The method of obtaining 2,5-dimethylpiperidine-4

 

(57) Abstract:

The use of the invention as an intermediate product for the synthesis of biologically active compounds. The inventive product: 2,5-dimethipin-4, 32.1%, the duration of the technological cycle 40 PM Reagent 1: acetoacetic ester. Reagent 2: ammonia. Reaction conditions: in the aquatic environment. Reagent 3: hydrogen. Reaction conditions: hydrogenation on Nickel catalyst at 60-80 ATM and 35-40°C. the Reagent 4: methyl methacrylate. Reaction conditions: at a molar ratio of reagent 4: intermediate (2-5) : 1 in the presence of acid catalyst in the environment of the proton-donor action of the solvent at 90-100°C. the Reagent 5: technical mutilatory. Reaction conditions: with simultaneous distillation of the liberated in the reaction of methyl and ethyl alcohol. 3 table.

The invention relates to organic chemistry, specifically to an improved method for producing 2,5-dimethylpiperidine-4.

These product can be used as an intermediate for the synthesis of plant growth regulators, fungicides, local anesthetic drug action.

A method of obtaining 2,5-dimethylpiperidine-4, containing the making. The mixture of ketones obtained by the hydration of vinylidenechloride (VIA) in the presence of sulphate of mercury [1].

Also known is a method of obtaining 2,5-dimethylpiperidine-4 in the installation of flow-type cyclization with ammonia mixtures of ketones. The basis of this method is the simultaneous filing system flow type at normal pressure and elevated temperature a mixture of methoxyethanol and ammonia in methyl alcohol, the feed speed of the original products 1:5 [2].

The prototype of the invention is a method of obtaining 2,5-dimethylpiperidine-4, consisting in cyclization with ammonia mixtures of ketones, consisting of isopropoxypropylamine, 1-methoxyisobutylisonitrile, 2-methoxypropyl - propylketone and 1-methoxyisobutyl-2-methoxypropylamine, at elevated temperature and pressure. The cyclization of the above-mentioned mixture of ketones is carried out in aqueous medium at a molar ratio of the mixture of ketones:ammonia = 1: (7-20), respectively, when 60-99aboutC. the mixture of ketones is the product that results from the hydration of vinylidenechloride in the presence of sulphate of mercury [3]. This method formed the basis for obtaining 2,5-dimethylpiperidine-4, intermediate for the synthesis of drug rihlokain. By OU is e to the original dimethylphenylcarbinol, time rock processing behaviour of the process of obtaining 2,5-dimethylpiperidine-4 from Carbonara is about 65 hours

However, this method suffers a number of disadvantages: the use of mercury as catalyst in the hydration of the VIA; the use of the easily polymerizing and hazardous reagents (dimethylphenylcarbinol, vinylsubstituted, a mixture of ketones); the formation of large amounts of a resinous, hazardous still bottoms and the need for their destruction by burning, which pollutes the environment; overall low yield of the target product in the calculation of the original dimethylphenylcarbinol and the total duration of the process.

The aim of the invention is to increase the yield of the target product, creating a safe and environmentally friendly technologies.

This objective is achieved in that in a method of producing 2,5-dimethylpiperidine-4 cyclization at elevated temperature on one of the stages of a stepwise chemical transformation of raw materials, followed by the separation of the target product using traditional methods, in contrast to known as a source of raw materials used acetoacetic ester and ammonia, the interaction of which are unsaturated amine risovaniya of monoether, added to which of methyl methacrylate in the ratio 1: (2-5) in the presence of acidic catalysts and proton donor solutes solvents at 90-100aboutTo receive fluids, which cyclist technical sodium methylate with simultaneous distillation in the form of azeotropic mixtures produced by the process of cyclization of methyl and ethyl alcohols.

The yield of 2,5-dimethylpiperidine-4 is 64,2% of theoretical calculated by taken the cyclization of fluids (At). The content of 2,5-dimethylpiperidine-4 in the sample is not less than 98%, so the need for the fractional distillation of the desired product in a vacuum oil pump no.

For a better understanding of the present invention are the following specific examples.

P R I m e R 1. In the reaction flask 2,52 l (2.65 kg) of acetoacetic ether and poured 2 litres (1,82 kg) of 25% aqueous ammonia solution. The molar ratio of reactants of 1:1,3. Include a stirrer and a descending refrigerator, maintain the reaction mass of 2 h at a temperature not exceeding 25aboutWith, then add 0,41 kg of salt and stir again 10-15 minutes the Reaction mass is transferred into a separating funnel, defend 20 minutes the Top layer is separated and distilled in vacuum oil pump. GTG is rhenium Workshop on organic chemistry T. II, M.: Mir, 1979, S. 58/.

In the autoclave is placed 1.29 kg (10 M) ethyl ester-aminocrotonic acid in 13 l of isopropyl alcohol and add 0.2 kg of skeletal Nickel in 2 l of isopropyl alcohol. The autoclave was washed twice with hydrogen, i.e., fill with gas and then down the pressure. After that, include a mixer and immediately record the amount of absorbed hydrogen, pressure and time. The temperature in the reaction mass was raised to 40aboutWith hydrogen fed into the autoclave under a pressure of 70 ATM. The process of hydrogenation is 12 h, the end of the process is controlled by GLC. After hydrogenation and full cooling, the autoclave is opened by twisting the valve and releasing the excess pressure through a steel capillary tube. The catalyst is filtered off, the solution is transferred into a distillation flask, the solvent is distilled off, the residue is dispersed in the vacuum of an oil pump and get 0,91 kg (69,5% of theoretical) of ethyl ether-aminobutyric acid (III) with a boiling point of 82aboutC./10 mm RT.art., nd201,4270.

To 0.65 kg (5M) ethyl ester-aminobutyric acid (III) add 5 g of ammonium chloride, 0.25 l of methanol and 1 kg (10M) of methyl methacrylate, stabilized with hydroquinone. The molar ratio R is S. The progress of the reaction is controlled by GLC. Then the excess methyl methacrylate is distilled off in a water-jet pump vacuum at a bath temperature of not higher than 50aboutC. Receive 1.15 kg technical diapir. The content of the basic substance in the sample to 85%.

In a reaction flask is charged with 9.2 liters (8.6 kg t.). 18% solution of sodium methylate is added 20 l of toluene and distilled azeotropic mixture of toluene with methanol for 2 h, the Stripping stop upon reaching a volume of distilled azeotropic mixture of 20 l and temperature of exhaust fumes 108aboutC. after distillation, azeotropic mixtures are loaded into the flask another 12.5 l of toluene and begin to add dropwise a solution of diapir in toluene at a temperature in the reaction mass 110aboutC. the Solution diapir in toluene are added dropwise within 40 minutes Total solution diapir in toluene 17,7 l, it 7,15 kg technical diapir (). The molar ratio of diapir and sodium methylate 1: 1,1. The rush of diapir lead with simultaneous distillation of the methyl and ethyl alcohols in the form of a second azeotropic mixture with toluene. At high tide solution diapir heating the reaction mass is carried out in such a mode that the amount privitogo solution diapir was approximately equal to the volume removed during this time azeotrope achieve the temperature of exhaust fumes 110aboutC. Upon reaching this temperature descending refrigerator include work as a back and give the extract with stirring for 30 minutes Then the reaction mass is then cooled to room temperature and acidified with 32 l 18% hydrochloric acid. An aqueous solution of hydrochloric acid are added within 30 minutes after the tide of hydrochloric acid, the reaction mass is maintained with stirring for another 30 minutes the Mass is transferred into a separating funnel, the bottom layer is separated and transferred into a round bottom flask, refluxed for 4 hours the Reaction mass is then cooled to room temperature, then in small portions with stirring, add 10 kg technical potash for 30 min and another 0.8 kg of sodium hydroxide, bringing the pH to 10-12. The upper oil layer is separated, the aqueous layer was extracted 5 times with chloroform. Oil and chloroform extracts combine, filtered and distilled chloroform in water-jet vacuum pump. Get 2,14 kg (64,2% of theoretical) in the calculation are taken in the cyclization of fluids 2,5-dimethylpiperidine-4 with nd201,4678. The content of 2,5-dimethylpiperidine-4 in the sample is 98%. Time cyclization 12 PM

The results of other experiments are shown in table.1, 2, 3. When the Ah below 35aboutWith the rate of hydrogenation decreases and the yield of the target product is reduced. With increasing temperature the yield of ethyl ether-aminobutyric acid is not increased, therefore, a further increase in temperature is impractical. In examples 4-6 as well as the selection pressure of the hydrogenation process. At pressures below 70 MPa yield of the target product is reduced, therefore lowering the pressure below 60 ATM impractical. Increasing the pressure up to 80 bar also does not increase the yield of the target product. In examples 7-9 justified optimal hydrogenation process. It is established that the highest yield of the desired product is achieved at a temperature of 40aboutC and a pressure of 70 ATM. Further increase in temperature (10-12) does not increase the target product.

In table. 2 justified temperature and the ratio of reagents when obrazovanii diapir. In examples 1-6 the choice of the ratio of the initial reagents. Found that when using one mol of monoether less than two moles of methyl methacrylate output diapir decreases. Further increase in the number of methyl methacrylate does not increase output diapir and therefore impractical. In examples 7-9 the choice of the reaction temperature. Installed, is tosini diapir and sodium methylate in cyclization. In examples 1-6 the choice of the ratio of initial reagents. Found that when using more than 10% excess of sodium methylate is the reduction of the yield of 2,5-dimethylpiperidine-4. Obviously, this is due to the fact that the excess of sodium methylate contributes ardolino-crotonic condensation of 2,5-dimethylpiperidine-4.

The proposed method of obtaining 2,5-dimethylpiperidine-4 was tested on polusovetskaya installation Anzhero-Sudzhensk himfarmzavod.

The yield of 2,5-dimethylpiperidine-4 in terms of raw materials (acetoacetic ester) is 32.1 per cent. The total duration of the technological cycle is 40 h, while in the prototype, the duration is 65 h at the output of the target product 20.6% in terms of raw materials. In addition, in the present method eliminates the use of salts of mercury as a catalyst, use non-explosive raw materials and eliminates the formation of a resinous bottoms, destroyed by burning. This increases the safety and environmental acceptability of the process.

The METHOD of OBTAINING 2,5-DIMETHYLPIPERIDINE-4, including the interaction of the original exocoetidae with ammonia and cyclization at elevated temperature, characterized in, h is the ACOM, subsequent hydrogenation of the intermediate amine Nickel catalyst at 60 - 80 ATM and 35 - 40oWith processing the obtained ethyl ester-aminobutyric acid methymethacrylate when the molar ratio monoether : methyl methacrylate 1 : 2 - 5 in the presence of acid catalyst in the environment of the proton-donor action of the solvent at 90 - 100oFollowed by cyclization in the presence of technical sodium methylate with simultaneous distillation of the liberated in the reaction of methyl and ethyl alcohols.

 

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16 cl, 365 ex, 42 tbl

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17 cl, 25 ex, 8 tbl, 15 dwg

FIELD: medicine, pharmaceutics.

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1 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula II:

,

where Ar1 represents a 6-10-member heteroaryl, where heteroaryl relates to a monocyclic or bicyclic heteroaryl containing 1, 2 or 3 heteroatoms selected from N, S or O, provided that two adjacent heteroatoms in ring can not both represent S or both represent O; Ar2 is phenyl; R1 is phenyl, 5-12-member heterocycloalkyl or 5-12-member heteroaryl (i), where each of said phenyl, heterocycloalkyl and heteroaryl is either unsubstituted or optionally independently substituted with 1, 2, 3, 4 or 5 substitutes, which can be identical or different and are independently selected from a group consisting of: halogen, cyano, alkyl, halogenalkyl, alkoxy, halogenalkoxy, -NRaRb, -CONaRb, -S(O)2-alkyl,-S(O)2N(alkyl)2, -(CH2)qaryl, -(CH2)qheteroaryl and -(CH2)qheterocycloalkyl, (ii) where each of said phenyl can further be unsubstituted or substituted with one or more substitutes, such as halogen, cyano, alkyl or alkoxy, or can be optionally condensed with independently selected arylheteroaryl or heterocycloalkyl; Ra and Rb independently represent H, alkyl,-S(O)2alkyl and cycloalkyl, or Ra and Rbcan form a 5- or 6-member heterocycloalkyl group together with a nitrogen atom to which they are bonded, where said heterocycloalkyl group may contain one or more additional heteroatoms selected from N, S or O; (iii) said 5-12-member heterocycloalkyl contains 1, 2 or 3 heteroatoms selected from N, S or O; (iv) said 5-12-member heteroaryl contains 1, 2 or 3 heteroatoms selected from N, S or O; R2 and R3 represent H, m, n, p and q independently are equal to 0, 1 or 2; and their pharmaceutically acceptable salts.

EFFECT: compounds can be used to inhibit NAMPT.

29 cl, 3 tbl, 5 ex

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