KR100214343B1 - Process for the preparation of alpha-pyridylcarbynol - Google Patents

Abstract

Preferred methods of preparing α-2-pyridyl α-aryl carbinol or α-4-pyridyl α-aryl carbinol compounds are described.

Description

[Name of invention]

Preparation of α-pyridyl carbinol

Detailed description of the invention

[Background of invention]

The present invention generally relates to a process for preparing the α-pyridyl carbinol compound. In particular, the present invention relates to a process for preparing α-2-pyridyl α-yl carbinol or α-aryl carbinol by reacting 2- or 4-cyanopyridine with an aromatic carbonyl compound.

Α-pyridyl carbinol compounds having Py-C-OH as the characteristic group, where Py is a pyridyl group, have been widely studied, for example, carbineoxamine, dioxylamine, azacyclool and antihistamine It has been used in large quantities as an intermediate in the preparation of antihistamines such as Saintldenadine (Seldane ') To date, several methods for preparing these α-pyridyl carbinols have received considerable attention. The Emmert reaction involves reacting pyridine and ketones in the presence of magnesium or aluminum amalgam The reaction product comprises a mixture of 2- and 4-pyridyl carbinols with pinacol produced as a byproduct. B. Emmert and E. Ssendorf, Ber., 72, 1188 (1939); B. Emmert and E. Pirot, Ber., 74, 714 (1941); and CH Tilford, RS Shelton and MGVan Campen, Jr., J. Am. Chem. Soc., 70, 4001 (1948)].

In the Hammick reaction, α-pyridyl carbinol is prepared by decarboxylation of picolinic acid in an excess of aldehyde or ketone. P. Dyson and D. L. Hammick, J. Chem. Soc., 1724 (1937); and K. Mislow, J. Am. Chem., 69, 2559 (1947).

Α-pyridyl carbinol can also be applied to pyridyl Grignard reagents on aldehydes or ketones (J. P. Wibaut and L. G. Heeringa, Recueil, 74, 1003 (1955); N. Furukawa, T. Shibutani, K. Matsumura, H. Fujihara, and S. Oae, Terahedron Lett., 27, 3899 (1986)] or by applying an aryl Grignard reagent to pyridyl aldehydes, ketones or esters [see : AE Tschtschibabin and SW Benewolenskaja, Ber., 61, 547 (1928); Y. Kasuya and K. Fujie, Yakugaku Zasshi., 78, 551 (1958) [Chem, Abstr., 52, 17196i (1958); and K. Nagarajan, P. K. Talwalker, R. K. Shah and S. J. Shenoy, Indan J, Chem., Sect. B, 24B, 112 (1985)].

Diphenyl ketyl radicals have been reported to undergo substitution reactions with cyano-substituted pyridinium ions resulting in α-pyridinium substituted carbinols. See B. M. Vittimberga, F. Minisci and S. Morrocchi, J. Am. Chem. Soc., 97, 4397 (1975) report this interaction in 1M sulfuric acid, in which the photophenyl production of diphenyl ketyl radicals is photochemically produced. In subsequent studies, in P. McDevitt and BM Vittimberga, J. Heterocyclic Chem., 27, 1903 (1990), this interaction is generated by thermally balanced decomposition of benzopinacol to generate diphenyl ketyl radicals. It is written. The interaction of thermally generated diphenyl ketyl radicals with cyano-substituted pyridine in neutral media is also described in the literature.

Diaryl heterocyclic carbinols are prepared by oxidizing the corresponding methylpyridine with sodium hydroxide and O ₂ in DMSO. TJ Kress and LL Moore, J. Heterocyclic Chem., 9, 1161 (1972).

As indicated in the above and other documents, there has been a continuing interest in identifying very effective and economically notable methods for preparing α-pyridyl carbinol, and still remains of considerable interest. However, there are many disadvantages to the methods that have been studied so far. For example, the Emmert reaction provides a mixture of 2- and 4-pyridyl carbinol, making it difficult to carry out highly selective production of one of them. Hammic reactions require stringent conditions and provide particularly low yields when treated at the 4-position of the pyridine ring (eg, with isiconicotinic acid). The difficulty of treating organometallic materials, along with the use of halopyridine as starting material, renders the use of Grignard reagent uninteresting in economic and other aspects. In addition, the above-described treatment with diphenyl ketyl radicals usually results in low yields and the generation of significant by-products, and the cost of the corresponding methane starting materials in the treatments disclosed above by Kress et al. Also makes the process relatively disadvantageous. Make.

therefore. There is a need for a process for the preparation of α-pyridyl carbinol that can be carried out under mild conditions using relatively inexpensive starting materials. Further preferred methods provide high yields and minimal production of byproducts.

[Summary of the Invention]

The present invention provides a method for preparing α-2-pyridyl α-yryl carbinol or α-4-pyridyl α-aryl carbinol compound in a preferred embodiment for the purpose of this and other needs. This process involves the reaction of 2- or 4-cyanopyridine with α-aryl ketones or α-aryl aldehydes in the presence of a metal or metal ion electron donor in an aromatic solvent and the α-2-pyridyl α-aryl carbinol or achieved by recovering the α-4-pyridyl α-aryl carbinol compound.

In another embodiment of the present invention, a very advantageous method was found to control the order of addition of the reactants to obtain better product yields and to minimize the formation of byproducts. Accordingly, another preferred embodiment provides a process for the preparation of α-2-pyridyl α-aryl carbinol or α-4-pyridyl α-aryl carbinol compounds. This preferred embodiment is characterized by the initial reaction of α-aryl aldehydes or ketones in the presence of a metal or metal ion electron donor. The product of this initial reaction is subsequently reacted with 2- or 4-cyanopyridine to recover the α-aryl pyridyl carbinol compound. The initial reaction (ie, the reaction of the electron donor with the aldehyde or ketone before the addition of 2- or 4-cyanopyridine) may comprise some or all of the total amount of aldehyde or ketone to react. For example, in one characteristic embodiment, the present invention initially reacts an electron donor with an aldehyde or ketone followed by addition of 2- or 4-cyanopyridine and an additional amount of aldehyde or ketone. The method of this aspect exhibits good yields while providing good selectivity and can be carried out using a variety of conditions.

Another preferred embodiment of the invention is α in the presence of a metal or metal ion electron donor selected from the group consisting of Group IB, IIA, IIB, IIIA, IIIB, IVA, IVB, VB, VIB and VIIB metals and their ions of the periodic table. Provided is a method for preparing an α-aryl pyridyl carbinol compound comprising reacting an aryl ketone or an aldehyde with 2- or 4-cyanopyridine. This recovers an α-aryl pyridyl carbinol compound.

Another preferred embodiment of the present invention is characterized by hydrogenating the α-aryl pyridyl carbinol compound in a benzene or alkylbenzene solvent in the presence of a palladium catalyst to produce an α-aryl piperidyl carbinol compound, Provided is a method of preparing an α-aryl piperidyl carbinol compound from an α-aryl pyridyl carbinol compound.

Preferred embodiments of the present invention can be carried out under appropriate conditions, using starting materials that are relatively inexpensive and readily available. In addition, the preferred process of the present invention provides a process for the production of 2- or 4-pyridyl carbinol with high selectivity with good yields which forms extremely small amounts of by-products. Still other objects and advantages of the invention will emerge from the following description and the appended claims.

[Description of Preferred Aspect]

To facilitate an understanding of the principles of the present invention, certain embodiments have been described with reference to and will be described using specific terms. Nevertheless, it is to be understood that variations, alternative modifications, and adaptations of the principles of the invention may be routinely attempted by those skilled in the relevant art of the invention, without limiting the scope of the invention.

As mentioned above, preferred embodiments of the present invention include the reaction of 2- or 4-cyanopyridine with an -aryl ketone or aldehyde. The cyanopyridine used in the preferred embodiment requires another substituent attached to its pyridine ring or hinders the reaction of the cyanopyridine with an aldehyde or ketone (hereinafter referred to as a carbonyl compound) to obtain the desired product. It may also include other substituents attached to a ring that does not. Such substituents that do not interfere can include, for example, alkyl groups (eg, methyl, ethyl, propyl, etc.), fused aryl (eg, naphthyl) groups, and other groups.

As mentioned, cyanopyridine is reacted with an α-aryl ketone or an aldehyde, for example a compound of the general formula Ar—CO—R ₁ , wherein Ar is aryl and R ₁ is hydrogen (eg aldehyde) Straight or branched chain alkyl (preferably about C ₁ -C ₁₀ alkyl, eg methyl, ethyl, propyl, butyl, etc.), alkenyl (eg straight or branched chain carbon groups, preferably one or more ethylenic About C ₁ -C ₁₀ alkenyl containing unsaturated groups, aryl, alkaryl (e.g. -alkenyl-aryl, where C ₁ -C ₁₀ alkylene group is preferred) alkenylaryl (e.g.- Alkenyl-aryl, where a C ₁ -C ₀ alkenyl group is preferred, such as a ketone. Additionally, in this general formula, -CO-R ₁ represents a fused 4,5 or 6 membered hydrocarbon ring which may be fused to another aryl group as occurring in a preferred reactant such as Ar, for example fluorenone. Substituent groups fused to Ar to be formed can be formed. Thus, presently preferred α-aryl carbonyl reactants are benzophenone, Michael ketone [4,4'-bis (dimethylamino) benzophenone], 4,4'-difluorobenzophenone, 4-methoxybenzophenone, fluorine Ketones such as lennon and chalcone and aldehydes such as benzaldehyde. Α-aryl ketones where no enol hydrogen is present (e.g., R ₁ does not have hydrogen enol atoms on carbon directly bonded to the carbonyl group -CO-), for example α, α- such as benzophenone Diaryl ketones are preferred. In this regard, the term aryl, as used herein, refers to aromatic cyclic or polycyclic groups containing at least one unsaturated 6-membered carbon-containing ring, eg, in which the ring may contain one or more heteroatoms such as nitrogen, oxygen or sulfur. For example, it means containing a pyridyl group. Such preferred aryl groups are, for example, groups containing phenyl groups and two or more fused benzene rings, typically two or three fused benzene rings (e.g. naphthyl, phenanthrenyl, anthracenyl, etc.) It contains. In addition, aryl groups may include unsubstituted substituents such as amino groups such as alkylamino (eg dimethylamino), amino groups (eg -NHCOCH ₃ ), alkoxy groups (eg methoxy and ethoxy), Alkylsilyl groups (eg trimethylsilyl) or other carboxyl derivatives (eg -COO-alkyl or -COO-aryl, halogen such as chlorine, bromine, fluorine).

The term α-aryl ketone or aldehyde means an aldehyde and a ketone in which an aryl group is bonded directly adjacent to a carbonyl group. Thus, the terms α, α-diaryl ketones include ketones containing two such aryl groups bonded directly adjacent to a carbonyl group.

The above-described α-aryl aldehyde or ketone is reacted with 2- or 4-cyano pyridine and its product (precursor of the corresponding carbinol salt) is hydrolyzed to yield Α- (2 or 4) -pyridyl α-aryl compound, wherein Ar is as defined above, Py is a 2- or 4-pyridyl group, X is the same as R ₁ , or an α-aryl ketone reactant When containing this enolated hydrogen, the two α-aryl carbonyl compound reactants may be groups produced by aldol condensation and subsequent dehydration reaction). For example, if X is equal to R ₁ , where R ₁ does not contain hydrogen enolide, then the reactants of the general formula Ar-CO-R ₁ are reacted with 2- or 4-cyanopyridine to each expression Of the α-2-pyridyl α-aryl carbinol or α-4-pyridyl α-aryl carbinol compound, wherein Ar, Py and R ₁ are as defined above (after hydrolysis, for example, water After the post-treatment, etc.).

On the other hand, in the case where R ₁ in the reactant α-aryl ketone compound has hydrogen enolated at the α position relative to the carbonyl group, for example. Only when R ₁ = -CH ₂ -R ₂ , where R ₂ is hydrogen, alkyl, alkenyl, aryl, alkaryl, alkenylaryl, etc., X is an aldol condensation and dehydration of the two reactants α-arylketones. It may be a group generated by the reaction. In other words, _two reactants having the molecular formula Ar—CO—CH ₂ —R ₂ are subjected to aldol condensation and subsequent dehydration to yield a general formula.

Α-aryl ketones of can be obtained. These α-aryl ketone compounds are reacted with 2- or 4-cyanopyridine in situ, respectively,

Α-2-pyridyl α-aryl carbinol or α-4-pyridyl α-aryl carbinol (after workup) of (where Py, R ₂ and Ar are as defined above) is formed.

If the ketone reactant contains hydrogen enolide, it is possible to obtain a mixture of carbinol products, in which X is in some cases —CH ₂ —R ₂ (eg X = R ₁ ) and in other cases a group produced by aldol condensation It may be understood that the degree of condensation of the reactants and the distribution of such products depends on a number of factors, such as the particular reactants, solvent, electron donor, temperature, and the like used in the reaction. In any case, whether or not R ₁ is hydrogen-enolated or not, the α-aryl ketone or aldehyde is reacted with 2- or 4-cyanopyridine according to the present invention and then post-treated by hydrolysis. α- (2 or 4) -pyridyl α-aryl carbinol product is obtained.

As mentioned, cyanopyridine and aldehyde or ketone react in the presence of a metal or metal ion electron donor. Such suitable donors include metals or metal ions having sufficiently high oxidation potentials for the reaction to proceed. For example, the metal or metal ion may be a Group IA [e.g. alkali metal (e.g., sodium, lithium and potassium metal)], Group IB (e.g. copper metal) Group IIA [e.g. alkaline earth metal (e.g. calcium and magnesium metal) )], Group IIB (eg zinc metal), Group IIIA (eg aluminum metal), Group IIIB [eg samarium (Sm ²⁺ )], Group IVA (eg tin metal), Group IVB [eg titanium ( Ti ²⁺ )], group VB (eg vanadium metal), group VIB (eg chromium metal) or group VIIB (eg magnesium metal).

Preferably. The electron donor has an oxidation potential of about 2.7 or more. Group IA or Group IIA metals such as sodium, lithium and calcium, in particular sodium, are the preferred electron donors currently in use.

Preferred processes can be carried out in various solvents in which the reactants are soluble, for example solvents ranging from xylene to liquid ammonia. It has now been demonstrated that toluene is a suitable solvent, and other solvents such as diglyme, acid containing protonic solvents, etc., will also be recognized and understood by those skilled in the art. As in the first embodiment mentioned above, the process is very advantageously carried out in an aromatic solvent.

Similarly, the reaction can be carried out over a wide range of temperatures, for example a temperature of about -80 ° C to about 200 ° C will be suitable. More preferred reactions carried out to date are preferably carried out in aromatic solvents with heating to temperatures above 80 ° C., more preferably refluxing aromatic hydrocarbons such as reflux, for example benzene or alkylbenzenes [eg xylene (About 135 ° C. to 145 ° C.) and toluene (about 110 ° C.). In addition, advantageous reactions are carried out in liquid ammonia without heating at a temperature of about −33 ° C.

Of course, when using sodium or other similar metals as electron donors, it is preferable to carry out the reaction under anhydrous inert atmosphere for safety reasons. For example, if necessary, the reaction can be carried out under a nitrogen atmosphere.

The product can be separated and recovered using conventional techniques, for example, if desired, with the corresponding salt of carbinol, such as M ⁺ -OCArPyX, where M ⁺ -is combined with the metal ion provided by the electron donor. The same cation, and Ar, Py and X are as defined above), which can be worked up with water to produce a carbinol product. Of course, for example, when acidic, protonic or aqueous conditions are used in the reaction step, hydrolysis will not be necessary under conditions which directly form carbinol. Once formed, the carbinol product can be filtered and washed with water and acetone and / or other suitable material.

In another preferred aspect, it has been found that the yield is improved when controlling the order and timing of addition of the reactants. In particular, when the reactants are added to the solvent at the reaction temperature, the yield is significantly improved by adding ketone or aldehyde and electron donor followed by cyanopyridine. Therefore, the most preferred method is to combine the electron donor and the ketone or the aldehyde in the solvent and react initially, followed by the addition of 2- or 4-cyanopyridine. The initial reaction without cyanopyridine is preferably continued for at least about 15 minutes, more preferably at least about 30 minutes, most preferably from about 30 to 60 minutes. Cyanopyridine can then be added and the reaction (eg under reflux) can be advantageously continued for at least about 2 hours, more preferably at least about 3 hours. The initial reaction may use some or all of the total amount of aldehyde or ketone and electron donor to react. For example, in some methods, all aldehydes or ketones are initially reacted and subsequently reacted with the added cyanopyridine (see Example 16). In another method, a small amount of aldehyde or ketone is electrons. React initially with the donor and add cyanopyridine and an additional amount of aldehyde or ketone (see Example 26). In this way of carrying out the process, cyanopyridine and additional aldehydes or ketones may be added together or alternately. In this process in which some or all of the aldehyde or ketone and the electron donor are initially reacted prior to the addition of cyanopyridine, the preferred yield of the carbinol product is obtained at least about 75% and the yield in the more preferred reaction is 90 It is obtained by more than%.

Certain other performances have also been found in the process in which aldehydes or ketones initially react with the electron donor. Applicants have experienced in the study that the yield was reduced by initially reacting the ketone and the electron donor followed by the rapid addition of cyanopyridine. Therefore, it is desirable to obtain the above-mentioned advantageous yields in such a way that the initial reaction is carried out and cyanopyridine is added to maximize the yield of the desired carbinol product, which is more progressive than the sudden or rapid addition of cyanopyridine. It may be easy by adding.

On the other hand, if cyanopyridine, ketone or aldehyde and electron donor are added to the solvent prior to raising the resulting mixture to the reaction temperature, advantageously an improved yield of at least about 70% may be obtained.

With regard to the ratio of reactants, 2- or 4-cyanopyridine is preferably added to the aldehyde or ketone in some stoichiometric excess, for example, preferably up to about 10% excess. The electron donor is preferably added to the ketone or aldehyde in a stoichiometric ratio of at least about 2: 1.

The α-aryl pyridyl carbinol compounds prepared as described above can be conventionally hydrogenated using well known techniques to produce the corresponding α-aryl piperidyl carbinol compounds. However, another more preferred feature of the present invention is that such a hydrogenation process is preferably used in solvents, preferably benzene or alkyl benzenes [ie, compounds having at least one alkyl group bonded to the benzene ring (e.g. Preferably in lower alkylbenzenes (eg, alkyl group (s) are from about C ₁ to C ₄ alkyl (eg xylene or toluene solvent)). In this regard, it has surprisingly been found that aromatic pyridine rings of these α-aryl pyridyl carbinols (eg α-pyridyl diphenyl carbinol) can be successfully hydrogenated without necessarily hydrogenating these aromatic hydrocarbon solvents. Thus, advantageously, the solvent used for the hydrogenation can be the same as the solvent used for the preparation of carbinols as described above. Palladium catalysts supported, for example, other similar catalysts for selectively hydrogenating palladium on carbon or pyridyl carbinol are preferred.

Although the invention has been described in detail in the foregoing paragraphs, it is intended to be illustrative, not limiting, and merely illustrative of preferred embodiments, without departing from the spirit and scope of the invention to be protected. Modifications are included in the present invention. The following specific examples are presented to further explain and describe these aspects, and are intended to be illustrative and not limiting.

Example 1

4-pyridyl diphenyl carbinol

A 500 mL RB flask was charged with 4-cyanopyridine (10.4 g, 0.1 mol) and benzophenone (18.2 g, 0.1 mol). To this, xylene (250 ml) and sodium metal (5.0 g, 0.22 mol) cut into small pieces are added. The flask is slowly heated and refluxed for 3 hours with magnetic stirring under an inert gas (eg nitrogen). During this time, the color of the reaction mixture changes from clear dark blue to dark brown. The reaction mixture is cooled to room temperature and water (150 mL) is added carefully. The solid product is filtered off and washed with water and acetone. Through this, 4-pyridyl diphenyl carbinol (18.3 g, yield 70%) having a melting point of 238 to 240 ° C is recovered.

Example 2

4-pyridyl diphenyl carbinol

A 500 ml three-necked flask equipped with a magnetic stirrer was charged with 4-cyanopyridine (10.4 g, 0.1 mol) and benzophenone (18.2 g, 0.1 mol). Anhydrous liquid ammonia (250 ml) is added carefully and the starting material is dissolved. Sodium metal (5.0 g, 0.22 ml) is then carefully added and the starting material is dissolved. Then sodium metal (5.0 g, 0.22 ml) is slowly added in small pieces. The reaction mixture is stirred for 1 hour and ammonia is evaporated. Toluene (150 mol) and water (150 ml) are then added to the residue and the resulting mixture is stirred for 15 minutes. The precipitated product is filtered off and then washed with water to afford 4-pyridyl diphenyl carbinol.

Example 3

4-pyridyl diphenyl carbinol

A 100 ml RB flask is charged with 4-cyanopyridine (0.52 g, 0.005 mol) and benzophenone (0.91 g, 0.005 mol). THF (25 mL) is added thereto and the starting material is dissolved. Subsequently, samarium diiodide (0.01 mol) in THF (100 mL) is added under an inert atmosphere (nitrogen). The complete mixture is then stirred at 30 ° C. for 3 hours. Work up with aqueous NaHCO ₃ (saturated) to give a solid which is then filtered. The filtrate is extracted with methylene chloride (100 mL) and the methylene chloride is evaporated to afford 4-pyridyl diphenyl carbinol.

[Examples 4 to 8]

Using a procedure similar to Examples 1 and 2 above, 4-pyridyl diphenyl carbinol is prepared by reacting 4-cyanopyridine and benzophenone with varying solvents, conditions and electron donors. The test results of Examples 1-3 and further examples are set forth in Table 1.

In Table 1, ammonia refers to liquid ammonia.

Example 9

2-pyridyl diphenyl carbinol

Example 1 is repeated except that 2-cyanopyridine is used instead of 4-cyanopyridine. 2-pyridyl diphenyl carbinol is prepared and recovered in 70% yield.

Example 10

4-pyridyl 4-methoxyphenyl phenyl carbinol

Example 1 is repeated using 4-methoxybenzophenone instead of benzophenone. Thereby, 4-pyridyl 4-methoxyphenyl phenyl carbinol is produced and recovered.

Example 11

4-pyridyl α-methylstyryl phenyl carbinol

Salsy Example 1 is repeated except that acetophenone is used instead of benzophenone to give 4-pyridyl α-methylstyryl phenyl carbinol as the product.

[Examples 12 to 15]

Using a process similar to that described above, other α-aryl carbonyls (ie, ketones and aldehydes) are reacted with 4-cyanopyridine to yield α-4-pyridyl α-aryl carbinol compounds. The test results of Examples 9-11 and this additional Example are set forth in Table 2.

In Table 2, ammonia means liquid ammonia.

Example 16

4-pyridyl diphenyl carbinol

Benzophenone (54.6 g, 0.3 mol) is introduced into a 1 liter round bottom three neck flask equipped with an automatic stirrer, reflux condenser and dropping funnel. Thereafter, xylene (300 mL) and sodium metal (16.6 g, 0.72 mol) cut into small pieces are added. The flask is slowly heated and refluxed for 30 minutes under automatic stirring under an inert atmosphere (nitrogen). Thereafter, 4-cyanopyridine (38.2 g, 0.37 mol) in xylene (200 ml) is added over 1 hour, and then the mixture is further refluxed for 3 hours. Thereafter, the reaction mixture is cooled to room temperature and water (300 mL) is added carefully. The solid is then filtered and washed with water and acetone to give 4-pyridyl diphenyl carbinol (73.1 g, 93%).

Example 17

4-pyridyl diphenyl carbinol

To a solution of 4-cyanopyridine (5.2 g, 0.05 mol) and benzophenone (9.1 g, 0.05 mol) in isopropanol is added acetic acid (6.0 g, 0.1 mol) and magnesium metal (1.2 g, 0.05 mol). The resulting mixture is stirred at rt for 4 h. The precipitated product is filtered off and washed with acetone and analyzed to find 4-pyridyl diphenyl carbinol.

Example 18

4-pyridyl diphenyl carbinol

The procedure of Example 17 is repeated except that the solvent is replaced with toluene / aqueous ammonium chloride (2 equivalents of solid in water) from isopropanol / acetic acid. GC of the organic layer shows the product 4-pyridyl diphenyl carbinol produced.

Example 19

4-pyridyl diphenyl carbinol

The procedure of Example 17 is repeated except that magnesium is replaced with zinc. The recovered product was found to be 4-pyridyl diphenyl carbinol.

Example 20

4-pyridyl diphenyl carbinol

The procedure of Example 18 is repeated except that magnesium is replaced with zinc and MeOH / aqueous ammonium chloride is used as solvent. 4-pyridyl diphenyl carbinol is recovered as a product.

Example 21

4-pyridyl diphenyl carbinol

A mixture of 4-cyanopyridine (5.2 g, 0.05 mol), benzophenone (9.1 g, 0.05 mol) and zinc (3.3 g, 0.05 mol) is refluxed in acetic anhydride (200 mL) under nitrogen atmosphere for 3 hours. GC analysis of the acetic anhydride layer showed the product to be 4-pyridyl diphenyl carbinol.

Example 22

4-pyridyl diphenyl carbinol

Example 17 is repeated except acetic acid is replaced with aqueous acetic acid and magnesium metal is replaced with aluminum. The mixture is refluxed for 5 hours, cooled and neutralized with base to afford the product 4-pyridyl diphenyl carbinol.

Example 23

4-pyridyl diphenyl carbinol

The same procedure as in Example 22 was carried out except that the solvent was MeOH / aqueous acetic acid and the metal was tin. The mixture is refluxed for 4 hours, cooled and neutralized with base. The mixture was extracted with xylene and then GC analyzed to give the product 4-pyridyl diphenyl carbinol in the xylene layer.

Example 24

4-pyridyl diphenyl carbinol

A mixture of 4-cyanopyridine (2.6 g, 0.025 mol), benzophenone (4.6 g, 0.025 mol) and chromium metal powder (1.3 g, 0.025 mol) is stirred in MeOH (100 ml). Aqueous hydrochloric acid (3 equivalents) is added to this mixture and the mixture is stirred at room temperature for 3 hours. Analysis of the MeOH solution shows 4-pyridyl diphenyl carbinol product.

Example 25

4-pyridyl diphenyl carbinol

The procedure of Example 24 is repeated except that manganese metal is used instead of chromium. GC analysis showed the product to be 4-pyridyl diphenyl carbinol.

Example 26

4-pyridyl diphenyl carbinol

Sodium metal (16.6 g, 0.72 mol) and xylene (150 mL) are introduced into a 1 liter round bottom three neck flask equipped with an autostirrer, reflux condenser and two dropping funnels.

The mixture is refluxed and the addition of benzophenone (54.6 g, 0.3 mol) begins. Add about 1/4 to 1/3 of benzophenone for 15 to 30 minutes to obtain a solution of 4-cyanopyridine (38.2 g, 0.37 mol) in xylene (200 mL) and cyanopyridine when the addition of benzophenone is complete. Start adding at the rate at which about 1/2 of the solution is added. The remaining cyanopyridine solution is added for an additional 30 minutes. After workup with water (300 mL), 4-pyridyl diphenyl carbinol is obtained in about 95% yield.

Example 27

Diphenyl 4-piperidyl carbinol (azacyclonol)

A 1.4 L hydrogenated shaker bomb was charged with 4-pyridyl diphenyl carbinol (46.5 g, 0.18 mol), platinum oxide (2.0 g) and glacial acetic acid (325 mL).

The spring is sealed and pressurized to 200 psi with hydrogen and heated to 75 ° C. for 3 hours under shaking.

After this, the spring is cooled and the contents are filtered and evaporated to remove acetic acid. After evaporation, the material is neutralized with aqueous sodium hydroxide (120 g of 50% NaOH and 300 ml of water). The solid material is then filtered, washed with cold water and dried to afford diphenyl 4-piperidyl carbinol (azacyclonol) (43.2 g, 91% yield). The ethanolic solution of azacyclonol was added to hydrogen chloride to give the azacyclolone hydrogen chloride.

Example 28

Diphenyl 4-piperidyl carbinol

In a 1.4 L hydrogenated shaker spring 43.00 g (0.165 mol) diphenyl-4-pyridylcarbinol, 8.00 g 50% HO wet 5% Pd / C (4 g dry weight) and 350 ml xylene are introduced. Seal the spring, pressurize to 900 psi with H and heat to 170 ° C. under shaking.

After 17 hours, the spring is cooled to 1075 psi (170 ° C). The contents are poured out, heated to 70 ° C. and carefully suction filtered to remove the catalyst. At this point, GC analysis of the filtrate and washes revealed 6.9% azacyclonol and 0.05% diphenol-4-pyridylcarbinol. Fill the filtrate to a constant weight (42,65 g) on a rotary evaporator. The tacky raw azacyclonol is removed and recrystallized from 200 ml of heptane and 165 ml of xylene. After cooling, filtration and oven drying (2 hours at 100 ° C. and 15 mm), azacyclool having a melting point of 163 to 166 ° C. is obtained in a yield of 37.84 g, or 86.0%.

Claims (39)

Initial reaction of the α-aryl aldehyde or ketone in the presence of a metal or metal ion electron donor followed by reaction of the initial reaction product with 2- or 4-cyanopyridine, from which the α-aryl pyridyl carbinol compound is recovered. Including, the method for producing an α-aryl pyridyl carbinol compound. The method of claim 1 wherein the reaction comprises reacting α-aryl ketones. The method of claim 1 wherein the reaction comprises reacting α-aryl aldehyde. The method of claim 2, wherein the reaction comprises reacting α, α-diaryl ketones. The method of claim 4, wherein at least one aryl group in the diaryl ketone is a phenyl group. The method of claim 4, wherein the diaryl ketone is benzophenone or fluorenone. The method of claim 6, wherein the diaryl ketone is benzophenone. 8. The method of any one of claims 1 to 7, wherein the electron donor is a Group IA or Group IIA metal. 8. The method of claim 7, wherein the electron donor is sodium metal. The method of claim 9, wherein the cyanopyridine is 2-cyanopyridine. The method of claim 9, wherein the cyanopyridine is 4-cyanopyridine. The method according to any one of claims 9, 10 and 11, wherein the initial reaction is carried out by initial reaction of a part of the total amount of α-aryl ketone or aldehyde to be reacted, followed by further reaction with 2- or 4-cyanopyridine. Charging ketone or aldehyde to the reaction mixture. 13. The process of claim 12, wherein the total amount of ketone or aldehyde to be reacted is filled before completing the filling of 2- or 4-cyanopyridine. Α-aryl including reacting α-aryl aldehydes or ketones with 2- or 4-cyanopyridine in an aromatic solvent in the presence of a metal or metal ion electron donor to recover the α-aryl carbonyl compound therefrom. Process for preparing pyridyl carbinol compound. The method of claim 14, wherein the reaction comprises reacting α-aryl ketones. The method of claim 14, wherein the reaction comprises reacting α-aryl aldehyde. The method of claim 15, wherein the reaction comprises reacting α, α-diaryl ketones. 18. The method of claim 17, wherein at least one aryl group in the diaryl ketone is a phenyl group. 19. The method of claim 18, wherein the diaryl ketone is benzophenone or fluorenone. The method of claim 19, wherein the diaryl ketone is benzophenone. 21. The method of any one of claims 14-20, wherein the electron donor is a Group IA or Group IIA metal. The method of claim 21, wherein the electron donor is sodium metal. The method of claim 21, wherein the cyanopyridine is 2-cyanopyridine. The method of claim 21, wherein the cyanopyridine is 4-cyanopyridine. The method of claim 23, wherein the reaction is carried out at a temperature of at least 80 ° C. 25. The process of claim 25 wherein the reaction is carried out in a refluxed aromatic solvent and the carbinol is recovered by hydrolysis of the corresponding carbinol salt. The method of claim 26, wherein the solvent is an aromatic hydrocarbon. The method of claim 27, wherein the solvent is xylene. 2- or α-aryl ketones or aldehydes in the presence of a metal or metal ion electron donor selected from the group consisting of Group IB, IIA, IIB, IIIA, IIIB, IVA, IVB, VB, VIB and VIIB metals and their ions A method of preparing an α-aryl pyridyl carbinol compound comprising reacting with 4-cyanopyridine and recovering the α-aryl pyridyl carbinol compound therefrom. The method of claim 29, wherein the electron donor is selected from the group consisting of Ca, Mg, Cu, Zn, Al, Sm ²⁺ , Sn, Ti ²⁺ , V, Cr, and Mn. Α from the corresponding α-aryl pyridyl carbinol compounds, including the hydrogenation of α-aryl pyridyl carbinol compounds in benzene or alkylbenzene solvents in the presence of a palladium catalyst to produce α-aryl piperidyl carbinol compounds A process for preparing α-aryl piperidyl carbinol compound from -aryl pyridyl carbinol compound. The method of claim 31, wherein the solvent is alkylbenzene. 33. The method of claim 32, wherein the solvent is toluene or xylene. 32. The method of claim 31 comprising hydrogenating the 4-pyridyl diphenyl carbinol to form 4-piperidyl diphenyl carbinol. 35. The method of claim 34, wherein the hydrogenation is carried out in the presence of a supported palladium catalyst. 36. The process of claim 35 wherein the hydrogenation is carried out in the presence of a palladium on carbon catalyst. The method of claim 36, wherein the solvent is alkylbenzene. 38. The method of claim 37, wherein the solvent is xylene or toluene. The method of claim 38, wherein the solvent is xylene.