The method of obtaining derivatives of pyrimidine, intermediate products and method of production thereof

 

(57) Abstract:

The invention relates to an improved process for the preparation of 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine of the formula I

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possibly in the form of R(+) or S(-) isomers, or salts of its accession acid. The specified connection has antiulcer action, inhibits the secretion of gastric acid and may be used in the pharmaceutical industry. The compound of formula I is produced by interaction of the compounds of formula II-A

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1-methyl-1,2,3,4-tetrahydroisoquinoline formula III

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possibly in the form of R(+) or S(-) isomer, possibly in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, n butanol, ethylene glycol, etc. in the presence of a base, such as triethylamine, N,N-dimethylaniline, pyridine, potassium acetate. The invention also relates to new compounds of the formula II

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where R is hydroxy or halogen, and production method of compound IIA. 3 S. and 7 C.p. f-crystals.

The invention relates firstly to a method for producing 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine represented by the following formula (I) and its salts connec, the new intermediate connection. More specifically, the present invention relates, firstly, to a method for producing 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine represented by the following formula (I),

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and its salts accession acids, where the pyrimidine derivative represented by the following formula (II-A),

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in which Hal represents halogen, is subjected to the interaction with 1-methyl-1,2,3,4-tetrahydroisoquinoline, represented by the following formula (III);

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secondly, the method of production of pyrimidine derivative represented by formula (II-A), and the compounds of formula (III); and, thirdly, to the new intermediate connection, including pyrimidine derivative represented by formula (II-A).

5,6-Dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl) pyrimidine of the above formula (I) inhibits the secretion of gastric acid by the reversible effect of inhibition of the proton pump and thus can be used as an antiulcer agent. This compound was developed by the authors of the present invention, which are then filed a patent application for connection and/or the method of its production in Korea and other Stroh 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4 - tetrahydroisoquinoline-2-yl) pyrimidine receive the following reaction scheme A:

Reaction scheme A

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Because the original product in the above reaction scheme has two reactive site (i.e., two atoms of Cl), the first reaction is inevitable side product, which reduces the yield of the target compound.

The authors of the present invention conducted extensive work to develop a new method to produce 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine of the formula (I) without the formation of by-products. In the result it was found that the target compound of formula (I) can be efficiently obtained without the formation of by-products by reacting pyrimidine derivative represented by formula (II-A) with 1-methyl-1,2,3,4-tetrahydroisoquinoline represented by the formula (III), and thus developed the present invention.

The present invention relates to a new process for the preparation of 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine represented by formula (I) and its salts accession acids.

More specifically, the present invention relates to a method for producing 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidinamine the following formula (II-A),

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in which Hal represents halogen, is subjected to the interaction with 1-methyl-1,2,3,4-tetrahydroisoquinoline represented by the formula (III);

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In addition, the present invention relates to a method for producing a pyrimidine derivative of the formula (II-A) and the compounds of formula (III). Further, the present invention relates to a new intermediate compound represented by the following formula (II), which includes a pyrimidine derivative represented by formula (II-A),

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in which R is hydroxy or halogen.

According to the present invention the compound of formula (I) can be obtained by reacting the compounds of formula (II-A) with 1-methyl-1,2,3,4-tetrahydroisoquinoline formula (III), as shown in the following reaction scheme 1:

Reaction scheme 1

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Because the original product in the reaction scheme 1 (i.e., the compound of the formula (II-A)) has only one reactive site (i.e., Hal), this reaction scheme makes no by-products and thus optimizes the output of the compounds of formula (I), the target product.

The present invention is described in more detail below.

Although 4-halogen-2-(4-forgenerating)-5,6-dimethylpyrimidin represented by the number of 1-methyl-1,2,3,4-tetrahydroisoquinoline, represented by formula (III), it is preferable to conduct the reaction using an excess, and is not equivalent to the number of the latter. Since the latter under the reaction conditions is fluid, unreacted 1-methyl-1,2,3,4-tetrahydroisoquinoline can be easily removed after the reaction is completed.

The reaction of the present invention is preferably carried out in the presence of a solvent. Solvents that can be used for this purpose include N,N-dimethylformamide, n-butanol, n-pentanol, n-hexanol, dimethyl sulfoxide, ethylene glycol, 1,2-propylene glycol and mixtures thereof. Most preferred are propylene glycol and ethylene glycol, as the use of any of them and minimizes the reaction time, and the formation of by-products.

According to the method of the present invention, the reaction scheme 1 is generally carried out in the presence of a base. The Foundation, which can be used for this purpose include triethylamine, N,N-dimethylaniline, pyridine and potassium acetate. The reaction temperature for the interaction of the compounds of formula (II-A) and 1-methyl-1,2,3,4-tetrahydroisoquinoline formula (III) preferably lies in the range from 110oC to 160oC, and the reaction time is l-1,2,3,4-tetrahydroisoquinoline - 2-yl) pyrimidine of the formula (I), obtained by the above method, can be converted into its salt accession acids, preferably cleaners containing hydrochloride salt in the usual way. The resulting product may be cleaned by conventional processing methods such as recrystallization, chromatography, etc.,

Since the compound of the formula (I) obtained by the method of the present invention contains an asymmetric carbon atom (i.e., the carbon atom marked with icon*in the formula below), this compound may be present in the form of (R)-(+)-isomer and (S)-(-)-isomer, or in the form of a racemate of R - and S-isomers are mixed in a ratio of 1:1. Unless otherwise indicated, the compound of formula (I) should be understood as including all of these isomers.

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(R)-(+)- and (S)-(-)-isomers of compounds of formula (I) can be easily obtained from the R - and S-isomers, respectively, the compounds of formula (III).

The compound of the formula (II-A), which is used as the initial product according to the method of the present invention is a new compound which can be obtained according to the method represented by the following reaction scheme 2:

The scheme of reactions 2

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In reaction scheme 2 Hal represents halogen.

As shown in the reaction is (V) gives 4-hydroxy-2-(4-forgenerating)-5,6 - dimethylpyrimidin formula (II-B), which can then interact with a halogenation agent to obtain 4 - halogen-2-(4-forgenerating)-5,6-dimethylpyrimidine formula (II-A).

4-Fortuneloungecasino formula (IV), which is used as the source of the product to obtain the compounds of formula (II-A) by reaction scheme 2, can be easily obtained from 4-foronline using known methods (see, for example. European patent N 0560726). In particular, the desired 4-fortuneloungecasino can be obtained by interaction of 4-foranyone with a 50% solution of cyanamide in acidic conditions using 30-37% hydrochloric acid and maintaining the temperature in the range from 75oC up to 95oC.

The first stage of the reaction scheme 2 can be carried out in the presence of a solvent. Solvents that can be used for this purpose include acetonitrile, N,N-dimethylformamide and dimethylsulfoxide. This reaction is preferably carried out at a temperature in the range from 110oC to 160oC.

In the second stage of the reaction scheme 2, the 4-hydroxy-2-(4-forgenerating)-5,6-dimethylpyrimidin formula (II-B) obtained in the first stage of the reaction scheme 2, is converted into the compound of the formula (II-A) by usai goals, include phosphorus oxychloride, oxalicacid, thionyl chloride and tribromide phosphorus. This halogenation reaction is carried out in the presence of a solvent. The reaction solvents that can be used for this purpose include, preferably, N,N-dimethylformamide, dimethylsulfoxide, 1,2-dichloroethane and 1,2-dichlorobenzene. It is preferable to maintain the reaction temperature in the range from 75oC up to 95oC.

Although the second stage of the reaction scheme 2 can be carried out by separating the intermediate product after completion of the first reaction stage, preferably the first and second stages in a single vessel. In particular, 4-hydroxy-2-(4-forgenerating)-5,6-dimethylpyrimidin formula (II-B) is obtained from 4-forforgiveness and then can be without releasing successfully subjected to interaction with a halogenation agent to obtain 4-halogen-2-(4-forfinal-amino)-5,6-dimethylpyrimidine (II-A).

The compound of the formula (II-A), which is used as starting material for obtaining the compounds of formula (I) according to the present invention, is new, as the compound of the formula (II-B) obtained as an intermediate compound in the reaction scheme 2. Both new connections can what toroi R is hydroxy or halogen.

1-Methyl-1,2,3,4-tetrahydroisoquinoline formula (III), which is also used as the initial product of the reaction scheme 1, is a known compound and can be obtained by known methods (see, for example. International publication WO 94/14795). In this known method (R)- or (S)-1-methyl-1,2,3,4-tetrahydroisoquinoline produced by interaction of (R)- or (S)-methylbenzylamine with chlorine--methylthio)acetylchloride and tin chloride (SnCl2) to obtain (R)- or (S)- 1-methyl-4-methylthio-1,2,3,4-tetrahydroisoquinoline-3-one, respectively, with the subsequent interaction of the compounds with Raney Nickel to remove metalcorp and by adding at the end the reducing agent. However, this method is disadvantageous because-chloro--(methylthio)acetylchloride, which is used as the source of the product is unstable and explosive, so this method cannot be used on an industrial scale. In addition, since the reaction stage is long, the overall yield is low, which makes this method uneconomical.

The authors of the present invention for a long time worked on the search for more effective ways to obtain 1-methyl-1,2,3,4-tetrahydroisoquinoline. It was found that 1-is-methylbenzylamine with 2 bromoethanol, brainwashin agent and a Lewis acid. This method of getting 1-methyl-1,2,3,4-tetrahydroisoquinoline is new and is included in the scope of the invention. This new way to obtain 1-methyl-1,2,3,4-tetrahydroisoquinoline explained in more detail below.

According to the present invention is 1-methyl-1,2,3,4-tetrahydroisoquinoline formula (III) can be obtained by the sequential interaction of methylbenzylamine with 2 bromoethanol, brainwashin agent and a Lewis acid. The method according to the present invention corresponds to the following reaction scheme 3.

Reaction scheme 3

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All used in reaction scheme 3 starting materials and reagents are known compounds and can be obtained as industrial products. At the first stage of methylbenzylamine interacts with 2-bromoethanol obtaining N-(2-hydroxyethyl) - methylbenzylamine, which in turn communicates with brainwashin agent with obtaining hydrobromide M-(2-bromacil)--methylbenzylamine. In the third stage, the hydrobromide of N-(2-bromacil)--methylbenzylamine interacts with the Lewis acid to give the desired 1-methyl-1,2,3,4-tetrahydroisoquinoline formula (III).

The reaction solvents that can be ispolzovanie preferably maintained within the range of from 40oC to 60oC. the Reaction solvents that can be used in the second stage, include 1,2-dichloroethane, acetic acid, water, and 1,2-dichlorobenzene, and the reaction temperature is preferably maintained within the range from 110oC to 145oC. Brainwashee agents that can be used in this reaction include bromine, bromobutyl acid, aqueous solution banowati acid and tribromide phosphorus.

Although the first and second stage reaction scheme 3 can be carried out with the excretion of N-(2-hydroxyethyl) - methylbenzylamine obtained as an intermediate connection after completion of the first stage reaction, it is preferable to carry out the first and second stages of the reaction without isolating the intermediate product. Thus, pomeroyi agent is added to the vessel, which contains the products of the first reaction stage.

Then N-(2-bromacil)--methylbenzylamine obtained in the second stage reaction, cyclist by interaction with a Lewis acid to obtain the target 1-methyl-1,2,3,4-tetrahydroisoquinoline formula (III). The reaction solvents that can be used in this reaction include decalin, 1,2-dichloroethane and 1,2-dichlorobenzene, and the Lewis acid for this reactionarytraditionalist can be economically obtained according to the above method, in accordance with the present invention when using this compound as a reagent can be economically obtained target 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl - 1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine of the formula (I).

In order to use the compound of the formula (III) as (R)-(+)- or (S)-(-)-isomer as the source of the product to obtain the compounds of formula (I) according to the present invention, each isomeric form of the compound of formula (III) can be efficiently obtained by using the corresponding (R)-(+)- or (S)-(-)-methylbenzylamine as the original product used according to the method represented by reaction scheme 3.

The present invention will be explained in detail in the following examples. It should, however, note that the present invention is in no way limited to these examples.

Preparative example: 4-fortuneloungecasino

882 (747 ml) of 32% hydrochloric acid is added to 1000 g (8.9 mol) 4-foranyone, the mixture is heated to 87oC and within 2 hours added to it dropwise 780 ml (9.9 mol) of a 50% solution of cyanamide. The reaction mixture was adjusted to pH 2.4 adding 120 ml of 32% hydrochloric acid, stirred for 3 hours and ohla the SUB>2CO3/water 578 g/ml 1640). The reaction mixture is stirred for 40 minutes and then cooled to 15oC. the Obtained gray solid product is filtered, washed first with 600 ml of water and then 2000 ml of ethyl acetate and finally dried, getting 1395 specified in the connection header with a light-grey color.

Output: 81,4%

So pl.: 175oC

NMR (DMSO-d6, M. D.): 5,50-6,88 (ush.s, 5H), 6.87 in (m, 2H), 7,17 (m, 2H)

Example 1: 4-Hydroxy-2-(4-forfinally)-5,6-dimethylpyrimidin

54,5 g (253,2 mmol) of 4-Forforgiveness obtained in Preparative example above, is suspended in 50 ml of N,N-dimethylformamide and 37.8 g (262,2 mmol) ethyl-2-methyl-acetoacetate, and the resulting suspension is refluxed at 140oC for 3 hours. The reaction solution is again diluted with 100 ml of N,N-dimethylformamide and cooled to 80oC. Add 160 ml of isopropyl alcohol and the resulting mixture is stirred for 30 minutes. The resulting solid product is filtered off, washed with 150 ml of acetone and at the end of the dry, receiving 41 g named in the connection header.

Output: 61,4%

So pl.: 256oC

NMR (DMSO-d6, M. D.): 1,83 (s, 3H), 2,19 (s, 3H), 7,18 (t, 2H), 7,68 (m, 2H), 9,36 (ush.s, 1H), 10,63 (ush.s, 1H).

Example rimidine, obtained in example 1 are suspended in 80 ml of N,N-dimethylformamide, and the resulting suspension is heated to 80oC. for one hour add to 31.9 g (to 19.4 ml, 210,1 mmol) of phosphorus oxychloride at a constant temperature of 85oC. the Reaction solution is stirred for 30 minutes and then under stirring is added 400 g of ice water. The mixture is brought to pH 11 by adding sodium hydroxide and then filtered resulting solid product. Selected solid product is washed with 150 ml of 50% aqueous methanol and then dried, obtaining 42,3 g named in the connection header.

Yield: 96.7% of

So pl.: 114oC

NMR (CDCl3, M. D.): of 2.21 (s, 3H), 2,41 (s, 3H), 7,01 (t, 2H), 7,18 (ush.s, 1H), 7,56 (t, 2H).

Example 3: 4-Chloro-2-(4-forgenerating)-5,6-dimethylpyrimidin

1390 g (7.6 mol) of 4-Fortunelounge carbonate, obtained in Preparative example above, suspended in 1300 ml of N,N-dimethylformamide and 1206 g (8.4 mol) of ethyl-2-mytilacea-acetate. The resulting suspension is heated to boiling under reflux for one hour and distilled under normal pressure up to 1100 ml) and then distilled off up until the temperature of the reaction solution reaches 160oC. To the residue is added to 1600 ml of N, N-dimethylfuran(840 ml, 9.1 mol) of phosphorus oxychloride. The reaction solution is stirred for 30 minutes and then diluted with 2000 ml of N,N-dimethylformamide. To the diluted solution within 40 minutes added under stirring 7000 ml of water. The reaction solution is stirred for 4 hours, the resulting product is filtered, washed with 1500 ml of 50% aqueous methanol and then dried. Thus obtained dried yellowish-brown powder is dissolved in 4000 ml of methanol at boiling under reflux and then cooled to 10oC. the resulting solid product is filtered and dried, obtaining 1186 named in the connection header.

Output: 62,4%

So pl.: 114oC

NMR (CDCl3, M. D.): of 2.21 (s, 3H), 2,41 (s, 3H), 7,01 (t, 2H), 7,18 (ush. s, 1H), 7,56 (t, 2H).

Example 4: 4-Bromo-2-(4-forgenerating)-5,6-dimethylpyrimidin

5 g (21,44 mmol) of 2-(4-Forgenerating)-4-hydroxy-5,6-dimethylpyrimidine obtained in example 1 are suspended in 40 ml of N,N-dimethylformamide, and the resulting suspension is heated to 65oC. To it is added dropwise within 20 minutes of 8.1 g (30 mmol) of tribromide phosphorus and the resulting mixture was left for reaction for 30 minutes at 75oC. the Reaction solution is cooled to room temperature, poured on odat pH to 5.5 with diluted hydrochloric acid. The obtained yellow solid product was washed with 100 ml of water and dried, obtaining 4.1 g specified in the connection header.

Output: 64,58%

So pl.: 123oC

NMR (CDCl3, M. D.): of 2.21 (s, 3H), 2,42 (s, 3H), 6,98 (t, 2H), 7,24 (s, 1H), 7,54 (kV, 2H).

Example 5: 1-Methyl-1,2,3,4-tetrahydroisoquinoline

(1) preparation of N-(2-hydroxyethyl) - methylbenzylamine:

103,08 g (0.86 mol) of Methylbenzylamine dissolved in 110 ml of dichloromethane and add 127,56 g (of 1.02 mol) of 2-bromoethanol. The mixture is stirred for 50 hours at 52oC until the reaction is completed. The reaction solution is concentrated under reduced pressure and the residue is subjected to fractional distillation, getting 109 g specified in the title compound, having a pale yellow color.

Yield: 76.7% of

So Kip.: 60oC/0.5 mm RT.article.

NMR (CDCl3, M. D.): to 1.38 (d, 3H), 2.40 a (ush. s, 1H), 2,61 (m, 2H), to 3.58 (m, 2H), 3,78 (kV, 1H), 7.18 in-7,38 (m, 5H).

(2) Obtaining hydrobromide N-(2-bromacil)--methylbenzylamine:

100 g (605,32 mmol) of N-(2-Hydroxyethyl) - methylbenzylamine obtained in example 5 (1) above, suspended in 515 ml of 48% aqueous Hydrobromic acid and conduct the reaction in the resulting suspension at 126oC for 30 minutes while boiling under reflux. Then the reaction solution of Hydrobromic acid and water by-products of the reaction. The residue is dissolved in 550 ml of acetone, and add 500 ml of ethyl acetate and 670 ml of ether. The reaction solution is stirred for 30 minutes, cooled to 0oC and then allowed to stand for 3 hours. The obtained solid product is filtered, washed with 400 ml of ethyl acetate and then dried, receiving 97 g of the first fraction specified in the connection header. Then the filtrate is concentrated. The residue is dissolved in 450 ml of acetone, diluted with 680 ml of ether and then allowed to stand at 0oC for 12 hours. The obtained solid product is filtered, collected and washed with 450 ml of ethyl acetate, receiving of 32.5 g of a second fraction specified in the connection header.

Output: 69,23%

So pl.: 186-187oC

NMR (CDCl3, M. D.): 1,94 (d, 3H), 3,21 (m, 2H), 3,82 (m, 2H), 4,42 (kV, 1H), 7,40-7,72 (m, 5H), 9,51 (ush.s, 1H), to 9.91 (ush.s, 1H).

(3) Obtain 1-methyl-1,2,3,4-tetrahydroisoquinoline:

50.0 g (161,8 mmol) to the Hydrobromide of N-(2-bromacil)--methylbenzylamine obtained in example 5 (2) above, are suspended in 450 ml of decalin and then heated to 140oC. To a suspension of 40 minutes add 64,70 g (485,4 mmol) of anhydrous aluminium chloride (AlCl3). The reaction solution further stirred for 30 minutes at a constant temperature and then cooling the I. Add 150 ml of concentrated hydrochloric acid and the mixture is stirred for 10 minutes. This solution is washed three times, each time 1000 ml of ethyl acetate, the resulting aqueous layer is separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time 2100 ml of ethyl acetate. The extracts are combined, washed 420 ml of a saturated saline solution, dehydrated with anhydrous magnesium sulfate and then evaporated under reduced pressure to remove the ethyl acetate. The residue is distilled, getting to 18.1 g specified in the connection header.

Output: 75,99%

So Kip.: 79-80o/0.5 mm RT.article.

NMR (CDCl3, M. D. ): to 1.59 (d, 3H), and 2.14 (s, 1H), was 2.76-to 3.02 (m, 2H), 3,10-up 3.22 (m, 1H), 3,34 is-3.45 (m, 1H), 4,22 (kV, 1H), 7.18 in-7,31 (m, 4H).

Example 6: 1-Methyl-1,2,3,4-tetrahydroisoquinoline

(1) preparation of the hydrobromide of N-(2-bromacil)--methylbenzylamine:

76,61 g (630 mmol) of Methylbenzylamine dissolved in 77 ml of dichloromethane and add back to 94.8 g (760 mmol) of 2-bromoethanol. The mixture was stirred at 51oC for 50 hours to complete the reaction. The reaction solution is concentrated under reduced pressure, add to it 286,4 ml (2500 mmol) of 48% aqueous Hydrobromic acid and left to react at 126oC for 30 minutes m the pressure at constant temperature and remove 250 ml of aqueous Hydrobromic acid and water, a by-product of the reaction. The residue is dissolved in 350 ml of isopropyl alcohol by boiling under reflux for 30 minutes, and the solution is cooled to 10oC and then allowed to stand for 3 hours. The resulting solid product is filtered off, washed with 50 ml of ethyl acetate and then dried, obtaining 128,9 g named in the connection header.

Output: 66,2%

So pl.: 186-187oC

NMR (CDCl3, M. D.): 1,94 (d, 3H), 3,21 (m, 2H), 3,82 (m, 2H), 4,42 (kV, 1H), 7,40-7,72 (m, 5H), 9,51 (ush.c, 1H), to 9.91 (ush.s, 1H).

(2) Obtain 1-methyl-1,2,3,4-tetrahydroisoquinoline:

10.0 g (30,1 mmol) to the Hydrobromide of N-(2-bromacil)--methylbenzylamine obtained in example 6 (1) above, are suspended in 60 ml of 1,2-dichlorobenzene and then heated to 145oC. Added dropwise within 40 minutes 13,47 g (96,54 mmol) of anhydrous aluminium chloride. The reaction solution is stirred for further 30 minutes at constant temperature, cooled to room temperature and poured with stirring, 250 g of ice water. Add 30 ml of concentrated hydrochloric acid and the mixture is stirred for 10 minutes the solution is washed three times, each time with 130 ml of dichloromethane, the resulting aqueous layer is separated, adjusted to pH 12 with sodium hydroxide and then extragere three times, kauswagan magnesium sulfate and then evaporated under reduced pressure, to remove the ethyl acetate. The residue is distilled, getting 2,90 g specified in the connection header

Output: 65,39%

So Kip.: 79-80oC/0.5 mm RT.article.

NMR (CDCl3, M. D. ): to 1.59 (d, 3H), and 2.14 (s, 1H), was 2.76-to 3.02 (m, 2H), 3,10-up 3.22 (m, 1H), 3,34 is-3.45 (m, 1H), 4,22 (kV, 1H), 7.18 in - 7,31 (m, 4H).

Example 7: 1-Methyl-1,2,3,4-tetrahydroisoquinoline

200 g (647,17 mmol) to the Hydrobromide of N-(2-bromacil)--methylbenzylamine obtained in example 5 (2) or in example 6 (1) above, are suspended in 700 ml of decalin and then heated to 150oC. To the suspension for 40 minutes add 261,5 g (1961 mmol) of anhydrous aluminium chloride. The reaction solution is stirred for further 30 minutes at constant temperature and then cooled to room temperature. Remove supernatant and the lower layer is poured with stirring at 3500 g of water with ice. Add 210 ml of concentrated hydrochloric acid and the mixture is stirred for 10 minutes. This solution is washed three times, each time 2500 ml of ethyl acetate, and then the aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time 3000 ml of ethyl acetate. The extracts are combined, washed 550 ml of a saturated saline solution, dehydrated with anhydrous magnesium sulfate and then evaporated under reduced pressure to remove>So Kip.: 79-80oC/0.5 mm RT.article.

NMR (CDCl3, M. D. ): to 1.59 (d, 3H), and 2.14 (s, 1H), was 2.76-to 3.02 (m, 2H), 3,10-up 3.22 (m, 1H), 3,34 is-3.45 (m, 1H), 4,22 (kV, 1H), 7.18 in-7,31 (m, 4H).

Example 8: (R)-(+)-1-Methyl-1,2,3,4-tetrahydroisoquinoline

(1) preparation of (R)-(+)-N-(2-hydroxyethyl) - methylbenzylamine:

51,45 g (0.43 mmol) of (R)-(+) - Methylbenzylamine dissolved in 52 ml of dichloromethane and add 63,78 g (0.51 mmol) 2-bromoethanol. This mixture was stirred at 51oC for 50 hours to complete the reaction. The reaction solution is concentrated under reduced pressure and the residue is subjected to fractional distillation, receiving 54 g specified in the title compound, having a pale yellow color.

Yield: 76%

So pl.: 60oC/0.5 mm RT.article.

[]20D: +55(C=1, CHCl3)

NMR (CDCl3, M. D.): to 1.38 (d, 3H), 2.40 a (ush.s, 1H), 2,61 (m, 2H), to 3.58 (m, 2H), 3,78 (kV, 1H), 7.18 in-7,38 (m, 5H).

(2) Obtaining hydrobromide (R)-(+)-N-(2-bromacil)--methylbenzylamine:

11,0 g (66,58 mmol) of (R)-(+)-N-(2-Hydroxyethyl)--methyl-benzylamine obtained in example 8 (1) above, suspended in 52 ml of 48% aqueous Hydrobromic acid and the resulting suspension conduct the reaction at 126oC for 30 minutes while boiling under reflux. The reaction rastvorov acid and water, a by-product of the reaction. The residue is dissolved in 55 ml of acetone and add 50 ml of ethyl acetate and 70 ml of ether. The reaction solution is stirred for 30 minutes, cooled to 0oC and then allowed to stand for 3 hours. The resulting solid product is filtered off, washed with 30 ml of ethyl acetate and then dried to give 10 g of the first fraction specified in the connection header. The filtrate is then concentrated. The residue is dissolved in 60 ml of ethanol and the resulting mixture was concentrated under reduced pressure. The residue is dissolved in 50 ml of acetone, diluted with 70 ml of ether and then allowed to stand at 0oC for 12 hours. The obtained solid product is filtered, collected and washed with 30 ml of ethyl acetate, receiving a second fraction specified in the connection header.

Yield: 64%

So pl.: 186-187oC

[]20D: +32,1(C=1, CHCl3)

NMR (CDCl3, M. D.): 1,94 (d, 3H), 3,21 (m, 2H), 3,82 (m, 2H), 4,42 (kV, 1H), 7,40-7,72 (m, 5H), 9,51 (ush.s, 1H), to 9.91 (ush.s, 1H).

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

5.0 g (16,18 mmol) Hydrobromide (R)-(+)-N-(2-bromacil)--methylbenzylamine obtained in (2) above, is suspended in 50 ml of decalin and the resulting suspension heated to 140oC. Add 40 the ri constant temperature and cooled down to room temperature. The supernatant is removed and the lower layer was added with stirring to 70 g of ice water. Add 20 ml of concentrated hydrochloric acid and the mixture is stirred for 10 minutes. This solution is washed three times, each time with 100 ml of ethyl acetate, the resulting aqueous layer is separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250 ml of ethyl acetate. The extracts are combined, washed with 40 ml saturated salt solution, dehydrated with anhydrous magnesium sulfate and then evaporated under reduced pressure to remove the ethyl acetate. The residue is distilled, receiving 1.70 g specified in the connection header.

Output: 71,4%

So Kip.: 79-80oC/0.5 mm RT.article.

[]20D: +85,5 (C=1, CHCl3)

NMR (CDCl3, M. D. ): to 1.59 (d, 3H), and 2.14 (s, 1H), was 2.76-to 3.02 (m, 2H), 3,10-up 3.22 (m, 1H), 3,34 is-3.45 (m, 1H), 4,22 (kV, 1H), 7.18 in-7,31 (m, 4H).

Example 9: (R)-(+)-1-Methyl-1,2,3,4-tetrahydroisoquinoline

(1) Obtaining hydrobromide (R)-(+)-N-(2-bromacil)--methylbenzylamine:

76,61 g (630 mmol) of (R)-(+) - Methylbenzylamine dissolved in 77 ml of dichloromethane and add to it to 94.8 g (760 mmol) of 2-bromoethanol. This mixture was stirred at 51oC for 50 hours to complete the reaction. This reaction solution was concentrated under reduced is tion at 126oC for 30 minutes while boiling under reflux. The reaction solution is then distilled for 2 hours under normal pressure at a constant temperature and remove 250 ml of aqueous Hydrobromic acid and water, a by-product of the reaction. The residue is dissolved in 350 ml of isopropyl alcohol by boiling under reflux for 30 minutes, the solution is cooled to 10oC and then allowed to stand for 3 hours. The obtained solid product is filtered off, washed with 50 ml of ethyl acetate and then dried, obtaining of 127.5 g specified in the connection header.

Output: 65,5%

So pl.: 186-187oC

[]20D: +32,1(C=1, CHCl3)

NMR (CDCl3, M. D.): 1,94 (d, 3H), 3,21 (m, 2H), 3,82 (m, 2H), 4,42 (kV, 1H), 7,40-7,72 (m, 5H), 9,51 (ush.s, 1H), to 9.91 (ush.s, 1H).

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

10.0 g (30,1 mmol) Hydrobromide (R)-(+)-N-(2-bromacil)--methylbenzylamine obtained in Example 9 (1) above, are suspended in 60 ml of 1,2-dichlorobenzene and then heated to 145oC. To a suspension of 40 minutes add 13,47 g (96,54 mmol) of anhydrous aluminium chloride (AlCl3). The reaction solution is stirred for further 30 minutes at the same temperature, cooled to room temperature and the is stirred for 10 minutes. This solution is washed three times, each time with 130 ml of dichloromethane, the resulting aqueous layer is separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250 ml of ethyl acetate. The extracts are combined, washed with 40 ml saturated salt solution, dehydrated with anhydrous magnesium sulfate and then evaporated under reduced pressure to remove the ethyl acetate. The residue is distilled, receiving a 3.06 g named in the connection header.

Yield: 69%

So Kip.: 79-80o/0.5 mm RT.article.

[]20D: +85,5(C=1, CHCl3)

NMR (CDCl3, M. D. ): to 1.59 (d, 3H), and 2.14 (s, 1H), was 2.76-to 3.02 (m, 2H), 3,10-up 3.22 (m, 1H), 3,34 is-3.45 (m, 1H), 4,22 (kV, 1H), 7.18 in - 7,31 (m, 4H).

Example 10: (R)-(+)-1-methyl-1,2,3,4-tetrahydroisoquinoline

73,45 g (240 mol) Hydrobromide (R)-(+)-N-(2-bromacil)--methylbenzylamine obtained in example 9 (1) above, are suspended in 260 ml of decalin and the resulting suspension heated to 150oC. To a suspension of 40 minutes add 95,10 g (710 mmol) of anhydrous aluminium chloride. The reaction solution is stirred for further 30 minutes at the same temperature and then cooled to room temperature. Remove supernatant and the bottom layer was poured under stirring at 1600 g of water with ice. Add 70 ml of concentrated with the ml acetic acid ethyl ester the resulting aqueous layer is separated, adjusted to pH 12 with sodium hydroxide and extracted three times, each time 900 ml of ethyl acetate. The extracts are combined, washed with 200 ml saturated salt solution, dehydrated with anhydrous magnesium sulfate and evaporated under reduced pressure to remove the ethyl acetate. The residue is distilled, obtaining of 28.2 g specified in the connection header.

Output: 79,7%

So Kip.: 79-80oC/0.5 mm RT.article.

[]20D: +85,5(C=1, CHCl3)

NMR (CDCl3, M. D. ): to 1.59 (d, 3H), and 2.14 (s, 1H), was 2.76-to 3.02 (m, 2H), 3,10-up 3.22 (m, 1H), 3,34 is-3.45 (m, 1H), 4,22 (kV, 1H), 7.18 in - 7,31 (m, 4H).

Example 11: (S)-(-)-1-methyl-1,2,3,4-tetrahydroisoquinoline

(1) preparation of (S)-(-)-N-(2-hydroxyethyl) - methylbenzylamine:

108,23 g (of 0.903 mmol) of (S)-(-) - Methylbenzylamine dissolved in 140 ml of dichloromethane and add 144, 0mm g (1,071 mmol) of 2-bromoethanol. This mixture was stirred at 51oC for 52 hours to complete the reaction. The reaction solution is concentrated under reduced pressure and the residue is subjected to fractional distillation, getting 117,4 g specified in the title compound, having a pale yellow color.

Output: 78,7%

So pl.: 60oC/0.5 mm RT.article.

[]20D: -55(C=1, CHCl
22.1 g (133,16 mmol) of (S)-(-)-N- (2-Hydroxyethyl) - methylbenzylamine obtained in example 11 (1) above, suspended in 105 ml of 48% aqueous Hydrobromic acid and the resulting suspension conduct the reaction at 126oC for 30 minutes while boiling under reflux. The reaction solution is distilled for 2 hours under normal pressure at a constant temperature and remove 95 ml of aqueous Hydrobromic acid and water, a by-product of the reaction. The residue is dissolved in 112 ml of acetone and add 100 ml ethyl acetate and 150 ml of ether. The reaction solution is stirred for 30 minutes, cooled to 0oC and then allowed to stand for 3 hours. The resulting solid product is filtered off, washed with 70 ml of ethyl acetate and then dried, obtaining 20 g of the first fraction specified in the connection header. The filtrate is then concentrated. The residue is dissolved in 130 ml of ethanol and the resulting mixture was concentrated under reduced pressure. The residue is dissolved in 104 ml of acetone, diluted with 143 ml of ether and then allowed to stand at 0oC for 12 hours. The obtained solid product is filtered, collected and washed with 75 ml ethyl acetate, gaining 6.7 g of a second fraction specified in the connection header.

You is, the.D.): of 1.94 (d, 3H), 3,21 (m, 2H), 3,82 (m, 2H), 4,42 (kV, 1H), 7,40-7,72 (m, 5H), 9,51 (ush.s, 1H), to 9.91 (ush.s, 1H).

(3) Obtain (S)-(-)-1-methyl-1,2,3,4-tetrahydroisoquinoline:

5.0 g (16,18 mmol) Hydrobromide (S)-(-)-N-(2-bromacil)--methylbenzylamine obtained in example (2) above, is suspended in 50 ml of decalin and the resulting suspension heated to 140oC. Added dropwise within 40 minutes 6,47 g (48,54 mmol) of anhydrous aluminium chloride (AlCl3). The reaction solution is stirred for further 30 minutes at constant temperature and cooled down to room temperature. The supernatant is removed and the lower layer was added with stirring to 70 g of ice water. Add 20 ml of concentrated hydrochloric acid and the mixture is stirred for 10 minutes. This solution is washed three times, each time with 100 ml of ethyl acetate, the resulting aqueous layer is separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250 ml of ethyl acetate. The extracts are combined, washed with 40 ml saturated salt solution, dehydrated with anhydrous magnesium sulfate and then evaporated under reduced pressure to remove the ethyl acetate. The residue is distilled, getting a 1.75 g specified in the connection header.

Output: 73,5%

So Kip.: 79-80oC/0.5 mm RT.article.

[]20D

Example 12: (S)-(-)-1-methyl-1,2,3,4-tetrahydroisoquinoline

(1) Obtaining hydrobromide (S)-(-)-N-(2-bromacil)--methylbenzylamine:

176,20 g (1449 mmol) of (S)-(-) - Methylbenzylamine dissolved in 185 ml of dichloromethane and add to it 218,04 g (1748 mmol) of 2-bromoethanol. This mixture was stirred at 51oC for 50 hours to complete the reaction. This reaction solution was concentrated under reduced pressure and add to it the 685 ml (5750 mmol) of 48% aqueous Hydrobromic acid and then carry out the reaction at 126oC for 30 minutes while boiling under reflux. The reaction solution is then distilled for 2 hours under normal pressure at a constant temperature and remove 580 ml of aqueous Hydrobromic acid and water, a by-product of the reaction. The residue is dissolved in 760 ml of isopropyl alcohol by boiling under reflux for 30 minutes, the solution is cooled to 10oC and then allowed to stand for 3 hours. The obtained solid product is filtered off, washed with 150 ml of ethyl acetate and then dried, obtaining 306,5 g specified in the connection header.

Yield: 68.4% of

So pl.: 185oC

[]20D: -32,1(class statement="ptx2">

(2) Obtaining (S)-(-)-1-methyl-1,2,3,4-tetrahydroisoquinoline:

10.0 g (30,1 mmol) Hydrobromide (S)-(-)-N-(2-bromacil)--methylbenzylamine obtained in example 12 (1) above, are suspended in 60 ml of 1,2-dichlorobenzene and then heated to 145oC. To a suspension of 40 minutes add 13,47 g (96,54 mmol) of anhydrous aluminium chloride (AlCl3). The reaction solution is stirred for further 30 minutes at constant temperature, cooled to room temperature and poured with stirring, 250 g of ice water. Add 30 ml of concentrated hydrochloric acid and the mixture is stirred for 10 minutes. This solution is washed three times, each time with 130 ml of dichloromethane, the resulting aqueous layer is separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250 ml of ethyl acetate. The extracts are combined, washed with 40 ml saturated salt solution, dehydrated with anhydrous magnesium sulfate and then evaporated under reduced pressure to remove the ethyl acetate. The residue is distilled, getting 3,10 g specified in the connection header.

Output: 69,96%

So Kip.: 79-80oC/0.5 mm RT.article.

[]20D: -85,5(C=1, CHCl3)

NMR (CDCl3, M. D. ): to 1.59 (d, 3H), and 2.14 (s, 1H), was 2.76-to 3.02 (m, 2H), 3,10-up 3.22 (m, 1H), 3,34 is-3.45 (m, 1H)MFA (S)-(-)-N-(2-bromacil)--methylbenzylamine, obtained in Example 12 (1) above, are suspended in 260 ml of decalin and the resulting suspension heated to 150oC. To a suspension of 40 minutes add 95,10 g (710 mmol) of anhydrous aluminium chloride. The reaction solution is stirred for further 30 minutes at constant temperature and then cooled to room temperature. Remove supernatant and the bottom layer was poured under stirring at 1600 g of water with ice. Add 70 ml of concentrated hydrochloric acid and the resulting mixture is stirred for 10 minutes. This solution is washed three times, each time 700 ml of ethyl acetate, the resulting aqueous layer is separated, adjusted to pH 12 with sodium hydroxide and extracted three times, each time 900 ml of ethyl acetate. The extracts are combined, washed with 200 ml saturated salt solution, dehydrated with anhydrous magnesium sulfate and evaporated under reduced pressure to remove the ethyl acetate. The residue is distilled, getting 27,6 g specified in the connection header.

Output: 78,1%

So Kip.: 79-80oC/0.5 mm RT.article.

[]20D: -85,5(C=1, CHCl3)

NMR (CDCl3, M. D. ): to 1.59 (d, 3H), and 2.14 (s, 1H), was 2.76-to 3.02 (m, 2H), 3,10-up 3.22 (m, 1H), 3,34 is-3.45 (m, 1H), 4,22 (kV, 1H), 7.18 in - 7,31 (m, 4H).

Getting 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4 - t the use of 1-methyl-1,2,3,4-tetrahydroisoquinoline, obtained by the method described in international publication WO 94/14795.

Example 14

2.65 g (27 mmol) of potassium Acetate and 4.0 g (26.9 mmol) of 1-methyl-1,2,3,4-tetrahydroisoquinoline added to 85 ml of n-hexanol and then heated to 80oC. There the same type of 6.17 g (24.5 mmol) of 4-chloro-2-(4-forgenerating)-5,6-dimethylpyrimidine and then carry out the reaction at 140oC for 28 hours boiling under reflux to obtain 5,6-dimethyl-2- (4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine.

The reaction solution is cooled to room temperature, diluted with 20 ml of acetone and then with stirring is added dropwise to 120 ml of water. After stirring the mixture for 2 hours resulting solid product is filtered, washed with water (30 ml), dissolved in 150 ml of dichloromethane and then washed successively with 20 ml 4n HCl, 20 ml of water and then 20 ml of a 4n solution of sodium hydroxide. The dichloromethane layer is dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure and then diluted with 100 ml of ethanol. To this reaction solution was added 30 g of concentrated hydrochloric acid and the resulting mixture is stirred for 5 hours. The obtained solid product anillina)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine.

Output: 62,4%

So pl.: 255oC

NMR (CDCl3, M. D.): was 1.58 (d, 3H), of 2.21 (s, 3H), of 2.38 (s, 3H), 2,84 (m, 1H), 3,12 (m, 1H), 3,61 (m, 2H), 4,23 (m, 1H), 5,38 (kV, 1H), 7,25 (m, 6H), to 7.61 (m, 2H), 10,33 (s, 1H), 13,43 (ush.s, 1H).

Example 15

8,12 g (11.2 ml of 80.3 mmol) of Triethylamine, 30 ml of n-butanol and to 6.58 g (to 44.1 mmol) of 1-methyl-1,2,3,4-tetrahydroisoquinoline added to 40 ml of ethylene glycol. There also added to 10.1 g (40,1 mmol) 4-chloro-2-(4-forgenerating)-5,6-dimethylpyrimidine and then carry out the reaction at 130oC for 30 hours boiling under reflux to obtain 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine. This product is treated according to the procedure described in Example 14, the receiving of 14.7 g of purified hydrochloride 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine.

Yield: 91%

So pl.: 256oC

NMR (CDCl3, M. D.): was 1.58 (d, 3H), of 2.21 (s, 3H), of 2.38 (s, 3H), 2,84 (m, 1H), 3,12 (m, 1H), 3,61 (m, 2H), 4,23 (m, 1H), 5,38 (kV, 1H), 7,25 (m, 6H), to 7.61 (m, 2H), 10,33 (s, 1H), 13,43 (ush.s, 1H).

Example 16

45 ml of Triethylamine, 50 ml of n-butanol and 32 g (217 mmol) of 1-methyl-1,2,3,4-tetrahydroisoquinoline added to 150 ml of ethylene glycol. There also add to 51.3 g (203,8 mmol) 4-chloro-2- (4-forgenerating)-5,6-dimethylpyrimidine and then carried out the reaction of p is but)-4- (1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine. This product is treated according to the procedure described in example 14, receiving 66 g of purified hydrochloride 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine.

Yield: 81.1% of

So pl.: 256oC

NMR (CDCl3, M. D.): was 1.58 (d, 3H), of 2.21 (s, 3H), of 2.38 (s, 3H), 2,84 (m, 1H), 3,12 (m, 1H), 3,61 (m, 2H), 4,23 (m, 1H), 5,38 (kV, 1H), 7,25 (m, 6H), to 7.61 (m, 2H), 10,33 (s, 1H), 13,43 (ush.s, 1H).

Example 17

75 ml of triethylamine and 65 g (442 mmol) of 1-methyl-1,2,3,4 - tetrahydroisoquinoline added to 100 ml of 1,2-propylene glycol. There also add to 100.9 g (0.40 mol) of 4-chloro-2-(4-forgenerating)-5,6-dimethylpyrimidine and then carry out the reaction at 120oC for 64 hours boiling under reflux to obtain 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine. This product is treated according to the procedure described in example 14, receiving 91 g of purified hydrochloride 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine.

Output: 57,1%

So pl.: 258oC

NMR (CDCl3, M. D.): was 1.58 (d, 3H), of 2.21 (s, 3H), of 2.38 (s, 3H), 2,84 (m, 1H), 3,12 (m, 1H), 3,61 (m, 2H), 4,23 (m, 1H), 5,38 (kV, 1H), 7,25 (m, 6H), to 7.61 (m, 2H), 10,33 (s, 1H), 13,43 (ush.s, 1H).

Example 18

720 ml of triethylamine and 695 g (4,72 mol) of 1-methyl-1,2,3,4-tetrahydropyrimidine and thus obtained mixture carry out the reaction at 130oC for 58 hours to obtain 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine. This product is treated according to the procedure described in example 14, receiving 1250 g of purified hydrochloride 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine.

Output: 66,9%

So pl.: 258oC

NMR (CDCl3, M. D.): was 1.58 (d, 3H), of 2.21 (s, 3H), of 2.38 (s, 3H), 2,84 (m, 1H), 3,12 (m, 1H), 3,61 (m, 2H), 4,23 (m, 1H), 5,38 (kV, 1H), 7,25 (m, 6H), to 7.61 (m, 2H), 10,33 (s, 1H), 13,43 (ush.s, 1H).

Example 19

110 ml of n-butanol, 240 ml of triethylamine and 236 g (1,60 mol) of 1-methyl-1,2,3,4-tetrahydroisoquinoline added to 600 ml of ethylene glycol. There add 400 g (1,59 mol) 4-chloro-2-(4-forgenerating)-5,6-dimethylpyrimidine and then carry out the reaction at 140oC within 48 hours from receipt of 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine. This product is treated according to the procedure described in example 14, getting 485 g of purified hydrochloride 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine.

Yield: 76.5% of

So pl.: 257oC

NMR (CDCl3, M. D.): was 1.58 (d, 3H), of 2.21 (s, 3H), of 2.38 (s, 3H), 2,84 (m, 1H), 3,12 (m, 1H), 3,61 (m, 2H), 4,23 (m, 1H), 5,38 (kV, 1H), 7,25 (m, 6H), to 7.61 (m, 2H), 10,33 (s, 1H), 13,43 (the Ute to 25 ml of 1,2-propylene glycol. Then there is added 15 g (51 mmol) of 4-bromo-2-(4-forgenerating)-5,6-dimethylpyrimidine and thus obtained reaction mixture is conducted at 110oC for 28 hours. The resulting product is treated according to the procedure described in Example 14, receiving 15,86 g purified hydrochloride 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine.

Yield: 78%

So pl.: 257oC

NMR (CDCl3, M. D.): was 1.58 (d, 3H), of 2.21 (s, 3H), of 2.38 (s, 3H), 2,84 (m, 1H), 3,12 (m, 1H), 3,61 (m, 2H), 4,23 (m, 1H), 5,38 (kV, 1H), 7,25 (m, 6H), to 7.61 (m, 2H), 10,33 (s, 1H), 13,43 (ush.s, 1H).

Example 21

8,12 g (11.2 ml of 80.3 mmol) of Triethylamine, 30 ml of n-butanol and to 6.58 g (to 44.1 mmol) of 1-methyl-1,2,3,4-tetrahydroisoquinoline obtained in example 5 is added to 40 ml of ethylene glycol. There also added to 10.1 g (40,1 mmol) 4-chloro-2-(4-forgenerating)-5,6-dimethylpyrimidine and conduct the reaction at 130oC for 30 hours boiling under reflux, getting 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine.

The reaction solution is cooled to room temperature, diluted with 30 ml of acetone and then with stirring is added dropwise 200 ml of water. After stirring for 2 hours, the resulting solid product otfiltrovana, and then 40 ml of a 4n solution of sodium hydroxide. The dichloromethane layer dehydration anhydrous magnesium sulfate, concentrated under reduced pressure and then diluted with 200 ml of ethanol. To this reaction solution was added 45 g of concentrated hydrochloric acid and the mixture is stirred for 5 hours. The obtained solid product is filtered off, washed with 30 ml of ethanol and then dried, obtaining 9,82 g purified hydrochloride 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1, 2, 3, 4-tetrahydroisoquinoline-2-yl)pyrimidine.

Output: 66,53%

So pl.: 255oC

NMR (CDCl3, M. D.): was 1.58 (d, 3H), of 2.21 (s, 3H), of 2.38 (s, 3H), 2,84 (m, 1H), 3,12 (m, 1H), 3,61 (m, 2H), 4,23 (m, 1H), 5,38 (kV, 1H), 7,25 (m, 6H), to 7.61 (m, 2H), 10,33 (s, 1H), 13,43 (ush.s, 1H).

Example 22

75 ml of triethylamine and 65 g (442 mmol) of 1-methyl-1,2,3,4-tetrahydroisoquinoline obtained in example 7, is added to 100 ml of 1,2-propylene glycol. There also add to 100.9 g (0.40 mol) of 4-chloro-2-(4-forgenerating)-5,6-dimethylpyrimidine and conduct the reaction at 120oC for 64 hours to obtain 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) pyrimidine. This product is treated according to the procedure described in example 21, receiving 95,1 g purified hydrochloride 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-t (d, 3H), of 2.21 (s, 3H), of 2.38 (s, 3H), 2,84 (m, 1H), 3,12 (m, 1H), 3,61 (m, 2H), 4,23 (m, 1H), 5,38 (kV, 1H), 7,25 (m, 6H), to 7.61 (m, 2H), 10,33 (s, 1H), 13,43 (ush.s, 1H).

Example 23

14 ml of triethylamine and 9.7 g (65,8 mmol) of 1-methyl-1,2,3,4-tetrahydroisoquinoline obtained in example 7, is added to 25 ml of 1,2-propylene glycol. There is added 15 g (51 mmol) of 4-bromo-2-(4-forgenerating)-5,6-dimethylpyrimidine and conduct the reaction at 120oC for 28 hours, to obtain 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine. This product is treated according to the procedure described in example 21, receiving 14.9 g of purified hydrochloride 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine.

Output: 73,28%

So pl.: 257oC

NMR (CDCl3, M. D.): was 1.58 (d, 3H), of 2.21 (s, 3H), of 2.38 (s, 3H), 2,84 (m, 1H), 3,12 (m, 1H), 3,61 (m, 2H), 4,23 (m, 1H), 5,38 (kV, 1H), 7,25 (m, 6H), to 7.61 (m, 2H), 10,33 (s, 1H), 13,43 (ush.s, 1H).

Example 24

8,12 g (11.2 ml of 80.3 mmol) of Triethylamine, 30 ml of n-butanol and to 6.58 g (to 44.1 mmol) of (R)-(+)-1-methyl-1,2,3,4-tetrahydroisoquinoline obtained in example 9, is added to 40 ml of ethylene glycol. There also added to 10.1 g (40,1 mmol) 4-chloro-2-(4-forgenerating)-5,6-dimethylpyrimidine and then carry out the reaction at 130oC for 30 hours boiling under reflux for the traditional solution is cooled to room temperature, dilute 30 ml of acetone and then with stirring is added dropwise 200 ml of water. After stirring the mixture for 2 hours resulting solid product is filtered, washed with 60 ml of water, dissolved in 250 ml of dichloromethane and then washed successively 35 ml of 4n HCl, 35 ml of water and then 40 ml of a 4n solution of sodium hydroxide. The dichloromethane layer is dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure and then diluted with 200 ml of ethanol. To this reaction solution was added 45 g of concentrated hydrochloric acid and the resulting mixture is stirred for 5 hours. The obtained solid product is filtered off, washed with 30 ml of ethanol and then dried, obtaining of 9.21 g of the pure hydrochloride of (R)-(+)-5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine.

Output: 62,4%

So pl.: 255oC

[]20D: +250(C=1, CHCl3)

NMR (CDCl3, M. D.): was 1.58 (d, 3H), of 2.21 (s, 3H), of 2.38 (s, 3H), 2,84 (m, 1H), 3,12 (m, 1H), 3,61 (m, 2H), 4,23 (m, 1H), 5,38 (kV, 1H), 7,25 (m, 6H), to 7.61 (m, 2H), 10,33 (s, 1H), 13,43 (ush.s, 1H).

Example 25

23 ml of Triethylamine and 16 g (108,5 mmol) of (R)-(+)-1-methyl-1,2,3,4-tetrahydroisoquinoline obtained in example 10, is added to 75 ml of ethylene glycol. There EXT is Yat reaction at 135oC for 28 hours boiling under reflux to obtain (R)-(+)-5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine. This product is treated according to the procedure described in example 24, receiving 33 g of purified hydrochloride 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1, 2, 3, 4-tetrahydroisoquinoline-2-yl)pyrimidine.

Yield: 81.1% of

So pl.: 257oC

[]20D: +250(C=1, CHCl3)

NMR (CDCl3, M. D.): was 1.58 (d, 3H), of 2.21 (s, 3H), of 2.38 (s, 3H), 2,84 (m, 1H), 3,12 (m, 1H), 3,61 (m, 2H), 4,23 (m, 1H), 5,38 (kV, 1H), 7,25 (m, 6H), to 7.61 (m, 2H), 10,33 (s, 1H), 13,43 (ush.s, 1H).

Example 26

14 ml of Triethylamine and 9.7 g (65,8 mmol) of (R)-(+)-1-methyl-1,2,3,4-tetrahydroisoquinoline obtained in example 10, is added to 25 ml of 1,2-propylene glycol. Then there is added 15 g (51 mmol) of 4-bromo-2-(4-forgenerating)-5,6-dimethylpyrimidine and thus obtained reaction mixture is conducted at 120oC for 28 hours. The reaction product is then treated according to the procedure described in example 24, receiving 16.2 g of purified hydrochloride 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine.

Output: 79,97%

So pl.: 257oC

[]20D: +250(c = 1, CHCl3), 0,33 (s, 1H), 13,43 (ush.s, 1H).

Example 27

8,12 g (11.2 ml of 80.3 mmol) of Triethylamine, 30 ml of n-butanol and to 6.58 g (to 44.1 mmol) of (S)-(-)-1-methyl-1,2,3,4-tetrahydroisoquinoline obtained in example 13, is added to 40 ml of ethylene glycol. There also added to 10.1 g (40,1 mmol) 4-chloro-2-(4-forgenerating)-5,6-dimethylpyrimidine and conduct the reaction at 130oC for 30 hours boiling under reflux to obtain (S)-(-)-5,6-dimethyl-2-(4-forgenerating)-4-(1-ethyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine.

The reaction solution is cooled to room temperature, diluted with 30 ml of acetone and then with stirring is added dropwise 200 ml of water. After stirring for 2 hours, the resulting solid product is filtered off, washed with 60 ml of water, dissolved in 250 ml of dichloromethane and washed successively 35 ml of 4n HCl, 35 ml of water and 40 ml of a 4n solution of sodium hydroxide. The dichloromethane layer is dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure and then diluted with 200 ml of ethanol. To this reaction solution was added 45 g of concentrated hydrochloric acid and the mixture is stirred for 5 hours. The obtained solid product is filtered off, washed with 30 ml of ethanol and then dried, obtaining of 8.95 g of cleansing the ptx2">

Output: 60,6%

So pl.: 255oC

[]20D: -250(C=1, CHCl3)

NMR (CDCl3, M. D.): was 1.58 (d, 3H), of 2.21 (s, 3H), of 2.38 (s, 3H), 2,84 (m, 1H), 3,12 (m, 1H), 3,61 (m, 2H), 4,23 (m, 1H), 5,38 (kV, 1H), 7,25 (m, 6H), to 7.61 (m, 2H), 10,33 (s, 1H), 13,43 (ush.s, 1H).

Example 28

15 ml of Triethylamine and 9.7 g (65,8 mmol) of (S)-(-)-1-methyl-1,2,3,4-tetrahydroisoquinoline obtained in example 13, is added to 25 ml of 1,2-propylene glycol. There is added 15 g (51 mmol) of 4-bromo-2-(4-forgenerating)-5,6-dimethylpyrimidine and then conduct a reaction at 110oC for 38 hours. The reaction product is then treated according to the procedure described in example 27, receiving 15,86 g purified hydrochloride 5,6-dimethyl-2-(4 - forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2 - yl)pyrimidine.

Yield: 78%

So pl.: 257oC

[]20D: -250(C=1, CHCl3)

NMR (CDCl3, M. D.): was 1.58 (d, 3H), of 2.21 (s, 3H), of 2.38 (s, 3H), 2,84 (m, 1H), 3,12 (m, 1H), 3,61 (m, 2H), 4,23 (m, 1H), 5,38 (kV, 1H), 7,25 (m, 6H), to 7.61 (m, 2H), 10,33 (s, 1H), 13,43 (ush.s, 1H).

1. The way to obtain 5,6-dimethyl-2-(4-forgenerating)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine represented by the following formula I

< / BR>
and its salts accession acids, wherein the pyrimidine derivative represented SL is a quinoline, represented by the following formula III:

< / BR>
2. The method according to p. 1, characterized in that the salt of the accession acid is hydrochloride.

3. The method according to p. 1, characterized in that the interaction is carried out in the presence of a solvent.

4. The method according to p. 3, wherein the solvent is N,N-dimethylformamide, n-butanol, n-pentanol, n-hexanol, dimethyl sulfoxide, ethylene glycol, 1,2-propylene glycol or a mixture thereof.

5. The method according to p. 1, characterized in that the interaction is carried out in the presence of a base.

6. The method according to p. 5, wherein the base is triethylamine, N,N-dimethylaniline, pyridine or potassium acetate.

7. The method according to p. 1, characterized in that the compound of formula I in the form of (R)-(+)-isomer get, using (R)-(+)-1-methyl-1,2,3,4-tetrahydroisoquinoline.

8. The method according to p. 1, characterized in that the compound of formula I in the form of (S)-(-)-isomer get, using (S)-(-)-1-methyl-1,2,3,4-tetrahydroisoquinoline.

9. A method of obtaining a 4-halogen-2-(4-forgenerating)-5,6-dimethylpyrimidine, represented by the following formula II-A:

< / BR>
in which Hal represents halogen, characterized in that 4-fortuneloungecasino, presents the following four is>/BR>to obtain 4-hydroxy-2-(4-forgenerating)-5,6-dimethylpyrimidine, represented by the following formula II-A:

< / BR>
which then interacts with a halogenation agent.

10. The derivative of a pyrimidine represented by the following formula II:

< / BR>
in which R is hydroxy or halogen.

Priority points:

04.05.1996, 29.10.1996 on PP.1 - 6, 9 - 10;

29.10.1996 on PP.7 and 8.

 

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