UA74808C2 - A process for the preparation of 6-methyl-2-(4-methyl-phenyl)-imidazo[1,2-a]pyridine-3-(n,n-dimethyl-acetamide) and intermediary compounds - Google Patents

Abstract

The invention relates to a new and improved process for the preparation of 6-methyl-2-(4-methyl-phenyl)-imidazo[1,2-a]pyrimi-dine-3-(N,N-dimethyl-acetamide) of Formula (I) and pharmaceutically acceptable acid addition salts thereof which comprises reacting an ester of general Formula (II) (wherein R is lower alkyl or phenyl-lower alkyl) in a polar protic or aprotic solvent with dimethyl amine and, if desired, converting the compound of the Formula (I) thus obtained into a pharmaceutically acceptable acid addition salt. The compound of Formula I is a known valuable sedative used in therapy. The invention also relates to new intermediates of general Formula (II) (wherein R is lower alkyl or phenyl-lower alkyl) useful in the process. , (I) , (II)

Description

Description of the invention

The invention relates to a new and improved method of obtaining 2b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|Ipyridine-3-(M,M-dimethylacetamide) of the formula:

For 2 of them

Shk

Y - Y and its pharmaceutically acceptable acid additive salts, new intermediate compounds used in the specified method, and the method of obtaining the specified intermediate compounds.

Compound Formula I! is an excellent sedative, sold under the INN (International Non-Patented

Name) Zolpidem. high school

There are two known methods of obtaining the compound of Formula |.

According to the method described in patent EP 50563, the known compound b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|pyridine (o) of the formula: i y - Ox o zo / sna o - UM sh-.

NC with "

IN v. converted by the Mannich reaction into 3-(M,M-dimethylaminomethyl)-6-methyl-2-(4-methyl-phenyl)imidazolo|1,2-a|pyridine of the formula: s p- M /y shlya aa sna b 2 -

The latter compound is converted with the help of methyl iodide into the quaternary salt obtained in this way with the trimethylammonium derivative of the formula:

F) name) 60 b5

N lot ,/ хХ / sna - M Sho i z y i

Shk 70 n. Z zo is subjected to a reaction with alkali metal cyanide, thus forming an acetonitrile derivative of the formula:

СНа - 2 on сч -ОМ о с and М и с are subjected to acid hydrolysis, after which the formed acetamide derivative of the formula: « и М как / м - з М и --

At "at 2:25 p.m." NNo

Un - and subject to alkaline hydrolysis. The acetic acid derivative obtained in this way has the following formula:

F Ok ime) 60 is converted into the required compound of Formula I by amidation. The amidation reaction can be carried out in two ways. According to one method, the compound of Formula MI! are subjected to a reaction with thionyl chloride, and the acid chloride of the formula is formed in this case:

s, n and x.

They are subjected to a reaction with dimethylamine. In patent EP 50563, this method is not explained by examples. When performing this method, the authors of this invention found that the reaction product of the compound of Formula MI and thionyl chloride is a black resin that cannot be processed. Thus, the method described above is not suitable for production on an industrial scale.

According to another method, an acetic acid derivative of Formula MI! react with carbonyldiimidazole in Ge) in the presence of dimethylamine, with the help of which the required compound of Formula I is obtained through the compound of Formula: opr / so zo Na y; (ав) cha r s 0 - no - as 7 « 7 | - with . and? in. The disadvantage of this method is that carbonyldiimidazole is expensive and is a toxic, allergenic and hygroscopic compound, the manipulation of which in industrial production is associated with great difficulties. Another disadvantage is that a compound of Formula | contaminated with decomposition products (ав) of carbonyldiimidazole. Thus, Zolpidem, which meets the extremely strict requirements of the Pharmacopoeia, can only be obtained using complex purification methods.

The purpose of patent EP 251589 is to eliminate the above-mentioned disadvantages of the considered method. As a starting compound, b-methyl-2-(4-methylphenyl)imidazolo|1,2-a)pyridine of formula I is used, which reacts with

M,M-dimethyl-2,2-dimethoxyacetamide of the formula o "c with Mu with CH 65 Kh

The c-hydroxy-M,M-dimethylacetamide derivative of the formula: y, CH ko n -- "7 "7 "ev is subjected to a reaction with thionyl chloride, after which the o-chloro-M,M-dimethylacetamide derivative of the formula:

M

N sna o

Hmmm

I sna o s « and - quin remove chlorine by means of a reduction reaction with sodium borohydride with the formation of the necessary compound Formula

Y. The disadvantage of this method is that M,M-dimethyl-2,2-dimethoxyacetamide of Formula X is not available on an industrial scale and can be obtained only with the help of special equipment. In addition, the compound of Formula XI is sensitive to trace amounts of moisture and acids. The complexity of obtaining the compound of the Formula XIiY -yd with its sensitivity to moisture and acids make it difficult to use this method on an industrial scale. The purpose of this invention is to eliminate the shortcomings of known methods, as well as to create a simple method of obtaining "» highly pure drug Zolpidem, which is used on an industrial scale.

The above-mentioned goal is achieved by the method of this invention.

In accordance with an aspect of the present invention, a method of preparation of -I b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|Ipyridine-3-(M,M-dimethylacetamide) Formula |! and its pharmaceutically acceptable acid additive salts, which includes the interaction of the ether of the general formula: g ШЙ / sna so with M -- yin

F) in the 60s

AND! 65 (where K is lower alkyl or phenyl-lower alkyl) with dimethylamine in a polar protic or aprotic solvent and, if necessary, conversion of the thus obtained compound of Formula I! its pharmaceutically acceptable acid addition salt.

According to another aspect of the present invention, novel esters of the general Formula II (where K is lower alkyl, excluding ethyl, or phenyl-lower alkyl) and their pharmaceutically acceptable acid addition salts are provided.

According to another aspect of the present invention, crystalline compounds of the general Formula I and their pharmaceutically acceptable acid addition salts (where K is lower alkyl or phenyl-lower alkyl) are provided.

According to another aspect of the present invention, there is provided a method for obtaining esters of the general Formula HER (where K is lower alkyl or phenyl-lower alkyl), which includes esterification of acetic acid derivatives of Formula MI.

This invention is based on the recognition that the compound of Formula | can be obtained in pure form, 70 without impurities, from new compounds of the general Formula II, not previously described, by means of a method also carried out on an industrial scale.

The term "lower alkyl" refers to straight or branched alkyl groups containing 1-6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl) . The term "phenyl-lower alkyl" refers to the lower alkyl groups defined above having as a /5 Substituent one or more phenyl groups (eg, benzyl, pD-phenylethyl, VD,3-diphenylethyl, etc.).

According to the best implementation of the method of the invention, compounds of the general Formula II are used as the starting material, in which K is methyl, ethyl, isopropyl or benzyl.

The reaction can be carried out in a polar protic or aprotic solvent. As a polar protic solvent, it is better to use lower alcohols (for example, methanol, ethanol, n-propanol, n-isopropanol or n-butanol). It is better to use acetonitrile, dimethylformamide, dimethylsulfoxide or hexamethylphosphoric acid diamide as an aprotic solvent. It is better to carry out the reaction in methanol, isopropanol or acetonitrile.

The reaction can be carried out at 5-502C, better at room temperature.

It is better to saturate the solvent used as a reaction medium with the reagent - Ga dimethylamine, and add ether of the general Formula II to the solution obtained in this way.

The reaction mixture can be processed using very simple techniques. The necessary compound of Formula | i) precipitates from the solution in crystalline form and can be easily separated by filtration or centrifugation.

According to the best implementation of the method of the invention, it is possible to proceed as follows:

After filtering the compound of Formula I, the mother solution is saturated with gaseous dimethylamine, and in this way the unreacted compound of Formula II is converted into the required compound of Formula I. Gaseous dimethylamine is absorbed at a low temperature, preferably at a temperature from -10 to "1020. The purity of the obtained second portion of the compound of Formula I is identical to the purity of the first portion of the product. (se)

The thus obtained compound of Formula | can be converted into a pharmaceutically acceptable acid addition salt. Pharmaceutically acceptable inorganic acids C (for example, hydrogen chloride, hydrogen bromide, nitric acid, phosphoric acid, sulfuric acid, etc.) and H-organic acids (for example, tartaric acid, succinic acid, maleic acid) can be used to form the salt , fumaric acid, lactic acid, p-toluenesulfonic acid, etc.). The formation of the salt is carried out by a well-known method, for example, by adding a solution of the appropriate acid, formed with an organic solvent, to a solution of the compound of Formula | in an organic solvent. It is better to obtain the tartaric acid salt of the compound of Formula I. The method of this invention has the following advantages: - c - the method can be simple and well executed; ts - no expensive or special equipment is required; "» - the use of raw materials and reagents that are difficult to process and/or toxic is excluded; - reaction products and mother liquors are not harmful to the environment; - heat energy is not required; - and - the necessary compound of Formula I can easily be isolated in pure form form. Most of the starting compounds of the general Formula II are new. In the journal (U. May. Spect. 40, 3109 (1997), a general method of obtaining the compound of the general Formula II, where K is ethyl, was disclosed. According to this method (ee) 2- amino-5-methylpyridine is subjected to a cyclocondensation reaction with the corresponding bromoketoether. o 50 Ethyl-1b-methyl-2-(4-methyl-phenyl)imidazolo|1,2-a|Ipyridin-3-yl)ioacetate is obtained in the form of an oil with a yield 10905.

Physico-chemical constants of the compound, suitable for its identification, are not given. On the other hand, the compound of general Formula II, where K is ethyl, obtained according to this invention, is a crystalline substance (see Example 4).

In the method of this invention, it is better to use the following compounds of general Formula I: methyl-|b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|pyridin-3-yl|Iacetate; ethyl 1b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|pyridin-3-yl acetate; o isopropyl-(b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|pyridine-Z-ilyacetate; imi)benzyl-1b-methyl-2-(4-methylphenyl)imidazolo|1,2- α|pyridin-3-yl acetate.

Compounds of general Formula II can be obtained by known conventional methods. 60 According to the method, the acetic acid derivative of the Formula MI is esterified with an alcohol of the general Formula: von hm (where K is as described above). 65 The reaction can preferably be carried out using an excess of alcohol of the general Chemical Formula, according to which it acts both as a reagent and as a solvent. The reaction is carried out in the presence of an acid catalyst,

preferably, hydrochloric acid, concentrated sulfuric acid or p-toluenesulfonic acid. The reaction can be carried out at a temperature from 202 to the boiling point of the reaction mixture; better to work at boiling temperature. An aromatic or chlorinated hydrocarbon (for example, toluene or chloroform) that is immiscible with water can also be used as a reaction medium. In this case, the water formed during the reaction is removed together with the solvent by azeotropic distillation. The reaction is carried out in the presence of an acid catalyst.

The compound of general Formula II is isolated from the reaction mixture by a known method. In some cases, the compound of the general Formula I! or its salt, formed with the catalyst, is precipitated from the reaction mass. The solid substance 70 is filtered and in an aqueous medium with the help of hydrogen carbonate or alkali metal carbonate, it is converted into a base. The base, which in most cases is precipitated from the solution in crystalline form, is filtered, washed and, if necessary, recrystallized. The base, which remains in solution, is extracted with an organic solvent that is immiscible with water, and isolated from the extract by evaporation or crystallization.

It is also possible to partition the reaction mass between a solvent immiscible with water and ice water to remove the catalyst, separate the layers, dry and evaporate the organic phase, and finally purify the product by recrystallization or chromatography. If the water formed during the reaction is driven off by azeotropic distillation, the reaction mass is decomposed with ice water, the layers are separated and processed as indicated above.

The compound of general Formula II can also be obtained by converting the acetic acid derivative of Formula 20 MIG into an alkali metal salt and alkylating the thus obtained alkali metal salt with a general

Formulas:

ВХ ХУ

(where K is as stated above, and X is a halogen). ch 25 Salt formation can be carried out using an alkali metal hydride (for example, sodium hydride or (SU potassium hydride), an alkali metal amide (for example, sodium amide or potassium amide) or an alkali metal hydroxide (for example, sodium hydroxide or potassium hydroxide). Preferably use alkali metal hydroxide and work in an aqueous, aqueous-alcohol or alcoholic medium. It is best to dissolve the acetic acid derivative of Formula MI in an aqueous, aqueous-alcohol or alcoholic solution of alkali metal hydroxide and CO 3o to conduct the reaction of the solution obtained in this way with the halide of Formula XM "ip zyi", i.e. without the release of salt "3 of the alkali metal of the compound of Formula MI. The reaction is carried out at a temperature from -20 C to the boiling point of the solvent, preferably at the boiling temperature. Aqueous-alcohol or alcoholic medium can be prepared using alcohol C..4 (for example, methanol, ethanol, isopropanol, butanol, etc.). "I 35 The reaction mass can be processed by the usual method. It is better to extra dilute the reaction mass with an organic solvent (ideally, a halogenated hydrocarbon, for example, dichloromethane or chloroform) followed by washing and evaporation of the extract.

Derivative of acetic acid Formula MI! is a known compound and can be prepared as described in EP 50563.

Compounds of the general Formula ХМ and ХМ are commercially available products. 20 Additional details of this invention should be found in the following non-limiting Examples. with

Example 1 c Methyl-|b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|pyridin-3-yl)Iacetate :c» To the suspension 28g (0.mol) (b-methyl-2- (4-methylphenyl)imidazolo|1,2-a|pyridin-3-yl)|acetic acid and 200Oml of methanol are added dropwise b, Uml (12.8g, 0.1Zmol) of concentrated sulfuric acid. The reaction mass is heated at boiling for 3 hours, after which, with the help of external cooling, it is first brought from -1 to room temperature, and then to 5-102C and stirred at this temperature for an hour. The precipitated crystalline product (sulphuric acid salt of the specified compound) is filtered off, washed with methanol and dried. The product obtained in this way is suspended in 500 ml of water, after which the pH is brought to 8 by adding a 1095% solution of sodium carbonate with intensive stirring. In this way, 27.4 g of methyl-|b-methyl-2-(4-methylphenyl)imidazolo!|1,2-a|Ipyridine-3-yl|ioacetate are obtained in the form of a crystalline substance of white color. Output 93,390,

T. pl.: 133-13626.

Elemental analysis: for the formula Si8Ni8M2O" (294.36) 5B calculated: C 73.45905, H 6.16905, M 9.5290 found: C 73.5895, H 6.1495, M 9.6295 (F. IK ( KVh) 2950, 1729, 1538, 1503, 1437, 1408, 1391, 1332, 1308, 1273, 1229, 1177, 1133, 1042, 994, 890, ko 823, 787, 753, 737, 706, 15, 538 , 417.

PMR (SOSI3): 5, m.d. 7.84 (IN, c, H-5), 7.69 (2H, d, U 80Hz, H-2.6), 7.56 (1H, d, U 9.2Hz, n-8), 7 .28 vo (H, d, U 8.0Hz, H-3.5), 7.06 (1H, dd, U 1.5 and 9.2Hz, H-7), 4.02 (2H, s, СН»), 3.76 (ЗН, с, СН»з), 2.40 (ЗН, с, СН3-4), 2.35 (ЗН, с, СН3-6).

YMR'ZS (SOSIsh): 8, m.d. 169.9 (C-0), 144.3 (C-Va), 143.9 (C-2), 137.5 (0-4), 131.2 (0-1), 1292 (0-35 ), 128.2 (0-26, 127.5 (0-7), 122.0 (0-5), 121.1 (0-6), 116.7 (С-8), 112.1 ( 0-3), 52.4 (СООСН»), 30.5 (СН»), 21.2 (СНИз-4), 18.3 (СНЗ-6). 65 Example 2

Methyl-|b-methyl-2-(4-methylPhenyl)imidazolo|1,2-a|Ipyridin-3-yl|acetate

Act as described in Example 1, except that sulfuric acid is replaced by TOml of a 2096% methanolic solution of hydrogen chloride and the reaction mass is heated at boiling for 8 hours. The methanol is removed, 200 ml of water is added to the residue, after which the pH is adjusted to 7 by adding a 1095 solution of sodium bicarbonate. The mixture is extracted three times with chloroform in portions of 5 Oml each. The combined organic phases are washed

B5Oml of water, dried over anhydrous sodium sulfate and evaporated. The crystalline residue is recrystallized from acetonitrile. In this way, 21.0 g of methyl-|b-methyl-2-(4-methylphenyl)-imidazolo|1,2-a|pyridin-3-yl]acetate are obtained. Output 71,595. The product is identical in all respects to the compound obtained according to Example 1. 70 Example C

Methyl-|b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|pyridin-3-yl)Iacetate

Act as described in Example 1, except that the methanol solution of hydrogen chloride is replaced by 5.0 g of the catalyst - p-toluenesulfonic acid - and the reaction mass is heated at boiling for 6 hours. The crystalline product is recrystallized from acetonitrile. In this way, 22.2 g of 7/5 methyl-|b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|pyridine-33-yl-acetate are obtained, yield 71.55. The product is identical in all respects to the compound obtained according to Example 1.

Example 4

Ethyl-(b-methyl-2-(4-methylphenyl)imidazolo!|1,2-a|pyridin-3-yl)acetate

Act as described in Example 1, except that methanol is replaced by ethanol. In this way, 24.0 g of ethyl Ib-methyl-2-(4-methylphenyl)imidazolo|1,2-a|pyridin-3-yl|acetate are obtained, yield 78.39.

T. pl.: 101-10396.

Elemental analysis: for the formula С19НооМ»2О» (308.43) calculated: C 7400905, H 6.54905, M 9.0890 found: C 74.1795, H 6.5895, M 8.979 s

IR (KVh) 2983, 1725, 1537, 1503, 1391, 1367, 1345, 1326, 1307, 1272, 1225, 1185, 1143, 1058, 1021, 875, 824, 788, 737, 703, 15.5, 584 at

PMR (SOSIz): 5, m.d. 7.88 (1H, c, H-5), 7.73 (2H, d, 9U 8.0Hz, H-26), 7.57 (1H, d, U 9.2Hz, H-8), 7 .28 (2H, d, U 8.0Hz, H-35, 7.07 (1H, dd, U 1.5 and 9.2Hz, H-7), 4.00 (2H, s, CH") 4.22 (2Н, кв. , At 7.2Hz6, СООСНоСН»). ee)

YMR'ZS (SOSIsh): 8, m.d. 1694 (C-0), 144.1 (C-Va), 143.8 (C-2), 137.5 (0-4), 131.0 (0-1), 1293 o (0-35) , 128.3 (0-26), 127.6 (0-7), 122.0 (0-5), 121.3 (0-6), 116.6 (С-8), 112.3 ( 0-3), 61.5 (СООСНоОСН»), 30.8 (СН»), 21.2 (СНУЗ-4), 18.4 (СНи-6), 14.0 (СООСНОСН»). with

Example 5 "

Isopropyl-(b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|pyridin-3-yl|Iacetate

Act as described in Example 1, except that methanol is replaced by isopropanol. In this way, 24.7 g of isopropyl-(b-methyl-2-(4-methylphenyl)-imidazolo|1,2-a|pyridin-3-yl|Iacetate are obtained, the yield is 76.7905.

T. pl.: 104-105.5 26.

Elemental analysis: for the formula С20Но»М»О» (322.41) « calculated: С 74.5195, Н 6.88905, М 8.6990 found: С 74.5795, Н 6.9295, М 8.619 o, с IR (KVh) 2980, 1730, 1613, 1536, 1503, 1460, 1420, 1390, 1376, 1340, 1320, 1270, 1228, 1185, 1108, 1053, "» 973, 945, 901, 176,798 757, 740, 726, 704, 625, 590, 559, 514. " PMR (SOSIz): 5, m.d. 7.91 (1H, c, H-5), 7.74 (2H, d, at 8.0Hz, H-26), 7.57 (1H, d, at 9.0Hz, H-8), 7 ... SNU)»), 3.97 (2Н, с, СН»), 2.40 (ЗН, 459 с, СНа-4), 2.36 (ЗН, с, СН3-6), 1.26 (6Н, d, at 6.2 Hz, SOOSN(SNZ)").

NMR'ZS (SOSIz): 5, md. 169.0 (C-0), 144.2 (C-Va), 143.8 (C-2), 137.5 (0-43, 131.1 (C-13), 1292 sh" (0- 35), 128.3 (0-26), 127.5 (0-7), 121.9 (C-5), 121.3 (0-6), 116.6 (C-8), 112, 5 (С-3), 6902 (СООСН(СНУ)»), 31.1 (СН»), 21.7 (СООСН(СНУ)»), 21.2 (СН3-4, 18.3 (СН3-6 ).

Me Example 6 (ав) 50 Benzyl-I|b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|pyridin-3-yl|Iacetate

To a solution of it (0.025 bmol) of sodium hydroxide in 4 Oml of water, 56 g (0.02 mol) of 1b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|Ipyridin-3-yl)|acetic acid is added, after to which 2.5 mL (3.6 g, 0.021 mol) of benzyl bromide is added dropwise. The reaction mass is heated at boiling for one and a half hours, then cooled to room temperature and extracted twice with dichloromethane in portions of 5 Oml each. The organic 59 phase is washed with 30 ml of a 1095 sodium hydroxide solution and 10 ml of water, dried over anhydrous sulfate

HF) sodium, filter and evaporate. The oily residue is triturated with petroleum ether. In this way, 5.3 g of benzyl-(b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|pyridin-3-ilyacetate are obtained, yield 71.0905.

T. pl.: 106-10726. in Elemental analysis: for the formula С2/Но»М»2О» (370.45) calculated: С 77.81905, Н 5.99905, М 7.5690 found: С 77.7495, Н 6.03905, М 7.599

IR (KVh) 3032, 2920, 1719, 1538, 1501, 1450, 1409, 1378, 1346, 1319, 1304, 1266, 1247, 1180, 1141, 1122, 1050, 1020, 998, 92, 82, 18, 18 740, 694, 581, 504.

PMR (SOSI3): 5, m.d. 7.79 (1Н, с, Н-5), 7.69 (2Н, d, У 8.0Hz, Н-26), 7.55 (1Н, d, в 91Hz, Н-8), -7, 3 (BN, m, AgH), 7.22 (2H, d, at 7.8Hz, H-3.5), 7.04 (1H, dd, 91Hz, H-7), 5.18 (2H, s, RYSN"), 4.04 (2H, s, CH"), 2.39

(ZN, s, SNi-8), 2.28 (ZN, s, SNU-6).

NMR'ZS (SOSI8): 5, m.d. 169.3 (C-0), 144.3 (C-Ba), 143.8 (C-2), 137.5 (0-4), 131.0 (0-1), 1292 (0-35 ), 128.3 (0-26), 127.6 (0-7), 122.0 (C-5), 121.3 (0-6), 116.6 (C-8), 112.1 (0-3), 67.2 (RAISN"), 30.8 (СН"), 521.2 (СНУ5-4), 18.3 (СН 3-6).

Example 7

Methyl-|b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|pyridin-3-yl)Iacetate

Add 1 ,bml (2.9m, 0.0Zmol) of concentrated sulfuric 70 acid. The reaction mass is refluxed for 4 hours with the removal of water, cooled to room temperature, after which 100 ml of water is added and the pH is adjusted to 7 with a 10906 solution of sodium bicarbonate. The layers are separated, and the aqueous phase is extracted with 500 ml of toluene. The combined organic fractions are washed with BbBOml of water, dried over anhydrous sodium sulfate, filtered and evaporated. The residue is recrystallized from acetonitrile. In this way, 241 g of 75 methyl-|1b-methyl-2-(4-methylphenyl)-imidazolo|1,2-a|Ipyridin-3-yl|Iacetate are obtained. The product is identical in all respects to the compound obtained according to Example 1.

Example 8

Methyl-|b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|pyridin-3-yl)Iacetate

Act as described in Example 7, except that concentrated sulfuric acid is replaced by bml of concentrated hydrochloric acid and the reaction mass is refluxed for 5 hours. In this way, 21.5 g of methyl-1|b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|Ipyridine-3-yl)acetate are obtained. The product is identical in all respects to the compound obtained according to Example 1.

Example 9 b-methyl-2-(4-methylphenyl)imidazol!|1,2-a|Ipyridine-3-(M,M-dimethylacetamide) He 30.7 g (0.6 vmol) of gaseous dimethylamine is absorbed in 45 ml of anhydrous methanol at temperature from about -5965 to 0°C, after which 25 g (0.085 mol) of methyl-|b-methyl-2-(4-methylphenyl)imidazolo!|1,2-a|Ipyridin-3-ilyacetate are added. The reaction mass is stirred at room temperature for 7 days. The precipitated crystalline product is filtered off and recrystallized from acetonitrile. In this way, 241 g of b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|pyridine-3-(M,M-dimethylacetamide) are obtained. Output 92.2960. at

T. pl.: 194-1962C; purity determined by HPLC: above 99.895.

Elemental analysis: for the formula Cl9H2iM3O (307.40) d) calculated: C 74.24905, H 6.8990, M 13.6790 " found: C 73.78905, H 6.85905, M 13.7390

IR (KVh) 2916, 1637, 1539, 1505, 1424, 1395, 1345, 1265, 1219, 1189, 1139, 1062, 824, 795, 728, 605, 518. and -

PMR (SOSIz): 5, m.d. 7.96 (IN, d, U 06bHz, H-5), 7.55 (2H, d, 9 8.0Hz, H-2.6), 7.52 (1H, d, u 9.2Hz,

H-8), 7.25 (2H, d, U 8.0Hz, H-3.5), 7.03 (1H, dd, 41.5 and 9.2Hz, H-7), 4.05 ( 2Н, с, СН»), 2.93 (ЗН, с, МОН»), 2.87 (ЗН, с, МОН»), 2.39 (ЗН, с, SNai-4), 2.32 (ЗН , c, CH3-6). "

NMR'ZS (SOSIsh): 8, ppm, 168.2 (C-0), 143.9 (C-Va), 143.5 (C-2), 137.4 (0-4), 131 .5 (0-1), 1293 t0 (0-35), 128.4 (0-26, 127.6 (0-7), 122.2 (С-5), 121.8 (0-6) , 116.4 (С-8), 113.6 (С-3), 37.4 (MSN»), 33.58 (MSN»), 8 s 30.2 (СН»), 21.2 (СНи -4), 18.4 (CH3-6). 5.0 g (0.11 mol) of gaseous dimethylamine is absorbed in the mother liquor of the product obtained according to

Example 9, at a temperature from -59C to 09C. The reaction mass is stirred for 2 days. In this way, an additional 1.7 g of the specified compound is obtained, the yield is 6.595. The purity of this part of the product is identical to the purity of 75 of the main mass.

Example 10 g» b-methyl-2-(4-methylphenyl)imidazolo!|1,2-a|Ipyridine-3-(N,M-dimethylacetamide) so Act as described in Example 9, except that the reaction carried out in a closed apparatus at 40 CU for 2 days. In this way, 24.5 g (a) 20 b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|pyridine-3-(M,M-dimethylacetamide) are obtained, yield 93.895o. The product is identical in all respects to the compound obtained according to Example 9.

Example 11 b-methyl-2-(4-methylphenyl)imidazolo!|1,2-a|Ipyridine-3-(M,M-dimethylacetamide)

Act as described in Example 9, except that the reaction mass is stirred at 59C for 10 days.

The resulting crystalline substance is recrystallized from acetonitrile. In this way, 16.1 g of (F) b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|pyridine-3-(M,M-dimethylacetamide) are obtained, the yield is 61.790. The product is in all respects identical to the compound obtained according to Example 9.

Example 12 in b-methyl-2-(4-methylphenyl)imidazolo!|1,2-a|Ipyridine-3-(M,M-dimethylacetamide)

Act as described in Example 9, except that methyl-|b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|pyridin-3-yl|Iacetate is replaced by 26.2 g (0.085 mol) ethyl-I|Ib-methyl-2-(4-methylphenyl)imidazolo|1,2-a|Ipyridin-3-ilyacetate, and methanol is replaced by anhydrous ethanol.

In this way, 20.7 g of b6-methyl-2-(4-methylphenyl)imidazolo|1,2-a|pyridine-3-(M,M-dimethylacetamide) were obtained, the yield was 79.395. The product is identical in all respects to the compound obtained according to Example 9.

Example 13 b-methyl-2-(4-methylphenyl)imidazolo!|1,2-a|Ipyridine-3-(M,M-dimethylacetamide)

Act as described in Example 9, except that methyl-|b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|pyridin-3-yl|Iacetate is replaced by 26.6 g (0.085 mol) isopropyl-I(b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|Ipyridin-3-yl)ioacetate, and methanol is replaced by anhydrous isopropanol. The reaction mass is stirred for 48 hours at 502C instead of room temperature. In this way, 13.6 bg of b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|Ipyridine-3-(M,M-dimethylacetamide) are obtained, the yield is 51.2905.

The product is identical in all respects to the compound obtained according to Example 9.

Example 14 70 b-methyl-2-(4-methylphenyl)imidazolo!|1,2-a|Ipyridine-3-(M,M-dimethylacetamide)

Act as described in Example 9, except that methyl-|b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|pyridin-3-yl|Iacetate is replaced by 31.5 g (0.085 mol) benzyl-1b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|pyridin-3-yl|acetate, and methanol is replaced by anhydrous acetonitrile. In this way, 18.1 g of 75 8-methyl-2-(4-methylphenyl)imidazolo|1,2-a|pyridine-3-(M,M-dimethylacetamide) are obtained, the yield is 69.595. The product is identical in all respects to the compound obtained according to Example 9.

Example 15 b-methyl-2-(4-methylphenyl)imidazol!|1,2-a|Ipyridine-3-(M,M-dimethylacetamide)-half-tartrate 10g (0.03 mol) b-methyl-2-(4- methylphenyl)imidazolo|1,2-a|pyridine-3-(M,M-dimethylacetamide) is dissolved in 4 Oml of anhydrous methanol, after which, with stirring, a solution of 2.44 g of I-(k)-tartaric acid in 1 Oml of methanol is added. The reaction mass is stirred at room temperature for an hour. The precipitated crystalline substance is kept overnight in the refrigerator, filtered and washed with a small amount of ethanol. In this way, 11.3 g of b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|pyridine-3-(M,M-dimethylacetamide)half-tartrate are obtained in the form of a white crystalline substance. Output 92.7905.

T. pl.: 195-19726, o

The purity of the product by HPLC is higher than 99.895; the total content of impurities is below 0.295. The product fully meets the requirements of the European Pharmacopoeia - Supplement 1998, 525.

Elemental analysis: for the formula C42NavMeOv in (764.9) ee calculated: C 65.95905, H 6.3390, M 10.9990 found: C 65.71905, H 6.23905, M 10.8290 o

IR (KVh) 3542, 3456, 2921, 1638, 1513, 1405, 1264, 1199, 1124, 1072, 918, 854, 797, 683, 599, 513. ee)

PMR (SOSIz): 5, m.d. 8.04 (IN, d, U О6bHz, H-5), 7.52 (2H, d, 9 8.0Hz, H-2.6), 7.51 (IN, d, in 9.2Hz,

H-8), 7.25 (2H, d, U 8.0Hz, H-3.5), 7.12 (1H, dd, U 1.6 and 9.2Hz, H-7), 4.31 (1Н, с), 4.12 (2Н, с, СН»), 3.13 (ЗН, с, З

MSN"), 2.90 (ZH, s, MON"), 2.34 (ZH, s, SNU-8), 2.30 (ZH, s, CHz-6). -

YMR'ZS (SOSIsh): 85, m.d. 173.4 (COOH), 168.2 (C-0), 142.9 (C-Ba), 142.5 (0-2), 136.7 (0-4), 132.0 (0-13 , 129.3 (0-35), 127.8 (0-26), 127.3 (0-7), 122.6 (0-5), 120.9 (0-6), 115.9 ( 0-8), 1154 (С-3), 72.3 (СН), 37.1 (МСН»), 35.5 (МСН»), 29.1 (СН»), 21.0 (СНаи-7 ), 18.0 (CH3-6). " - p

Claims (12)

The formula of the invention. -» 1. The method of obtaining b-methyl-2-(4-methylphenyl)imidazolo|1,2-a|pyridine-3-(M,M-dimethylacetamide) of the formula: what is the IAC. t sn t p YAM Y Z iy 50 ne o o i o us osn" ime) and its pharmaceutically acceptable acid addition salts, which includes the interaction of an ester of the general formula: b5 ay tih; SCHO sn, no yin de K - lower alkyl or phenyl-lower alkyl, with dimethylamine in a polar protic or aprotic solvent and, if necessary, conversion of the thus obtained compound of Formula I! into its pharmaceutically acceptable acid addition salt. 2. The method according to claim 1, which includes the use as a starting material of a compound of the general Formula I, where K is methyl, ethyl, isopropyl or benzyl. 3. The method according to claims 1 or 2, which includes carrying out the reaction at a temperature of 5-50. 4. The method according to any one of claims 1-3, which includes carrying out the reaction in methanol, ethanol, isopropanol or acetonitrile. 5. The method according to any one of claims 1-4, which includes the isolation of a compound of the general Formula I! from the reaction mixture, with the addition of dimethylamine to the mother liquor and isolation of the thus obtained compound of the general formula | Ge) from the uterine solution. 6. The method of obtaining esters of the general Formula ЯИ, where K means lower alkyl or phenyl lower alkyl, which differs in that they esterify an acetic acid derivative of the formula: M (ee) ay p o (ee) y, sn, o M « no - 10 on With "» 7. The method according to point b, which differs in that the compound of Formula MIII is esterified with an alcohol of the general formula: " KOH, KHM where K has the same value as defined in claim 6. 8. The method according to claim 7, which differs in that the reaction is carried out in the presence of an acid catalyst. - 9. The method according to claim 8, which differs in that hydrogen chloride, their concentrated sulfuric acid or p-toluenesulfonic acid is used as an acid catalyst. 10. The method according to claim 6, which differs in that the acid Formula MI! convert into an alkali metal salt and alkylate the specified salt with a halide of the general formula XM: o 20 ЕХ, XM where K is as specified in claim 6, and X means halogen. co 11. The method according to claim 10, which is characterized by the fact that an alkali metal salt is obtained by interaction with an alkali metal hydroxide in an aqueous, aqueous-alcoholic or alcoholic solution. 12. The method according to claims 10 or 11, which differs in that it uses a compound of the general Formula XM, where X represents chlorine or bromine. name) 60 b5