KR100193080B1 - Method for preparing (R) -pyrimidine derivative - Google Patents

Abstract

The present invention provides a method for preparing (R)-(+)-1-methyl-1, 2, 3, 4-tetrahydroisoquinoline and (R)-(+)-5, 6-dimethyl-2- ( Regarding the method for producing 4-fluorophenylamino) -4- (1-methyl-1, 2, 3,4-tetrahydroisoquinolin-2-yl) pyrimidine hydrochloride, more specifically, (R) and a method for producing (R)-(+)-1-methyl-1, 2, 3, 4-tetrahydroisoquinoline from-(+)-α-methylbenzylamine (R)-(+)-5, characterized in that reacted (R)-(+)-1-methyl-1, 2, 3, 4-tetrahydroisoquinoline with a compound of formula (1) , And 6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3,4-tetrahydroisoquinolin-2-yl) pyrimidine hydrochloride .

In the above, X represents halogen.

Description

Method for preparing (R) -pyrimidine derivative

The present invention provides a method for preparing (R)-(+)-1-methyl-1, 2, 3, 4-tetrahydroisoquinoline and (R)-(+)-5, 6-dimethyl-2- ( It relates to a method for producing 4-fluorophenylamino) -4- (1-wh; til-1, 2, 3,4-tetrahydroisoquinolin-2-yl) pyrimidine hydrochloride, and more specifically, ( R)-(+)-α-methylbenzylamine relates to a method for producing (R)-(+)-1-methyl-1, 2, 3, 4-tetrahydroisoquinoline, and also to (R)-(+)-(+), characterized by reacting (R)-(+)-1-methyl-1, 2, 3, 4-tetrahydroisoquinoline with a compound of formula (1) To a method for producing -5,6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3,4-tetrahydroisoquinolin-2-yl) pyrimidine hydrochloride It is about.

In the general formula (l), X represents halogen.

5, 6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3, 4-tetrahydroisoquinolin-2-yl) pyrimidine hydrochloride is a very good reversible As a compound which can effectively inhibit gastric acid secretion by proton pump inhibitory effect and can be used as an anti-ulcer agent, the present inventors have developed and completed a patent application in Korea and abroad (International Publication WO 96/05177).

The present inventors also found that 5, 6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3, 4-tetrahydroisoquinoline in high yield without producing byproducts. -2-yl) Pyrimidine hydrochloride has developed a method for the completion of the patent application to the Republic of Korea Patent Application No. 14538 and No. 1439 (May 4, 1996).

On the other hand, 5, 6-dimethyl-2- (4-fluorophenylamino)-by the production method developed by the present inventors (International Publication No. WO 96/05177, Korean Patent Publication Nos. In the case of preparing 4- (1-methyl_1, 2, 3, 4-tetrahydroisoquinolin-2-yl) pyrimidine hydrochloride, the (R) and (S) 5, 6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl_1, 2, 3, 4-tetra in the form of a racemic compound in which the stereoisomer of the Hydroisoquinolin-2-yl) pyrimidine hydrochloride has a problem that can only be obtained.

Therefore, the present inventors used 5, 6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3, 4-tetrahydroisoquinolin-2-yl) pyrimidine hydrochloride. (R)-(+)-5, 6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3, 4-tetrahydroiso), not in the form of racemic compounds Quinolin-2-yl) pyrimidine hydrochloride or (S)-(-)-5, 6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3, In order to develop a new manufacturing method that can be produced from 4-tetrahydroisoquinolin-2-yl) pyrimidine hydrochloride, research has been conducted. As a result, the core intermediate, 1-methyl-1, 2, 3, 4-tetrahydro Isoquinoline to (R)-(-)-1-methyl-1, 2, 3, 4-tetrahydroisoquinoline and (S)-(-)-1-methyl-1, 2, 3, 4-tetrade A new process for producing isoquinoline has been discovered and from each of these 5, 6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3, 4-tetra Heathrow When quinolin-2-yl) pyrimidine hydrochloride was prepared, 5, 6-dimethyl-2- (4-fluoro in the form of (R)-(+) and (S)-(-) rather than racemic compounds The present invention was completed by developing a method for preparing phenylamino) -4- (1-methyl-1, 2, 3, 4-tetrahydroisoquinolin-2-yl) pyrimidine hydrochloride.

Hereinafter, the present invention will be described in detail.

The present invention is characterized by sequentially reacting (R)-(+)-α-methylbenzylamine with 2-bromoethanol, a brominating agent, and Lewis acid (R)-(+)-1-methyl- It is an object to provide a method for producing 1, 2, 3, 4-tetrahydroisoquinoline.

In addition, an object of the present invention is characterized by reacting the compound of formula (l) with (R)-(+)-1-methyl-1, 2, 3, 4-tetrahydroisoquinoline prepared as described above. (R)-(+)-5, 6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3, 4-tetrahydroisoquinolin-2-yl) It provides the manufacturing method of pyrimidine hydrochloride.

Hereinafter, the present invention will be described in more detail.

The preparation method of (R)-(+)-1-methyl-1, 2, 3, 4-tetrahydroisoquinoline is shown in the following scheme.

(R)-(+)-α-methylbenzylamine is commercially available (Aldrich, USA), and the reaction of (R)-(+)-α-methylbenzylamine with 2-bromoethanol (R )-(+)-N- (2-hydroxyethyl) -α-methylbenzylamine is obtained, and when the brominating agent is reacted again, (R)-(+)-N- (2-bromoethyl) -α Methylbenzylamine. A hydrobromide salt is obtained, and when the acid is reacted with Lewis acid again, (R)-(+)-1-methyl-1, 2, 3, 4-tetrahydroisoquinoline can be effectively obtained.

Usable to react (R)-(+)-α-methylbenzylamine with 2-bromoethanol to produce (R)-(+)-N- (2-hydroxyethyl) -α-methylbenzylamine As the reaction solvent, acetonitrile, N, N-dimethylformamide, dichloromethane, 1, 2-dichloroethane and the like are preferable, and the reaction temperature is preferably maintained at 40 ° C to 60 ° C.

Further, the resulting (R)-(+)-N- (2-hydroxyethyl) -α-methylbenzylamine was reacted with a brominating agent to give (R)-(+)-N- (2-bromoethyl) -α-methylbenzylamine. The reaction solvent usable for preparing the hydrobromide salt is preferably 1, 2-dichloroethane, acetic acid, water, or 1, 2-dichlorobenzene, and the reaction temperature is preferably maintained at 110 ° C to 145 ° C. The brominating agent usable in the present invention is preferably bromine, aqueous bromic acid, phosphorus tribromide and the like.

In the above two steps, (R)-(+)-N- (2-hydroxyethyl) -α-methylbenzylamine was prepared using a reaction solvent obtained by substituting (R)-(+)-α-methylbenzylamine. Bromination agent may be added without separation to prepare (R)-(+)-N- (2-bromoethyl) -α-methylbenzylamine in a single reaction system (1 pot).

The resulting (R)-(+)-N- (2-bromoethyl) -α-methylbenzylamine was reacted with Lewis acid to carry out a cyclization reaction to thereby give (R)-(+)-1-methyl- 1, 2, 3, 4-tetrahydroisoquinoline can be effectively prepared, and the reaction solvent that can be used is preferably decalin, 1, 2-dichloroethane, or 1, 2-dichlorobenzene, and the reaction temperature is It is desirable to maintain 120 ° C to 165 ° C. The Lewis acid used for the cyclization reaction is preferably aluminum (lll) chloride, zinc chloride, iron chloride and the like.

When preparing 1-methyl-1, 2, 3, 4-tetrahydroisoquinoline according to the production process of the present invention as described above it can protect the carbon position in the entire reaction process (R)-(+) -1-methyl-1, 2, 3, 4-tetrahydroisoquinoline can be prepared effectively.

The present invention also relates to (R)-(+)-5, 6-dimethyl-2- from (R)-(+)-1-methyl-1, 2, 3, 4-tetrahydroisoquinoline prepared as above. It provides a method for preparing (4-fluorophenylamino) -4- (1-methyl-1, 2, 3, 4-tetrahydroisoquinolin-2-yl) pyrimidine hydrochloride, and this scheme It is as follows.

In the above scheme, X represents halogen. 4-Halogeno-2- (4-fluorophenylamino) -5 and 6-dimethylpyrimidine of general formula (l) have been developed by the inventors of the Korean Patent Application Nos. It can be manufactured effectively by the manufacturing method disclosed in (May 4, 1996).

4-halogeno-2- (4-fluorophenylamino) -5, 6-dimethylpyrimidine of formula (l) is (R)-(+)-1-methyl-1, 2, 3, 4- Tetrahydrosuquinoline reacts with equivalent weight equivalents, but since (R)-(+)-1-methyl-1, 2, 3, 4-tetrahydroisoquinoline is liquid, it is easy to remove unreacted substances. It is preferable to use excess rather than.

4-halogeno-2- (4-fluorophenylamino) -5, 6-dimethylpyrimidine and (R)-(+)-1-methyl-1, 2, 3, 4- of general formula (l) As a reaction solvent used for the reaction of tetrahydroisoquinoline, n-butanol, ethylene glycol, 1, 2-propylene glycol or a mixture thereof can be used, and considering the reaction time and the presence of side reactions, propylene Glycol or ethylene glycol is preferable. In addition, the base that can be used is preferably triethylamine or pyridine, the reaction temperature is preferably maintained at 110 ℃ to 160 ℃, the reaction time is preferably 16 hours to 72 hours.

5, 6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3, 4-tetrahydroisoquinolin-2-yl by the preparation method according to the present invention When preparing pyrimidine hydrochloride, (S)-(-)-5 by using (R)-(+)-1-methyl-1, 2, 3, 4-tetrahydroisoquinoline as its core intermediate , 6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3,4-tetrahydroisoquinolin-2-yl) pyrimidine hydrochloride is not produced easily (R)-(+)-5, 6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3, 4-tetrahydroisoquinolin-2-yl) pyridine Only midine hydrochloride can be manufactured.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, this does not limit the present invention.

Example 1

(R)-(+)-N- (2-hydroxyethyl) -α-methylbenzylamine

(R)-(+)-α-methylbenzylamine (51.54 g, 0.43 mol) was dissolved in dichloromethane (52 ml), 2-bromoethanol (63.78 g, 0.51 mol) was added, and the mixture was then heated to 51 ° C. The reaction was completed by stirring at 50 h. The reaction solution was concentrated under reduced pressure, and the residue was fractionated to obtain the title compound (54 g) which was light yellow.

Example 2

(R)-(+)-N- (2-bromoethyl) -α-methylbenzylamine. Hydrobromide salts

(R)-(+)-N- (2-hydroxyethyl) -α-methylbenzylamine (11.0 g, 66.58 mmol) prepared in Example 1 was suspended in 48% aqueous hydrogen bromide solution (52 ml), It was refluxed at 126 degreeC for 30 minutes. Thereafter, the mixture was maintained at the same temperature for 2 hours at atmospheric pressure to remove by-product water and hydrogen bromide solution (47 ml). Acetone (55 ml) was poured into the residue to dissolve it, and ethyl acetate (50 ml) and ether (70 ml) were added thereto. After stirring for 30 minutes, the mixture was cooled to 0 ° C. and left for 3 hours to filter the resulting solid. This was washed with ethyl acetate (30 ml) and dried to give the primary title compound (10 g). The filtrate was then concentrated, and the residue was dissolved in ethanol (60 ml) and concentrated under reduced pressure again. This residue was dissolved in acetone (50 ml) and then diluted by addition of ether (70 ml). The solid produced by standing at 0 ° C. for 12 hours was collected by filtration and washed with ethyl acetate (30 ml) to obtain a secondary title compound (3.1 g).

Example 3

(R)-(+)-1-methyl-1, 2, 3, 4-tetrahydroisoquinoline

(R)-(+)-N- (2-bromoethyl) -α-methylbenzylamine prepared in Example 2. Hydrobromide salt (5.0 g, 16.18 mmol) was suspended in decalin (50 ml) and then 140 Heated to ℃. Anhydrous AICI ₃ (6.47 g, 48.54 mmol) was added thereto for 40 minutes. After stirring for 30 minutes while maintaining this temperature, the mixture was cooled to room temperature, the upper layer was separated and discarded, and the lower layer was stirred while adding to ice water (70 g). Concentrated hydrochloric acid (20ml) was added thereto and stirred for 10 minutes. The solution was washed three times with ethyl acetate (100 ml) and the aqueous layer was separated and sodium hydroxide was added to adjust the pH to 12. Extracted three times with ethyl acetate (250ml) and collected and washed with saturated brine (40ml) and then dehydrated with anhydrous magnesium sulfate. Ethyl acetate was evaporated under reduced pressure and the residue was distilled off to obtain the title compound (1.70 g).

Example 4

(R)-(+)-N- (2-hydroxyethyl) -α-methylbenzylamine

(R)-(+)-α-methylbenzylamine (76.61 g, 630 mmol) was dissolved in dichloromethane (77 ml), 2-bromoethanol (94.8 g, 760 mmol) was added, and the mixture was stirred at 50C for 50 ° C. Stirred for time to complete the reaction. The reaction solution was concentrated under reduced pressure and the residue was fractionated to obtain the title compound (81.2 g), which was light yellow.

Example 5

(R)-(+)-N- (2-bromoethyl) -α-methylbenzylamine hydrobromide salt

(R)-(+)-α-methylbenzylamine (76.61 g, 630 mmol) was dissolved in dichloromethane (77 ml), 2-bromoethanol (94.8 g, 760 mmol) was added, and the mixture was stirred at 50C for 50 ° C. Stirred for time to complete the reaction. The reaction mixture was concentrated under reduced pressure, and 48% hydrogen bromide solution (286.4 ml, 2500 mmol) was added thereto. It was refluxed at 126 degreeC for 30 minutes. Thereafter, the mixture was maintained at the same temperature for 2 hours at atmospheric pressure to remove by-product water and hydrogen bromide solution (250ml). Isopropyl alcohol (350 ml) was poured into the residue to reflux for 30 minutes to dissolve, and then cooled to 10 ° C and left for 3 hours to filter the resulting solid. It was washed with ethyl acetate (50 ml) and dried to give the title compound (127.5 g).

Example 6

(R)-(+)-1-methyl-1, 2, 3, 4-tetrahydroisoquinoline

(R)-(+)-N- (2-bromoethyl) -α-methylbenzylamine prepared in Example 5. A hydrobromide salt (10.0 g, 30.1 mmol) was prepared in 1,2-dichlorobenzene ( 60 ml) and then heated to 145 ° C. Anhydrous aluminum chloride (13.47 g, 96.54 mmol) was added thereto for 40 minutes. After stirring for 30 minutes while maintaining this temperature, the mixture was cooled to room temperature and stirred while adding the reaction solution to ice water (250 g). Concentrated hydrochloric acid (30 ml) was added thereto and stirred for 10 minutes. The solution was washed three times with dichloromethane (130 ml) and the aqueous layer was separated and sodium hydroxide was added to adjust the pH to 12. Extracted three times with ethyl acetate (250ml) and collected and washed with saturated brine (40ml) and then dehydrated with anhydrous magnesium sulfate. Evaporation of ethyl acetate and distillation of the residue gave the title compound (3.06 g).

Example 7

(R)-(+)-1-methyl-1, 2, 3, 4-tetrahydroisoquinoline

(R)-(+)-N- (2-bromoethyl) -α-methylbenzylamine prepared in Example 5. A hydrobromide salt (73.45 g, 240 mmol) was suspended in decalin (260 ml) and then 150 캜. Heated to. Anhydrous aluminum chloride (95.10 g, 710 mmol) was added thereto for 40 minutes. After stirring for 30 minutes while maintaining this temperature, the reaction mixture was cooled to room temperature, the upper layer was separated and discarded, and the lower layer was stirred while adding to ice water (1600 g). Concentrated hydrochloric acid (70 ml) was added thereto and stirred for 10 minutes. The solution was washed three times with ethyl acetate (700 ml) and the aqueous layer was separated and sodium hydroxide was added to adjust the pH to 12. Extracted three times with ethyl acetate (900 ml), collected and washed with saturated brine (200 ml) and dehydrated with anhydrous magnesium sulfate. Ethyl acetate was evaporated under reduced pressure and the residue was distilled off to obtain the title compound (28.2 g).

Example 8

Ethylene glycol (40 ml) triethylamine (8.12 g, 11.2 ml, 80.3 mmol) and n-butanol (30 ml) and (R)-(+)-1-methyl-1, 2, 3, prepared in Example 6; 4-tetrahydroisoquinoline (6.58 g, 44.1 mmol) was added, followed by 4-chloro-2- (4-fluorophenylamino) -5, 6-dimethylpyrimidine (10.1 g, 40.1 mmol), and 130 DEG C. Under reflux for 30 hours at (R)-(+)-5, 6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3, 4-tetrahydroiso Quinolin-2-yl) pyrimidine hydrochloride was prepared.

The reaction solution was cooled to room temperature, diluted with acetone (30 ml), and stirred with dropwise addition to water (200 ml). After stirring for 2 hours, the resulting solid was filtered and washed with water (60 ml), and then the resulting solid was dissolved in dichloromethane (250 ml) and washed with 4N hydrochloric acid (35 ml) and washed with water (35 ml). After washing with water (35ml), it was washed with 4N- sodium hydroxide solution (40ml). The dichloromethane layer was dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure, diluted with ethanol (200 ml), stirred with hydrochloric acid (45 g) for 5 hours, and the resulting solid was filtered and washed with ethanol (30 ml). And dried to (R)-(+)-5, 6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3, 4-tetrahydroisoquinoline-2- I) pyrimidine hydrochloride (9.21 g) was prepared.

Example 9

Triethylamine (23 ml) and (R)-(+)-1-methyl-1, 2, 3, 4-tetrahydroisoquinoline (16 g, 108.5 mmol) prepared in Example 7 were added to ethylene glycol (75 ml). After the addition, 4-chloro-2- (4-fluorophenylamino) -5 and 6-dimethylpyrimidine (25.7g, 101.8mmol) were added thereto, and the mixture was refluxed at 135 ° C for 28 hours to give (R)-(+)- 5, 6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3, 4-tetrahydroisoquinolin-2-yl) pyrimidine hydrochloride was prepared. This was purified in the same manner as in Example 8 to give (R)-(+)-5, 6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3, 4- Tetrahydroisoquinolin-2-yl) pyrimidine hydrochloride (33 g) was obtained.

Example 10

Triethylamine (14 ml) in 1, 2-propylene glycol (25 ml) and (R)-(+)-1-methyl-1, 2, 3, 4-tetrahydroisoquinoline (9.7 g) prepared in Example 7. , 65.8 mmol) were added, and the mixture was heated to 80 ° C. 4-Bromo-2- (4-fluorophenylamino) -5 and 6-dimethylpyrimidine (15 g, 51 mmol) were added thereto, reacted at 120 DEG C for 28 hours, and then purified in the same manner as in Example 8. (R)-(+)-5, 6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3, 4-tetrahydroisoquinolin-2-yl) Pyrimidine hydrochloride (16.2 g) was obtained.

Claims (6)

(R)-(+)-1-methyl-1, 2 characterized by sequentially reacting (R)-(+)-α-methylbenzylamine with 2-bromoethanol, a brominating agent, and a Lewis acid. , 3, 4-tetrahydroisoquinoline. 2. The (R)-(+)-1-methyl-1, 2, 3, 4-tetrahydroisoiso of claim 1, wherein the brominating agent is selected from the group consisting of bromine, aqueous bromic acid and phosphorus tribromide. Method for preparing quinoline. 2. The (R)-(+)-1-methyl-1, 2, 3, 4-tetrahydroisoiso of claim 1, wherein the Lewis acid is selected from the group consisting of aluminum (lll) chloride, zinc chloride and iron chloride. Method for preparing quinoline. (R)-(+)-5, characterized by reacting a compound of formula (l) with (R)-(+)-1-methyl-1, 2, 3, 4-tetrahydroisoquinoline; 6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3,4-tetrahydroisoquinolin-2-yl) pyrimidine hydrochloride. In the above, X represents halogen. (R)-(+)-5, 6-dimethyl-2- (4-, wherein the reaction solvent is n-butanol, ethylene glycol, 1, 2-propylene glycol or a mixture thereof. Method for producing fluorophenylamino) -4- (1-methyl-1, 2, 3, 4-tetrahydroisoquinolin-2-yl) pyrimidine hydrochloride. (R)-(+)-5, 6-dimethyl-2- (4-fluorophenylamino) -4- (6) according to claim 4 or 5, wherein the base is triethylamine or pyridine. 1-methyl-1, 2, 3, 4-tetrahydroisoquinolin-2-yl) pyrimidine hydrochloride.