TW201738229A - Process for the preparation of N-[(5-pyrimidinyl)methyl]-2-pyridinamines - Google Patents

Abstract

Disclosed is a method for preparing a compound of Formula 1wherein R1 is H or C1-C3 alkyl, and the use of a compound of Formula 1 in a method for preparing mesoionic compounds, comprising: (A) contacting a compound of Formula 2 with 2-aminopyridine (3) in the presence of an inert solvent, optionally in the presence of an acid catalyst, to form a compound of Formula 4(B) contacting the compound of Formula 4 with an alcohol R2OH to form a compound of Formula 5 in the presence of an inert solvent wherein R2 is C1-C4 alkyl; and (C) contacting the compound of Formula 5 with a borohydride reducing agent in the presence of an inert solvent to form a reaction mixture comprising the compound of Formula 1.

Description

Method for preparing N-[(5-pyrimidinyl)methyl]-2-pyridinamine

The present invention relates to a process for the preparation of N -[(5-pyrimidinyl)methyl]-2-pyridinamine.

A method for preparing N -[(5-pyrimidinyl)methyl]-2-pyridinamine and as a preparation thereof for the preparation of the insecticide trifluoropyrimidine (2,4-di- oxy-1-(5) - pyrimidin-ylmethyl) -3- [3- (trifluoromethyl) phenyl] -2 H - pyrido [1,2- a] pyrimidin-inner salt, CAS No. 1263133-33-0 intermediate registration) of The use of the body is described in PCT Patent Application Publication No. WO 2012/092115. There is a need for new or improved processes for the preparation of N -[(5-pyrimidinyl)methyl]-2-pyridinamine.

The invention provides a method for preparing a compound of formula 1 Wherein R ¹ is H or C ₁ -C ₃ alkyl, the method comprises: (A) making a compound of formula 2 With 2-aminopyridine ( 3 ) Contacting in the presence of an inert solvent, in the presence of an inert catalyst, as appropriate to form a compound of formula 4 (B) contacting the compound of the formula 4 with an alcohol R ² OH in the presence of an inert solvent S ² to form a compound of the formula 5 Wherein R ² is C ₁ -C ₄ alkyl; and (C) contacting the compound of formula 5 with a borohydride reducing agent in the presence of an inert solvent S3 to form the compound of formula 1.

The invention also relates to a method for preparing a compound of formula 6 Wherein R ¹ is H or C ₁ -C ₃ alkyl, the method comprising contacting a compound of formula 1 with compound ( 7 ), Wherein the compound of formula 1 is prepared by the method described above.

[Detailed Description of the Invention]

The terms "including", "comprising", "including", "including", "having", "having", "containing", "containing", "characterized" or any other Variations are intended to cover non-exclusive inclusions, subject to any expressly stated limitations. For example, a composition, mixture, process, method, article, or device that comprises a series of elements is not necessarily limited to those elements, but may include other elements not specifically listed, or such compositions, mixtures, processes, methods, An element inherent in an article or device.

The connection phrase "consisting of" excludes any element, step or component that is not indicated. If in the scope of the patent application, such phrases will make the scope of the patent application closed so that it does not contain materials other than those described, except for the conventional impurities associated therewith. When the phrase "consisting of" appears in the clause of the subject of the patent application, not immediately before the preamble, It is limited only to the elements mentioned in this clause; other elements are not excluded as a whole from the scope of the patent application.

When the Applicant has defined the invention or a part thereof in an open-ended term such as "comprising", it should be readily understood (unless otherwise indicated) that the specification is to be construed as the use of the term "consisting essentially of" or The "consisting of" describes the invention.

In addition, unless expressly stated to the contrary, “or” is an inclusive “or” rather than an exclusive “or”. For example, condition A or B satisfies any of the following: A is true (or exists) and B is false (or non-existent), A is false (or non-existent) and B is true (or exists), and A and B Both are true (or exist).

Also, the indefinite article "a" or "an" or "an" or "an" The singular <RTI ID=0.0> </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt;

The term "ambient temperature" or "room temperature" as used in this disclosure refers to a temperature between about 18 ° C and about 28 ° C.

In the above detailed description, the term "alkyl" includes straight-chain or branched alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, or different butyl isomers. As used herein, a halogenated alkane is an alkane partially or completely substituted with a halogen atom (fluorine, chlorine, bromine or iodine). Examples of halogenated alkanes include CH ₂ Cl ₂ , ClCH ₂ CH ₂ Cl, ClCH ₂ CH ₂ CH ₂ CH ₃ , and CCl ₃ CH ₃ . A halogenated benzene is a benzene partially or completely substituted by a halogen atom (fluorine, chlorine, bromine or iodine). Examples of the halogenated benzene include chlorobenzene, 1,2-dichlorobenzene, and bromobenzene. The C ₇ -C ₁₀ aromatic hydrocarbon is a compound containing a benzene ring substituted with an alkyl group. Examples of the C ₇ -C ₁₀ aromatic hydrocarbon include toluene, xylene, ethylbenzene, and cumene (isopropylbenzene). The C ₅ -C ₁₀ aliphatic hydrocarbon is a linear or branched hydrocarbon. Examples of the C ₅ -C ₁₀ aliphatic hydrocarbon include n-hexane, mixed hexane, n-heptane, and mixed heptane. The C ₅ -C ₁₀ alicyclic hydrocarbon is a cyclic hydrocarbon which may be substituted by a linear or branched alkyl group. Examples of the C ₅ -C ₁₀ alicyclic hydrocarbon include cyclopentane, methylcyclopentane, cyclohexane, and methylcyclohexane.

Embodiments of the invention include: Embodiment 1. A method of preparing a compound of Formula 1 Wherein R ¹ is H, the method comprises: (A) making a compound of formula 2 With 2-aminopyridine ( 3 ) Contacting in the presence of an inert solvent, in the presence of an inert catalyst, as appropriate to form a compound of formula 4 (B) contacting the compound of the formula 4 with an alcohol R ² OH in the presence of an inert solvent S ² to form a compound of the formula 5 Wherein R ² is C ₁ -C ₄ alkyl; and (C) contacting the compound of formula 5 with a borohydride reducing agent in the presence of an inert solvent S3 to form a reaction mixture comprising the compound of formula 1.

Embodiment 2. The method of Embodiment 1, wherein R ² is CH ₃ or CH ₂ CH ₃ .

The method of embodiment 1 or 2, wherein the step (C) further comprises (i) contacting the reaction mixture with water and adjusting the pH of the reaction mixture to pH less than 5 with acid, (ii) separating The obtained aqueous and organic phases of the reaction mixture, (iii) the pH of the aqueous phase is adjusted to pH 5 or more with an aqueous alkali solution, and (iv) the compound of the formula 1 is extracted into the organic solvent S4.

Embodiment 3. The method of Embodiment 1, wherein the inert solvent S1 in Step A is toluene or xylene.

Embodiment 4. The method of Embodiment 3 wherein the inert solvent S1 in Step A is toluene.

The method of any of embodiments 1 to 4, wherein an acid catalyst is present in step A, and the acid catalyst is as its para-isomer or as a mixture of isomers of toluene Sulfonic acid.

Embodiment 5A. The method of Embodiment 5 wherein the amount of the acid catalyst used is between 0.0001 and 0.01 molar equivalents relative to the amount of the compound of Formula 2 used in Step A. .

Embodiment 6. The method of Embodiment 1, wherein the alcohol in Step B is methanol.

Embodiment 6A. The method of Embodiment 6 wherein the amount of methanol used is between 3 and 6 mole equivalents of methanol relative to the amount of the compound of Formula 2 used in Step A.

Embodiment 7. The method of Embodiment 1, wherein the inert solvent S2 in Step B is toluene or xylene.

Embodiment 8. The method of Embodiment 7, wherein the inert solvent S2 in Step B is toluene.

Embodiment 9. The method of Embodiment 1, wherein the reaction temperature of Step B is between 10 ° C and 30 ° C.

Embodiment 10. The method of Embodiment 1, wherein the borohydride reducing agent in Step C is sodium borohydride, lithium borohydride or potassium borohydride.

The method of embodiment 10, wherein the borohydride reducing agent is between about 0.30 and 0.40 molar equivalents relative to the amount of the compound of formula 2 used in step A. The amount of reducing agent used is used.

Embodiment 12. The method of Embodiment 10 wherein the borohydride reducing agent in Step C is sodium borohydride.

Embodiment 13. The method of Embodiment 1, wherein the reaction time of Step C is between 1 and 6 hours.

Embodiment 14. The method of Embodiment 1, wherein the inert solvent S3 used in the step C is the same as the inert solvent S2 used in the step B.

Embodiment 15. The method of embodiment 14, wherein the inert solvents S2 and S3 are both toluene or both are xylene.

The method of embodiment 15, wherein the inert solvents S2 and S3 are toluene.

Embodiment 17. The method of Embodiment 1, wherein the inert solvent S1 of the step A, the inert solvent S2 of the step B, and the inert solvent S3 of the step C are the same.

Embodiment 18. The method of Embodiment 17, wherein the inert solvent S1 of the step A, the inert solvent S2 of the step B, and the inert solvent S3 of the step C are toluene or xylene.

Embodiment 19. The method of Embodiment 18, wherein the inert solvent S1 of the step A, the inert solvent S2 of the step B, and the inert solvent S3 of the step C are toluene.

Embodiment 20. A method for preparing a compound of Formula 6 Wherein R ¹ is H or C ₁ -C ₃ alkyl, the method comprising contacting a compound of formula 1 as described in claim 1 of the patent with compound ( 7 ), Wherein the compound of the formula 1 is prepared by the method as described in the first item of the patent application.

Embodiment 21. The method of Embodiment 20 wherein R ¹ is H.

Embodiment 22. A compound of formula 5 Wherein R ¹ is H or C ₁ -C ₃ alkyl and R ² is C ₁ -C ₄ alkyl.

The compound of embodiment 22, wherein R ¹ is H and R ² is CH ₃ .

Combinations of embodiments of the invention include:

Embodiment A. A Method of Preparing a Compound of Formula 1

Wherein R ¹ is H, the method comprises: (A) making a compound of formula 2 With 2-aminopyridine ( 3 ) Contacting in the presence of an inert catalyst S1 and an acid catalyst of toluenesulfonic acid as a mixture thereof or as a mixture of isomer catalysts to form a compound of formula 4 (B) contacting the compound of the formula 4 with an alcohol R ² OH in the presence of an inert solvent S ² to form a compound of the formula 5 Wherein R ² is CH ₃ or CH ₂ CH ₃ ; and (C) contacting the compound of formula 5 with a sodium borohydride reducing agent in the presence of an inert solvent S3 to form the compound of formula 1.

Embodiment B. A method of preparing a compound of Formula 1

Wherein R ¹ is H, the method comprises: (A) making a compound of formula 2 With 2-aminopyridine ( 3 ) Contacting in the presence of a toluene solvent and an acid catalyst of toluenesulfonic acid as a mixture thereof or as a mixture of isomer catalysts to form a compound of formula 4 (B) contacting the compound of formula 4 with an alcohol R ² OH in the presence of a toluene solvent to form a compound of formula 5 Wherein R ² is CH ₃ or CH ₂ CH ₃ ; and (C) contacting the compound of formula 5 with a sodium borohydride reducing agent in the presence of a toluene solvent to form the compound of formula 1.

Embodiments of the invention, including the above embodiments 1-23 and any other embodiments described herein, may be combined in any manner, and the description of the variables in the embodiments relates not only to the foregoing for the preparation of Formulas 1 and 6 . The method of the compound, but also the starting compound and the intermediate compound useful for the preparation of the compounds of the formulae 1 and 6 by this method.

In the following schemes, the definitions of R ¹ in the compounds of formulas 1, 2, 4, 5 and 6 and R ² in the compounds of formula 5 are as defined above in the description of the invention and the description of the embodiments, unless otherwise Indicate.

In step A of the process of the invention, as shown in Scheme 1, the compound of formula 4 is treated with 2-aminopyridine ( 3 ) in the presence of an inert solvent, optionally in the presence of an acid catalyst. A compound of formula 2 is prepared in which azeotropic removal of water. Although the reaction is carried out without the addition of an acid catalyst, it may be beneficial to add an acid catalyst to accelerate the rate of formation of the compound of Formula 4. An acid catalyst in an amount between 0.0001 and 0.01 mole equivalents is generally sufficient to provide a significant increase in reaction rate, relative to the amount of the compound of formula 2 used in step A, although any amount of acid catalyst can be used.

Examples of the acid catalyst which can be used in the step A of the method include (a) a sulfonic acid such as p-toluenesulfonic acid, toluenesulfonic acid as a mixture of isomers, and methanesulfonic acid, and (b) a mineral acid such as hydrochloric acid. , sulfuric acid and phosphoric acid, and (c) organic acids such as acetic acid and propionic acid. Since step A involves azeotropic removal of water by distillation, the acid catalyst can be loaded as a hydrate, as an aqueous solution or in anhydrous form. A useful acid catalyst is as its para isomer or as a mixture of isomers of toluenesulfonic acid. The inert solvent typically used in step A of the process comprises (a) a C ₇ -C ₁₀ aromatic hydrocarbon (eg toluene, xylene (as pure ortho, meta and para isomers, as a mixture thereof) Or as a mixture with ethylbenzene), ethylbenzene and cumene (cumene), (b) halogenated benzene (for example, chlorobenzene and 1,2-dichlorobenzene) and (c) Halogenated alkane (for example, 1,2-dichloroethane). Useful solvents are those suitable for use in all steps of the process, such as toluene and xylene. In one embodiment of step A of the method, the solvent is toluene.

The reaction temperature, reaction pressure and reaction time of the process of Step A are selected depending on the reaction solvent. The process of Step A is conveniently carried out at the standard boiling point of the reaction solvent. Depending on the solvent used, the reaction can be carried out at a pressure above or below atmospheric pressure. The reaction time will depend on the level of conversion desired (whether or not the catalyst is used), as well as the choice of solvent. Typical reaction times range from 1 to 24 hours.

Scenario 2

In step B of the process according to the present invention, as shown in Scheme 2, the compound of formula 5 is prepared by using the compound C ₁ -C ₄ alcohol of formula 4 of process in the presence of an inert solvent S2. The C ₁ -C ₄ alcohols which can be used in the step B of the process include methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, 2-methyl-1-propanol and 2-methyl 2-propanol. Although any amount of C ₁ -C ₄ alcohols, but is generally more practical amount of the compound used in Step A of Formula 2 with respect to the use of between 1 and 10 molar equivalents of the amount of a C ₁ -C ₄ alcohol. In one embodiment of step B, the alcohol is methanol. In another embodiment of step B, the amount of methanol is between 3 and 6 mole equivalents of methanol relative to the amount of the compound of formula 2 used in step A. The inert solvent typically used in step B of the process comprises (a) a C ₇ -C ₁₀ aromatic hydrocarbon (eg, toluene, xylene (as pure ortho, meta and para isomers) as its a mixture, or as a mixture with ethylbenzene), ethylbenzene and cumene (isopropylbenzene), (b) halogenated benzene (for example, chlorobenzene and 1,2-dichlorobenzene), (c) halogenated alkane (for example, dichloromethane, 1,2-dichloroethane and 1-chlorobutane) and (d) ether (for example, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether and two ). Mixtures of such inert solvents can also be used. In one embodiment of step B, the inert solvent S2 is toluene or xylene. In another embodiment of step B, the inert solvent S2 is toluene.

In step B of the process, the addition of R ² OH alcohol to the compound of formula 5 can be carried out at any temperature; for convenience, the reaction temperature is typically kept below the boiling point of the alcohol to avoid evaporation loss of the alcohol. In one embodiment of step B, the reaction temperature is between 10 ° C and 30 ° C.

The compound of Formula 5 is more stable than the compound of Formula 4 and is less prone to decompose into the compounds of Formulas 2 and 3 than the compound of Formula 4. Thus, a solution of the compound of Formula 5 can be stored for an extended period of time prior to use in Step C of the method.

In step C of the process of the invention, as shown in Scheme 3, the compound of formula 1 is prepared by treating a compound of formula 5 with a borohydride reducing agent in the presence of an inert solvent S3. The borohydride reducing agent that can be used in step C of the process includes, but is not limited to, sodium borohydride, lithium borohydride, potassium borohydride, sodium triethoxy borohydride, and sodium trimethoxyborohydride. In one embodiment of step C, the borohydride reducing agent is sodium borohydride.

In the case of the borohydride reducing agent sodium triacetoxyborohydride or sodium trimethoxyborohydride, 1.0 to 1.5 moles is typically used relative to the amount of the compound of formula 2 charged in step A. Ear equivalent of borohydride reducing agent. In the case of the borohydride reducing agent sodium borohydride, lithium borohydride or potassium borohydride, the amount of the compound of formula 2 of step A can typically be reduced using 0.25 to 1.0 molar equivalent of borohydride. Agent. In one embodiment of step C, the borohydride reducing agent is sodium borohydride, lithium borohydride or potassium borohydride, and is present in an amount of 0.30 and 0.40 molar equivalents relative to the amount of the compound of formula 2 of step A. The amount of borohydride reducing agent is used.

The inert solvent typically used in step C of the process comprises (a) a C ₇ -C ₁₀ aromatic hydrocarbon (eg, toluene, xylene (as pure ortho, meta and para isomers) as a mixture, or as a mixture with ethylbenzene), ethylbenzene and cumene (isopropylbenzene), (b) halogenated benzene (for example, chlorobenzene and 1,2-dichlorobenzene), (c) halogenated alkane (for example, dichloromethane, 1,2-dichloroethane and 1-chlorobutane) and (d) ether (for example, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether and two ). Mixtures of such inert solvents can also be used. In one embodiment of step C, the inert solvent S3 is toluene or xylene. In another embodiment of step C, the inert solvent S3 is toluene.

The reaction temperature in step C of the process is typically in the range of from -10 °C to 50 °C. In one embodiment of step C, the reaction temperature is in the range of from 0 to 30 °C. In another embodiment of step C, the reaction temperature is in the range of from 5 to 15 °C. The reaction time in step C of the process is typically in the range of from 1 hour to more than 24 hours. In one embodiment of step C, the reaction time is between 1 and 6 hours.

In one embodiment of the invention, the inert solvent S3 used in step C is the same as the inert solvent S2 used in the previous step B. In one embodiment of the invention, the inert solvents S2 and S3 used in steps B and C are both toluene or both are xylene. In another embodiment of the invention, both of the inert solvents S2 and S3 used in steps B and C are toluene.

In one embodiment of the invention, the inert solvent S2 used in step B is the same as the inert solvent S1 used in the previous step A. In one embodiment of the invention, the inert solvents S1 and S2 used in steps A and B are both toluene or both are xylene. In another embodiment of the invention, both of the inert solvents S1 and S2 used in steps A and B are toluene.

In one embodiment of the present invention, the inert solvent S1 used in the step A, the inert solvent S2 used in the step B, and the inert solvent S3 used in the step C are the same. In one embodiment of the present invention, the inert solvent S1 used in the step A, the inert solvent S2 used in the step B, and the inert solvent S3 used in the step C are toluene or xylene. In another embodiment of the present invention, the inert solvent S1 used in the step A, the inert solvent S2 used in the step B, and the step C The inert solvent S3 used in the system is toluene.

The compound of formula 1 can be isolated from the reaction mixture of step C by standard techniques known in the art for isolating products from borohydride reduction. Typically, water is added to the reaction mixture or the reaction mixture is added to water to dissolve and/or digest the boron complex and/or any remaining borohydride reagent. The pH of the aqueous phase can be reduced as appropriate by the addition of a base or by the addition of an acid to promote digestion of any residual borohydride reagent and intermediate boron complex. Suitable bases include alkali metal hydroxides, carbonates and hydrogencarbonates. Suitable acids include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, and organic acids such as acetic acid.

Once the boron complex and/or any remaining borohydride reagent is digested, the reaction mixture consists of a single liquid phase or two liquid phases, depending on the selected reaction solvent and the amount of water charged relative to the organic solvent. the elements of.

If the reaction mixture consists of a single phase, the compound of formula 1 can be extracted from the aqueous phase using a water-immiscible organic solvent.

If the reaction mixture consists of two liquid phases, it may be advantageous to separate the organic phase from the reaction mixture at this point to remove any impurities present in the organic phase. Therefore, it may be advantageous to select an organic solvent which produces a reaction mixture consisting of two liquid phases. In this case, adjusting the pH of the aqueous phase to pH 5 or below minimizes the loss of the product of Formula 1 to the organic phase because at pH 5 or below, the compound of Formula 1 will be partitioned into the aqueous layer. Once the organic phase is separated, the compound of Formula 1 can be isolated by extraction from the aqueous phase into a water-immiscible organic solvent. The ease of extracting the compound of formula 1 from the aqueous phase will depend on factors such as the pH of the aqueous phase, the amount of water charged relative to the amount of the compound of formula 1, and the solvent selected for extraction. It is generally advantageous at this point to maintain the pH of the aqueous phase at about 5 to 7 during extraction to promote extraction of the compound of formula 1 while inhibiting the extraction of process impurities. Therefore, the pH of the aqueous phase is adjusted to pH 5 or more with an aqueous alkali solution, and the compound of the formula 1 is extracted into the organic solvent S4. Typical organic solvent S4 includes C ₇ -C ₁₀ aromatic hydrocarbons and halogenated alkanes. In one embodiment, the organic solvent S4 is toluene, dichloromethane, 1,2-dichloroethane or 1-chlorobutane.

In one embodiment of the method, step (C) further comprises (i) contacting the reaction mixture with water and adjusting the pH of the reaction mixture to a pH of less than 5 with acid, (ii) separating the resulting water of the reaction mixture The phase and the organic phase, (iii) the pH of the aqueous phase is adjusted to pH 5 or greater with an aqueous base solution, and (iv) the compound of formula 1 is extracted from the aqueous phase into the organic solvent S4. In another embodiment, the pH of the aqueous phase in (iii) above is adjusted to between pH 5 and 7 with an aqueous base solution. In another embodiment, the pH of the aqueous phase in (iii) above is adjusted to between pH 5 and 6 with an aqueous base solution.

If the compound of formula 1 is a solid at ambient temperature, it can be separated from the organic layer and the organic extract by solvent exchange into a suitable crystallization solvent. The crystallization solvent is then cooled, the solid product is isolated by filtration, and the product is washed as appropriate with a suitable organic solvent to provide the purified compound of formula 1.

As shown in Scheme 4, a compound of Formula 1 can be coupled with Compound ( 7 ) to provide a compound of Formula 6; such a coupling method is described in PCT Patent Application Publication No. WO 2013/090547. When R ^{1 in} Formula 6 is H, the resulting compound is the insecticide trifluorophenylpyrimidine (2,4-di-oxy-1-(5-pyrimidinylmethyl)-3-[3-(trifluoro) Methyl)phenyl]-2 H -pyrido[1,2- a ]pyrimidineindol, CAS Registry Number 1263133-33-0). Trifluorophenylpyrimidines are described in PCT Patent Application Publication No. WO 2011/017351 and WO 2012/092115.

Option 4

The process of the invention for preparing a compound of formula 1 can therefore be used to prepare an insecticidally active compound of formula 6.

In the following examples, proton-NMR analysis was performed on a Varian VNMRS 300 MHz instrument. ^{The 1} H NMR spectrum is reported in ppm from the low field of tetramethylnonane. "s" means a single peak, "brd" means a broad doublet, and "m" means a multiplet.

High pressure liquid chromatography (HPLC) analysis was performed using a Hewlett Packard Series 1100 instrument equipped with a diode array UV detector (monitored at 230 nm) equipped with a Zorbax Eclipse XDB C18 (150 mm x 4.6 mm x 3.5 μ) column. The column was maintained at 25 ° C and the flow rate was 1 mL/min. The mobile phase consisted of 46.2 mM ammonium bicarbonate in water (A) and acetonitrile (B). The mobile phase procedure was 85% A: 15% B for 12 minutes, 40% A: 60% B in 4 minutes, and then 20% A: 80% B in 4 minutes.

Preparation example 1 Step A: Preparation of N- (5-pyrimidylmethylene)-2-pyridinamide

Add 400.0g to a 1L 3-neck round bottom flask equipped with an overhead stirrer, thermocouple, Dean-Stark trap (approximately 25 mL total volume) and a condenser with a nitrogen inlet 2.1% by weight solution of pyrimidine-5-formaldehyde in dichloromethane (8.4 g, 77.7 mmol containing pyrimidine-5-formaldehyde) and 7.39 g of 99.0% by weight 2-aminopyridine (77.7 mmol) ear). The reaction mixture was heated to reflux under a nitrogen blanket and 349 g of dichloromethane was removed from &quot;D&A&gt; Toluene (126 mL) was added to the reaction mixture at about 48 ° C, followed by 31 mg of 98.5% by weight of p-toluenesulfonic acid monohydrate (0.16 mmol). The resulting reaction mixture was heated to reflux and the distillate was removed via a Dean-Stark trap until the temperature of the reaction mixture reached 110 ° C, at which time another 40 g of distillate had been removed. 50 mL of toluene was added to the reactor, and the reaction mixture was refluxed at 112-114 ° C under atmospheric pressure for about 3.75 hours, and water was removed via a Dean-Stark trap. HPLC analysis of the reaction mixture indicated 94.1 area% of N- (5-pyrimidinylmethyl)-2-pyridinamine.

Step B: Preparation of N- [methoxy(5-pyrimidinyl)methyl]-2-pyridinamine

The reaction mixture from Step A was cooled to 21 ° C and 7.5 g (234 mmol) of methanol was added. The reaction mixture was stirred at 16-24 ° C for about 1 hour and then allowed to stand at room temperature overnight (about 16 hours), after which HPLC analysis of the reaction mixture indicated 91.1 area% N- [methoxy (5-pyrimidine) Methyl]-2-pyridinamine.

Step C: Preparation of N -[(5-pyrimidinyl)methyl]-2-pyridinamine

To a 500 mL jacketed resin kettle equipped with an overhead stirrer, thermocouple, recirculating heating and cooling bath, and nitrogen inlet was added 1.05 g of 98% sodium borohydride powder (27.2 mmol) followed by 50 mL of toluene. The resulting slurry was covered with nitrogen, cooled to 9 ° C, and the reaction mixture from step B was added over 50 minutes using a metering pump while maintaining the temperature of the reaction mixture between 9 ° C and 12 ° C. After the addition was completed, the reactor used in the step B was rinsed with 10 mL of toluene, and the rinse was added to the reaction mixture. The step C reaction mixture was stirred at 11-12 ° C for about 3 hours, after which HPLC analysis of the reaction mixture indicated 92.7 area% N -[(5-pyrimidinyl)methyl]-2-pyridinamine. About 3.5 hours after the completion of the addition of the solution in Step B, water (33.6 g) was added, followed by 11.2 g of 37% by weight of HCl. The reaction mixture was allowed to warm to about 20 °C during the addition process and then stirred at room temperature (21-22 °C) for about one hour, after which the pH of the aqueous layer was about 3.8. An additional 0.2 grams of 37% by weight HCl was added to adjust the pH of the aqueous layer to about 3.5. The reaction mixture was then stirred at room temperature overnight (about 16 hours). The aqueous layer was then separated from the organic layer and the pH of the aqueous layer was adjusted to 6.0 by the addition of 4.0 g of 50% NaOH. The aqueous layer was then extracted with dichloromethane (5 X 34 mL) with 50% NaOH added periodically to keep the aqueous layer between pH 5.4 and 6.0. The combined dichloromethane extracts were concentrated to dryness using a rotary evaporator to yield 11.1 g.

The solid was transferred to a 250 mL jacketed resin kettle equipped with an overhead stirrer, thermocouple, recirculating heating and cooling bath, and a nitrogen inlet, and 22.9 g of dichloromethane was added. The resulting solution was cooled to 5 ° C and 51.5 mL of mixed heptane was added with stirring while maintaining the temperature at 5-7 °C. Heptane is slowly added until a thick slurry is formed, after which the rate of addition is increased to make the slurry thin. The mixture was warmed to 14 ° C in 15 minutes and held at 14-15 ° C for 15 minutes. The mixture was then cooled to 2 ° C in one hour and held at 2-3 ° C for one hour, after which time the product was collected by filtration, washed with 25 mL of cold heptane and dried in a vacuum oven at about 45 ° C to leave The next 10.69 g product. Analysis of the product by HPLC indicated 96.3 wt% (98.4 area%) of N -[(5-pyrimidinyl)methyl]-2-pyridinamine (71% yield).

Characterization of N- [methoxy(5-pyrimidinyl)methyl]-2-pyridinamine by NMR

To a 250 mL 3-neck round bottom flask equipped with a magnetic stirrer, a heating mantle, a thermocouple, a Dean-Stark trap, and a condenser with a nitrogen inlet were added 5.0 g of pyrimidine-5-formaldehyde and 75 mL of toluene. The reaction mixture was stirred at room temperature for about 10 minutes, and then 2-aminopyridine (4.35 g, 1.0 equivalent) and p-toluenesulfonic acid monohydrate (20 mg, 0.2 mol%) were added at room temperature. The Dean-Stark trap was filled with 20 mL of toluene, and the resulting reaction mixture was heated to reflux (112-113 ° C) under a nitrogen blanket for 3.5 hours. The reaction mixture was then concentrated through a Dean-Stark trap to remove 90 mL of the distillate. The reaction mixture was then transferred to a clean 1 neck round bottom flask where the yellow solid crystallized. The residual solvent was removed using a rotary evaporator having a bath temperature of 60 ° C, methanol (about 30 mL) was added to the residue, and the mixture was stirred at room temperature overnight. The next day, about 10mL solution using a rotary evaporator and concentrated to an oil by NMR (CDCl ₃₎ analysis, for which NMR and methanol containing a small amount of N - (5- pyrimidin-ylmethylene) -2- The N- [methoxy(5-pyrimidinyl)methyl]-2-pyridinamine of pyridylamine is consistent. The signal system from N- [methoxy(5-pyrimidinyl)methyl]-2-pyridinamine δ 9.15 (s, 1H), 8.87 (s, 2H), 8.11 (m, 1H), 7.47 (m, 1H), 6.72 (m, 1H), 6.54 (m, 1H), 6.40 (brd, 1H), 5.77 (brd, 1H), 3.48 (s, 3H).

Claims (8)

Method for preparing compound of formula 1 Wherein R ¹ is H or C ₁ -C ₃ alkyl, the method comprises: (A) making a compound of formula 2 With 2-aminopyridine ( 3 ) Contacting in the presence of an inert solvent, in the presence of an inert catalyst, as appropriate to form a compound of formula 4 (B) contacting the compound of the formula 4 with an alcohol R ² OH in the presence of an inert solvent S ² to form a compound of the formula 5 Wherein R ² is C ₁ -C ₄ alkyl; and (C) contacting the compound of formula 5 with a borohydride reducing agent in the presence of an inert solvent S3 to form a reaction mixture comprising the compound of formula 1. The method of claim 1, wherein R ¹ is H. The method of claim 2, wherein R ² is CH ₃ or CH ₂ CH ₃ . The method of any one of claims 1-3, wherein the step (C) further comprises (i) contacting the reaction mixture with water and adjusting the pH of the reaction mixture to a pH of less than 5 with acid, ( Ii) separating the aqueous phase and the organic phase of the obtained reaction mixture, (iii) adjusting the pH of the aqueous phase to pH 5 or more with an aqueous alkali solution, and (iv) extracting the compound of the formula 1 to the organic solvent S4 in. Method for preparing a compound of formula 6 Wherein R ¹ is H or C ₁ -C ₃ alkyl, the method comprising contacting a compound of formula 1 as described in claim 1 of the patent with compound ( 7 ), Wherein the compound of the formula 1 is prepared by the method as described in the first item of the patent application. The method of claim 5, wherein R ¹ is H. a compound of formula 5 Wherein R ¹ is H or C ₁ -C ₃ alkyl and R ² is C ₁ -C ₄ alkyl. The compound of claim 7, wherein R ¹ is H and R ² is CH ₃ .