FI95468B - Improved process for preparing useful piperidine derivatives - Google Patents

Description

, 95468

Improved Process for the Preparation of Useful Piperidine Derivatives The present invention describes an improved, more economical process for the synthesis of selected 1 - [(diazinyl-piperidinyl) methyl] -2-pyrrolidinones of formula I suitable for large scale production.

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In the compounds of formula I, Z is R1-, R2-disubstituted diazine from pyramidine, pyridazine and pyrazine. R 1 and R 2 are independently hydrogen, alkyl, alkoxy, alkylthio, cyano, trifluoromethyl, pentafluoroethyl and halogen. In particular, this method can be used in the preparation of diazinylpiperidine derivatives that increase brain function and can be used to restore brain function in dullness due to degenerative processes; recovering memory after memory loss; and improving memory and learning processes.

These compounds, their synthesis and use have been described by: Mattson, et al .; U.S. Patent No. 4,826,843, which is incorporated herein by reference. The synthesis of 1- (4-diazinyl) piperidinyl derivatives of N-methylene-2-pyrrolidinone was generally described in Scheme 2 and described as Method (b). This prior art method is described below in Scheme A.

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Scheme A

Prior art method 5

Phase 1.

10 IV X 111

Step 2. „, ^, 0 catalytic converter il _

III II

Step 3.

· d. o ·· “s? e-- -o-

MeCN

11 I

20

In Scheme A, Z is a suitable diazine (pyridazine, pyrimidine or pyrazine), and Q is a leaving group of the organic synthetics.

Examples 2-6 were given as examples of the method shown in Scheme A.

The improved process, which is described more fully herein, differs from the prior art process by the addition of several modifications, which produce significant reductions in time, labor, and processing work, as well as allowing for an increase in manufacturing scale. '*

Those skilled in the art of process development will recognize that many methods, procedures, and / or reactions are not suitable for large scale performance, as is done in a test facility or manufacturing plant. Some exemplary situations where scaling may be problematic may involve the use of hazardous or toxic reagents and / or solvents; highly exothermic 5 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; reduced yield when scaling up and the like. A more topical issue to be considered in large-scale 10 operations is the restrictions on certain emissions, as well as the disposal of waste from chemical processes. Processes involving these elements have higher levels of production costs.

It is an object of the present invention to modify the original synthetic process so that it can be used economically on a large scale.

In the improved process of the present invention, the synthetic sequence of reactions is maintained with little variation, but the process steps themselves have been changed by combining the steps and adding a number of unique and non-obvious modifications that allow this process to be successfully scaled up.

This invention relates to an improved synthetic method that can be applied to psychocognitive characteristics.

for the large-scale preparation of 1- (4-diazinyl) piperidinyl derivatives of N-methylene-2-pyrrolidinone. This improved method has advantages in terms of economy of reagents, time and labor costs, as well as improved suitability for the use of larger scale standard chemical process equipment.

The products of the process of this invention are the 1- (4-diaz-35-sinyl) piperidinyl derivatives of N-methylene-2-pyrrolidinone of formula I.

In formula I, the N-methylene-2-pyrrolidinone group may be attached at the 2-, 3- or 4-position of the piperidine ring; and Z is R 1, R 2 disubstituted diazine attached to one of its carbon atoms, wherein R 1 and R 2 are independently hydrogen, lower alkyl, lower alkoxy, lower alkylthio, cyano, trifluoromethyl, pentafluoroethyl and halogen. These substituents are attached to the carbon atoms of a suitable diazine ring. The descriptive term "lower" refers to a group of substituents containing 1 to 4 carbon atoms.

The improved process involves the addition of a number of process modifications to the previously described reaction cycle, and it is these modifications that allow this process to be applied on a large scale required for commercialization. It should be noted that material costs are the most important factor in the commercialization of a product, and modifications that improve the cost-effectiveness of production become extremely important.

An improved method for efficient scale-up is outlined in Scheme B.

25 Diagram B ...

♦ «. ·

Improved method

Phase 1.

0 .0 o »· -o o - * '- © IV« 1S-20 *

III

Step 2. · · .. o H. cataly- f o "1 o cJ-O"? d-O Έ d-O ·.

tetty H "Y h ^ 111 * HV II 1

Step 3.

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In Scheme B, Y is halogen (chlorine, bromine or iodine), preferably chlorine; Q is a leaving group for organic synthesis; and Z is as defined above. It would be expected that other suitable substitution groups (Q) could act in the same way in Scheme B instead of Y, the leaving halogen group. Examples of such suitable leaving groups (Q) are set forth in U.S. Patent No. 4,826,843 to Mattson et al., Which is incorporated herein by reference.

The first step 10 of the initial process involved the preparation of the 2-pyrrolidinone anion by reaction

With NaH in DMF. Chloromethylpyridine was then added to react with the anion to give an intermediate compound of formula III. The formation of an anion with the evolution of hydrogen is simultaneously followed by significant foaming of the foam, and the stability and accumulation of this foam stops the addition of 2-pyrrolidinone. Stable foam prevents the reaction from proceeding to completion within a reasonable time on a large scale.

The first attempts to minimize foaming 20 either did not work or caused additional problems in the enlarged scale process. Changes in the liquid reaction medium caused a decrease in the solvent efficiency obtained with DMF, and this resulted in the solidification of the reaction mixture as a strongly exothermic process. Removal of mineral-25 oil from the NaH reagent had a large , guaranteeing foaming little effect. Replacement of other strong bases such as sodium isopropoxide, KH and LiNH2 did not yield an isolatable intermediate of formula III. The experiments showed that the formation of a stable foam could be due to the surface activity properties of the pyrrolidinone ion in DMF. However, the addition in the reverse order (chloromethylpyridine hydrochloride is first added to the sodium hydride / DMF suspension, and then the 2-pyrrolidinone starting material is added) resulted in reduced product formation and apparent polymerization at a higher reaction mass. The problem of anti-scale foaming was finally eliminated by a seemingly simple but effective modification in which a mixture of equimolar amounts of 2-pyrrolidinone of formula IV and chloromethylpyridine of formula X was added to a DMF suspension of sodium hydride at about 20 ° C. C. The yield of the product decreases at temperatures above 20 ° C, while the reaction rate decreases at temperatures below about 0 ° C sufficiently to allow the accumulation of starting materials, thus creating the potential for an uncontrolled, predatory reaction on a large scale.

Another problem with the preparation and subsequent use of an intermediate of formula III in a large scale process is that the intermediate of formula III was initially purified by vacuum distillation, and without this purification step the process following to reduce the compound of formula III does not work very well.

20 It was found that by extracting the improved method; ...

the reaction residue of step 1 with hot isopropyl ether could give a suitably pure compound of formula IV without the required vacuum distillation.

In the improved process, steps 2 and 3 are combinable and are performed in water using a water-soluble acid addition salt of a compound of formula III. Although most acid addition salts of a compound of formula III would be suitable, hydrogen halide salts are preferred, and the HCl salt is most preferred. After hydrogenation at low pressure and removal of the catalyst, the pH of the aqueous solution is adjusted to basic with aqueous NaOH, and the solution is treated with a suitable diazine reagent of formula 'Z-Q'. The addition of a small amount of acetonitrile, on the order of about 10% of the solvent volume, apparently improves the coupling process, thus increasing the yield of the product. The product of formula I precipitates and is isolated by filtration. This results in significant work, reagent and process time efficiencies. The main improvement of the new method is that the reduction is carried out in water, which is much cheaper, non-flammable and easy to use; followed by direct coupling in aqueous solution. In contrast to the old method involving reduction in alcohol; intermediate insulation; coupling in a heterogeneous reaction mixture (solid sodium carbonate and DMF); filtering; Removal of DMF in vacuo; and, at a minimum, recrystallization of the product from an organic solvent. In the previously described method, most of the diazine products of formula I required chromatography for separation / purification. As previously mentioned, Kro-15 mapping methods are best avoided in larger-posterior fabrications. The improved process increases both the overall yield and purity of the product (without chromatography), as well as the work, material, and process time efficiencies mentioned above. In addition, the amount of material passing through the process increases.

In summary of the above, an improved process for the preparation of a compound of formula I at 60 ° C has been described, the structural aspects of which have been described above.

This improved process involves steps a) and b), wherein: a) an equimolar mixture of 2-pyrrolidinone and halomethylpyridine is added to a DMF suspension of sodium hydride at 95468 δ at 0-20 ° C to form 1- (pyridinylmethyl) of formula III. ) -2-pyrrolidinone.

By filtration of the reaction mixture and concentration of the filtrate in vacuo to a residue, the intermediate of formula III is obtained in a form suitable for use in the next step. Extraction of the residue with hot isopropyl ether gives a compound of formula III which can be isolated by filtration from cooled ether extracts.

b) catalytically hydrogenating under reduced pressure an aqueous solution of an acid addition salt of a compound of formula III, for example the HCl salt, to which some acetonitrile has been added, to give a compound of formula II which is adjusted to basic pH and treated with a diazine reagent of formula ZQ, the product of formula I is obtained.

This improved process meets the requirements by providing a practical synthesis that can be used to prepare diazinylpiperidine derivatives that are economically useful on a large scale.

The process is essentially a 2-step process that is compatible with large-scale chemical process equipment. Process modifications have been invented and added to control the formation of a reaction-limiting foam; eliminate the requirements for vacuum distillation and chromatographic purification; replacement organic solvents with water; minimize the isolation and purification of reaction intermediates, and produce the final product in improved yield and purity.

The process of this invention is described in more detail by the following examples, which relate to preferred embodiments of the process steps described hereinabove. However, these examples should not be construed as limiting the scope of the invention in any way.

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Example 1 1- (4-Pyridinylmethyl) -2-pyrrolidinone, Compound III, Step 1

To a stirred suspension of sodium hydride 5 (60% dispersion in mineral oil, 9.4 kg, 235 mol) in N, N-dimethylformamide (119 kg, 125 L) was added a mixture of 2-pyrrolidinone (10 kg, 117.5 mol) and 4-chloromethylpyridine hydrochloride (19.3 kg, 117.5 mol) starting at a reaction temperature of 0 ° C and allowing the temperature to rise to 15 ° C and then maintain at 15 ° C. The addition lasted 3 hours and the addition was made as fast as temperature and foaming control allowed. The reaction mixture was stirred at approximately 25 ° C for 16 hours. Next, the mixture was clarified into diatomaceous earth through a filter-15 club. The solids were removed. The filtrate was concentrated in vacuo and the residue was extracted with boiling isopropyl ether (2 x 167 L). The combined extracts were heated to reflux and the solution was slowly cooled to 30 ° C. The product precipitated. The mixture was stirred for 16 hours and then cooled to 5 ° C for 3 hours. Compound of formula III: ---- was isolated by filtration and dried in vacuo at 30 ° C to give 16 kg of product, yield 77.7%. Elemental analysis for C10H12N2O:

Calculated: C, 68.16; H, 6.87; N, 15.90.

Found: C, 67.93; H, 6.78; N, 15.78. . :.

By appropriate modification of the procedure described above, in fact using 2-halomethylpyridine or 3-halomethylpyridine as starting materials, intermediate compounds of formula III can be obtained for the synthesis of 1,2- and 1,3-piperidinyl compounds of formula I.

Example 2 1- (Diazinylpiperidinyl) -2-pyrrolidinone, I, Step 2

To a solution of 1- (4-pyridinylmethyl) -2-35 pyrrolidinone (intermediate III, 905 g, 5.14 moles) in 10,446,88 drinking water (11 L) was added reagent grade hydrochloric acid (470 mL, ca. 5.65 moles) and platinum (IV) oxide (25 g). The stirred mixture was treated with low hydrogen pressure (12.7 cm water pressure), and when hydrogen uptake was complete (about 3 days), the catalyst was removed by filtration, and sodium hydroxide (50% solution, 130 g, 14.1 mol) was added. . The solution was cooled to 25 ° C with rapid stirring, and the appropriate halodiazine was added in portions or dropwise over about 2 hours. The heat-10 state is generally maintained at or below 25 ° C during this addition. In most cases, the product separates during this addition and can be removed by filtration. In some cases, extraction of an aqueous reaction solution is required, and although many of the standard organic solvents used in the extraction processes may be used, methylene chloride is preferred. The desired product of formula I is obtained by concentrating the extracts in a standard manner.

Below are some specific examples for illustrative purposes.

Example 3 1 - [[1- [2- (Trifluoromethyl) -4-pyrimidinyl] -4-piperidinyl] methyl] -2-pyrrolidinone To an aqueous solution of a piperidine intermediate of formula II adjusted to basic pH was added 4-chloro-25 ° C. -2-trifluoromethylpyrimidine (938 g, 5.14 mol) with vigorous stirring of the aqueous solution and maintaining at about 25 ° C.

The addition of diazine was completed in about 2 hours, and the product separated during the addition process. The mixture was further stirred for one hour, and the product of formula I was filtered and washed as filter with cold water (5 ° C, 41). Dried in vacuo at 50 ° C to constant weight to give 1529 g, 90.7%, m.p. 115.5 - 117 eC.

Elemental analysis for C15H19F3N4O:

Calculated: C, 54.87; H, 5.83; N, 17.06.

Found: C, 54.61; H, 5.89; N, 16.91.

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

To a solution of 1- (4-pyridinylmethyl-2-5 pyrrolidinone (intermediate of formula III, 905 g, 5.14 mol) in drinking water (11 L) was added reagent grade hydrochloric acid (470 mL, ca. 5.65 mol). and platinum (IV) oxide (25 g) The stirred mixture was treated with low hydrogen pressure (12.7 cm water pressure), and when hydrogen uptake was complete (about 3 days), the catalyst was removed by filtration, and sodium hydroxide ( 50% solution, 130 g, 14.1 mol) Acetonitrile (1.68 L) was then added, and the solution was cooled to 25 ° C with rapid stirring, and 5.14 mol of 4.6- dichloro-2-trifluoromethylpyrimidine dropwise over about 2 hours The temperature is generally maintained at or below 25 ° C during this addition, the product separates during this addition or by stirring overnight, and can be removed by filtration.

The solid was rinsed well with water as a filter and then air dried overnight to give 85% yield of the last compound of formula II. The sample was dried at 50 ° C under vacuum for 4 hours without any weight loss, and then subjected to analysis.

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Elemental analysis for C15H18ClF3N4O:

Calculated: C, 49.66; H, 5.00; N, 15.04.

Found: C, 49.32; H, 4.94; N, 15.65.

IR and NMR corresponded to the product.

Example 5 1 - [[1- (2-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone 2'-chloropyrimidine (2.86 g, 25 mmol) was added to a vigorously stirred solution at 0 ° C. wherein 35 was 1 - [(4-piperidinyl) methyl-2-pyrrolidinone hydrochloride (5.46 g, 25 mmol) of formula II and sodium hydroxide (2.5 g, 62.5 mmol) in water (55 The mixture was allowed to warm to room temperature over 18 h, cooled to 0 ° C, saturated brine (25 mL) was added, and then the product was collected as a white precipitate and dried in vacuo (yield: 2.7 g, 42%; m.p .: 144-147 ° C).

Example 6 1-C [1- (2-Chloro-4-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone 2,4-Dichloropyrimidine (3.7 g, 25 mmol) was added to a vigorously stirred solution of was a compound of formula II (5.46 g, 25 mmol), and sodium hydroxide (2.5 g, 62.5 mmol) in water (55 mL). The mixture was stirred at room temperature overnight and the crude product of formula I was extracted off with methylene chloride. The extracts were concentrated and dried in vacuo to give the product as an oil which solidified on standing (yield: 5.9 g, 80%).

The improved synthetic process of the invention is described herein below as a process suitable for the large scale preparation of useful diazinylpiperidine products. The method comprises 2 synthetic process steps, a) and b). Example 1 describes a preferred detailed procedure for the preparation of an intermediate compound of formula III. Step b) is described generally in Example 2, and specific examples of preferred process steps b) leading to the final product are shown in Examples 3-6.

To illustrate variations of the process for producing other specific diazinylpiperidine products, the following representative compound preparations are disclosed. These examples are prepared using the methods of Example 1 (step a) and Examples 2 and 5 (step b), suitably modified in amounts and with a suitable halodiazine starting material.

These method modifications are likely to be well known to those skilled in the art of chemical synthesis.

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Example 7 1 - [[1- (6-chloro-3-pyridazinyl) -4-piperidinyl] methyl] -2-pyrrolidinone

The procedure of Example 5 was followed using 1,4-dichloropyridazine as the halodiazine and extending the reaction time from 18 hours to 40 hours to give the compound of formula I in 61% yield, m.p. 138.5-15 ° C.

Elemental analysis for CX4H19C1N40:

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

Found: C, 57.07; H, 6.37; N, 18.91.

MS (CDI, i-C4H10): found mp .: 294 IR and NMR were consistent.

Example 8 1 - [[1- (6-chloro-4-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone

The procedure of Example 5 was followed using 4,6-dichloropyrimidine as the halodiazine and extending the reaction time from 18 hours to 40 hours to give the compound of formula I in 83% yield, mp 142.5-35 143 ° C.

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Elemental analysis for C14H19ClN40:

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

Found: C, 57.06; H, 6.49; N, 18.94.

MS (CDI, i-C4H10): observed mp .: 294 IR and NMR were consistent.

Example 9 1 - [[1- (6-chloro-2-pyrazinyl) -4-piperidinyl] methyl] -2-pyrrolidinone 10 1 h

Cl 15

The procedure of Example 5 was followed using 2,6-dichloropyrazine as the halodiazine and extending the reaction time from 18 hours to 40 hours to give the compound of formula I in 36% yield, mp 139.5-201 ° C.

Elemental analysis for C14H19ClN40:

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

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

MS (CDI, i-C4H10): found mp .: 294 IR and NMR were consistent.

Similarly, other desired products of formula I may be prepared with the required modifications as will be known to those skilled in the art.

Claims (8)

15 95468 An improved process for the preparation of diazinylpiperidines selected from 1,2-, 1,3- and 1,4-disub-5-substituted piperidines of formula (I) wherein Z is R '-, R2- disubstituted diazine attached through its carbon atom and selected from pyrimidine, pyridazine and pyrazine, wherein R 1 and R 2 are independently hydrogen, lower (C 1-4 alkyl), lower alkoxy, lower alkylthio, cyano, trifluoromethyl, pentafluoroethyl or halogen and are attached to the carbon atoms of the diazine ring; characterized in that it comprises the steps of a) adding to a suspension of sodium hydride in onin, Ν-dimethylform-: amide at about 0-20 ° C a mixture of 2-pyrrolidinone and halomethylpyridine to form the 1- (pyridinylmethyl) -2-pyrrolidinone intermediate (b) and catalytically hydrogenating the hydrogen halide of the intermediate of formula III in aqueous solution to give the compound of formula (II) 1 - 95468, and recovering the compound of formula III by extraction with hot isopropyl ether; Wherein Y is a halide; treated in an alkaline aqueous solution with a diazine reagent of formula Z-Q, wherein Q is a leaving group used in organic syntheses, to give a product compound of formula (I) Process according to Claim 1, characterized in that Y is chloride. Process according to Claim 1, characterized in that Z is pyrimidine. Process according to Claim 1, characterized in that the compound of the formula I is: 1,4-disubstituted piperidine. Process according to Claim 1, characterized in that R 1 and R 2 are, independently of one another, hydrogen, halogen and trifluoromethyl. Process according to Claim 1, characterized in that the compound of the formula I is 1 - [[1- [2-trifluoromethyl) -4-pyrimidinyl] -4-piperidinyl] methyl] -2-pyrrolidinone. Process according to Claim 1, characterized in that Z is pyridazine. Process according to Claim 1, characterized in that Z is pyrazine. * 17 95468