HK1032397B - Process for preparing 2-phenyl-3-aminopyridine, substituted phenyl derivatives thereof, and salts thereof - Google Patents

Description

Process for preparing 2-phenyl-3-aminopyridines, substituted phenyl derivatives thereof and salts thereof

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The present invention relates to a process for the preparation of 2-phenyl-3-aminopyridines, substituted phenyl derivatives thereof and salts thereof. 2-phenyl-3-aminopyridines, substituted phenyl derivatives thereof, are useful in the preparation of compounds useful as substance P antagonists.

Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides which exert a rapid stimulatory effect on smooth muscle tissue. Substance P is a pharmaceutically acceptable active neuropeptide produced in mammals and has the characteristic amino acid sequence described in u.s4,680,283. Substance P and other tachykinins have been well reported in the art as being involved in the pathophysiology of a number of diseases. For example, substance P has been shown to be involved in the transmission of pain or migraine, and central nervous system disorders such as anxiety and schizophrenia, respiratory and inflammatory disorders such as asthma and rheumatoid diseases, and gastrointestinal disorders such as ulcerative conjunctivitis, irritable bowel syndrome and Crohn's disease. Tachykinin antagonists have been reported to be useful in the treatment of these diseases and in the treatment of cardiovascular diseases, allergic diseases, immunomodulation, vasodilation, bronchospasm, reflex or neuronal control of the gut, senile dementia of alzheimer's type, emesis, sunburn, helicobacter pylori infection.

Various substances P can be prepared from 2-phenyl-3-aminopyridine. For example, U.S. patent 5,323,929 discloses substance P antagonists of the formula

Wherein R is³Is a substituted or unsubstituted aryl, heteroaryl or cycloalkyl group. These antagonists may be prepared by reduction of 2-phenyl-3-aminopyridine followed by the appropriate compound of formula R³CHO aldehyde is reduced and aminated to produce 2-phenyl-3-aminopiperidine. Alternatively, these substance P antagonists may be prepared by reacting 2-phenyl-3-aminopyridine with a compound of formula R³CHO or R³CH²X (wherein X is a leaving group) to give a pyridine analog of a substance P antagonist. The pyridine analog is then reduced to give the final product.

Additional substance P antagonists which may be prepared from 2-phenyl-3-aminopyridine are disclosed in U.S. patent 5,773,450 and WO 97/08114 and PCT/IB 97/01466. A process for preparing substance P antagonists using 2-phenyl-3-aminopyridine is also disclosed in U.S. patent 5,232,929.

However, the conventional methods for preparing 2-phenyl-3-aminopyridine described by Miller and Farrell (tetrahedron letter, 1998, 39, 6441-.

The present invention relates to a process for the preparation of 2-phenyl-3-aminopyridine, substituted phenyl derivatives thereof and salts thereof. In one aspect, the invention comprises reacting a compound of formula III or VIII with IV in an inert reaction solvent in the presence of a base and a palladium catalyst,

or

To obtain the compound of the formula V or X,

or

Wherein:

x is Cl, Br or I;

z is H, (C)₁-C₄) Alkyl, methoxy, trifluoromethoxy, F or Cl;

ar is optionally substituted with 1-3R⁵Radical substituted (C)₆-C₁₀) An aryl group;

R¹is (C)₁-C₆) Straight or branched alkyl, (C)₃-C₇) Cycloalkyl, or (C)₆-C₁₀) Aryl, said alkyl, cycloalkyl and aryl being optionally substituted with 1-3R⁵Substituted by groups;

R³and R⁴Independently selected from H, (C)₁-C₆) Alkyl, wherein when R³And R⁴Is (C)₁-C₆) When alkyl groups are present, they are fused together to form a ring structure; and

each R⁵Independently selected from halogen, cyano, nitro, (C)₁-C₆) Halogen-substituted alkyl, (C)₁-C₆) Alkoxy group, (C)₆-C₁₀) Aryloxy group, (C)₁-C₆) Halogen-substituted alkoxy, (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, (C)₂-C₆) Alkynyl, (C)₁-C₆) Alkyl sulfur, (C)₁-C₆) Sulfinyl group, (C)₁-C₆) Alkyl sulfonyl radicalBase, (C)₁-C₆) alkyl-OC (O) -, (C)₁-C₆) alkyl-OC (O) - (C)₁-C₆) Alkyl, (C)₁-C₆) alkyl-C (O) O-, (C)₁-C₆) alkyl-C (O) - (C)₁-C₆) alkyl-O-, (C)₁-C₆) alkyl-C (O) -, (C)₁-C₆) alkyl-C (O) - (C)₁-C₆) Alkyl-, (C)₆-C₁₀) Aryl-, (C)₆-C₁₀) Aryl radical- (C)₁-C₆) Alkyl-, and (C)₃-C₇) Cycloalkyl, wherein one or two carbon atoms of said cycloalkyl may be optionally substituted by nitrogen, oxygen or sulfur.

In a preferred embodiment, the compounds of the formulae III or VIII are prepared by reacting a compound of the formula I with a compound of the formula II or VII in an inert reaction solvent,

or ArCHO

VII

Wherein

Y is Cl, Br, I or-C (O) R²；

R²Is (C)₁-C₆) Straight or branched alkyl, (C)₃-C₇) Cycloalkyl, or (C)₆-C₁₀) Aryl, said alkyl, cycloalkyl and aryl being optionally substituted with 1-3R⁵Substituted by groups; wherein said reaction of compound III or VIII with compound IV is carried out substantially simultaneously with or subsequent to said reaction of compound I with compound II or VII.

Deprotection of a compound of formula V in aqueous acid preferably affords a salt of compound X.

In a preferred embodiment of the present inventionIn embodiments, Z is hydrogen, R¹And R²Are the same and are independently selected from (C)₁-C₆) Straight or branched chain alkyl and phenyl, wherein said R¹And R²Optionally substituted by 1-3R⁵Radical substitution, R³And R⁴Is hydrogen and each R⁵Independently selected from (C)₁-C₆) Straight or branched chain alkyl, phenyl, benzyl, trifluoromethyl, (C)₁-C₆) Alkoxy and trifluoromethoxy. In one aspect of the above method, the present invention comprises the steps of:

(a) reacting a compound of formula I with a compound of formula II in an inert reaction solvent in the presence of a base,

to obtain the compound shown in the formula III,

(b) reacting a compound of formula III with a compound of formula IV in an inert reaction solvent in the presence of a base and a palladium catalyst to obtain a compound of formula V

(c) Deprotecting the compound of formula V in aqueous acid to give a salt of compound X,

x, Y, Z, R therein¹、R²、R³、R⁴And R⁵The definition is the same as above.

In another aspect of the above method, the present invention comprises the steps of:

(a) reacting a compound of formula I with a compound of formula VII in a reaction inert solvent to obtain a compound of formula VIII,

and

(b) substantially simultaneously, or following step (a), reacting a compound of formula VIII with IV in the presence of a base and a palladium catalyst in a reaction inert solvent to give a compound of formula X

Wherein step (a) is further carried out in the presence of a base while steps (a) and (b) are carried out substantially simultaneously,

and wherein Ar, X, Z, R³、R⁴And R⁵The definition is the same as above.

In a preferred embodiment of the invention Z is H, R³And R⁴Is hydrogen, each R⁵Independently selected from (C)₁-C₆) Straight or branched chain alkyl, phenyl, benzyl, trifluoromethyl, (C)₁-C₆) Alkoxy and trifluoromethoxy, X is chloro and Ar is phenyl. In a preferred embodiment of the invention, X is Cl, Z is H, and, where relevant, Y is Cl.

In a preferred embodiment, Ar is optionally substituted with 1-3R⁵Phenyl or naphthalene substituted with a group.

In another embodiment, R¹And R²Identical and preferably both are methyl.

In another embodiment, R¹Is a firstRadical and R²Is a tert-butyl group.

In another embodiment, R¹And R²Independently selected from (C)₁-C₆) Straight or branched chain alkyl and phenyl.

In a preferred embodiment, R³And R⁴Is hydrogen.

In another preferred embodiment, each R is⁵Independently selected from (C)₁-C₆) Straight or branched chain alkyl, phenyl, benzyl, trifluoromethyl, (C)₁-C₆) Alkoxy, F, Cl, and trifluoromethoxy.

In a preferred embodiment, Z is H; r¹And R²Same, independently selected from (C)₁-C₆) Straight or branched chain alkyl, phenyl, and optionally substituted by 1-3R⁵Substituted by groups; r³And R⁴Is hydrogen; each R⁵Independently selected from (C)₁-C₆) Straight or branched chain alkyl, phenyl, benzyl, trifluoromethyl, (C)₁-C₆) Alkoxy and trifluoromethoxy.

The term "alkyl" as used herein, unless otherwise specified, refers to a saturated monovalent hydrocarbon group, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

The term "alkenyl" as used herein, unless otherwise specified, refers to a monovalent hydrocarbon group having at least one carbon-carbon double bond, including, but not limited to, vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1, 3-butadienyl, and isomers of these alkenyl groups including E and Z.

The term "alkynyl", as used herein, unless otherwise specified, refers to a monovalent hydrocarbon radical having at least one carbon-carbon triple bond, including, but not limited to, ethynyl, 2-propynyl, and 3-butynyl.

The term "aryl" as used herein, unless otherwise specified, refers to an aromatic group, including, but not limited to, phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl.

The term "alkoxy" as used herein, unless otherwise specified, refers to-O-alkyl, including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

The term "halogen" as used herein, unless otherwise indicated, includes fluorine, chlorine, bromine and iodine.

The term "halo-substituted alkyl" as used herein, unless otherwise specified, refers to alkyl substituted with one or more halogens, including, but not limited to, chloromethyl, difluoromethyl, trifluoromethyl, and 2, 2, 2-trichloroethyl.

The term "halo-substituted alkoxy" as used herein, unless otherwise specified, refers to alkoxy substituted with one or more halogens, including, but not limited to, chloromethoxy, difluoromethoxy, trifluoromethoxy, and 2, 2, 2-trichloroethoxy.

The term "alkylthio" as used herein, unless otherwise specified, refers to-S-alkyl, including, but not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, and tert-butylthio.

The term "alkylsulfinyl", as used herein, unless otherwise indicated, refers to-SO-alkyl groups, including, but not limited to, methylsulfinyl, ethylsulfinyl, isopropylsulfinyl.

The term "alkylsulfonyl", as used herein, unless otherwise indicated, refers to-SO₂Alkyl groups including, but not limited to, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl.

All publications, patents, and patent applications cited in this application are herein incorporated by reference in their entirety.

The process of the present invention can produce 2-phenyl-3-aminopyridine, substituted derivatives thereof in higher yields than conventional methods of production, and the process is not as sensitive to air.

The preparation of the 2-phenyl-3-aminopyridine of the present invention is illustrated by the following reaction scheme.

Scheme 1

Scheme 2

Scheme 3

Step 1 of scheme 1 involves protecting the compound. Specifically, the compound I and an acetylating agent of the formula II react in the presence of alkali and an inert reaction solvent at a temperature of-20 ℃ to 60 ℃ for 1 to 48 hours to obtain an acetylated aniline compound of the formula III. Suitable bases include, but are not limited to, triethylamine, diisopropylethylamine, 2, 6-lutidine, N, N, N ', N' -tetramethylethylenediamine, potassium carbonate, sodium hydroxide, and potassium hydroxide. Suitable inert reaction solvents include, but are not limited to, methylene chloride, ethylene dichloride, and toluene. For example, in one embodiment, step 1 of scheme 1 is performed in the presence of triethylamine and dichloromethane at 0 ℃ to room temperature for about 14 hours.

Step 2 of scheme 1 comprises formula IIISuzuki coupling of the compound and the compound of formula IV (Chem. Rev.1995, 95: 2457 to Miuaura et al) gives a biaryl group of formula V. Step 2 reacting in an inert reaction solvent in the presence of an alkali and a palladium catalyst at a temperature of between room temperature and 125 ℃ for 30 minutes to 48 hours to obtain the compound of formula V. Suitable bases include, but are not limited to, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydrogen hydride, sodium hydroxide, potassium fluoride, and barium hydroxide. Suitable palladium catalysts include, but are not limited to, tetrakis (triphenylphosphine) palladium (O), dichlorobis (triphenylphosphine) palladium (II), palladium (II) acetate, allylpalladium chloride dimer, and tris (dibenzylideneacetone) dipalladium (O). The reaction medium also optionally includes tris (C)₆-C₁₀) Aryl phosphine or tri (C)₁-C₆) Alkyl phosphines, examples of which include, but are not limited to, triphenylphosphine, tri-t-butyl phosphine, and tri-o-tolyl phosphine. Suitable inert reaction solvents include, but are not limited to, tetrahydrofuran, toluene, dioxane, dimethoxyethane, ethanol, dimethylformamide, and dimethylacetamide, optionally containing water. For example, in one embodiment, step 2 of scheme 1 reacts a compound of formula III with phenyl boronic acid in the presence of sodium carbonate and a palladium catalyst tetrakis (triphenylphosphine) palladium (O) in a mixture of toluene, ethanol and water at a temperature of about 100 ℃ for about 8 hours.

Scheme 1 step 3 involves deprotecting compound V. Specifically, the acetylated aniline of compound V is reacted with an aqueous acid at room temperature to reflux temperature for 1 to 48 hours to obtain a salt of 2-phenyl-3-aminopyridine (compound VI). Suitable acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, and trifluoroacetic acid. For example, in one embodiment, step 3 is carried out in hydrochloric acid at reflux temperature for about 14 hours to provide the hydrochloride salt of 2-phenyl-3-aminopyridine.

Step 1 of scheme 2 involves the formation of the imine. The aniline compound of formula I is treated with the aldehyde compound of formula VII in a reaction inert solvent with a dehydrating agent or device at room temperature to reflux temperature for 4-48 hours to give the compound of formula VIII. Suitable reaction inert solvents include, but are not limited to, toluene, xylene, tetrahydrofuran, heptane, dioxane, and dimethoxyethane. Suitable dehydrating agents include, but are not limited to, magnesium sulfate, titanium tetrachloride, and sodium sulfate; alternatively, a Dean-Stark apparatus may be used. For example, in one embodiment, a compound of formula I is reacted with a compound of formula VII in toluene using a Dean-Stark apparatus for about 18 hours to provide a compound of formula VIII.

Step 2 of scheme 2 involves the coupling of a compound of formula VIII with a compound of formula IV to give a 2-phenyl-3-aminopyridine (formula IX). Specifically, the compound of formula VIII is treated with the compound of formula IV in a reaction inert solvent optionally containing water, in the presence of a base and a palladium catalyst at a temperature of from room temperature to 125 ℃ for about 10 minutes to 24 hours to give 2-phenyl-3-aminopyridine (formula IX). Suitable bases include, but are not limited to, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydrogen hydride, sodium hydroxide, and barium hydroxide. Suitable palladium catalysts include, but are not limited to, tetrakis (triphenylphosphine) palladium (O), dichlorobis (triphenylphosphine) palladium (II), palladium (II) acetate, allylpalladium chloride dimer, and tris (dibenzylideneacetone) dipalladium (O). The reaction medium also optionally includes tris (C)₆-C₁₀) Aryl phosphine or tri (C)₁-C₆) Alkyl phosphines, examples of which include, but are not limited to, triphenylphosphine, tri-tert-butyl phosphine, and tri-o-oxa-tolyl phosphine. Suitable reaction inert solvents include, but are not limited to, tetrahydrofuran, toluene, dioxane, dimethoxyethane, ethanol, dimethylformamide, and dimethylacetamide. For example, in one embodiment, a compound of formula III is reacted with phenylboronic acid in the presence of sodium carbonate and tetrakis (triphenylphosphine) palladium (O) in a mixture of toluene and water at a temperature of about 100 ℃ for about 30 minutes to provide 2-phenyl-3-aminopyridine.

Scheme 3 relates to an embodiment of the present invention that is similar to the process of scheme 2, but which proceeds with the in situ protection of the aniline compound of formula I, i.e., steps 1 and 2 as in scheme 2, the formation of the protected compound and the coupling step with the phenyl compound are performed substantially simultaneously. Specifically, in scheme 3, the compound of formula I is treated with an aldehyde of formula VII and a compound of formula IV in a reaction inert solvent in the presence of a base and a palladium catalyst at a temperature of room temperature to 125 ℃ for about 10 minutes to 48 hours to provide 2-phenyl-3-aminopyridine (formula IX). Suitable bases include, but are not limited to, sodium hydroxide, carbonSodium, sodium bicarbonate, potassium carbonate, potassium hydrogen hydride, and barium hydroxide. Suitable palladium catalysts include, but are not limited to, tetrakis (triphenylphosphine) palladium (O), dichlorobis (triphenylphosphine) palladium (II), palladium (II) acetate, allylpalladium chloride dimer, and tris (dibenzylideneacetone) dipalladium (O). The reaction medium also optionally includes tris (C)₆-C₁₀) Aryl phosphine or tri (C)₁-C₆) Alkyl phosphines, examples of which include, but are not limited to, triphenylphosphine, tri-t-butyl phosphine, and tri-o-tolyl phosphine. Suitable reaction inert solvents include, but are not limited to, toluene, tetrahydrofuran, dioxane, dimethoxyethane, ethanol, dimethylformamide, and dimethylacetamide. The reaction medium may also contain water. For example, in one embodiment, a compound of formula I is reacted with a compound of formula VII and phenylboronic acid in the presence of sodium hydroxide and palladium acetate and triphenylphosphine (II) in a mixture of toluene and water at a temperature of about 100 ℃ for about 18 hours to provide 2-phenyl-3-aminopyridine.

Derivatives of 2-phenyl-3-aminopyridine in which the phenyl group is substituted with Z as defined above (and Z is not hydrogen) can be reacted in the reaction scheme shown with the corresponding compounds of the formula

In place of PhB (OR)³)(OR⁴) And then the preparation.

2-phenyl-3-aminopyridine can be converted to substance P antagonists by the methods described in U.S. Pat. Nos. 5,323,929, 5,232,929, 5,773,450 and WO 97/08114 and PCT/IB 97/01466.

The substance P antagonists thus prepared may form a variety of different salts with a variety of inorganic and organic acids. While these salts must be pharmaceutically acceptable for mammalian administration, it is often desirable to actually initially isolate the basic compound from the reaction mixture as a pharmaceutically unacceptable salt, which is then converted to the free basic compound by treatment with an alkaline agent, and the free base is then converted to a pharmaceutically acceptable acid addition salt. Acid addition salts are readily prepared by treating the basic compound with approximately equal amounts of the selected inorganic or organic acid in an aqueous solvent or a suitable organic solvent such as methanol or ethanol. The desired solid salt was obtained by evaporation of the solvent. The acids used to prepare the pharmaceutically acceptable acid addition salts of the base compounds are those which form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or phosphoric acid, acetate, lactate, citrate or citric acid, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts (i.e., 1' -methylene-bis- (2-hydroxy-3-naphthoate)).

Substance P antagonists formed using 2-phenyl-3-aminopyridine as an intermediate have significant substance P receptor binding activity and are therefore of great value in the treatment of a variety of clinical conditions in which excessive substance P activity occurs. These diseases include, but are not limited to: cardiovascular diseases, allergic diseases, angiogenic diseases, gastrointestinal diseases, central nervous diseases, inflammation, emesis, urinary incontinence, pain, migraine, severe anxiety disorders, stress disorders, anxiety, severe anxiety depression, sunburn, sexual dysfunction, bipolar disorder, substance abuse disorders, schizophrenia, movement disorders, cognitive disorders, and helicobacter pylori-induced diseases, disorders and side effects in mammals, particularly humans. For the treatment of emesis, 5HT can be combined₃Receptor antagonists are used together.

The substance P antagonists and pharmaceutically acceptable salts thereof may be administered to the mammal orally, parenterally (i.e., intravenously, intramuscularly, or subcutaneously) or topically. It is generally most desirable that these compounds be administered in a dosage of about 0.3mg to about 750mg per day, but will vary depending upon the weight and condition of the patient being treated and the particular route of administration chosen. However, a dosage of about 0.06mg to about 6mg per kg body weight per day is most preferred.

The substance P antagonist may be administered by any of the above either alone or in combination with other pharmaceutically acceptable carriers or diluents, either in single or multiple doses. More specifically, the substance P antagonists may be conveniently administered in a variety of dosage forms including tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, ointments, suppositories, gels, jellies, pastes, lotions, ointments, aqueous suspensions, injections, elixirs, syrups, and the like. Suitable pharmaceutical carriers include, for example, solid diluents or fillers, sterile aqueous solutions, and various anhydrous organic solvents. Oral pharmaceutical compositions may be suitably sweetened and/or flavored. Typically, the P-substance antagonist is present in such dosage forms at a concentration of about 5.0% to about 70% by weight.

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine may be employed together with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are also frequently used for tablets. Similar solid compositions may also be used as fillers in gelatin capsules. Preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and if desired emulsifying and/or suspending agents, as well as diluents such as water, ethanol, propylene glycol, glycerin.

For parenteral administration, solutions of the substance P antagonist in sesame or peanut oil or in aqueous propylene glycol solution may be used. These aqueous solutions should be suitably buffered (preferably to a pH greater than 8) if necessary, and first rendered isotonic by the liquid diluent. These aqueous solutions are suitable for intravenous administration. The oil solution is suitable for intra-articular, intramuscular and subcutaneous injection administration. The preparation of all these solutions under sterile conditions can be readily carried out by standard methods known to the person skilled in the art.

The invention is illustrated by the following examples, but is not limited to the details thereof.

Example 1

N- (2-chloro-pyridin-3-yl) -acetamide

To a solution of 2-chloro-3-aminopyridine (51.4g, 400mmol) in dichloromethane (800ml) was added triethylamine (31.0ml, 440mmol) followed by acetyl chloride (62.0ml, 440mmol) at 0 ℃. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into water (800ml) and the layers were separated. Darco for organic layer^TM-G-60 (activated charcoal) treatment, heating to reflux, in Celite^TM(diatomaceous earth manufactured by Celite corp., Santa Barbara, CA) and concentrated to an oil. The oil crystallized in diisopropyl ether and the solid was filtered to give 42.4g (62% yield) of N- (2-chloro-pyridin-3-yl) -acetamide.

M.p.＝81-83℃.¹H NMR(400MHz，CDCl₃)δ2.23(s，3)，7.21(dd，1，J＝8.1，4.7)，7.67(bs，1)，8.06(dd，1，J＝4.7，1.3)，8.66(d，1，J＝7.9).¹³C NMR(100MHz，CDCl₃)δ24.93，123.34，129.06，131.89，143.81，144.08，168.79.

Example 2

N- (2-phenyl-pyridin-3-yl) -acetamide hydrochloride

To a mixture of N- (2-chloro-pyridin-3-yl) -acetamide (50.0g, 29.3mmol), phenylboronic acid (39.3g, 32.2mmol), sodium carbonate (49.7g, 46.9mmol) in toluene (400ml), ethanol (100ml) and water (200ml) was added tetrakis (triphenylphosphine) palladium (O) (1.02g, 0.883 mmol). The reaction mixture was heated to reflux for 8 hours, cooled to room temperature and the layers separated. The aqueous layer was extracted with ethyl acetate (500ml) and the organic layers were combined and concentrated to a yellow solid. The crude solid was dissolved in methanol (500ml) and concentrated hydrochloric acid (10ml) was added. The solution was concentrated to low volume and tetrahydrofuran (500ml) was added. The solid was triturated, filtered and dried to give N- (2-phenyl-pyridin-3-yl) -acetamide hydrochloride (62.5g, 86%).

M.p.＝262-263℃.¹H NMR(300MHz，DMSO_d6)δ2.52(s，3)，6.30(bs，2)，7.64-7.72(m，6)，7.78(dd，1，J＝1.2，8.6)，8.06(dd，1，J＝1.2，5.2)

Example 3

2-phenyl-3-aminopyridine hydrochloride

To a solution of N- (2-phenyl-pyridin-3-yl) -acetamide hydrochloride (61.9g, 24.9mmol) in tetrahydrofuran (100ml) was added concentrated hydrochloric acid (100 ml). The reaction mixture was heated to reflux overnight and concentrated to low volume. 2000ml tetrahydrofuran was added and the volume was reduced to about 1000ml when the product started to precipitate. The mixture was cooled to 0 ℃ and granulated for 2 hours. The solid was filtered to give 2-phenyl-3-aminopyridine hydrochloride (46.2g, 90%).

M.p.＝226-227℃.¹H NMR(300MHz，CDCl₃) δ 6.35(bs, 3), 7.61-7.74(m, 6), 7.82(dd, 1, J ═ 1.4, 8.6), 8.05(dd, 1, J ═ 1.5, 5.4)₁₁H₁₁ClN₂: c, 63.93; h, 5.36; n, 13.55, found C, 63.64; h, 5.20; n, 13.49.

Example 4

2-phenyl-3-aminopyridines

To 2-chloro-3-aminopyridine (1.06g, 8.24mmol) [ in toluene (25ml) ] was added benzaldehyde (0.878g, 8.27 mmol). The reaction mixture was stirred in a Dean-Stark apparatus at reflux until GC/MS analysis of the reaction mixture showed no more starting material. The reaction mixture was cooled to room temperature and a solution of benzylidene- (2-chloro-pyridin-3-yl) -amine in toluene was added to a mixture of phenylboronic acid (1.30g, 10.7mmol), sodium carbonate (2.66g, 25.1mmol), and tetrakis (triphenylphosphine) palladium (O) (47mg, 0.38% mol) in 10ml of water. The reaction mixture was heated to 100 ℃ for 30 minutes, cooled to room temperature and poured into 1N aqueous sodium hydroxide (10 ml). The aqueous layer was removed and the toluene layer was extracted with 1N aqueous hydrochloric acid (15 ml each twice). The aqueous layer was neutralized with 6N aqueous sodium hydroxide solution to pH 12 and extracted with MTBE (twice each with 20 ml). The MTBE extract was dried over magnesium sulfate, filtered, and concentrated to give 2-phenyl-3-aminopyridine (1.26g, 90% yield) as a solid crystallized from diisopropyl ether.

M.p.＝67-68℃.¹H NMR(300MHz，CDCl₃)δ3.88(bs，2)，7.02-7.11(m，2).7.28-7.53(m，3)，7.67-7.71(m，2)，8.13-8.16(m，1).¹³C NMR(100MHz，CDCl₃)δ122.57，122.96，128.14，128.38，128.72，138.54，139.86，139.93，144.93.

Example 5

2-phenyl-3-aminopyridines

A solution of palladium acetate (224.5mg, 1.00mmol) and triphenylphosphine (1.05g, 4.00mmol) in toluene (1000ml) was stirred at room temperature for 15 min. Phenylboronic acid (114g, 935mmol), 2-chloro-3-aminopyridine (100g, 778mmol), benzaldehyde (83.4g, 786mmol) and toluene (500ml) were then added, followed by a solution of sodium carbonate (200g, 1.89mol) in water (1500 ml). The mixture was heated to reflux for 18 hours, cooled to room temperature and the layers separated. The organic layer was washed with water (500ml) and 2.5M aqueous hydrochloric acid (630ml) was added. The aqueous layer was separated and washed with toluene (300 ml). The pH was adjusted to 12-13 with 50% aqueous sodium hydroxide solution and the mixture was extracted with methyl-tert-butyl ether (500 ml). The organic layer was concentrated and the product crystallized from diisopropyl ether to give 2-phenyl-3-aminopyridine (128g, 97% yield). M.p. ═ 67-68 ℃.¹H NMR(300MHz，CDCl₃)δ3.88(bs，2)，7.02-7.11(m，2).7.28-7.53(m，3)，7.67-7.71(m，2)，8.13-8.16(m，1).¹³C NMR(100MHz，CDCl₃)δ122.57，122.96，128.14，128.38，128.72，138.54，139.86，139.93，144.93.

Claims (10)

1. A process for the preparation of a compound of formula V or X comprising reacting a compound of formula III or VIII with a compound of formula IV in the presence of a base and a palladium catalyst in an inert reaction solvent,

to obtain the compound of the formula V or X,

wherein:

x is Cl, Br or I;

z is H, (C)₁-C₄) Alkyl, methoxy, trifluoromethoxy, F or Cl;

ar is optionally substituted with 1-3R⁵Radical substituted (C)₆-C₁₀) An aryl group;

R¹is (C)₁-C₆) Straight or branched alkyl, (C)₃-C₇) Cycloalkyl, or (C)₆-C₁₀) Aryl, said alkyl, cycloalkyl and aryl being optionally substituted with 1-3R⁵Substituted by groups;

R³and R⁴Independently selected from H, (C)₁-C₆) Alkyl, wherein when R³And R⁴Is (C)₁-C₆) When alkyl groups are present, they may be fused together to form a ring structure; and

each R⁵Independently selected from halogen, cyano, nitro, (C)₁-C₆) Halogen-substituted alkyl, (C)₁-C₆) Alkoxy group, (C)₆-C₁₀) Aryloxy group, (C)₁-C₆) Halogen-substituted alkoxy, (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, (C)₂-C₆) Alkynyl, (C)₁-C₆) Alkylthio group, (C)₁-C₆) Alkylsulfinyl (C)₁-C₆) Alkylsulfonyl group, (C)₁-C₆) alkyl-OC (O) -, (C)₁-C₆) alkyl-OC (O) - (C)₁-C₆) Alkyl, (C)₁-C₆) alkyl-C (O) O-, (C)₁-C₆) alkyl-C (O) - (C)₁-C₆) alkyl-O-, (C)₁-C₆) alkyl-C (O) -, (C)₁-C₆) alkyl-C (O) - (C)₁-C₆) Alkyl-, (C)₆-C₁₀) Aryl-, (C)₆-C₁₀) Aryl radical- (C)₁-C₆) Alkyl-, and (C)₃-C₇) Cycloalkyl, wherein one or two carbon atoms of said cycloalkyl may be optionally substituted by nitrogen, oxygen or sulfur.

2. A process according to claim 1, wherein the compound of the formula III or VIII is prepared by reacting a compound of the formula I with a compound of the formula II or VII in a reaction-inert solvent,

wherein

Y is Cl, Br, I or-OC (O) R²；

R²Is (C)₁-C₆) Straight or branched alkyl, (C)₃-C₇) Cycloalkyl, or (C)₆-C₁₀) Aryl, said alkyl, cycloalkyl and aryl being optionally substituted with 1-3R⁵Substituted by groups; wherein said reaction of compound III or VIII with compound IV is carried out substantially simultaneously with or subsequent to said reaction of compound I with compound II or VII,

each R⁵Independently selected from halogen, cyano, nitro, (C)₁-C₆) Halogen-substituted alkyl, (C)₁-C₆) Alkoxy group, (C)₆-C₁₀) Aryloxy group, (C)₁-C₆) Halogen-substituted alkoxy, (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, (C)₂-C₆) Alkynyl, (C)₁-C₆) Alkylthio group, (C)₁-C₆) Alkylsulfinyl (C)₁-C₆) Alkylsulfonyl group, (C)₁-C₆) alkyl-OC (O) -, (C)₁-C₆) alkyl-OC (O) - (C)₁-C₆) Alkyl, (C)₁-C₆) alkyl-C (O) O-, (C)₁-C₆) alkyl-C (O) - (C)₁-C₆) alkyl-O-, (C)₁-C₆) alkyl-C (O) -, (C)₁-C₆) alkyl-C (O) - (C)₁-C₆) Alkyl-, (C)₆-C₁₀) Aryl-, (C)₆-C₁₀) Aryl radical- (C)₁-C₆) Alkyl-, and (C)₃-C₇) Cycloalkyl, wherein one or two carbon atoms of said cycloalkyl may be optionally substituted by nitrogen, oxygen or sulfur.

3. The process of claim 1 wherein a compound of formula V is produced in said process, further comprising deprotecting the compound of formula V in an aqueous acid to produce a salt of compound X.

4. The method of claim 2 wherein Z is hydrogen and R is¹And R²Are the same and are independently selected from (C)₁-C₆) Straight or branched chain alkyl and phenyl, wherein said R¹And R²Optionally substituted by 1-3R⁵Radical substitution, R³And R⁴Is hydrogen and each R⁵Independently selected from (C)₁-C₆) Straight or branched chain alkyl, phenyl, benzyl, trifluoromethyl, (C)₁-C₆) Alkoxy and trifluoromethoxy.

5. The method of claim 2, wherein R¹And R²Is methyl.

6. The method of claim 2, wherein R¹Is methyl and R²Is a tert-butyl group.

7. The method of claim 2, wherein X is Cl and Y is Cl.

8. A process for preparing a compound of formula X, comprising:

(a) reacting a compound of formula I with a compound of formula VII in a reaction-inert solvent,

to obtain the compound of the formula VIII,

and

(b) substantially simultaneously, or following step (a), reacting a compound of formula VIII with IV in a reaction inert solvent in the presence of a base and a palladium catalyst

To obtain the compound of the formula X,

wherein step (a) is further carried out in the presence of a base, while steps (a) and (b) are carried out substantially simultaneously,

and wherein:

x is Cl, Br or I;

z is H, (C)₁-C₄) Alkyl, methoxy, trifluoromethoxy, F or Cl;

ar is optionally substituted with 1-3R⁵Radical substituted (C)₆-C₁₀) An aryl group;

R³and R⁴Independently selected from H, (C)₁-C₆) Alkyl, wherein when R³And R⁴Is (C)₁-C₆) When alkyl groups are present, they are fused together to form a ring structure; and

each R⁵Independently selected from halogen, cyano, nitro, (C)₁-C₆) Halogen-substituted alkyl, (C)₁-C₆) Alkoxy group, (C)₆-C₁₀) Aryloxy group, (C)₁-C₆) Halogen-substituted alkoxy, (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, (C)₂-C₆) Alkynyl, (C)₁-C₆) Alkylthio group, (C)₁-C₆) Sulfinyl group, (C)₁-C₆) Alkylsulfonyl group, (C)₁-C₆) alkyl-OC (O) -, (C)₁-C₆) alkyl-OC (O) - (C)₁-C₆) Alkyl, (C)₁-C₆) alkyl-C (O) O-, (C)₁-C₆) alkyl-C (O) - (C)₁-C₆) alkyl-O-, (C)₁-C₆) alkyl-C (O) -, (C)₁-C₆) alkyl-C (O) - (C)₁-C₆) Alkyl-, (ii) alkyl-),(C₆-C₁₀) Aryl-, (C)₆-C₁₀) Aryl radical- (C)₁-C₆) Alkyl-, and (C)₃-C₇) Cycloalkyl, wherein one or two carbon atoms of said cycloalkyl may be optionally substituted by nitrogen, oxygen or sulfur.

9. The method of claim 8, wherein steps (a) and (b) are performed substantially simultaneously.

10. The method of claim 8, wherein Z is H, R³And R⁴Is hydrogen, each R⁵Independently selected from (C)₁-C₆) Straight or branched chain alkyl, phenyl, benzyl, trifluoromethyl, (C)₁-C₆) Alkoxy and trifluoromethoxy, X is chloro and Ar is phenyl.