PT95712B - APPROPRIATE PROCESS FOR THE PREPARATION OF DIAZINYLPIPERIDINE DERIVATIVES - Google Patents

Description

IMPROVED PROCESS FOR THE PREPARATION OF DERIVATIVES

DIAZINYLPIPERIDINE

BRISTOL-MYERS__SQUIBB__COMPANY

BACKGROUND OF THE PRESENT INVENTION

The present invention relates to an improved and more economical process for the synthesis of 1 - [(diazinylpiperidyl) -methyl] -2-pyrrolidinones of general formula

in which the symbol Z represents a substituted diazine R 2, R 2 ^- dissubs' selected from pyrimidine, pyridazine and pyrazine; R 2 and R 2 being independently chosen from a hydrogen or halogen atom or an alkyl, alkoxy, alkylthio, cyano, trifluoromethyl, and pentafluoroethyl group. This process can be adapted to large-scale production. This process can be used, in particular, for the preparation of diazinylpiperidine derivatives which enhance brain function, and which can be used to restore brain function in cases of dementia due to degenerative processes; amnesia regression; and improvement in processes associated with memory and learning.

Αν '• ’Χ

These compounds, their synthesis and use, were disclosed by Mattson et al., In U.S. Patent No. 4,826,843, which is included here by reference. The synthesis of the 1- (4-diazinyl) -piperidinyl derivatives of N-methylene-2-pyrrolidinone, is described, in general, in the case 2 and in process b) of said patent. This process of the prior art is illustrated below in Scheme A.

SCHEME A

J

PREVIOUS TECHNICAL PROCESS

3 In Scheme A, the symbol Z represents a suitable diazine (pyridazine, pyrimidine or pyrazine) and the symbol Q represents an organic, synthetic, removable group.

Exemplary, in Examples 2-6, for reference, the process indicated in Scheme A.

The improved process described here, in a more complete way, differs from the prior art process by incorporating several modifications that lead to significant reductions in time, work and processing, also allowing for an increase in production.

The specialist will verify that many of the processes, procedures and / or reactions are not likely to be carried out on a large scale, as they are carried out in a pilot unit or in an industrial installation. Some examples of situations where large-scale production can be problematic may involve the use of dangerous or toxic reagents and / or solvents; highly exothermic reactions; high pressure or high vacuum processes, such as those required for certain high pressure reactions or high vacuum distillations; chromatographic separation and / or purification; large-scale reduced production and the like. A more recent consideration for large-scale operations is based on limitations resulting from certain emissions as well as the rejection of waste products from chemical processing. The processes involving these elements have higher production costs.

-4One of the objectives of the present invention is to modify the original synthesis process so that it can be used, in an economical way, in a large scale production.

In the improved process of the present invention, the sequence of synthesis of the reactions is maintained, with small variations, but the process steps themselves have been changed, by combining steps and incorporating several unique and non-evident modifications that allow the present process to be successfully applied on a large scale.

SUMMARY AND DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention relates to an improved synthesis process that can be adapted for large-scale preparation of 1- (4-diazinyl) -pieridinyl derivatives of N-methylene-2-pyrrolidinone which have psycho-cognitive properties. This improved process has the advantages of saving reagents, time and labor costs, as well as a greater ability to be used with standardized large-scale chemical process equipment.

The products of the present process, the 1- (4-diazinyl) -piperinidyl derivatives of N-methyl-2-pyrrolidinone, are characterized by the general structural formula

N-Z

(I)

-5 In general formula I, the N-2-methylene-2-pyrrolidinone radical can be attached at the 2, 3 or 4 position of the piperidine ring; and Z represents a diazine R ^, _R2 disubstituted, connected via one of its carbon atoms; being and R ₂ , are collected, independently of, between a hydrogen or halogen atom or a lower alkyl, lower alkoxy, lower alkylthio, cyano, trifluoromethyl and pentafluoroethyl group. These substituents are attached to the carbon atoms in the appropriate diazine ring. The lower descriptive term refers to substituent groups that contain 1 to 4 carbon atoms.

The perfected process consists of the incorporation of numerous procedural modifications, in the reaction sequence, previously described, which allow the adaptation of the process that constitutes the object of the present invention to a large-scale production necessary for commercialization. It should be noted that the cost of products is one of the main factors to take into account when marketing a product and that modifications that improve the economic efficiency of production are extremely important.

improved process that allows an efficient production increase is indicated in Scheme B.

SCHEME Β

IMPROVED PROCESS

II CHY

HY H

In Scheme Β, the symbol Y represents a halogen atom (chlorine, bromine or iodine) preferably a chlorine atom; the symbol Q represents a removable, synthetic, organic group, and the symbol Z has the meaning defined above. It is assumed that other suitable removable groups (Q) also function similarly in place of Y, the removable halogen group, in Scheme B. Examples of such suitable removable groups (Q) are given in the US patent. American ηθ 4 826 843, granted to Mattson and others, which is included here as a reference.

the initial step of the original process involved the formation of the 2-pyrrolidinone anion by reaction in DMF with NaH. Then, chloromethylpyridine was introduced to react with the anion and give intermediate III. The formation of the anion with release of hydrogen was accompanied by considerable foam formation, but the stability of this foam and its accumulation interrupted the addition of 2-pyrrolidinone. The stable foam acted to prevent the reaction from being completed in a reasonable period, when carried out on a large scale.

Initial attempts to minimize foaming have not resulted or caused other problems in the process on a large scale. The changes in the reaction liquid medium led to a reduction in the efficiency of the solvent, which he observed with DMF, which led to a solidification of the reaction mixture with a strongly exothermic process. The removal of mineral oil from the NaH reagent had little effect on foaming in large-scale production. The substitution of other strong bases, such as sodium isopropoxide, KH and LiNH ^ resulted in the non-isolation of intermediate III. Experience has shown that stable foaming could be attributed to the surfactant properties of the pyrrolidinone anion in DMF. The reverse addition (addition of chloromethylpyridine to sodium hydride first and then to 2-pyrrolidinone) resulted in reduced product formation and apparent polymerization of the chloromethylpyridine reagent when the reaction was carried out on a large scale. The problem of foam that prevented the increase in production was eliminated, through an effective modification, although apparently simple, according to which an equimolar mixture of 2-pyrrolidinone, IV, and chloromethylpyri is added. dine, X, to a suspension of sodium hydride in dimethylformamide at a temperature between about 0 ° and about 20 ° C. The production of the product is reduced at temperatures above 20 ° C, and at temperatures below 0 ° C the reaction rate is slow enough to allow the accumulation of ini compounds.

thus creating the potential for a large-scale uncontrolled reaction.

Another problem in the preparation and subsequent use of intermediate compound III, in a large scale process, is that intermediate compound III was initially put under vacuum distillation and, without this purification, the subsequent process for reducing the compound III is not convenient. It was found that, by extracting the reaction residue from step 1 with isopropyl ether, compounds III of adequate purity could be obtained without having to distill under vacuum.

In the improved process, steps 2 and 3 are combined and carried out in water using an acid addition salt of compound III, soluble in water. Although most forms of acid addition salts of compound III may be suitable, halogenhydrates are preferred, with hydrochloride being most preferred. Following hydrogenation at low pressure and removal of the catalytic agent, the aqueous solution was basified with an aqueous sodium hydroxide solution and treated with the appropriate diazine reagent, of the general formula Z-Q. The addition of a small amount, of about 10% of the solvent volume, of acetonitrile seems to improve the coupling process, increasing the yield of the product. Product I precipitated and was isolated by filtration. This results in greater work efficiency, reagents and processing time. The reduction in water, which is cheaper, non-flammable and easily obtainable, followed by direct coupling in the aqueous solution, constitutes the main improvement of this new process. On the other hand, the old process included the reduction of alcohol; isolating the intermediate compound; coupling in a heterogeneous reaction mixture (solid sodium carbonate and DMF); filtration; DMF removal under vacuum; and, at a minimum, recrystallization of the product in an organic solvent. In the process previously described, most diazinic products of general formula I required chromatography to carry out their separation / purification. As mentioned above, chromatographic processes are the most avoided in large scale preparations. In the perfected process, the total yield and purity of the product are higher, as well as the working efficiency, reagents and processing time, as previously mentioned.

In addition, the processed loads are higher.

To summarize the above, an improved process for the preparation of a compound of general formula is described

(I) in which the structural aspects have the meanings defined before. This improved process comprises steps a) and b):

(a) adding an equimolar mixture of 2-pyrrolidinone and halo genomethylpyridine to a suspension of sodium hydride in dimethyl. formamide at a temperature between 0 ° and 20 ° C, to obtain the compound 1- (pyridinylmethyl) -2-pyrrolidinone (III).

Intermediate III was obtained in a form suitable for use in the next step, filtering the reaction mixture and concentrating the filtrate in vacuo, until a residue was obtained. Extracting the residue with hot isopropyl ether, obtained with post III, which was isolated by filtration, cooling the ether extracts.

b) Catalytic hydrogenation of an aqueous solution of an acid addition salt of compound III, for example, the hydrochloride, to which a little acetonitrile had been added, under reduced pressure, to obtain the compound II which was alkalinized and treated with the diazine reagent, ZQ, to obtain the compound of general formula I.

This improved process corresponds to the intended objective, which is to provide a practical synthesis that can be used, economically, in a large scale production, to obtain useful diazinylpiperidine derivatives. This process essentially consists of a two-step process, compatible with large-scale chemical process equipment. Modifications have been incorporated into the process that control the formation of the reaction limiting foam; eliminate the need for vacuum distillation and chromatography purification; replace the. organic solvents by water; minimize the isolation and purification of the intermediate compounds and provide a final product with higher yields

-11 and purity.

DESCRIPTION OF THE SPECIFIC ASPECTS

The process of the present invention is illustrated more and more in the following examples, which refer to the preferred aspects of the process steps previously described. However, these examples should in no way be considered as a limitation on the scope of the present invention.

J

Example 1

1- (4-pyridinylmethyl) -2-pyrrolidinone. Compound III. Step 1

To a stirred solution of sodium hydride (dispersion in 60% mineral oil; 9.4 kg, 235 moles) in N, N-dimethylformamide (119 kg, 125 liters), a mixture of 8 moles was added 2-pyrrolidinone (10 kg, 117.5 moles) and 4-chlorome tilpyridine hydrochloride (19.3 kg, 117.5 moles), and the reaction started at 0 ° C, allowing the temperature to reach 15 ° C and then keeping it at 15 ° C. The addition took 3 hours, making the addition as fast as the temperature and foaming allowed. The reaction mixture was stirred at about 25 ° C for 16 hours. Then, the mixture was clarified through diatomaceous earth. Solids were discarded. The filtrate was concentrated in vacuo and the residue was extracted with boiling isopropyl ether (2 x 167 liters). The combined extracts were heated until they boiled and the solution was cooled slowly to 30 ° C. The product precipitated. The mixture was stirred

-12 / ..

for 16 hours and then cooled to 5 ° C for 3 hours. Compound III was isolated by filtration and dried under vacuum at 30 ° C, obtaining 36 kg of product, with a yield of 77.7%.

Anal. Shut up, for C

Ç

Found: C

10 ^H 12 ^N 1 ^Os , 68.16;

, 67.93;

6.87; N, 15.90.

6.78; N, 15.78.

According to a suitable modification of the previous procedure, using, as starting compounds, 2-halomethylpyridine or 3-halomethylpyridine, the intermediate compounds III can be obtained by synthesis of 1,2 and 1,3-piperidinyl compounds of general formula I.

Example 2

1- (diazinylpiperidinyl) -2-pyrrolidinone. Compound I. Step 2

J

To a solution of 1- (4-pyridinylmethyl) -2-pyrrolidinone (intermediate compound III; 905 g, 5.14 moles) in drinking water (11 liters) was added reagent grade hydrochloric acid (470 ml, approximately 5.65 moles) and platinum (IV) oxide (25 g). The stirred mixture was treated with hydrogen at low pressure (9.4 mmHg; 5 inches of water pressure) and, after the hydrogen absorption was completed (about 3 days), the catalyst was removed by filtration and sodium hydroxide (50% solution; 130 g, 14.1 moles) was added. The solution was cooled to 25 ° C while stirring rapidly, and a suitable halogenodiazine was added portionwise or dropwise over a period of about 2 hours. In general, the temperature was maintained at 25 ° C or a lower temperature during this addition. In most cases, the product separated during this addition and could be removed by filtration. In some cases it was necessary to carry out the extraction of the aqueous reaction solution and, although it can be used here, many of the standard organic liquids that are commonly used in the extraction processes, methylene chloride is preferred. The concentration of the extracts according to standard procedures produced the desired compound, of general formula I.

Below are some specific examples for illustrative purposes.

Example 3

1 - [[1- [2- (trifluoromethyl) -4-pyridinyl] -4-piperidinyl] -methyl] -2-pyrrolidinone

J

To an alkaline aqueous solution of the intermediate piperidine compound II, 4-chloro-2-trifluoromethyl-pyrimidine (938 g, 5.14 moles) was added, quickly stirring the aqueous solution and maintaining the temperature at about 25 ° C. The addition of diazine was completed in about 2 hours and the product was separated during the addition phase. The mixture was stirred for an additional 1 hour and product I was filtered, the filter was washed with cold water (5 ° C, 4 liters). Drying under vacuum at 50 ° C to constant weight gave 1529 g (90.7%); mp 115.5 ° -117 ° C.

14Anal. Shut up to

C, 54.87; H, 5.83; N, 17.06. Found: C, 54.61; H, 5.89; N, 16.91.

Example 4

1- [[l- [6-chloro-2- (trifluoromethyl) -4-piperidinyl] -methyl] -2-pyrrolidinone

To a solution of the compound 1- (4-pyridinylmethyl) -2-pyrrolidine. ninth (intermediate compound III; 905 g, 5.14 moles), in drinking water (11 liters), reagent grade hydrochloric acid (470 ml, about 5.65 moles) and platinum (IV) oxide ( 25 g). The stirred mixture was treated with hydrogen at low pressure (9.4 mmHg; 5 inches of water pressure) and, after the hydrogen absorption was completed (about 3 days), the catalyst was removed by filtration and sodium hydroxide (50% solution, 130 g, 14.1 moles) was added. Then, acetonitrile (1.68 liters) was added, the solution was cooled to 25 ° C while stirring rapidly, and 5.14 moles of 4.6 were added portionwise or dropwise. -dichloro-2-trifluoromethylpyrimidine, V, for a period of about 2 hours. In general, the temperature was maintained at 25 ° C or below during this addition. In most cases, the product separated during this addition or by continuous stirring. naked, overnight and can be separated by filtration. The solid was washed well with water over the filter and then dried in air for one night, yielding 85% of the penultimate compound, II. A sample was dried in an oven, under vacuum, at 50 ° C, for 4 hours, with no weight loss observed and subjected,

then the analysis.

Anal. Shut, for C _nC H _1st ClF-N.0:

^r 15 18 34

C, 49.66; H, 5.00; N, 15.44. Found: C, 49.32; H, 4.94; N, 15.65.

The IV and NMR were consistent.

Example 5

1 - [[1- (2-pyrimidinyl) -4- (piperidinyl] -methyl-2-pyrrolidinone

2-Chloropyrimidine (2.86 g, 25 brothers) was added to a vigorously stirred solution at 0 ° C of 1 - [(4-piperidinyl) methyl-2-pyrrolidinone hydrochloride, II, (5.46 g, 25 brothers) and sodium hydroxide (2.5 g, 62.5 mmoles) in water (55 ml). The mixture was allowed to resume at room temperature for 18 hours. The mixture was cooled to 0 ° C, saturated sodium chloride solution (25 ml) was added, the product was collected as a white precipitate and dried in vacuo (production: 2.7 g; 42% yield; mp: 144 ° -147 ° C).

Example 6

1 - [[1- (2-chloro-4-pyrimidinyl) -4-piperidinyl] -methyl] -2-pyrrolidinone

2,4-dichloropyrimidine (3.7 g, 25 mmoles) was added to a vigorously stirred solution of II (5.46 g, 25 mmoles) and sodium hydroxide (2.5 g, 62.5 mmoles) in water (55 ml). Stirred

the mixture at room temperature overnight, and then the crude product was extracted with methylene chloride. The extracts were concentrated and dried in vacuo, obtaining the product as an oil which solidified on standing (yield: 5.9 g; 80% yield).

Additional Detailed Description of the Present Invention

The synthesis process contemplated by the present invention was previously described as a process adaptable to the large-scale preparation of useful diazinylpieridine products. The process comprises two procedural synthesis steps, a) and b). In Example 1, the preferred process for the preparation of intermediate compound III is described in detail. Step b) is generally described in Example 2, with Examples 3 to 6 indicating the specific examples of the preferred processes in step b) leading to the final product.

To illustrate the modification of the process to obtain other specific diazinylpieridine products, the following preparations of representative compounds are presented. These examples are carried out using the procedures of Example 1 (step a) and Examples 2 and 5 (step b), modified appropriately for the starting halodiazinic compounds and in the appropriate amounts.

These changes in the process of knowledge of the specialist of chemical processes of synthesis.

Example 7

1 - [[1- (6-chloro-3-pyridazinyl) -4-piperidinyl] -methyl] -2-pyrrolidinone

J

Using 1,4-dichloropyridazide, such as halogenodiazine, the procedure of Example 5 was followed, extending the reaction time from 18 to 40 hours, to obtain a product of general formula I in 61% yield and with a dot melting temperature 138.5 ° -140 ° C.

Anal. Shut up to ^C 14 H ₁₉ C1N ₄ O: ç, 57.05; H, 6.50; N, 19.01. Found: Ç, 57.07; H, 6.37; N, 18.91. MS (CDI, i-C ^ H ^ g): weight bad observed: 294

The IV and NMR were consistent.

Example 8

1 - [[1- (6-chloro-4-pyrimidinyl) -4-piperidinyl] -methyl] -2-pyrrolidinone

O

Using 4,6-dichloropyrimidine as halogenodiazine, the procedure of Example 5 was followed, extending the reaction time from 18 to 40 hours, obtaining the compound of formula I in 83% yield and with a melting 142.5 ° -143 ° C.

Anal. Stop, for C ^^ H ^ gClN ^ O:

C, 57.06; H, 6.50; N, 19.01.

Found: C, 57.06; H, 6.49; N, 18.94. MS (ICD, ί-σ ^ Η ^ θ): poorly observed weight: 294 The IV and NMR were consistent.

Example 9

1- [[1- (6-chloro-2-pyrazinyl) -4-piperidinyl] -methyl] -2-pyrrolidinone

Using 2,6-dichloropyrazine as halogenodiazine, the procedure of Example 5 was followed, extending the reaction time from 18 to 40 hours, obtaining a compound of formula I in a yield of 36%, and with a dot melting temperature 139.5 ° -141 ° C.

-19i ‘Sν.

Anal. Calc, for C ^ H ^ gClN ^ O:

C, 57.05; H, 6.50; N, 19.01.

Found: C, 56.94; H, 6.21; N, 18.86.

MS (ICD, ϊ-σ ^ Η ^ θ): poorly observed weight: 294 The IV and NMR were consistent.

Other desired compounds of the general formula I can be prepared in a similar manner by making the necessary modifications which are known to the skilled person.

Claims (8)

Claims 1, - Improved process for the preparation of a diazinylpiperidine selected from the group of 1,2-1,3 and 1,4-disubstituted piperidines of the general formula α // cyj Ν — Z in which Z represents a diazine substituted by a carbon atom and selected from pyrimidine, pyridazine and pyrazine, R ₂ and R _{2 being} independently chosen from a hydrogen atom or a halogen atom or a lower (C1 -C4) alkyl, lower alkoxy, lower alkylthio, cyano, trifluoromethyl and pentafluoroethyl group and attached to the carbon atoms in the diazine ring; characterized by the fact: a) a mixture of 2-pyrrolidinone and a halomethylpyridine is added to a suspension of sodium hydride in Ν, Ν-dimethylformamide at a temperature between about 0 and 20 ° C to provide intermediate compound 1- (pyridimylmethyl) - 2-pyrrolidinone. general formula 1 I I b) to catalytically hydrogenate an aqueous solution of a halide of the intermediate of general formula III to obtain a compound of general formula II, in which Y represents a halide CT-1S78A HY I I -22- />' ^y 7 i ο which, is alkalinized and treated with a diazine of general formula Z-Q, in which Q represents a removable organic synthetic group, to obtain the compound of general formula I 2. Process according to claim 1, for the preparation of compounds of general formula I in which Y represents a chloride, characterized in that correspondingly substituted starting compounds are used. 3. A process according to claim 1 for the preparation of compounds of general formula I in which Z represents pyridinine, characterized in that correspondingly substituted starting compounds are used. 4. A process according to claim 1 for the preparation of a 1,4-disubstituted piperidine, characterized in that correspondingly substituted starting compounds are used. 5. A process according to claim 1 for the preparation of compounds of formula I in which R and R ₂ are independently selected from a hydrogen atom or a halogen atom and a trifluoromethyl group, characterized by f ac. to use correspondingly corresponding starting compounds. replaced 6. - Process according to claim 1, for a) Preparation of l- / 7 / 7lto72 "trifluoromethyl) -4-pyrimidinyl ^r £ -4-pip-ridinil_7 metil_7-2-pyrrolidinone, characterized in that correspondingly substituted starting compounds use. 7. A process according to claim 1 for the preparation of compounds of general formula I in which Z represents. a pyridazine group, characterized. because correspondingly substituted starting compounds are used 8. - Process according to. claim 1, for the preparation of compounds of general formula I in which Z represents a pyrazine group, characterized. because they are used with correspondingly replaced starting positions. Lisbon, October 26, 1990