HU206877B - Process for producing diazinyl-piperidines - Google Patents

Abstract

Field of the Invention The present invention relates to a novel process for the preparation of known 1,2-1,3, or 1,4-disubstituted piperidine-based diazinyl piperidines, wherein Z is R1, R2-disubstituted diazin, attached via one of its carbon atoms. diazinon may be pyridine, pyridazine or pyrazine, and R 1 and R 2 are independently selected from hydrogen, lower alkyl, lower alkoxy, lower alkyl thio, cyano, trifluoromethyl, pentafluoro- Ethyl or halogen, and attached to the carbon atoms of the diazin ring, such that the process comprises the following steps: a) a mixture of 2-pyridone and a halomethylpyridine is added to sodium hydride at 0-20 ° C To a suspension of β-dimethylformamide in the form of a 1-pyridinylmethyl-2-pyrrolidinone intermediate (III); b) an aqueous solution of the hydrogen halide salt of the intermediate of formula (III) is catalytically hydrogenated to a compound of formula (II) wherein Y is halogen, and this product is alkalized and reacted with a diazine of the formula ZQ in which Q is a leaving point necessary for organic synthesis. to obtain the compounds of formula (I). (I) EN 206 877 Scope of the description: 8 pages (including 3 sheets)

Description

The present invention relates to an improved, more economical process for the synthesis of certain 1 - ((diazinylpiperidinyl) methyl) -2-pinolidinones of general formula (I) which can be used in high volume production.

For compounds of formula I, Z is R ', R ^{2 is a} disubstituted diazine, one of pyrimidine, pyridazine and pyrazine, and one of R ¹ and R ² is independently selected from hydrogen, C 1-4 alkyl, alkoxy. , alkylthio, cyano, trifluoromethyl, pentafluoroethyl or halogen. The method of the invention is particularly suitable for the production of diazinylpiperidine derivatives that stimulate brain function, which can be used to restore the brain function of dementia sufferers due to degenerative processes, reverse memory loss, and improve memory and learning processes.

These compounds are described in Mattson et al., No. 4,826,843, for their synthesis and use. U.S. Pat. In this specification, the synthesis of the corresponding piperidinyl derivative of N-methylene-2-pyrrolidinone is generally given in Scheme 2 and described in Method (b). This patent history is illustrated herein by Reaction Scheme A, wherein Z is the corresponding diazine (pyridazine, pyrimidine or pyrazine) and Q is the leaving group used for organic synthesis.

The process described in Scheme A is described in Sections 2-6 of this specification. examples.

The improved process of the present invention, which will be described in detail below, differs from the previous one in that it incorporates a number of modifications that significantly reduce the time and labor required, the processing work, and enable scale-up in production.

Those skilled in the art of technology know that many processes, processes, and / or reactions are not suitable for larger scale implementation in a pilot plant or manufacturing plant. Some examples of cases where scaling may cause problems are: the use of hazardous or toxic reagents and / or solvents; highly exothermic reactions; high pressure or high vacuum reactions, such as high pressure reactions or high vacuum distillation; chromatographic separation and / or purification; reduction in yield due to scale up, etc. Another aspect of high volume production is certain emissions or waste disposal problems in a chemical process. In processes containing such elements, production costs are higher.

It is an object of the present invention to modify the process of the original synthesis in such a way as to be economically large-scale.

In the improved process of the present invention, the reaction sequence of the synthesis is maintained, with little change, but the individual steps of the process are modified by combining sub-processes and a number of specific, non-obvious modifications that allow successful scaling of the process.

FIELD OF THE INVENTION The present invention relates to an improved synthetic process for the high volume synthesis of piperidinyl numerals of formula I having the psychocognitive properties of N-methylene-2-pyrrolidinone. This improved process offers benefits in terms of economical reagent utilization, reduced time and labor requirements, and favorable applicability of conventional, larger-scale chemical equipment.

The products of this process are represented by the formula (I) wherein the N-methylene-2-pyrrolidinone unit is attached at the 2-, 3- or 4-position of the piperidine ring through one of its carbon atoms and Z is R ¹ , R ² -substituted. diazine formed via a carbon atom wherein R 1 and R ² are independently selected from hydrogen, lower alkyl, lower alkoxy, lower alkylthio, cyano, trifluoromethyl, pentafluoroethyl, and halogen . These substituents are attached to the carbon atoms of the corresponding diazine ring. The term "low carbon" refers to substituents having from 1 to 4 carbon atoms.

The improved process involves the introduction of a number of technological modifications in the reaction sequence described above. These modifications allow large-scale application of the process in question for industrial implementation. It has to be stated that the price of the product is a major consideration in commercial production and the modifications that improve the unit production costs are extremely important.

The improved process for high volume production is illustrated in Scheme B.

In Scheme B, Y is halogen (chlorine, bromine or iodine), preferably chlorine; Q is a leaving group for organic synthesis; Z corresponds to the above definition. It is expected that other leaving organic groups (Q) may function similarly in the reaction scheme B instead of the halogen Y to be replaced.

The initial step in the original process is the formation of the 2-pyrrolidinone anion by reaction with NaH in DMF. Chloromethylpyridine is then reacted with the anion to give intermediate III. The formation of anion by hydrogen evolution is accompanied by significant foaming, but the stability and accumulation of the foam stops the addition of 2-pyrrolidinone. The stable foam prevents the reaction from occurring within a reasonable time when carried out on a large-scale apparatus.

The first attempts to minimize foam formation were either unsuccessful or caused further problems in scale-up of the process. Changing the solvent results in a decrease in solvent efficiency for DMF, which results in solidification of the reaction mixture in a highly exothermic process. Elimination of mineral oil from NaH reagent has little effect on foaming in the large scale process. Substitution with other strong bases such as sodium isopropoxide, KH or LiNH ₂ does not result in an isolable amount of intermediate (III). Experiments have shown that the formation of a stable foam is a pyrrolidinone anion dissolved in DMF

EN 206 877 B due to its surfactant properties. Reverse addition (first adding chloromethylpyridine to NaH followed by 2-pyrrolidinidinone) reduces product formation and promotes the polymerization of the chloromethylpyridine reagent if the reaction is carried out on a larger scale. The problem of scaling foaming is finally overcome by apparently introducing a simple yet effective modification by adding an equimolar mixture of 2-pyrrolidinone (IV) and chloromethylpyridine (X) to DMF suspension of NaH 0 to 20 ° C. The yield decreases above 20 ° C, but below 0 ° C the reaction rate slows down so that the starting material can accumulate, making the large-scale reaction unmanageable.

Another problem in the preparation of the intermediate (III) and its subsequent use in the large-scale process is that the intermediate (III) is initially purified by vacuum distillation, without this purification the subsequent process, the compound (III), does not proceed well .

It has been found that extraction of the residue of Step 1 with hot diisopropyl ether affords the appropriately purified compound of formula (III) without vacuum distillation.

In the improved process, steps 2 and 3 can be combined and carried out in an aqueous medium using a water-soluble acid addition salt of a compound of formula (III). Although most of the acid addition salts of the compound of Formula III are suitable, hydrohaloid salts are preferred and hydrochloric acid salts are most preferred. After hydrogenation under reduced pressure and removal of the catalyst, the aqueous solution is made basic with aqueous NaOH and treated with the appropriate diazine reagent Zr-Q. Addition of a small amount of acetonitrile in the order of 10% by volume of the solution appears to improve the coupling reaction, thereby increasing the yield. The product of formula I precipitates and can be isolated by filtration. This results in significant work, chemical and time savings. If the reduction is carried out in cheap, non-flammable and easily removable water, the subsequent coupling reaction in the aqueous medium will greatly improve the new process. In contrast, in the known process, the reduction is carried out in alcohol, the intermediate must be prepared, the coupling reaction performed in a heterogeneous reaction mixture (solid sodium carbonate and DMF), filtered, the DMF removed in vacuo and finally in at least one organic solvent. recrystallization should also be performed. In the known process, most of the products of formula (I) require chromatographic separation / purification. As mentioned above, chromatographic procedures are best avoided in large-scale production. In the improved process, both gross yield and product purity are increased, while the aforementioned labor, material and time savings are realized. Moreover, even the production capacity is increasing.

In summary, the improved process of the present invention is for the preparation of compounds of formula (I). The improved procedure consists of two steps:

i) An equimolar mixture of 2-pyrrolidinone and a halomethylpyridine is added at 0-20 ° C to a suspension of sodium hydride in DMF. Thus, 1- (pyridinylmethyl) -2-pyrrolidinone of formula (III) is formed.

The intermediate of formula (III), as formed, is suitable for use in the next step if the reaction mixture is filtered and the filtrate is concentrated in vacuo. This residue is preferably extracted with warm diisopropyl ether, and the compound of formula (III) is isolated by filtration from the cooled ether extract.

ii) The addition salt of the compound of formula III, for example hydrochloric acid salt, is formed which is catalytically hydrogenated in aqueous solution, preferably after the addition of some acetonitrile under low pressure. This gives the compound of formula (II) which is made basic and treated with the diazine reagent of formula Z-Q. This gives the product of formula (I).

This improved process fulfills the intended purpose of providing a practical synthesis that is economically viable on a large scale and provides appropriate diazinylpiperidine derivatives. This is essentially a two-step process that can be implemented with large-scale chemical equipment. It includes process modifications that control the reaction-limiting foam formation; eliminates vacuum distillation and chromatographic purification; replaces organic solvents with water; minimizes the need for isolation and purification of intermediates; and ultimately provides the final product with improved yield and purity.

The invention is further illustrated by the following examples of preferred embodiments of the process steps described above.

Example 1

Preparation of 1- (4-Pyridinylmethyl) -2-pyrrolidinone of Formula III (Step I)

A 60% mineral oil dispersion of sodium hydride (9.4 kg, 235 moles) was suspended in 119 kg (125 dm ³ ) Ν, Ν-dimethylformamide with stirring, and 10 kg (117.5 moles) was added under stirring in 8 moles. mole) of 2-pyrrolidinone and 19.3 kg (117.5 mole) of 4-chloromethylpyridine hydrochloride. The initial reaction temperature is 0 ° C, which rises to 15 ° C, and must be maintained at this temperature. The addition takes 3 hours to control the addition rate so that the temperature and foam formation can be controlled. The reaction mixture was stirred for an additional 16 hours at about 25 ° C. The mixture is then purified by filtration through diatomaceous earth. The solid was removed and the filtrate concentrated in vacuo. The residue was extracted with boiling diisopropyl ether (2x167 dm ³ ). The combined extracts were heated to reflux and the solution was slowly cooled to 30 ° C. The product precipitates. The mixture was stirred for 16 hours and then cooled to 5 ° C over 3 hours. The compound of formula (III) is isolated by filtration and

HU 206 877 Β vacuum dried at 30 ° C. 16 kg of product were obtained in 77.7% yield.

Elemental Analysis ₀ H | Calculated for ₂ N ₂ O: Theory: C: 68.16 H: 6.87 N: 15.90 Found: 67.93 6.78 15.78

Suitable modifications of the process may also provide the intermediate (III) from the starting material 2-lialogenomethylpyridine or 3-halomethylpyridine for the synthesis of 1,2- or 1,3-piperidinyl derivatives (1).

Preparation of Compound of Formula 1 (Step 2) (Generally)

1- (4-Pyridinylmethyl) -2-pyrrolidinone (Intermediate III) (905 g, 5.14 mol) was dissolved in drinking water (11 dm ³ ) and 470 cm ³ (about 5.65 mol) of reagent grade hydrochloric acid and 25 g platinum (IV) oxide. Stirring the reaction mixture at a low pressure (l, 25xl0 ³ psi) with hydrogen. After the uptake of hydrogen ceases (about 3 days), the catalyst is removed by filtration and 130 g (14.1 mol) of sodium hydroxide in a 50% solution are added. The solution was cooled to 25 ° C with high speed stirring and the corresponding halo-diazine was added dropwise or dropwise over 2 hours. The temperature is maintained at or below 25 ° C throughout. In most cases, the product precipitates during this addition and can be isolated by filtration. In some cases, the aqueous reaction mixture must be extracted. Although many organic liquids commonly used for extraction can be used, methylene chloride is most preferred. Concentration of the extract provides the desired compound of formula (1) in a conventional manner.

Here are some specific examples to illustrate:

Example 2

Preparation of {[1- (2- (trifluoromethyl) -4-pyrimidinyl) -4-piperidinyl] methyl} -2-pyrrolidinone To a basic aqueous solution of the 4-substituted piperidine intermediate (II) was added 938 g (5%). (14 mol) of 4-chloro-2- (trifluoromethyl) pyrimidine while stirring the aqueous solution at high speed and maintaining the temperature at about 25 ° C. The diazine addition is complete within about 2 hours and the product precipitates during the addition. After stirring for an additional hour, the compound of formula (I) is filtered off, washed with 4 liters of cold water (5 ° C). Drying at 50 ° C in vacuo to constant weight gave 1529 g (90.7%) of product, mp 115.5-117 ° C.

Elemental Analysis C | _{Calculated for} C ₅ H 19 F ₃ N ₄ O: Theory C: 54.87 'H: 5.83 N: 17.06 Found: 54.61 5.89 16.91

Example 3

Preparation of {[N - (6-chloro-2- (trifluoromethyl) -4-pyrimidinyl) -4-piperidinyl] methyl} -2-pyrrolidinone

905 g (5.14 mol) of 1- (4-pyridinylmethyl) -2-pyrrolidinone (Intermediate (ΠΙ)) are dissolved in 11 d ^{3 of} potable water and then 470 cm ³ (about 5.65 mol) of reagent grade hydrochloric acid and 25 g platinum (IV) oxide. The mixture was treated with hydrogen under low pressure (1.25 x ^{10 3} Pa) with stirring. After the uptake of hydrogen ceases (about 3 days), the catalyst is removed by filtration and 130 g (14.1 mol) of sodium hydroxide in a 50% solution are added. An additional 1680 cm ^{3 of} acetonitrile was added, the solution was cooled to 25 ° C with rapid stirring and 5.14 moles of 4,6-dichloro-2- (trifluoromethyl) pyrimidine (V) were added dropwise over about 2 hours. The temperature during the addition is maintained at or below 25 DEG C. The product precipitates during the addition or stirring overnight and can be recovered by filtration.

The solid was washed well with water on the filter and air-dried overnight. This gave the title compound in 85% yield. The product sample for elemental analysis was dried to constant weight for 4 hours in a 50 ° C vacuum oven.

Elemental Analysis ClF ₃ N ₅ H _l8 calculated to O _4: Theory: C: 49.66 H: 5.00 N: 15.44 Found: 49.32 4.94 15.65

IR and NMR data are consistent with the proposed structure.

Example 4

- Preparation of [(142-pyrimidinyl-4-piperidinyl) methyl] -2-pyrrolidinone

5.46 g (25 mmol) of 1- (4-piperidinyl) methyl-2-pyrrolidinone hydrochloride (II) and 2.5 g (62.5 mmol) of sodium hydroxide are dissolved in 55 cm @ ^{3 of} water. The reaction mixture was cooled to 0 ° C and 2.86 g (25 mmol) of 2-chloropyrimidine was added with vigorous stirring. The mixture was allowed to warm to room temperature over 18 hours. At this time, it was re-cooled to 0 ° C and 25 cm ^{3 of} saturated NaCl solution was added, whereupon the product precipitated as a white precipitate. The collected precipitate was dried in vacuo. Yield: 2.7 g (42%), m.p. 144-147 ° C.

Example 5

Preparation of 1 - ((1- (2-chloro-4-pyridinidinyl-4-piperidinyl) methyl) -2H-pyrrolidinone

5.46 g (25 mmol) of the 4-piperidinyl compound of formula II and 2.5 g (62.5 mmol) of sodium hydroxide are dissolved in water to 55 cm ³ and 3.7 g of (4 g) are added with vigorous stirring. 25 mmol) 2,4-dichloropyrimidine. After stirring at room temperature overnight, the crude compound of formula (I) is extracted with methylene chloride. The extract was concentrated and dried in vacuo. The oil thus obtained solidifies on standing. Yield: 5.9 g (80%).

Claims (6)

1. A 1,2- (I) formula, 1,3- or 1,4-disubstituted piperidines - in which Z is R ^1, R ² and disubstituted through a carbon atom linked diazinyl, pyrimidinyl namely , pyridazinyl or pyrazinyl, and the like HU 206 877 B R ¹ and R ² are independently hydrogen, C 1-4 alkyl, C 1-4 alkoxy or C 1-4 alkylthio group, cyano, trifluoromethyl or pentafluoroethyl, attached to the carbon atoms of the diaz ring or a halogen atom for its preparation by reaction of 2-pyrrolidinone with sodium hydride and halomethylpyridine by reduction and coupling with a diazine compound, i) adding a mixture of 2-pyrrolidinone and a halomethylpyridine at 0-20 ° C to a suspension of sodium hydride in Ν, Ν-dimethylformamide; ii) then converting the resulting intermediate of formula (III) into an aqueous solution of its hydrogen halide salt, catalytically hydrogenating, basifying the resulting compound of formula (II) wherein Y is a halogen atom and a diazine of formula ZQ where Z is and Q represents the leaving group of the reaction. Process according to claim 1, characterized in that the intermediate (III) is converted into the hydrochloride salt. 3. A process according to claim 1 for the preparation of compounds of formula I wherein the Z substituent is pyrimidine, wherein the appropriate starting materials are used. A process according to claim 1 for the preparation of compounds of formula I wherein piperidine is 1,4-disubstituted, wherein the appropriate starting materials are used. A process for the preparation of a compound of formula I according to claim 1, wherein R ¹ and R ² are independently selected from hydrogen, halogen and trifluoromethyl, wherein the appropriate starting materials are used. 6. A process according to claim 1 for the preparation of 1 - {[1- (2-trifluoromethyl-4-pyrimidinyl) -4-piperidinyl] methyl} 2-pyrrolidinone, wherein the appropriate starting materials are used.