JP3114153B2 - Method for producing α-pyridyl carbinols - Google Patents

Description

Description: BACKGROUND OF THE INVENTION The present invention relates generally to a method for producing an α-pyridyl carbinol compound. More specifically, the present invention relates to a method for producing α-2-pyridyl α-arylcarbinol or α-4-pyridyl α-arylcarbinol by reacting 2- or 4-cyanopyridine with an aromatic carbonyl compound.

Α-Pyridyl carbinol compounds having a characteristic Py—C—OH group (Py is a pyridyl group) have been studied extensively, for example, carbinoxamine, dioxylamine, azacyclonol and antihistamine terfenadine (Seld.
ane ^R), such as, are heavily used as intermediates in the preparation of antihistamines. To date, these α
-Several processes for the preparation of pyridyl carbinols are of substantial interest. For example, the "Emmert reaction" includes the reaction of a pyridine with a ketone in the presence of a magnesium or aluminum amalgam. The reaction product comprises a mixture of 2-pyridylcarbinol and 4-pyridylcarbinol with pinacol formed as a by-product. For example, B. Emmert and E. Asendorf, Ber., 72 , 1188 (193
9); B. Emmert and E. Pirot, Ber., 74 , 714 (1941); CHTilf
ord, RSShelton and MGVan Campen, Jr., J. Am. Chem. S
oc., 70 , 4001 (1948). In the “Hammick reaction”, α-pyridylcarbinol is produced by decarboxylation of picolinic acid in excess aldehyde or ketone. For example, P. Dyson and DL Hammick, J. Chem. Soc., 1724 (193
7) and K. Mislow, J. Am. Chem. Soc., 69 , 2559 (1947).

α-Pyridyl carbinols can also be produced by the action of pyridyl Grignard reagents on aldehydes or ketones, for example, JPWibaut and LGHeerin
ga, Recueil, 74 , 1003 (1995); N. Furukawa, H. Shibutani,
K.Matsumura, H.Fujihara and S.Oae, Tetrahedron Let
t., 27 , 3899 (1986); or can also be prepared by the action of aryl Grignard reagents on pyridyl aldehydes, ketones or esters, for example, AETschitschibabin and SWBenowolenskaja, Be.
r., 61 , 547 (1928); Y.Kasuya and K.Fujie, Yakugaku Zass
hi., 78 , 551 (1958) [Chem. Abst., 52, 17196i (195
8)]; and K. Nagarajan, PKShah and SJShenoy, Indi
See J. Chem., Sect. B , 24B , 112 (1985).

It has been reported that a diphenylketyl radical undergoes a substitution reaction with a cyano-substituted pyridinium ion to form an α-pyridinium-substituted carbinol. BMVi
ttimberga, F. Minisci and S. Morrocchi, J. Am. Chem. Soc.,
97 , 4397 (1975) report such an interaction in 1 M sulfuric acid where the diphenylketyl radical is formed photochemically. Later studies, P. McDevitt and BMVittim
In berga, J. Heterocyclic Chem., 27 , 1903 (1990),
Such an interaction has been described in which the diphenylketyl radical is formed via thermal homolysis of benzopinacol. The interaction between the thermally formed diphenylketyl radical and the cyano-substituted pyridine in a neutral medium is also described in subsequent studies.

Diaryl heterocyclic carbinols have been prepared by oxidation of the corresponding methyl pyridine with sodium hydroxide and O ₂ in DMSO. TJKress and LLMoore, J. Heteroc
See yclic Chem., 9 , 1161 (1972).

As the above and other documents demonstrate, the discovery of a very effective and economically attractive method of producing α-pyridyl carbinol has, to date and still remains of considerable interest. I have. However, the routes studied so far have a number of disadvantages. For example, the Emmert reaction produces a mixture of 2-pyridylcarbinol and 4-pyridylcarbinol, so that it is not possible to achieve highly selective production of either one. The Hammick reaction requires stringent conditions, especially when acting at the 4 position of the pyridine ring (eg, by isonicotinic acid)
This results in low yields. The difficulty in handling organometallic materials with the use of halopyridines as starting materials makes the use of Grignard reagents less economical or otherwise attractive. In addition, the low yields and significant by-product formation commonly encountered in the above studies with diphenylketyl radicals, and the cost of the corresponding methane starting material in the above studies by Kress et al. Make these routes relatively disadvantageous. .

Therefore, there is a need for a process for preparing α-pyridylcarbinol that can be carried out under mild conditions using relatively inexpensive starting materials. Further, particularly preferred routes are those that allow for high yields and minimal by-product formation.

SUMMARY OF THE INVENTION The present invention addresses the above and other needs and provides, as a preferred embodiment, a method for producing an α-2-pyridyl α-arylcarbinol or α-4-pyridyl α-arylcarbinol compound. This production method is carried out in an aromatic solvent in the presence of a metal or metal ion electron donor.
Heating and reacting a cyanopyridine or 4-cyanopyridine with an α-aryl ketone or an α-aryl aldehyde, the α-pyridyl α-aryl carbinol or α
Performed by recovering the 4-pyridyl α-arylcarbinol compound.

In another aspect of the present invention, a highly advantageous method of controlling the order of addition of reactants to obtain excellent product yields and minimize by-product formation has been discovered. Accordingly, another preferred embodiment provides a method for preparing an α-2-pyridyl α-aryl carbinol or α-4-pyridyl α-aryl carbinol compound. This preferred embodiment is characterized by first reacting the α-aryl aldehyde or ketone in the presence of a metal or metal ion electron donor. The first reaction product is then reacted with 2-cyanopyridine or 4-cyanopyridine before recovering the α-arylpyridylcarbinol. The first reaction (ie, the reaction of the electron donor with the aldehyde or ketone before adding the 2-cyanopyridine or 4-cyanopyridine) involves reacting some or all of the total amount with the aldehyde or ketone. Can be. For example, in one particular aspect, the present invention provides a method wherein the electron donor is first reacted with an aldehyde or ketone, and then 2-cyanopyridine or 4-cyanopyridine and an additional amount of the aldehyde or ketone. . The method of this embodiment has demonstrated excellent yields while providing good selectivity and can be performed using a variety of conditions.

Another preferred embodiment of the present invention is directed to Group IB, IIA
Tribe, IIB, IIIA, IIIB, IVA, IV
Converting an α-aryl aldehyde or ketone to a 2-cyanopyridine in the presence of a metal or metal ion electron donor selected from the group consisting of Group B, Group VB, Group VIB and Group VIB metals and their ions Or a method for producing an α-arylpyridylcarbinol compound, which comprises reacting the compound with 4-cyanopyridine. Next, the α-arylpyridyl carbinol compound is recovered.

Another preferred embodiment of the present invention comprises hydrogenating an α-arylpyridylcarbinol compound in a benzene or alkylbenzene solvent in the presence of a palladium catalyst to produce the corresponding α-arylpyridylcarbinol compound. Provided is a method for producing α-arylpiperidyl carbinol from an arylpyridyl carbinol compound.

The preferred embodiment of the present invention can be carried out under mild conditions using relatively inexpensive and readily available starting materials. A further preferred method of the present invention provides a very selective process for producing either 2-pyridylcarbinol or 4-pyridylcarbinol with good yield and little formation of by-products. Other objects and advantages of the present invention will become apparent from the following description and the appended claims.

DESCRIPTION OF THE PREFERRED EMBODIMENTS To assist in understanding the principles of the invention, certain embodiments will now be described, and the terminology will be used to describe the same. Nevertheless, no limitation of the invention is intended thereby, and modifications, further improvements and applications of the principles of the invention, which would normally occur to those skilled in the art to which the invention pertains, are considered. It will be understood.

As noted above, a preferred embodiment of the present invention involves the reaction of 2-cyanopyridine or 4-cyanopyridine with an α-aryl ketone or aldehyde. The cyanopyridine used in the preferred embodiment can no longer have other substituents attached to its pyridine ring, or it can be a cyanopyridine and an aldehyde or ketone (hereinafter, sometimes, (Also sometimes referred to as "carbonyl compounds"). Such non-interfering substituents can include, for example, alkyl groups such as methyl, ethyl, propyl, and the like, fused aryl (eg, naphthyl) groups, and the like.

As mentioned above, the cyanopyridine is converted to an α-aryl ketone or aldehyde, such as the formula: Ar-CO-R _{1 where} A
r is aryl and R ₁ is hydrogen (ie, an aldehyde); or an organic group such as a branched or non-molecular alkyl (preferably about C ₁ -C ₁₀ alkyl, eg, methyl, ethyl, propyl, butyl) etc.), alkenyl (e.g., including one or more ethylenically unsaturated bonds, preferably branched carbon chain group or unbranched carbon chain group of C ₁ -C _10), aryl, alkaryl (eg, C ₁ -C including ₁₀ alkylene group - alkylene - aryl is preferred), Ali Ke alkenyl aryl (e.g., including a C ₁ -C ₁₀ alkenyl group - represented by aryl is preferred) (i.e., ketone)] - alkenyl React with compound. Furthermore, within this formula, -CO-R ₁ can form an alicyclic group fused to Ar, for example, preferably a fused 4, 5 or 6 membered ring, which can be It can also be condensed to other aryl groups, such as occurs in preferred reactants, for example, fluorenone. Thus, the preferred α-arylcarbonyl reactants to date are, for example, benzophenone, Micher's ketone (4,4'-bis (dimethylamino) benzophenone), 4,4'-difluorobenzophenone, 4-methoxybenzophenone, fluorenone and charcon. Such ketones and aldehydes such as, for example, benzaldehyde. For example, like benzophenone,
does not contain an enolizable hydrogen, such as is formed as an α, α-diaryl ketone (ie, has no enolizable hydrogen at the carbon where R ₁ is directly attached to the carbonyl group “—CO—”) α-Aryl ketones are preferred. In this regard, the term "aryl" as used herein refers to an aromatic group having one or more unsaturated 6-membered carbon-containing rings that may include heteroatoms such as, for example, nitrogen, oxygen or sulfur, such as a pyridyl group. It is meant to include cyclic or polycyclic groups. As such, preferred aryl groups include, for example, phenyl groups and groups having two or more fused benzene rings, typically two to three fused benzene rings, such as naphthyl, phenanthrenyl, anthracenyl, and the like. Further, these aryl groups may be non-interfering substituents, such as alkylamino groups (eg, dimethylamino), amide groups (eg, —NHCOCH ₃ ), alkoxy groups (eg, methoxy and ethoxy), alkylsilyl groups (eg, trimethylsilyl), or other (For example, -COO-alkyl or -COO aryl) and halogen (for example, chlorine, bromine, fluorine and the like).

In this case, the term α-aryl ketone or aldehyde means that the aryl group is immediately adjacent to the carbonyl group,
It is meant to include bound aldehydes or ketones. Thus, the term α, α-diaryl ketone includes ketones having two such aryl groups immediately adjacent to a carbonyl group.

Reacting the α-aryl aldehyde or ketone with 2-cyanopyridine or 4-cyanopyridine, hydrolyzing the product (corresponding carbinol salt precursor),
formula: Wherein Ar is as defined above, Pr is a 2- or 4-pyridyl group, and X can be the same as R ₁ ,
Or, for example, where the α-aryl ketone reactant contains an enolizable hydrogen, may be a group resulting from the aldol condensation of two molecules of the α-arylcarbonyl compound reactant followed by dehydration. 2 or 4) -pyridyl α-aryl compounds are formed. When the R ₁ does not contain the enolizable hydrogen, examples X is the same as R _1, wherein: Ar-CO
The reactant represented by -R ₁ is 2-cyanopyridine or 4-cyanopyridine.
Reacts with cyanopyridine to form (after hydrolysis, for example, workup with water or the like) a formula: Wherein Ar, Py and R ₁ are as defined above, to form an α-2-pyridyl α-arylcarbinol or α-4-pyridyl α-arylcarbinol, respectively.

On the other hand, when R ₁ of the reactant α-aryl ketone compound has an enolizable hydrogen at the position α with respect to the carbonyl group, for example, R ₁ = —CH ₂ —R _{2 wherein} R ₂ is Hydrogen, alkyl, alkenyl, aryl, alkaryl,
X can be a group resulting from the aldol condensation and dehydration of two molecules of the reactant α-aryl ketone. That is, the reactants
2 molecules of Ar-CO-CH ₂ -R ₂ is subjected to and the subsequent dehydration aldol condensation, wherein: Can be produced. This α-aryl ketone compound is then
-Reacting with cyanopyridine or 4-cyanopyridine,
formula: Wherein Py, R ₂ and Ar are as defined above, respectively (after treatment) to form an α-2-pyridyl α-arylcarbinol or α-4-pyridyl α-arylcarbinol I do.

If the ketone reactant contains enolizable hydrogen, in some cases X = —CH ₂ —R ₂ (ie, X = R ₁ )
A mixture of carbinol products, in which X is a group resulting from an aldol condensation, is obtained, the degree of condensation of the reactants and the distribution of such products being determined, for example, by the specific reaction used in the reaction. It will be appreciated that it will depend on many factors, such as material, solvent, electron donor, temperature, and the like. In any case, regardless of whether R ₁ contains an enolizable hydrogen or not, the reaction of the α-aryl ketones or aldehydes according to the invention with 2-cyanopyridine or 4-cyanopyridine, after treatment by hydrolysis , Α- (2 or 4) -pyridyl α-aryl compounds.

As mentioned above, cyanopyridine reacts with an aldehyde or ketone in the presence of a metal or metal ion electron donor. Suitable such donors include metals or metal ions that have a sufficiently high oxidation potential to drive the reaction. For example, the metal or metal ion can be a Group IA (eg, an alkali metal such as sodium, lithium and potassium metals), a Group IB (eg,
Group IIA (eg, alkaline earth metals such as calcium and magnesium metals), Group IIB (eg, zinc metals), Group IIIA (eg, aluminum metals), Group IIIB (Eg, samarium (Sm ²⁺ )), I
Group VA (eg, tin metal), Group IVB (eg, titanium (Ti ²⁺ )), Group VB (eg, vanadium metal),
It is selected from Group VIB (eg, chromium metal) or Group VIIB (eg, manganese metal). Preferably, the electron donor has an oxidation potential of about 2.7 or higher. Group IA or I, such as sodium, lithium and calcium
Group IA metals, especially sodium, are the preferred electron donors in research to date.

This preferred method can be performed in a wide range of solvents, including those in which the reactants are soluble, for example, ranging from xylene to liquid ammonia. Toluene has been proven to be a suitable solvent to date, but other solvents such as, for example, diglyme, protic solvents containing acids, etc. are recognized by those skilled in the art as suitable solvents that have been highly appreciated. is there. As explained in the above-mentioned first embodiment, very advantageous processes can be carried out in aromatic solvents.

Similarly, the reaction can be carried out over a wide range of temperatures, for example, temperatures from about -80C to about 200C are suitable. A more preferred reaction performed to date is when heated in an aromatic solvent, preferably at a temperature of at least 80 ° C., and even more preferably in a refluxing aromatic solvent.
In a refluxing aromatic solvent such as benzene or alkyl benzene, for example, xylene (e.g., about 135-145
C.) and toluene (eg, at about 110.degree. C.). A promising reaction has been carried out in liquid ammonium at a temperature of about minus 33 ° C without heating.

Of course, if sodium or other similar metal is used as the electron donor, the reaction is preferably carried out under a dry inert atmosphere for safety reasons. For example, if appropriate, the reaction can be carried out under a nitrogen atmosphere.

The product can be isolated and recovered using conventional methods, for example, if necessary, the corresponding salt of carbinol (ie, M ⁺ -OCArPyX, where M ⁺ is formed by an electron donor A cation, such as a metal ion, where Ar, Py and X are as defined above) can be treated with water to form a carbinol product. Of course, hydrolysis is not required under conditions that result in the direct formation of carbinol, such as when acidic, protic or aqueous conditions are used in the reaction step. Once formed, the carbinol product can be filtered and washed with water and acetone and / or other suitable materials.

In another preferred embodiment, it has been found that yield is improved when controlling the order and timing of addition of reactants. Especially when the reactants are added to the solvent already at the reaction temperature, greatly improved yields are obtained when the cyanopyridine is added after the addition of the ketone or aldehyde and the electron donor. Therefore, it is most preferable from the studies so far that the electron donor and the ketone or aldehyde are blended in a solvent and reacted first, and then 2-cyanopyridine or 4-cyanopyridine is added. The first reaction without cyanopyridine preferably lasts for at least about 15 minutes, more preferably at least about 30 minutes, and most preferably about 30-60 minutes. Next, cyanopyridine is added and the reaction (eg, under reflux) is advantageously continued for at least about 2 hours, more preferably at least about 3 hours. The first reaction involves reacting some or all of the total amount of the aldehyde or ketone with the electron donor. For example, one method involves reacting all of the aldehyde or ketone first, followed by the addition of cyanopyridine (see, eg, Example 16). In another method, a portion of the aldehyde or ketone is first reacted, and then the cyanopyridine and an additional amount of the aldehyde or ketone are added (see, eg, Example 26). In this embodiment of the method, the cyanopyridine and the additional amount of aldehyde or ketone can be added together or alternately. This method of first reacting some or all of the aldehyde or ketone with the electron donor prior to adding the cyanopyridine comprises at least about 75
% Of the carbinol product has been obtained, and very preferred reactions have yields of 90% or more.

Other favorable conditions have also been found in the process of first reacting the aldehyde or ketone with the electron donor. Applicants' work has experienced reduced yields when first reacting the ketone with the electron donor and then very quickly adding the cyanopyridine. Therefore, in order to obtain the advantageous yields as described above, it is preferable to carry out the initial reaction and the addition of the cyanopyridine in such a way as to maximize the yield of the desired carbinol product. Can be assisted by adding the cyanopyridine all at once or slowly rather than quickly.

On the other hand, even if the cyanopyridine, ketone or aldehyde and the electron donor are all added to the solvent and the resulting mixture is brought to the reaction temperature, advantageously improved yields of about 70% or more can be obtained.

With respect to the proportion of reactants, 2-cyanopyridine or 4
-It is preferred to add the cyanopyridine to the ketone or aldehyde in a slight stoichiometric excess, for example preferably up to about a 10% excess. Preferably, the electron donor is added in a stoichiometric ratio of about 2: 1 to ketone or aldehyde or higher.

The α-arylpyridyl carbinol compound prepared as described above is usually hydrogenated using well-known techniques,
The corresponding α-arylpiperidyl carbinol compounds can be formed. However, yet another preferred feature of the present invention relates to such hydrogenation, wherein the hydrogenation comprises one or more benzene or alkyl benzenes (i.e., one or more attached to a benzene ring, such as a mono-, di- or trialkylbenzene). an alkyl having a group) in a solvent, preferably, for example, such as xylene or toluene, a lower alkylbenzene (e.g., even when the alkyl group (s) is about C ₁ -C ₄ alkyl) is carried out in a solvent . In this regard, the aromatic pyridine ring of these α-arylpyridyl carbinols, such as α-pyridyl diphenyl carbinol, essentially hydrogenates these aromatic hydrocarbon solvents successfully without hydrogenating them. be able to. Thus, advantageously, the solvent used for the hydrogenation can be the same as the solvent used for the production of carbinols as described above. Preferred is a supported palladium catalyst that selectively hydrogenates pyridyl carbinol, such as palladium on carbon support, or other similar catalysts.

Although the present invention has been described in detail in the above paragraphs, the above description should be regarded as examples in nature, not as limitations, but as preferred embodiments described only, all within the spirit of the invention It will be appreciated that changes and changes in the data should be protected. The following specific examples are provided to further describe and elaborate these embodiments, but these examples are intended to be illustrative and not limiting of the invention.

Example 1 4-Pyridyldiphenylcarbinol In a 500 ml RB flask, 4-cyanopyridine (10.4 g, 0.1
Mol) and benzophenone (18.2 g, 0.1 mol). To this was added xylene (250 ml) and sodium metal (5.0 g, 0.22 mol) cut into small pieces. The flask was gradually heated and refluxed for 3 hours under an inert atmosphere (eg, nitrogen) with magnetic stirring. The color of the reaction mixture changed from clear to dark blue to dark brown during this time. The reaction mixture was cooled to room temperature and water was carefully added (150 ml). The solid product was filtered and washed with water and acetone. Thus, 4-pyridyldiphenylcarbinol (18.3 g, 70% yield) having a mp, 238-240 ° C. was recovered.

Example 2 4-Pyridyldiphenylcarbinol A 500 ml three neck RB flask equipped with a mechanical stirrer was charged with 4-cyanopyridine (10.4 g, 0.1 mol) and benzophenone (18.2 g, 0.1 mol). Dry liquid ammonium was carefully added (250 ml) to dissolve the starting material. Next, sodium metal was gradually added little by little (5.
0 g, 0.22 mol). The reaction mixture was stirred for 1 hour and the ammonia was evaporated. Next, toluene (150ml) and water (150m
l) was added to the residue and the resulting mixture was stirred for 15 minutes.
The precipitated product was filtered and washed with water to give 4-pyridyldiphenylcarbinol.

Example 3 4-Pyridyldiphenylcarbinol In a 100 ml RB flask, 4-cyanopyridine (0.52 g, 0.0
05 mol) and benzophenone (0.91 g, 0.005 mol). To this was added THF (25 ml) to dissolve the starting material. Under an inert atmosphere (nitrogen), samarium diiodide (0.01 mol) in THF (100 ml) was added. Then the complete mixture was stirred at 30 ° C. for 3 hours. Treatment with aqueous NaHCO ₃ (sat.) Gave a solid which was filtered off. The filtrate was extracted with methylene chloride (100ml) and the methylene chloride was evaporated to give 4-pyridyldiphenylcarbinol.

Examples 4-8 Using a method similar to Examples 1 and 2 above, 4-pyridyldiphenylcarbinol was prepared by reacting 4-cyanopyridine with benzophenone using various solvents, conditions and electron donors. Tables 1 to 3 show the results of Examples 1 to 3 and the results of the tests. In Table 1,
"Ammonia" means liquid ammonia.

Example 9 Example 2 was repeated except that 2-cyanopyridine was used instead of 2-pyridyldiphenylcarbinol 4-cyanopyridine. 2-Pyridyldiphenylcarbinol was produced and recovered in 70% yield.

Example 10 Example 1 was repeated using 4-methoxybenzophenone instead of 4-pyridyl 4-methoxyphenylphenylcarbinol benzophenone. This gives 4
-Pyridyl 4-methoxyphenylphenyl carbinol was produced and recovered.

Example 11 4-Pyridyl α-methylstyrylphenylcarbinol Example 4 was repeated, except that acetophenone was used in place of benzophenone, to give 4-pyridyl α-methylstyrylphenylcarbinol as a product.

Examples 12-15 Various α-arylcarbonyls (ie, ketones and aldehydes) were converted to 4-
Reaction with cyanopyridine yielded an α-4-pyridyl α-arylcarbinol compound. Table 2 shows the results of Examples 9 to 11 and furthermore, this test. In Table 2, "ammonia" means liquid ammonia.

Example 16 4-Pyridyldiphenylcarbinol Benzophenone (54.6 g, 0.3 mol) was charged to a 1 liter round bottom three-necked flask equipped with a mechanical stirrer, a reflux condenser, and a dropping funnel. Next, xylene (3
00ml) and metallic sodium cut into small pieces (16.6g, 0.72
Mol) was added. The flask was slowly heated and refluxed under mechanical stirring for 30 minutes under an inert atmosphere (nitrogen). Xylene (200 ml) was then added to the dissolved 4-cyclopyridine (38.2 g, 0.37 mol) over 1 hour, after which the mixture was refluxed for another 3 hours. next,
The reaction mixture was cooled to room temperature and water (300 ml) was added meticulously. The solid is then filtered, washed with water and acetone, and the 4-pyridyldiphenylcarbinol (7
3.1 g, 93% yield).

Example 17 4-Pyridyldiphenylcarbinol 4-cyanopyridine in isopropanol (5.2 g, 0.0
5 mol) and benzophenone (9.1 g, 0.05 mol) in a solution of acetic acid (6.0 g, 0.1 mol) and magnesium metal (1.2 g,
0.05 mol). The resulting mixture is allowed to stand at room temperature for 4 hours.
Stirred for hours. The precipitated product was filtered and washed with acetone, which was found at analysis to be 4-pyridyldiphenylcarbinol.

Example 18 4-Pyridyldiphenylcarbinol The procedure of Example 17 was repeated except that the solvent was changed from i-propanol / acetic acid to toluene / aqueous ammonium chloride solution (2 equivalents of solid in water). GC of the organic phase indicated the formation of the product, 4-pyridyldiphenylcarbinol.

Example 19 4-Pyridyldiphenylcarbinol The method of Example 17 was repeated except that magnesium was changed to zinc. The recovered product was identified as 4-pyridyldiphenylcarbinol.

Example 20 4-Pyridyldiphenylcarbinol The method of Example 18 was repeated except that magnesium was changed to zinc and MeOH / aqueous ammonium chloride solution was used as a solvent. As a product, 4-pyridyldiphenylcarbinol was recovered.

Example 21 4-Pyridyldiphenylcarbinol Under nitrogen, 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) was treated with acetic anhydride. (200 ml) for 3 hours. The acetic anhydride layer was 4-
Pyridyl diphenyl carbinol product was indicated.

Example 22 4-Pyridyldiphenylcarbinol In this case, the method of Example 17 was repeated except that an aqueous acetic acid solution was used instead of acetic acid and aluminum was used instead of metal magnesium. The mixture was refluxed for 5 hours, cooled and neutralized with a base to give the product, 4-pyridyldiphenylcarbinol.

Example 23 4-Pyridyldiphenylcarbinol The reaction was carried out as in Example 22, except that the solvent was MeOH / acetic acid in water and the metal was tin. The mixture was refluxed for 4 hours, cooled and neutralized by base. GC analysis after extraction of the mixture with xylene showed the product, 4-pyridyldiphenylcarbinol, in the xylene layer.

Example 24 4-Pyridyldiphenylcarbinol 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) was stirred in MeOH (100 ml).
To this mixture was added an aqueous hydrochloric acid solution (3 equivalents) and the mixture was stirred at room temperature for 3 hours. Analysis of this MeOH solution showed 4-pyridyldiphenylcarbinol as product.

Example 25 The procedure of Example 24 was repeated except that manganese metal was used instead of 4-pyridyldiphenylcarbinol chromium. Again, GC analysis showed 4-pyridyldiphenylcarbinol product.

Example 26 4-Pyridyldiphenylcarbinol A sodium (16.6 g, 0.72 mol) metal and xylene (150 ml) were placed in a 1 liter round bottom three-necked flask equipped with a mechanical stirrer, a reflux condenser, and two dropping funnels. ) And charged. The mixture was refluxed and benzophenone (5
(4.6 g, 0.3 mol) was started. About benzophenone
When 1/4 to 1/3 was added over 15 to 30 minutes, 4-cyanopyridine (38.2 g, 0.37 mol) in xylene (200 ml)
Was started at a rate such that when the addition of benzophenone was complete, about 1/2 of the cyanopyridine solution had been added. The remaining cyanopyridine was added over a further 30 minutes. After treatment with water (300 ml), 4-pyridyldiphenylcarbinol was obtained in about 95% yield.

Example 27 Diphenyl 4-piperidylcarbinol (azacyclonol) 4-pyridyldiphenylcarbinol (46.5 g, 0.18 mol), platinum oxide (2.0 g), and glacial acetic acid (325 ml) in a 1.4-litre hydrogenated carbon dioxide vessel And was charged. The bomb was sealed, pressurized to 200 psi with hydrogen, and heated to 75 ° C. with shaking for 3 hours. The cylinder was then cooled, the contents were filtered and evaporated to remove acetic acid.
After evaporation, the material is washed with aqueous sodium hydroxide (50% Na
(OH 120 g and water 330 ml). Thereafter, the solid material is filtered, washed with cold water and, after drying, diphenyl 4-pyridylicarbinol (azacyclonol) (4
3.2 g, 91% yield). Hydrogen chloride was added to an ethanol solution of azacyclonol to obtain azacyclonol hydrochloride.

Example 28 Diphenyl 4-piperidyl carbinol In a 1.4 liter hydrogenated schaegbon, diphenyl 4-pyridyl carbinol (43.00 g, 0.165 mol) was added
8.00 g (4 g dry weight) of 5% Pd with% H ₂ O wet carbon carrier and 350 ml of xylene were charged. Seal the cylinder, 900psi
Pressurized with H ₂ and heated to 170 ° C. with shaking. After 17 hours, the cylinder was allowed to cool when the pressure was 1075 psi (at 170 ° C.). Pour out the contents, 70
The mixture was heated to ° C. and carefully suction-filtered to remove the catalyst. Analysis of the filtrate and washings at this time showed 6.9% azacyclonol and 0.05% diphenyl-4-pyridylcarbinol. The filtrate is put on a rotary evaporator at a constant weight (4
2.65 g). The sticky crude azacyclonolol was removed and recrystallized from 200 ml heptane and 165 ml xylene. After quenching, filtration and oven drying (2 hours, 100 ° C., 15 mm), 37.84 g of an azacyclonol having a melting point of 163-166 ° C. was obtained in a yield of 86%.

────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Skriven, Eric F. V. Lazy Lane, Indiana 46142, Greenwood, USA 515 (72) Inventor Go, Gerald El. 46142, Indiana United States, Greenwood, West・ Fairview Road 4021 (56) References JP-A-56-120668 (JP, A) Chemical Abstracts, Abstract No. 115: 71411p (1991) (58) Fields investigated (Int. Cl. ⁷ , DB name) ) C07D 211/22 C07D 213/00-213/38 CA (STN) REGISTRY (STN)

Claims (39)

(57) [Claims] (1) first reacting an α-aryl aldehyde or ketone in the presence of a metal or metal ion electron donor; and then reacting the first reaction product with 2-cyanopyridine or 4
-A method for producing an α-arylpyridylcarbinol compound, comprising reacting the compound with cyanopyridine and recovering the α-arylpyridylcarbinol compound therefrom. 2. The method of claim 1 wherein said reaction comprises the reaction of an α-aryl ketone. 3. The method of claim 1 wherein said reaction comprises the reaction of an α-aryl aldehyde. 4. The method of claim 2 wherein said reaction comprises the reaction of α, α-dialyl ketone. 5. The method according to claim 4, wherein at least one aryl group of said diaryl ketone is a phenyl group. 6. The method according to claim 4, wherein said diaryl ketone is benzophenone or fluorenone. 7. The method according to claim 6, wherein said diaryl ketone is benzophenone. 8. The method according to claim 1, wherein the electron donor is a Group IA or Group IIA metal. 9. The method according to claim 7, wherein said electron donor is sodium metal. 10. The method according to claim 9, wherein said cyanopyridine is 2-cyanopyridine. 11. The method according to claim 9, wherein said cyanopyridine is 4-cyanopyridine. 12. An initial reaction in which a portion of the total amount of α-aryl ketone or aldehyde to be reacted is first reacted, followed by the addition of 2-cyanopyridine or 4-cyanopyridine with an additional amount of ketone or aldehyde. A method according to any of claims 9 to 11, comprising feeding to the reaction mixture. 13. The total amount of the α-aryl ketone or aldehyde to be reacted before the supply of the 2-cyanopyridine or 4-cyanopyridine ends.
The described method. 14. An α-aryl aldehyde or ketone is heated and reacted with 2-cyanopyridine or 4-cyanopyridine in an aromatic solvent in the presence of a metal or metal ion electron donor, and then reacted with α-aryl aldehyde or ketone. A method for producing an α-arylpyridylcarbinol compound, comprising recovering an arylcarbonyl compound. 15. The method of claim 14, wherein said reaction comprises the reaction of an α-aryl ketone. 16. The method of claim 14, wherein said reaction comprises a reaction of an α-aryl aldehyde. 17. The method of claim 15, wherein said reaction comprises the reaction of α, α-dialyl ketone. 18. The method according to claim 17, wherein at least one aryl group of said diaryl ketone is a phenyl group. 19. The method according to claim 18, wherein said diaryl ketone is benzophenone or fluorenone. 20. The method according to claim 19, wherein said diaryl ketone is benzophenone. 21. The method according to claim 14, wherein the electron donor is a Group IA or Group IIA metal. 22. The method according to claim 21, wherein said electron donor is sodium metal. 23. The method according to claim 21, wherein said cyanopyridine is 2-cyanopyridine. 24. The method according to claim 21, wherein said cyanopyridine is 4-cyanopyridine. 25. The method according to claim 23, wherein the reaction is carried out at a temperature of at least 80.degree. 26. The method of claim 25, wherein the reaction is carried out in a refluxing aromatic solvent, and wherein said recovering comprises hydrolyzing a corresponding carbinol salt to produce carbinol. 27. The method according to claim 26, wherein the solvent is an aromatic hydrocarbon. 28. The method according to claim 27, wherein the solvent is xylene. 29. Groups IB, IIA, IIB, IIIA
Tribe, IIIB, IVA, IVB, VB, VIB
An α-aryl aldehyde or ketone in the presence of a metal or metal ion electron donor selected from the group consisting of Group VI and Group VIB metals and their ions;
A method for producing an α-arylpyridylcarbinol compound, comprising reacting a cyanopyridine or 4-cyanopyridine and recovering the α-arylpyridylcarbinol compound therefrom. 30. An electron donor comprising Ca, Mg, Cu, Zn, Al, S
^30. The method of claim 29, wherein the method is selected from the group consisting of m2 ⁺ , Sn, Ti2 ⁺ , V, Cr, and Mn. 31. The method according to claim 1, further comprising hydrogenating the α-arylpyridyl carbinol compound in a benzene or alkylbenzene solvent in the presence of a palladium catalyst to produce an α-aryl piperidyl carbinol. Method. 32. The solvent according to claim 31, wherein the solvent is an alkylbenzene.
The described method. 33. The method according to claim 32, wherein the solvent is toluene or xylene. 34. The method of claim 31, comprising hydrogenating the 4-pyridyldiphenylcarbinol compound to form 4-piperidyldiphenylcarbinol. 35. The method according to claim 34, wherein the hydrogenation is carried out in the presence of a supported palladium catalyst. 36. The method according to claim 35, wherein the hydrogenation is carried out in the presence of a palladium on carbon catalyst. 37. The solvent according to claim 36, wherein the solvent is an alkylbenzene.
The described method. 38. The method according to claim 37, wherein the solvent is toluene or xylene. 39. The method according to claim 38, wherein the solvent is xylene.