Method for synthesis of delmopinol and derivatives thereof

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of a compound of formula , where R1 is an alkyl or aryl group, or a pharmaceutically acceptable salt or solvate thereof, including hydrate, involving reaction of a compound of formula with a Grignard reagent of formula , where X is a halogen selected from Cl, Br and I, and R1 is an alkyl or aryl group; and optional conversion of the obtained free base compound of formula (I) to a pharmaceutically acceptable salt. The invention also relates to a compound of formula II; a compound of formula , where X is a halogen selected from O, Br and I and to use of formula II and IIIA compounds in synthesis of delmopinol and a derivative of the formula I compound.

EFFECT: novel method for synthesis of a compound of formula I using novel intermediate compounds of formulae II and IIIA.

18 cl, 11 ex

 

The technical FIELD

The present invention relates to a method for delmopinol or its derivative, as well as to intermediate compounds useful in this method of receipt.

PRIOR art

Delmopinol is the international nonproprietary name (INN) 3-(4-propylheptyl)-4-morpholinoethyl (CAS No. 79874-76-3). Cleaners containing hydrochloride salt delmopinol (CAS No. 98092-92-3) is intended for use in the treatment of gingivitis. The structure of the hydrochloride delmopinol corresponds to the formula:

In this area there are various ways to obtain delmopinol and its salts. In EP-A-038785 described several ways to obtain this compound. In particular, in EP-A-038785 disclosed receipt delmopinol by alkylation of 3-substituted of the research, dialkylamino primary amine substituted bis(halogenated)ether or substituted by dieselenginefoam, recovery diatomologica or transformation of the N-substituent morpholine in hydroksyetylowy group. In EP-A-0426826 describes a method for delmopinol, including the addition of the oxide of the research with the receipt of morphosyntactically, rehabilitation erection cycle with subsequent transformation of the functional groups present in the side chain, and, finally, alkylation of the nitrogen with getting dlmopen the La.

Known methods for producing delmopinol are long and require the use of some very toxic chemicals that make their industrial use is difficult and expensive. Therefore, highly desirable to provide a novel method of obtaining delmopinol.

The INVENTION

The present invention is based on the surprising discovery that delmopinol and its derivatives can be obtained in the short and convergent synthesis, which occurs through the reaction between the compound of oxazolidin[2,3-C]of the research and the Grignard reagent.

According to the first aspect of the present invention is a method of obtaining the compounds of formula (I), where R1represents an alkyl or aryl group, or its pharmaceutically acceptable salt or MES, including a hydrate,

this involves reacting the compounds of formula (II) with a Grignard reagent of the formula (III), where X is a halogen selected from Cl, Br and I, and R1represents an alkyl or aryl group, and, optionally, converting the obtained free base of compounds of formula (I) and its pharmaceutically acceptable salt.

The inventors have also found an effective way floor the ing new oxazolidin[2,3-C]of the research (II) using as the starting material commercially available diethanolamin, which provides high yields and purity. Therefore, in the second aspect of the present invention, a method for obtaining oxazolidin[2,3-C]of the research, including the interaction of diethanolamine with (C1-C4)alkylhalogenide with obtaining well-known 4-(2-hydroxyethyl)morpholine-3-one, followed by reduction with obtaining oxazolidin[2,3-C]of the research. Both stages can be combined in dorectory ("one-pot"reaction, without costing allocation 4-(2-hydroxyethyl)morpholine-3-one.

According to a third aspect of the present invention having the particular Grignard reagent (IIIA) is carried out by treatment of 1-halogeno-4-propylheptanol magnesium.

According to a fourth aspect of the present invention proposed compounds (II) and (IIIA). These compounds are useful as intermediates for obtaining the compounds of formula (IA).

According to the fifth aspect of the invention, the compound (II) and (III) use in obtaining the compounds of formula (I).

The method according to the present invention is a lightweight and efficient alternative manufacturing delmopinol derived delmopinol and/or its pharmaceutically acceptable salts in Islena scale. The method is advantageous because it is a short and convergent synthesis, which do not require the use of toxic and flammable reagents, use a mild reaction conditions and get delmopinol with high yields and high purity.

INFORMATION CONFIRMING the POSSIBILITY of carrying out the INVENTION

The compound of formula (I) are obtained according to the present invention.

In the compound of formula (I) R1represents an alkyl or aryl group. Alkyl or aryl group may be of any length, can be remotemachine or branched and may be substituted, i.e. it may contain other atoms than carbon atoms in the carbon skeleton. Used in this description, the terms "alkyl" and "aryl" should be attributed to their normal values in this area. Preferably, the alkyl or aryl group contains from 1 to 30 carbon atoms, more preferably from 2 to 20 carbon atoms, for example, 6, 7, 8, 9 or 10 carbon atoms. Were obtained the compounds of formula (I), where R1is a 1-through, benzyl, 1-aktiline, 1-heptylene, 1-(2-ethyl)hexoloy or 1-(2-propyl)hexoloy group. Obtaining these compounds is described in Examples 6-11.

A preferred compound of formula (I) present the focus of delmopinol, which is represented in the following formula (IA). In delmopinol R1is a 4-propylheptanol chain.

According to the present invention the compound of formula (I) obtained by the interaction between oxazolidin[2,3-C]morpholine (II) and the Grignard reagent (III), where X is a halogen selected from Cl, Br and I, and R1represents an alkyl or aryl group, as defined above, and most preferably 4-propylheptanol chain. A preferred compound of formula (III), where R1is a 4-propylheptanol circuit, shown below as formula (IIIA).

Most preferably, the compound of formula (III) is a 4-propylheptyl bromide. Used in this description the term "Grignard reagent" should be attributed to its default value, which is well known in this field, i.e. magyarkanizsa connection.

For the avoidance of doubt, the compound of formula (I) are obtained by reacting the compounds of formula (II) with a Grignard reagent of the formula (III). The preferred form of this basic reaction includes obtaining delmopinol (formula (IIIA)) by reacting the compounds of formula (II) with the preferred Grignard reagent of the formula (IIIA).

The formation of rectovaginal (III) and its subsequent interaction with oxazolidine (II) is carried out in a suitable solvent, such as (C4-C12) ethers, and mixtures of these ethers with (C5-C8)aliphatic or (C6-C8)aromatic hydrocarbons. Preferably, the solvent is selected from the group consisting of diethyl ether, tetrahydrofuran, methyltetrahydrofuran, dibutylamino ether and the following mixtures: tetrahydrofuran-toluene, tetrahydrofuran-xylene, methyltetrahydrofuran-toluene, methyltetrahydrofuran-xylene, disutility ether-xylene, disutility ether-toluene.

The compound of formula (I), for example delmopinol obtained by the method according to the present invention, can be converted into a pharmaceutically acceptable salt, preferably cleaners containing hydrochloride salt, and salt delmopinol can be turned into delmopinol known methods in this field. As an example, delmopinol hydrochloride can be obtained from delmopinol by reacting with hydrochloric acid in a suitable solvent. Examples of suitable solvents are, for example, toluene, xylene, methyl isobutyl ketone, disutility ether, methyl tert-butyl ether, ethyl acetate and mixtures thereof.

The compound of formula (II) can be obtained by the method presented in Scheme I, which can be done in two stages or in one dorectory reaction. Used in this description the term "od is reactora reaction" should be attributed to its normal value in this field, i.e. the compound of formula (II) are obtained in one reaction vessel so that at least part of the compounds (V) and (VI) into the compound (IV) and then the compound (II), without the isolation of intermediate compounds.

Alternative dorectory reaction is a two-step reaction where the compound of formula (IV) are obtained in the first stage and the second stage of transformation (IV) (II) carry out separately.

SCHEME I:

In the formula (VI), X represents a halogen selected from Cl, Br and I, a R1is a (C1-C4)alkyl radical. Preferably, the compound of formula (VI) represents methylchloride.

The reaction between diethanolamine (V) and halogenoacetyl formula (VI) is preferably carried out in the presence of a suitable base and a suitable solvent. Examples of suitable bases are sodium hydride, sodium methylate, tert-butyl potassium and tert-butyl sodium. The best results are obtained with tert-butyl potassium. Suitable solvents are, for example, tetrahydrofuran, xylene, toluene or disutility ether.

The reaction between diethanolamine (V) and halogenoacetyl (VI) can be performed at a temperature ranging from room temperature to the temperature of reflux distilled solvent used. Preferably, the reaction is carried is given at high temperatures (i.e. slightly lower temperature than the temperature of the reflux distilled solvent, for example, 50% temperature reflux distilled or higher, preferably 60%, 70%, 80% or 90% temperature reflux distilled) in order to avoid thickening of the crude mixture due to insolubility of diethanolamine alcoholate at low temperatures. The compound (IV) can be isolated from the reaction medium with a high output in the form of oil, which can be used without purification in the next stage. If necessary, it can be purified by distillation.

3 Morpholine (IV) can be also obtained by a method described in the literature (Australian Journal of Chemistry, 1996, vol.49, pp.1235-1242). However, this method uses excess Alliluyeva reagent, it is carried out through an unstable intermediate compound and provides a low output.

Recovery of 3-morpholino (IV) obtaining oxazolidine (II) is carried out using a reducing agent. Examples of reducing agents are bis(2-methoxyethoxy)alumoweld sodium (vitric), sodium borohydride, alumoweld lithium and biotoxicological sodium. Preferred regenerating agent is bis(2-methoxyethoxy)alumoweld sodium. The reduction is carried out in a solvent selected from (C6-C8aromatic hydrocarbon such as toluene or xylene, and (C4-C 12simple ether, such as diethyl ether, tetrahydrofuran, disutility ether, methyl tert-butyl ether and dietilenglikoluretan ether.

Preferably, when the method of obtaining the compounds of formula II is carried out in one reactor, then the alcohol formed during the reaction between diethanolamine and the compound of the formula (VI)is subjected to distillation prior to adding the reducing agent.

The compound of formula (III) can be obtained by the interaction of alkyl - or helgaleena with magnesium. Preferably, the halide is in end position or the second position. In the preferred embodiment, as illustrated in Scheme II, the compound of formula (IIIA) previously obtained by processing the compounds of formula (VII), where X is a halogen selected from Cl, Br and I, and magnesium. Any suitable solvent for Grignard reactions, such as (C4-C12)ethers, and mixtures of such ethers with (C5-C8)aliphatic or (C6-C8)aromatic hydrocarbons, can be used for the formation of the Grignard reagent. The Grignard reagent of the formula (III) is not isolated and used in the solution. Its formation can be easily detected by the disappearance of the magnesium and the colour of the solution in a brown color.

SCHEME II:

The compound of formula (VII) can be obtained from the corresponding hydroxycodone formula (VIII) with a halogenation reaction.

Preferably, in the compound of formula (VII), X represents bromine and preferably obtained by the reaction of the synthesized compounds (VIII) aqueous Hydrobromic acid. The compound of formula (VIII) can be obtained by the method described in Justus Liebigs Annalen Chemie, 1966, vol.693, p.90, the content of which is incorporated in this description by reference.

Throughout the description and claims the word "contain" and variations of this word, such as "contains", do not exclude other technical features, auxiliary materials, components or stages. Additional objects, advantages and features of the invention will become apparent to experts in this field after studying the description, or can be found in the practical implementation of the invention.

DESCRIPTION of embodiments of the INVENTION

The following examples are provided as illustrations and are not intended to limit the present invention.

Example 1: Obtain 4-(2-hydroxyethyl)morpholine-3-one (IV)

tert-Butyl potassium (176 g, 1.1 EQ.) added to 1440 ml of toluene. The suspension was heated to 75°C and maintained for 30 min to complete the RA is the creation of a white solid. At this temperature, was slowly added diethanolamine (150 g, 1 EQ.). Thick pale yellow suspension was maintained under vigorous stirring for 30 min and slowly added methylchloride (163 g of 1.05 EQ.). The solution was maintained at the same temperature for two hours. To the warm mixture was added methanol (600 ml) and cooled at room temperature, the salts were filtered, and the organic layer was concentrated to dryness. The compound (IV) was obtained as an orange oil (204 g, 98%)which was subjected to distillation in high vacuum to obtain it in the form of high-purity colorless oil (80%, TC 180°C). IR (infrared) (film) (n cm-1): 3410, 2934, 2874, 1633, 1501, 1350, 1141. MS (mass spectrometry) (EI (elektrorazpredelenie)), (m/z, %): 145 (M+., 12), 114 (M-CH2OH, 100), 86 (M-NC2H4OH, 65), 74 (M-71, 7), 56 (M-89, 41), 42 (M-103, 44).

Example 2: Getting oxazolidin[2,3-C]of the research (II)

To a solution of 3-morpholino (IV) (207 g, 1 EQ.) in toluene (1450 ml) was slowly added a solution of Vitrea (412 g, 2 EQ., 70% in toluene) at room temperature. The reaction was maintained for 15 min at this temperature. Was slowly added 50%aqueous sodium hydroxide solution (360 g, 3,15 equiv.) maintaining the mixture at room temperature. The mixture was heated to 50-60°C, and the aqueous layer was separated and was extracted at the same temperature toluene (924 ml). Both organic SL which I have concentrated together dry. Oxazolidin (II) received (154,5 g, 84%) as a brownish oil, which was subjected to distillation to obtain high-purity colorless oil (65 g, as 2 80°C). IR (film), (n cm-1): 2865, 1676, 1457, 1297, 1113, 1046. MS (EI), m/z, %): 129 (M+., 50), 99 (M-CH2O, 100), 98 (M-CH3Oh, 90), 84 (M-C2H5O, 10), 71 (M-C3H6OH, 51), 56 (M-73, 37), 42 (M-87, 47), 41 (M-88, 65).

Example 3: Getting oxazolidin[2,3-C]of the research (II) in dorectory reaction, starting from diethanolamine

tert-Butyl potassium (176 g, 1.1 EQ.) added to 1440 ml of toluene. The suspension was heated to 75°C and maintained for 30 minutes to dissolve the white solid substance. At this temperature, was slowly added diethanolamine (150 g, 1 EQ.). Thick pale yellow suspension was maintained under vigorous stirring for 30 min and slowly added methylchloride (163 g of 1.05 EQ.). The solution was maintained at the same temperature for two hours. The reaction mixture was cooled at 30°C and slowly added to the solution of Vitrea (412 g, 2 EQ., 70% in toluene) at room temperature. The reaction was maintained for 30 min at this temperature. Was slowly added 50%aqueous sodium hydroxide solution (360 g, 3,15 equiv.) maintaining the mixture at room temperature. The mixture was heated to 50°C., and the aqueous layer was separated and was extracted at the same temperature toluene (924 ml). Both organic layers conc the Wali together dry. Oxazolidin (II) received (147 g, 80%) as a brownish oil.

Example 4: Obtain 4-(2-hydroxyethyl)-3-(4-propylheptyl)of the research (IA)

To a suspension of 1.3 g of magnesium (1 EQ.) in 24 ml of toluene and 18 ml of tetrahydrofuran was added a small crystal of iodine. The mixture was heated to 64°C and slowly added 12 g of 1-bromo-4-propylheptanol (VII) (1 EQ.), controlling esotericist reaction. The mixture was maintained at the same temperature for 2 hours and cooled at room temperature, obtaining a solution of compound (III). A solution of 7 g of oxazolidine (II) (1 EQ.) in 7 ml of toluene was added to the previously obtained Grignard reagent (III) at room temperature over 30 minutes was Added 50 ml of toluene and 50 ml of a saturated aqueous solution of ammonium chloride, and the resulting mixture was stirred at 40°C. until complete dissolution of the salts, receiving a two-phase mixture. The organic layer was separated at 40°C. the Aqueous layer was extracted with 50 ml of toluene at 40°C. the Organic layers were concentrated together to dryness, obtaining 8.8 g of 4-(2-hydroxyethyl)-3-(4-propylheptyl)the research in the form of an orange oil. IR (film), (n cm-1): 3446, 2951, 2925, 2859, 1628, 1458, 1128, 1048. MS (EI), m/z, %):

271 (M+., 1), 270 (M-H, 1), 240 (M-CH2OH, 46), 130 (M-141, 100), 100 (M-171, 29).

Example 5: Obtain 4-(2-hydroxyethyl)-3-(4-propylheptyl)the research hydrochloride

To a solution of 7.4 g untreated the military 4-(2-hydroxyethyl)-3-(4-propylheptyl)the research in 22 ml of isobutyl ketone was added concentrated hydrochloric acid (2.7 g, 1 EQ.) at room temperature. The solution was concentrated to dryness at 60°C. the Oil was again dissolved in 21 ml of isobutyl ketone, the solution was made of the seed and was stirred for 2 hours at 0°C. the White solid was filtered off, washed with 20 ml of cold isobutyl ketone and dried to obtain 5.9 g of 4-(2-hydroxyethyl)-3-(4-propylheptyl)the research hydrochloride (delmopinol hydrochloride).1H-NMR (CDCl3, 400 MHz), (d million-1): 0,88 (6N, m, n), 1,2-1,4 (13H, m), of 1.8-2.0 (2H, m), 2.8 to a 3.4 (5H, m), 3,4-4,4 (6N, m).13C-NMR (CDCl3, 400 MHz), (d million-1): 14,26 (C15), 19,47, 19,52 (C14), 22,87 (C10), 27,11 (C9), 33,25 (C11), 35,54, 35,62 (C13), 36,59 (C12), 49,25 (C5), 53,20 (C7), 55,93 (C3), 57,08, 59,89 (C8), 63,1, 63,2, 65,0 (C6), 67,7 (C2).

Example 6: Synthesis of 4-(2-hydroxyethyl)-3-propiolactone (IB)

43 g of oxazolidine (II) was dissolved in 215 ml of THF (tetrahydrofuran). At room temperature was slowly added a 20%solution of n-propylaniline in THF (172 g, 1 EQ.). The mixture was stirred for 15 min. the Mixture was concentrated to dryness under vacuum and added 100 ml of toluene and 64 g of a saturated aqueous solution of ammonium chloride, and the resulting mixture was stirred at room temperature until complete dissolution of the salts, receiving a two-phase mixture. The organic layer was separated, and the aqueous layer was extracted with 265 ml of toluene at room temperature. The organic layers were concentrated together on the dry, receiving of 33.4 g of 4-(2-hydroxyethyl)-3-propiolactone in the form of an orange oil which was further purified by column chromatography on silica gel, elwira a mixture of CH2Cl2/MeOH/NH3(99/1/1), receiving the specified product as colourless oil.

1H-NMR (CDCl3, 300 MHz), (d million-1): to 0.92 (3H, t, J=7.2 Hz, H11), of 1.36 (4H, m, H9/H10), a 2.36 (3H, m, H3/H7), 2,82 (1H, ddd, J1=12,3, J2=4,9, J3=3.0 Hz, H5), to 2.94 (1H, ddd, J1=12,3, J2=7,8, J3=4,8 Hz, H5), 3,44 (1H, dd, J1=11,2, J2=6.9 Hz, H2), 3,88 (1H, dd, J1=11,2, J2=4.9 Hz, H2), 3,62 (1H, dd, J1=4,8, J2=7.8 Hz, h6), to 3.67 (1H, dd, J1=7,8, J2=4.9 Hz, H6 in), 3.75 (2H, m, H8).13C-NMR (CDCl3, 75 MHz), (d million-1): 14,3 (C11), And 19.3 (C10), 29,2 (C9), A 49.9 (C5), 54,6 (C7), 57,7 (C8), 59,5 (C3), 66,9 (C6), 70,4 (C2). IR (film), (n cm-1): 3444, 2958, 2863, 1456, 1366, 1129, 1052. MS (EI), m/z, %): 173 (M+., 42), 142 (M-CH2OH, 100), 130 (M-C3H7, 100), 112 (M-C3H7-N2OH, 14), 100 (M-73, 48), 84 (10), 71 (5), 56 (20), 42 (14).

Example 7: Synthesis of 4-(2-hydroxyethyl)-3-(1-heptyl)of the research (IC)

200 g of 1-brometane was slowly added at 65°C to a suspension of 32.6 g of magnesium, 0.5 g of iodine and 2.4 ml of dibromethane in a mixture of 182 ml of THF and 400 ml of toluene. The reaction mixture was stirred at the same temperature for 3 hours When the formation of the corresponding Grignard reagent was completed, the mixture was cooled at room temperature was added a solution of 158 g of oxazolidine (II) in 500 ml of toluene in 1 hour. The mixture was stirred for 30 min and then added the 795 ml of aqueous 5%HCl solution. The organic layer decantation and concentrated to dryness. The compound (IC) was obtained as an orange oil (179 g). MS (El), m/z, %): 229 (M+., 1), 198 (M-CH2HE, 25), 130 (M-C7H15, 100), 112 (M-C7H15-H2O, 4), 100 (M-73, 30), 86 (5), 56 (10), 41 (8).

Example 8: Synthesis of 4-(2-hydroxyethyl)-3-benzylmorphine (ID)

Following the same procedure described for (1C), and starting with 10 g benzylchloride and 11 g of oxazolidine (II), obtained 7.9 g of compound (ID) in the form of a light yellow oil. MS (EI), m/z, %): 221 (M+., 1), 190 (M-CH2OH, 5), 130 (M-C7H7, 100), 91 (CH2With6H5, 8).

Example 9: Synthesis of 4-(2-hydroxyethyl)-3-(1-octyl)of the research (IE)

25 g of 1-bromooctane was slowly added to a suspension of 3.5 g of magnesium and 7.5 mg of iodine in 41 ml of THF at 65°C. the Reaction mixture was stirred at the same temperature for 2 hours When he received an appropriate Grignard reagent, the mixture was cooled at 5°C was added a solution of 16.7 g of oxazolidine (II) in 40 ml of toluene in 1 hour. The mixture was stirred at 5°C for 30 min, and the reaction mixture was heated to room temperature. The mixture was added to aqueous 5%increase HCl solution and was stirred for 30 minutes the Organic layer decantation, dried and concentrated to dryness to obtain 19 g of the desired compound as a brown oil. MS (EI), m/z, %): 243 (M+., 5), 242 (M-H, 5), 212 (M-CH2OH, 50), 198(M-(CH 2)2OH, 8), 130 (M-C8H17, 100), 112 (M-C8H17-H2O, 8), 100 (M-73, 30), 86 (8), 71 (8), 56 (9), 41 (14).

Example 10: Synthesis of 4-(2-hydroxyethyl)-3-(1-(2-ethylhexyl))of the research (IF)

Following the same procedure described for (IE), and starting from 25.5 g of 1-bromo-2-ethylhexane bromide and 16.2 g of oxazolidine (II)received and 19.8 g of compound (IF) in the form of a dark orange oil. MS (EI), m/z, %): 243 (M+., 1), 214 (M-C2H5, 6), 212 (M-CH2HE, 11), 186 (M-C4H9, 4), 156 (8), 130 (M-C8H17, 100), 100 (46).

Example 11: Synthesis of 4-(2-hydroxyethyl)-3-(1-(2-propylpentyl))of the research (IG)

Following the same procedure described for (IE), and starting with 5.8 g of 1-bromo-2-propylpentyl and 4 g of oxazolidine (II)received a 3.3 g of compound (IF) in the form of a dark yellow oil. MS (EI), m/z, %): 243 (M+., 1), 212 (M-CH2OH, 8), 200 (M-C3H7, 6), 170 (10), 130 (M-C8H17, 100), 100 (50).

1. The method of obtaining the compounds of formula (I), where R1represents an alkyl or aryl group, or its pharmaceutically acceptable salt, or MES, including hydrate:

including the interaction of the compounds of formula (II) with a Grignard reagent of the formula (III), where X is a halogen selected from Cl, Br and I, a R1represents an alkyl or aryl group; and, optionally, transforming the floor is built of free base of the compounds of formula (I) into a pharmaceutically acceptable salt:

2. The method according to claim 1, where in formula (III), X represents bromine.

3. The method according to claim 1, where the formula (III) represents the formula (IIIA)

4. The method according to claim 3, where the compound of formula (I), which is obtained, is a compound of formula (IA).

5. The method according to claim 1, where the reaction is carried out in a solvent selected from the group consisting of (C4-C12) ethers, and mixtures of such ethers with (C5-C8)aliphatic or (C6-C8)aromatic hydrocarbons, or combinations thereof.

6. The method according to claim 1, where the compound of formula (II) obtained by using the reduction reaction of the compounds of formula (IV)

7. The method according to claim 6, where the reduction is performed with regenerating agent selected from bis(2-methoxyethoxy)aluminum hydride, sodium, sodium borohydride, lithium aluminum hydride and biotoxicological sodium.

8. The method according to claim 7, where the reducing agent is a bis(2-methoxyethoxy)alumoweld sodium.

9. The method according to claim 6, where the reduction is carried out in a solvent selected from (C6-C8)aromatic hydrocarbon and (C4-C12simple ether.

10. The method according to claim 6 where the compound of formula (IV) receive the but by reacting diethanolamine of the formula (V) with the compound of the formula (VI), where X represents a halogen selected from Cl, Br and I, a R1is a (C1-C4)-alkyl radical, in the presence of a base:

11. The method according to claim 10, where the base is selected from sodium hydride, sodium methylate, of potassium tert-butylate and tert-butyl sodium.

12. The method according to claim 10 where the compound of formula (VI) represents methylchloride.

13. The method according to claim 6, where receiving the compounds of formula (II) is carried out in one reaction vessel.

14. The method according to claim 3, where the Grignard reagent of the formula (IIIA) previously obtained by reacting the compounds of formula (VII), where X is a halogen selected from the group consisting of Cl, Br and I, with magnesium:

15. The compound of formula (II)

16. The compound of formula (IIIA), where X is a halogen selected from Cl, Br and I:

17. Connection P16, where X represents bromine.

18. The use of compounds according to any one of p-17 in the manufacture of delmopinol.



 

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FIELD: chemistry.

SUBSTANCE: invention relates to organometallic synthesis, specifically to a method of producing 2,3-dialkyl-5-alkylidenemagnesacyclopent-2-enes of general formula (1): characterised by that, disubstituted acetylene of general formula R-≡-R, where R is as described above, is reacted with 1,2-alkadiene of general formula R'-=·=, where R' is as described above, ethylmagnesium bromide (EtMgBr) and magnesium metal (Mg) in the presence of a titanocenedichloride catalyst (Cp2TiCl2) with ratio R-≡-R : R'-=·= : EtMgBr : Mg : Cp2TiCl2 equal to 10:(10-14):(22-26):10:(1.0-1.4) in an argon atmosphere at normal pressure in tetrahydrofuran as a solvent for 10 to 14 hours.

EFFECT: obtaining new 2,3-dialkyl-5-alkylidenemagnesacyclopent-2-enes with high selectivity, which can be used as components of catalyst systems in oligomerisation and polymerisation processes of olefins and diene hydrocarbons in fine, industrial organic and organometallic synthesis, as well in synthesis of biologically active preparations.

1 cl, 1 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention concerns organic synthesis, particularly method of obtaining new organic magnesium compounds, namely (9-ethyl-1-cyclononenyl)magnesium halogenides. Method involves reaction of 1,2-hohadiene with ethylmagnesium halogenide in the presence of zirconocene dichloride catalyst in argon atmosphere at room temperature in tetrahydrofurane for 6-10 hours.

EFFECT: application as catalytic system component in oligomerisation and polymerisation processes for olefin, diene and acetylene hydrocarbons, and in fine organic synthesis.

1 cl, 1 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns organic magnesium synthesis, particularly method of obtaining 10,11-dialkyl-9-magnesabicyclo[6.3.0]undeca-1(8),10-dienes. Method involves interaction of equimolar mix of cyclooctine and dialkylacetylene with n-BuMgCl in the presence of zirconocene dichloride catalyst in argon atmosphere at room temperature in diethyl ether for 5-7 hours.

EFFECT: obtained organic magnesium compounds can be applied as catalytic system components in polymerisation and oligomerisation processes for olefins and diene hydrocarbons, in fine organic, industrial-scale organic and metal-organic synthesis, and in bioactive medicine synthesis.

1 cl, 1 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns method of obtaining alcohol adduct particles of magnesium halide and their application in production of olefin polymerisation catalysts. The claimed method involves: (1) magnesium halide contact to alcohol in inert liquid medium for obtaining alcohol adduct melt of magnesium halide; (2) dispersion of inert liquid medium mix with alcohol adduct melt of magnesium halide obtained at stage (1), by rotation in high gravitation field to obtain dispersed alcohol adduct melt of magnesium halide; dispersion is performed in high-gravitation rotation mill-type reactor at rotation rate of 100 to 3000 rpm, high-gravitation rotation mill-type reactor is packed with Sultzer filler with average pore size of 0.1 to 8 mm, porosity of 90 to 99 percent, specific surface area of 100 to 3000 m2/m3 and wire diametre of 0.05 to 0.5 mm; and (3) cooling of melt dispersion obtained at stage (2), to form alcohol adduct particles of magnesium halide.

EFFECT: simple and easy method of obtaining alcohol adduct particles of magnesium halide with narrow spread of particle size.

12 cl, 1 tbl, 1 dwg, 9 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to method of obtaining 3,5-bis(trifluoromethyl)benzyl alcohol which includes interaction of 3,5-bis(trifluoromethyl)phenylmafnesium halogenide with solid paraformaldehyde in solvent and hydrolysis of obtained adduct with water solution of inorganic acid, as well as to method of obtaining 3,5-bis(trifluoromethyl)benzylhalogenide by interaction of 3,5-bis(trifluoromethyl)benzyl alcohol with HX, where X represents halogen.

EFFECT: obtaining product with output comparable with output obtained using gaseous fomaldehyde, but to avoid using toxic gaseous folmaldehyde and critical conditions of work with it.

18 cl, 2 ex

FIELD: chemistry of metalloorganic compounds, chemical technology.

SUBSTANCE: invention relates to methods for synthesis of novel organomagnesium compounds. Method involves interaction of disubstituted acetylenes with butylmagnesium bromide in the presence of a catalyst, in argon atmosphere, under atmosphere pressure and temperature ˜200C, in ether solvent medium for 3 h followed by vacuum evacuation of ether, addition of 1,4-naphthoquinone at temperature -50C and stirring the reaction mass at temperature ˜200C in toluene medium for 6-8 h. The yield of the end product is 44-54%. Proposed method provides preparing compound of the formula (1): wherein R means ethyl (Et), n-propyl (n-Pr), n-butyl (n-Bu) with high selectivity. Synthesis of these compounds is not described in special literature. Synthesized compound can be used in fine organic and metalloorganic synthesis, as co-catalysts in processes of oligo- and polymerization of olefins and coupled dienes.

EFFECT: improved method of synthesis.

1 tbl, 10 ex

FIELD: chemistry of metalloorganic compounds, chemical technology.

SUBSTANCE: invention relates to methods for synthesis of novel organomagnesium compounds. Method involves interaction of disubstituted acetylenes with butylmagnesium bromide in the presence of a catalyst, in argon atmosphere under atmosphere pressure and temperature ˜200C, in ether solvent medium for 3 h followed by vacuum evaporation of ether, addition of N-methylmaleinimide at temperature -50C and stirring the reaction mass at temperature ˜200C in toluene medium for 6-8 h. The yield of the end product is 47-56%. Proposed method provides preparing the end compounds of the formula (1): wherein R means ethyl (Et), n-propyl (n-Pr), n-butyl (n-Bu) with high selectivity. Synthesis of these compounds is not describes in special literature. Synthesized compounds can be used in fine organic and metalloorganic synthesis, as co-catalysts in processes of oligo- and polymerization of olefins and coupled dienes.

EFFECT: improved method of synthesis.

1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula I or its pharmaceutically acceptable salt , where R, R9, Z, X, Q and Y are defined in the formula of invention. The compounds are chemokine receptor 2 and chemokine receptor 5 antagonists and can be used as a medicinal agent for preventing, relieving or treating autoimmune or inflammatory diseases or conditions.

EFFECT: obtaining a formula (I) compound, a pharmaceutical composition based on the formula (I) compound, use of the compound in paragraph 1 to prepare a medicinal agent for treating an autoimmune or inflammatory disease or condition, as well as use of the compound in paragraph 1 to prepare a medicinal agent for treating HIV infection or AIDS.

11 cl, 181 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula I. In general formula I A is C or N; B, D and E independently represent CR4, NR5, N, O or S; and a ring containing groups A, B, D, E, selected from thienyl, furan, imidazole, oxazole, isothiazole, thiazole, pyrrol, pyrazole; provided that: b) when A is N, not any of B, D, E can be O or S; and c) when A is C, B is CR4 and one of D or E is N or NR5, when any of D or E cannot be NR5 or N; G is N or C; R1 represents one or more substitutes selected from H, Ra halogen, -OH and -ORa; R2 represents one or more substitutes selected from H, halogen and C1-6-alkyl, and also one of substitutes R2 can be -ORb' , -NRb' Rb', -SRb', -SORb', -SO2Rb', -SO2NRb' Rb'; R3 is H, or Cy, selected from phenyl optionally substituted with one or more substitutes selected from Rc , where Rc independently represents halogen, -ORg', where Rg' independently represents a Rg group, where Rg is C1-6-alkyl; each R4 independently represents H, Re, halogen, -CORe', -CO2Re', -CONRe'Re', -NRe'Re'; R5 independently represents H, Re, -CORe, -CONReRe, -SORe or -SO2Re; each Ra independently represents C1-6-alkyl or halogen- C1-6-alkyl; each R independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rb' independently represents H or Rb; each Rc independently represents halogen, -ORg', -CONRg'Rg', -NRg'Rg'; Rd is Cy optionally substituted with one or more Rf substitutes; each Rc independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rc and Cy*, or Re is Cy, where any of the groups Cy or Cy* can optionally be substituted with one or more substitutes selected from Rc and Rg ; each Re' independently represents H or Re; each Rf independently represents a halogen, -ORh', -CO2Rh; each Rg independently represents Rd or C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rg' independently represents H or Rg; each Rh independently represents C1-6-alkyl, halogen-C1-6-alkyl or hydroxy- C1-6-alkyl; each Rh' independently represents H or Rh; and Cy or Cy* given in definitions above is a partially saturated, saturated or aromatic 3-7-member monocyclic carbocyclic ring which optionally contains 1-2 heteroatoms selected from N and O, and where the ring or rings can be bonded to the remaining part of the molecule through a carbon or nitrogen atom.

EFFECT: obtaining formula I compounds with p38-kinase inhibitory properties which can be used in making drugs for treating such diseases as tumour immune and autoimmune diseases etc.

21 cl, 10 dwg, 8 tbl, 57 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are derivatives of 5H-pyrazolo[1,5-c][1,3]benzoxasin-5-yl)phenylmethanon of formula , possessing ability to inhibit HIV replication, where values of R1, R2, R3 substitutes are given in invention formula. Also describes is pharmaceutical preparation and application of compound for obtaining medication applied for treatment of conditions associated with HIV infection.

EFFECT: claimed compounds are applicable for prevention or treatment of HIV-produced infection and for AIDS treatment.

15 cl, 3 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I with anti-HIV activity , where R1 represents C1-6(Ar1)alkyl or C1-6(Ar1)oxyalkyl; R2 represents hydrogen or OR14; R3 represents hydrogen, halogen, hydroxyl, cyano, C1-6alkyl, C5-7cycloalkenyl, C1-6halogenalkyl, C1-6alkoxy, C1-6alkylthio, N(R8)(R9), NHAr2, N(R6)COR7, OCON(R8)(R9), OCH2CON(R9)(R9), CO2R6, CON(R8)(R9), SOR7, S(=N)R7, SO2R7, SO2N(R6)(R6), PO(OR6)2, C2-4(R12)alkynyl, R13, Ar2 or Ar3; R4 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy; R5 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy; R6 represents hydrogen or C1-6alkyl; R7 represents C1-7alkyl; R8 represents hydrogen or C1-6alkyl; R9 represents hydrogen, C1-6alkyl, C1-6hydroxyalkyl or C1-6(C1-6dialkylamino)alkyl; or N(R8)(R9) taken together represent azetidinyl, pyrrolydinyl, (R10)-piperidinyl, N-(R11)-piperazinyl, morpholinyl or dioxothiazinyl; R10 represents hydrogen; R11 represents hydrogen, C1-6alkyl, COR6 or CO2R6 ; R12 represents hydrogen, hydroxyl, N(R6)(R6), OSO2R7 or dioxothiazinyl; R13 represents dioxothiazinyl; R4 represents hydrogen or C1-6alkyl; Ar1 represents ,,,,,,,,; or Ar2 represents tetrazolyl, triazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, furanyl, thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridinyl, quinolinyl or indolyl, and is substituted with 0-2 substitutes selected from a group consisting of halogen, benzyl, C1-6alkyl, C1-6alkoxy, N((R8)(R9), CON(R8)(R9) and CO2R8; Ar3 represents phenyl substituted with 0-2 substitutes selected from a group consisting of halogen, cyano, hydroxy, C1-6alkyl, C1-6alkoxy, (C1-6alkoxy)methyl, C1-6halogenalkoxy, N(R8)(R9), CON(R6)(R6) and CH2N(R8)(R9), or represents dioxolanylphenyl; and X-Y-Z represents C(R14)2OC(R14)2C(R14)2, C(R14)2OC(R14)2C(R14)2C(R14)2; or pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition.

EFFECT: bicyclic heterocycles are disclosed, as well as their use HIV integrase inhibitors.

21 cl, 38 dwg, 8 tbl, 282 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a morpholine type cinnamide derivative with general formula I or its pharmacologically acceptable salt, where (a) R1, R2 , R3 and R4 are identical or different and each represents a hydrogen atom or C1-6alkyl group; X1 represents a C1-6alkylene group, where the C1-6alkylene group can be substituted with 1-3 hydroxyl groups or C1-6alkyl groups, or a C3-8cycloalkyl group formed by two C1-6alkyl groups all bonded to the same carbon atom of the C1-6alkylene group; Xa represents a methoxy group or a fluorine atom; Xb represents an oxygen atom or a methylene group, under the condition that Xb represents only an oxygen atom when Xa represents a methoxy group; and Ar1 is an aryl group, pyridinyl group which can be substituted with 1-3 substitutes selected from A1 group of substitutes; (b) Ar1-X1- represents a C5-7cycloalkyl group condensed with a benzene ring, where one methylene group in the C5-7cycloalkyl group can be substituted with an oxygen atom, the C5-7cycloalkyl group can be substituted with 1-3 hydroxyl groups and/or C1-6alkyl groups, and R1, R2, R3, R4, Xa and Xb assume values given in (a); (d) Ar1-X1- and R4 together with the nitrogen atom bonded to the Ar1-X1- group and the carbon atom bonded to the R4 group form a 5-7-member nitrogen-containing heterocyclic group which is substituted with an aryl group or a pyridinyl group, where one methylene group in the 5-7-member nitrogen-containing heterocyclic group can be substituted with an oxygen atom, and the aryl or pyridinyl group can be substituted with 1-3 substitutes selected from A1 group of substitutes, Xb is an oxygen atom, and R1, R2, R3 and Xa assume values given in (a) and (b); group A1 of substitutes: (1) halogen atom. The invention also relates to a pharmaceutical composition containing a formula I compound, which is useful in treating Alzheimer's disease, senile dementia, Down syndrome or amyloidosis.

EFFECT: obtaining novel morpholine type cinnamide derivatives with inhibitory effect on amyloid-β production.

17 cl, 9 tbl, 113 ex

FIELD: chemistry.

SUBSTANCE: invention relates to benzopyran derivatives of formula or

or their pharmaceutically acceptable salts, where R1 and R2 independently represent a hydrogen atom or a C1-6alkyl group, R3 is a hydroxyl group, R4 is a hydrogen atom, m is an integer ranging from 1 to 4, n is an integer ranging from 0 to 4, V is a single bond, CR7R8 or NR9, R5 is a hydrogen atom, R6 is a hydrogen atom, C1-6alkyl group, C3-8cycloalkyl group, C3-8cycloalkenyl group, amino group, C1-6alkylamino group, C6-14aryl group, C2-9heteroaryl group or C2-9heterocyclic group, A is a 5- or 6-member ring condensed with a benzene ring, and the ring can contain an oxygen atom, a nitrogen atom or a sulphur atom numbering from 1 to 3 or separately, or combined, the number of unsaturated bonds in the ring equals 1, 2 or 3, including the unsaturated bond in the condensed benzene ring, carbon atoms in the ring can represent carbonyl or thiocarbonyl.

EFFECT: compounds can be used as antiarrhythmic agents.

47 cl, 1 tbl, 98 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts. The disclosed compounds have inhibitory effect on HsEg5. In formula (I) A is C=O or CH2; B is optionally substituted C1-6alkyl, D is O or N, where O is substituted with one R8, and where N is substituted with one or more R8, R1 and R2 together with the carbon atoms with which they are bonded form optionally substituted isothiazole or isoxazole, condensed with a pyrimidine ring, optionally substituted with a substitute which is C1-6 alkyl. Values of the rest of the radicals are given in the formula of invention.

EFFECT: invention relates to use of disclosed compounds in making medicinal agents with inhibitory effect on HsEg5, to a method of obtaining inhibitory effect on HsEg5, to a pharmaceutical composition which contains the disclosed compound as an active ingredient.

22 cl, 31 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 2,3-dihydro-6-nitroimidazo[2,1-b]oxazol of general formula (1), as well as to their optically active forms and pharmacologically acceptable salts: where values of R1, R2 and n are given in i.1 of invention formula.

EFFECT: development of compounds, which have bactericidal action against Mycobacterium tuberculosis, polyresistant Mycobacterium tuberculosis and can be applied as antituberculosis medication.

3 cl, 16 ex, 183 tbl, 1515 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel derivatives of 2,6-dihydro-7H- pyrazolo[3,4-d]pyradazin-7-one, 1,4-dihydropyrazolo[3,4-b]thiazin-5(6H)-one; N-acylated 4-imidazo[1,2-a]pyridin-2-yl- and 4-imidazo[1,2-a]pyrimidin-2-yl- anilines; amides of [(4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]pyperidin-4-carboxylic acid; amides of 2-(4-carbamoylpyperidin-1-yl)isonicotinic acid; amides of N-sulfonyl-1,2,3,4-tetrahydrochinolin-6-carboxylic acid; as well as to N-acylated 3-azolyl derivatives of 2-amino-4,5,6,7-tetrahydtithieno[2,3-c]pyridine possessing properties of Hh-signal cascade inhibitors.

EFFECT: compounds can be applied for use in pharmaceutical compositions and medications for treating diseases induced by abberant activity of Hedgehog (Hh) signal system, in particular, oncological diseases, for instance, for pancreatic carcinoma treatment.

23 cl, 13 dwg, 11 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: in adamantane amino-derivatives of general formula (1), R=OH, R1=R2=R3=H, R4=C2H5, X=Cl, n=1 (I); R=Br, R1=R2=R3=H, R4=C2H5, X=Br, n=1 (II); R=OH, R1=R2=H, R3+R4=-CH2CH2CH2CH2-, X=Cl, n=1 (III); R=Br, R1=R2=H, R3+R4=-CH2CH2CH2CH2-, X=Br, n=1 (IV); R=OH, R1=R2=CH3, R3=R4=H, X=CI, n=1 (V); R=CH3, R1=-CH2OH, R2=R3=R4=H, X=Cl, n=1 (VI).

EFFECT: higher antiviral activity of derivatives towards influenza virus.

1 cl, 1 tbl, 9 ex

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