and dried under vacuum at 40 ° C to obtain 78.2 kg of 2- [3- (4-bromo-2-fluorobenzyl) -7-chloro-1, 2,3,4- tetrahydro-2,4,4-dioxoquinazolin-1-yl] acetic acid. (Yield: 91% from 2- (7-chloro-1,2,3,4-tetrahydro-2, -dioxoquinazolin-1-yl) ethyl acetate).

Example 3 40 kg of 2- (7-chloro-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl) ethyl acetate, 280 liters of acetone and 21.5 kg of pulverized potassium carbonate were supplied in a 1000-liter reaction vessel and suspended. 38.7 kg of 4-bromo-2-fluorobenzyl bromide was added to the mixture and 1.2 kg of water were added additionally and then reacted with the mixture for 2 to 3 hours at an internal temperature of 45 to 55 ° C. Subsequently, 21.2 kg of 80% industrial acetic acid were added to the mixture, and 320 liters of methanol were added thereto at the same temperature. After cooling to 0 ° C or less, the crystals were filtered. The crystals were washed with 80 liters of methanol and with 400 liters of water successively, to obtain 2 - [3 - (4-bromo-2-fluorobenzyl) -7-chloro-l, 2,3,4-tetrahydro-2 , 4-dioxoquinazolin-1-yl] ethyl acetate in a wet state. Subsequently, the obtained 2 - [3 - (4-bromo-2-fluorobenzyl) -7-chloro-1, 2,3, 4-etrahydro-2,4-dioxoquinazolin-1-yl] acetic acid (wet state), 520 liters of 2-propanol and 180 liters of water were supplied to a 1000-liter reaction vessel and suspended. Subsequently, 27.8 kg of a 30% aqueous potassium hydroxide solution was added to the mixture, the reaction was carried out for 1 to 2 hours at an internal temperature of 50 to 60 ° C. The reaction liquid was clarified and filtered with a filter, and then washed with a mixture of 40 liters of 2-propanol and 40 liters of water. After filtration and washing were transferred to a 1500 liter reaction vessel, 16.7 kg of 35% industrial hydrochloric acid was added thereto dropwise in about 30 minutes at an internal temperature of 70 to 75 ° C. The mixture was stirred for approximately 30 minutes at the same temperature. The temperature was lowered to 5 ° C or less, and crystals were obtained by filtration. The crystals were washed with 400 liters of water and dried under vacuum at 40 ° C to obtain 58.1 kg of the acid 2 - [3- (4-bromo-2-fluorobenzyl) -7-chloro-1,2,3,4 - tetrahydro-2,4,4-dioxoquinazolin-1-yl] acetic acid. (Yield: 93% from ethyl 2- (7-chloro-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl) acetate).

Example 4 g of ethyl 2 - (7-chloro-l, 2, 3, 4-tetrahydro-2,4-dioxoquinazolin-1-yl) acetate, 175 ml of acetone and 13.4 g of pulverized potassium carbonate were supplied inside a one liter reaction vessel and suspended. 24.9 g of 4-bromo-2-fluorobenzyl bromide were added to the mixture and 0.75 g of water was subsequently added, and then reacted with the mixture for 3 hours at an internal temperature of 45 to 55 ° C. Subsequently a solution of 12.3 g of potassium hydroxide in 150 ml of water was added to the mixture, the reaction was carried out for 2 hours at an internal temperature of 50 to 55 ° C. Subsequently, 75 ml of acetone, 31.8 g of industrial hydrochloric acid at 35% were added at the same temperature, and 50 ml of water were added dropwise thereto. After stirring for about 30 minutes at the same temperature and subsequently cooling to 5 ° C or less, the crystals were filtered. The crystals were then washed with a mixture of 37.5 ml of acetone and 37.5 ml of water, and successively with 250 ml of water, and dried under vacuum at 40 ° C to obtain 37.5 g of 2- [3- (4- bromo-2-fluorobenzyl) -7-chloro-1, 2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl] acetic acid. (Yield: 96% from 2- (7-chloro-l, 2, 3, 4 • tetrahydro-2,4-dioxoquinazolin-l-yl) ethyl acetate).

Claims (6)

1. A process for the preparation of a quinazoline derivative represented by the general formula: wherein R1 is hydrogen or halogen, R2 is protected carboxyl, R3 is ar (lower alkyl) which may have one or more suitable substituents, Z is lower alkylene, or a salt thereof, by the reaction of a compound represented by The general formula: (II) in which R1, R2 and Z are each as defined above, or a salt thereof, with a compound represented by the general formula: R3-X (III) wherein R3 is as defined above, X is an acid residue, or a salt thereof in a suitable solvent in the presence of alkali metal carbonate and furthermore a small amount of water, as necessary.

2. A process for the preparation according to claim 1, wherein R1 is halogen, R2 is esterified carboxyl, R3 is dihalophenyl (lower alkyl), and X is halogen.

3. A process for the preparation according to claim 1, wherein R 1 is chloro, R 2 is ethoxycarbonyl, R 3 is 2-fluoro-4-bromobenzyl, X is bromine and Z is methylene.

4. A process for the preparation according to any of claims 1 to 3, wherein the alkali metal carbonate is potassium carbonate.

5. A process for the preparation according to any of claims 1 to 4, wherein 1 to 5% by weight of water is added to the compound (II) or a salt thereof.

6. A process for the preparation according to any of claims 1 to 4, wherein 2 to 4% by weight of water is added to the compound (II) or a salt thereof. SUMMARY OF THE INVENTION This invention provides a novel industrial process for the preparation of a quinazoline derivative (I) represented by the general formula: wherein R1 is hydrogen or halogen, R2 is protected carboxyl, R3 is ar (lower alkyl) which may have one or more suitable substituents, Z is lower alkylene, or a salt thereof, by the reaction of a compound represented by The general formula: (ID in which R1, R2 and Z are each as defined above, or a salt thereof, with a compound represented by the general formula: R3-X (III) wherein R3 is as defined above, X is an acid residue, or a salt thereof in a suitable solvent in the presence of alkali metal carbonate and furthermore a small amount of water, as necessary.