DE102009016374A1 - Preparing a 2-amino pyridine derivative comprises reacting an open-chain nitrile precursor with a nitrogen containing compound in a cyclization reaction - Google Patents

Abstract

Preparing a 2-amino pyridine derivative comprises reacting an open-chain nitrile precursor with a nitrogen containing compound in a cyclization reaction. Preparing a 2-amino pyridine derivative of formula (II) comprises reacting an open-chain nitrile precursor of formula (NC-CH(R 1>)-C(R f)(OR 2>)-CH=CH-OR 3>) (I) or (NC-CH(R 1>)-C(R f)(OR 2>)-CH 2-CH(OR 6>)-OR 3>) (III) with a nitrogen containing compound of formula (N(H)(R 4>)(R 5>)) (IV) in a cyclization reaction. R fC nH (2n+1-m)X m; m : 1 to 2n+1; X : F, Cl or Br; n : 1-8; R 1>1-8C alkyl, 6-14C aryl, 1-13C heteroaryl, COOR, CN, SO2R, SOR or PO(OR) 2(all optionally substituted) or H; R 2>H or protecting group for alcohols; R 3>, R 6>1-8C alkyl, 1-8C acyl, 6-14C aryl or R 3silyl (all optionally substituted); either R 4>, R 5>1-8C alkyl, 6-14C aryl, 1-13C heteroaryl, 1-8C acyl or CONR 2(all optionally substituted) or H; or R 4>R 5>optionally substituted 4-8C alkylene chain, where a CH 2group is replaced by NH or O; and R : 1-8C alkyl, 6-14C aryl or 1-13C heteroaryl. Provided that when m is greater than 1, x is identical or different. [Image].

Description

The inventive method relates to the reaction suitable nitrile precursors with nitrogen compounds to the desired substituted pyridines. The production of the starting products takes place generally by addition of an alpha-metalated nitrile to a carbonyl compound.

pyridine are important structural elements in a variety of products chemical and pharmaceutical industries and there are in the literature described many different methods of preparation. These can be roughly divided into procedures in which the Pyridine ring is constructed and those in which substituents are introduced (eg by electrophilic or nucleophilic substitution on the aromatic) or modified.

If 2-aminopyridine derivatives are required, the preparation is usually carried out by introducing the amine substituent into an already existing pyridine ring. Examples of such reactions are the chitibabine reaction (see eg. DE-B-37 42 91 ), ie the reaction of pyridines with sodium amide with the elimination of sodium hydride or the reaction of 2-halopyridines with nitrogen compounds (see eg. Chem. Ber. 1936, 69, 2593 for the reaction of 3-amino-2-chloropyridine to 2,3-diaminopyridine ).

However, these reactions have the disadvantage that either quite drastic conditions are necessary (chichibabin reaction, reaction of 2-halopyridines with aqueous ammonia) or that in the newer catalytic variants for the implementation of expensive precious metals and ligands are required (eg. Org. Lett. 2001, 3, 3417 ).

One Another disadvantage of the reactions described is the fact that for the synthesis of difficultly substituted pyridines the corresponding preliminary stages must be available, which is often not the case. In addition, must for introducing the desired substituent into the desired position a technically feasible Procedures are available that will transform the Pre-stage also allowed beyond the laboratory scale.

oder die Umwandlung von Methylgruppen in Trifluormethylgruppen durch Einwirkung von Chlor und Flußsäure.This is especially often not the case when perfluoroalkyl groups (usually trifluoromethyl groups) are to be introduced into the pyridine ring. Although some reactions in the literature are described here, such as the reaction of iodopyridines with (trifluoromethyl) trimethylsilane

or the conversion of methyl groups into trifluoromethyl groups by the action of chlorine and hydrofluoric acid.

All However, previously known methods have disadvantages that the use unattractive for the preparation of the desired aminopyridines makes or excludes. So are the aminopyridines under the drastic conditions of the conversion of methyl into trifluoromethyl groups not stable. So it would have to be first other pyridine derivatives, e.g. B. halopyridines are manufactured and in a separate step, the conversion of halogen to amine be carried out, resulting in elaborate and expensive procedures results. The introduction of a trifluoromethyl group by Conversion of an iodopyridine with (trifluoromethyl) trimethylsilane is for the technical scale because of the high Prices of starting materials also hardly attractive.

task Accordingly, it was a method of the present invention to provide, with the help of the desired 2-aminopyridine derivatives manufactured with high flexibility with respect to the substitution pattern can be and with the particular perfluoroalkyl-substituted, preferably prepared trifluoromethyl-substituted 2-aminopyridines can be.

A similar process has already been described for 2-halopyridines ( WO 2007/000249 ). In this process, a nitrile is first metallated and then reacted with a suitable carbonyl compound to the hydroxynitrile. The final ring closure then takes place under strongly acidic conditions with HX (HCl, HBr, HI) or inorganic esters of these substances (eg SOCl ₂ , POCl ₃ , PCl ₅ , PBr ₃ etc.) under very strongly acidic conditions. This reaction is exemplified for the synthesis of 4-trifluoromethyl-2-chloropyridine.

However, in order to be able to produce the corresponding 2-aminopyridine, further reaction with ammonia is necessary, which proceeds only under drastic conditions (see US Pat EP-B-0 228 846 or Dunn et al. in J. Fluor. Chem 1999, page 153 ) and high temperatures and pressure.

In front In this background, the task was an economic one and technically easy to carry out method for to develop the preparation of 2-amino-4- (fluoroalkyl) pyridine derivatives.

It has now been found that this task is achieved by direct implementation of in WO 2007/000249 solve nitrile precursors described with ammonia or other suitable nitrogen compounds.

This is surprising because working under strongly acidic Conditions in the above-described reaction to the halopyridine was considered crucial to success.

This results in a general and flexible process by means of which substituted 2-aminopyridines, in particular 2-aminopyridines with halogen-substituted alkyl substituents, can be prepared by constructing the pyridine ring:

The various radicals in the above scheme are the following substituents:
R _f : C _n H _{(2n + 1-m)} X _m
X: F, Cl, Br, where for m> 1 X is identical or different
n: positive integer between 1 and 8
m: positive integer between 1 and 2n + 1
R ¹ : hydrogen, C ¹ -C 8 -alkyl, C 6 -C 14 -aryl, C ₁ -C -heteroaryl, COOR, CN, SO ₂ R, SOR, PO (OR) ₂ , where these alkyl, aryl, heteroaryl, -COOR, -CN, -SO ₂ R, -SOR and -PO (OR) ₂ radicals are unsubstituted or monosubstituted or polysubstituted,
R ² : hydrogen or a protecting group for alcohols
R ³ , R ^{6 are} C 1 -C 8 -alkyl, C 1 -C 8 -acyl, C 6 -C 14 -aryl, R _{3 is} silyl, where the alkyl, acyl and aryl radicals are unsubstituted or monosubstituted or polysubstituted,
R ⁴ , R ⁵ : hydrogen, C 1 -C 8 alkyl, C 6 -C 14 aryl, C 1 -C 13 heteroaryl, C 1 -C 8 acyl, -CONR ₂ , where these alkyl, aryl, heteroaryl, acyl and -CONR 2 radicals being unsubstituted or mono- or polysubstituted, or R ⁴ and R ⁵ together form a C4-C8-alkylene, where one CH ₂ group can be replaced by NH or O, and said C4-C8-chain unsubstituted or mono- or polysubstituted
R: C1-C8-alkyl, C6-C14-aryl, C1-C13-heteroaryl

"Alkyl" in the context of the invention is - unless otherwise stated - a branched or unbranched C ₁ - to C ₂₀ -, preferably a C ₁ - to C ₁₀ alkyl understood, in particular methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, tert-butyl, pentyl or hexyl, more preferably methyl, ethyl, propyl or butyl.

Unless otherwise stated, "aryl" (or an "aromatic" radical) is a C ₆ to C ₁₄ aryl radical, especially phenyl, naphthyl, diphenyl. These aromatic substituents may in turn additionally carry alkyl or other aryl substituents.

Unless otherwise stated, "heteroaryl" (or a "heteroaromatic" Radical) to a C ₅ - to C ₁₃ -aryl radical in which 1, 2 or more carbon atoms can be replaced independently of one another by O, S, N, N-alkyl, in particular furyl, thiophenyl, oxazolyl, thiazolyl, pyridyl, pyrimidyl, Indolyl, quinoxalinyl or pyrrolyl.

Under "halogen" or "halide" is, unless otherwise stated, a fluorine, chlorine, bromine or Understood iodine radical, preferably a bromine or chlorine radical.

Typical "protecting groups for alcohols" are e.g. Acyl, alkyl, 2-tetrahydropyranyl or R ₃ silyl (with R = methyl, ethyl, propyl, tert-butyl). The respective radicals R can either be the same or different.

"One- or polysubstituted or substituted in Meaning of the invention means that the respective remainder or if possible, two, three or more times by halogen, preferably chlorine or bromine, and / or by nitro, cyano, hydroxy, Alkyl, alkyloxy, aryl, aryloxy, arylalkyl, aryloxyalkyl, arylalkyloxy, Amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, Alkylthio, arylthio, carboxy, alkylcarbonyl and / or alkyloxycarbonyl is substituted.

The preparation of the required nitrile precursors can be carried out by methods familiar to the person skilled in the art. In most cases, however, the preparation according to one of the two following schemes starting from the unsaturated ketone IV or from the acetal V should be particularly economical:

The meaning of the radicals R is the same as explained above. Additionally, M stands for the following metals:
M: Li, Na, K, MgY, Mg _0.5 , CaY, Ca _0.5 , ZnY, Zn _0.5 , CdY, Cd _0.5 , Cu, TiY ₃
Y: X (as defined above), I, OR, O-CO-R (with R as defined above)

to Synthesis of the nitriles required for cyclization is as described above in the formulas, generally access from the ketones IV or V and a salt of an acetonitrile derivative the cheapest way. This is first acetonitrile or a substituted derivative is metallated in a suitable solvent and then the resulting salt with a ketone of the general formula IV or V implemented.

For this reaction, all solvents are suitable, which can be used for metallation reactions. These are in particular ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, diisopropyl ether, di-n-butyl ether, dioxane, 1,2-dimethoxyethane, Diethylengylcoldimethylether, Diethylenglcoldi-n-butyl ether, tetraethylene glycol dimethyl ether or mixtures of these solvents with each other or with an inert other solvent such as Benzene, toluene, xylene, cyclohexane or petroleum ethers (hydrocarbon substance mixtures). In special cases, however, pure hydrocarbons such as benzene, toluene, xylene, cyclohexane or petroleum ether may be suitable or in the case of strongly acidic acetonitrile derivatives (R ¹ strong acceptor substituent) even alcohols such as methanol, ethanol, isopropanol or butanols.

Suitable metalating reagents are all bases which are sufficiently basic to abstract a hydrogen atom from the optionally substituted acetonitrile. For acetonitrile itself or alkyl-substituted acetonitriles, mainly very strong bases are used, such as n-butyllithium, sec-butyllithium, t-butyllithium, n-hexyllithium, lithium N, N-diisopropylamide (IDA), lithium 2,2,6, 6-tetramethylpiperidide (Li-TMP), lithium hexamethyldisilazane (LiHMDS), sodium hexamethyldisilazane (NaHMDS) or potassium hexamethyldisilazane (KHMDS). For slightly more acidic acetonitrile derivatives such as aryl-substituted (R ¹ = aryl), bases such as sodium amide, lithium hydride, sodium hydride or potassium hydride are suitable in addition to those mentioned above. In the most acidic acetonitrile derivatives (R ¹ = COOR, CN, SO ₂ R, SOR, PO (OR) ₂ ), in addition to the strong bases already mentioned, alkoxides, such as the lithium, sodium or potassium salts of methanol, Ethanol or t-butanol suitable as bases.

The reaction conditions which are expediently to be observed during the metallation depend in turn on the acetonitrile derivatives used. Thus, in the case of the least acidic acetonitrile derivatives (R ¹ = alkyl or hydrogen), preference is given to working at temperatures below -25 ° C., and more preferably below -45 ° C., in order to avoid the decomposition of the salts formed. Owing to the greater stability of the salts formed, the more acidic acetonitrile derivatives can also be metallated at higher temperatures (for R ¹ = aryl up to about 0 ° C., for R ¹ = CN, COOR, SO ₂ R, SOR even at room temperature or even above).

The subsequent reaction with suitable ketones of general formula IV or V is best carried out at the same temperature as the metallation and is generally carried out by adding the ketones to the metallated acetonitrile or acetonitrile derivative. However, the order of addition may also be reversed. Finally, the reaction mixture is usually worked up by neutralizing the base it contains with a suitable acid (eg, sulfuric acid, acetic acid, citric acid, hydrochloric acid) and removing the salt formed with water. The resulting product is purified by conventional techniques such as distillation or crystallization or can often be used crude in the subsequent stage. In some cases, it may also be advantageous not to quench with a proton source but with other electrophiles. The alcohols (R ² = H) are not formed, but corresponding derivatives (R ² = alkyl, acyl, 2-tetrahydropyranyl, R ₃ silyl) as starting materials for the cyclization.

The cyclization of the precursors I or III to the desired aminopyridine derivatives II can be carried out with all suitable nitrogen compounds, ie those in which R ⁴ and R ^5, as indicated above, independently of one another are hydrogen, alkyl, aryl, heteroaryl, acyl or -CONR ₂ , Both substituents can also be part of a ring system. The cyclization reaction is generally carried out in a suitable solvent. In the simplest case, this is the nitrogen compound itself or a mixture of the nitrogen compound with other solvents or solvent mixtures. Suitable solvents are all that do not hinder the reaction so z. As ethers (dioxane, THF, MTBE, diisopropyl ether, di-n-butyl ether), aromatics (toluene, xylene, benzene, chlorobenzene, anisole), alcohols (methanol, ethanol, propanol, isopropanol, butanol) or water.

The Reaction is carried out by simply heating the precursors I or III with the nitrogen compounds in one optional solvent to be used. Typical temperatures are 40 ° C to 250 ° C, preferably 60 ° C. to 200 ° C and more preferably 80 ° C to 150 ° C. The addition of a catalyst is to achieve the cyclization normally not necessary, but it can be at Need to add acidic or alkaline additives to the cyclization reaction to accelerate. Preferred acidic salts are salts of used nitrogen compounds used, more preferably Salts of hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, acetic acid or citric acid. Suitable basic additives are hydroxides, carbonates, oxides, alcoholates and other strongly basic compounds, preferably those that are stronger are basic, as the nitrogen compounds used.

The workup is carried out depending on the properties of the product by distillation or crystallization. Example 1: Preparation of 5-ethoxy-3-hydroxy-3- (trifluoromethyl) pent-4-enenitrile as Cyclisierungsvorstufe

500 ml of 1,2-dimethoxyethane were cooled to -72 ° C and at this temperature, first with 126 ml of n-BuLi (2.5 molar in hexane) and then within 2 h also at -72 ° C with 12.8 g Acetonitrile added. The mixture was then allowed to stir for 90 minutes to complete the formation of the anion. Subsequently, at -72 ° C within 2 h with a solution of 50 g of 1,1,1-trifluoro-but-3-en-2-ones (preparation according to Chem. Ber. 1989, 122, 1179-1186 ) in 100 ml of 1,2-dimethoxyethane and then allowed to stir for 1 h at this temperature. The mixture was then warmed to 0 ° C and added to neutralize with a solution of 16.1 g of sulfuric acid (96%) in 50 ml of water.

Subsequently, 500 ml of toluene were added, the phases were separated and the aqueous phase was counter-extracted twice with a further 100 ml of toluene. The combined organic phases were dried with sodium sulfate and then concentrated on a rotary evaporator. Finally, the product was distilled in full oil pump vacuum (about 0.2 mbar). It was thus 48.5 g of product (78%) of boiling point 95 to 110 ° C are obtained. This was identified by its mass spectrum (M + = 209, other fragments at m / e = 169, 141 and 71). Example 2: Preparation of 2-amino-4- (trifluoromethyl) pyridine from 5-ethoxy-3-hydroxy-3- (trifluoromethyl) pent-4-enenitrile with aqueous ammonia

Fifty grams of 5-ethoxy-3-hydroxy-3- (trifluoromethyl) pent-4-en-nitrile were mixed with 600 grams of aqueous ammonia (25%) and the resulting mixture was autoclaved to 125 ° C for 24 hours heated, with a pressure of about 14 bar built up. The reaction mixture was then cooled and the resulting biphasic mixture extracted several times with dichloromethane. The combined organic phases were carefully concentrated by rotary evaporation and the product was subsequently recrystallised from cyclohexane. There was thus obtained 26.3 g of 2-amino-4- (trifluoromethyl) pyridine (68%) as a yellowish brown solid. The spectroscopic data agreed with those reported in the literature ( AD Dunn et al. in J. Fluorine Chem. 1999, 93, 153-157 ). Example 3: Preparation of dimethyl (4-trifluoromethylpyridin-2-yl) -amine from 5-ethoxy-3-hydroxy-3- (trifluoromethyl) pent-4-enenitrile with aqueous dimethylamine solution

The procedure was analogous to Example 2, but instead of 600 g of aqueous ammonia, 600 g of aqueous dimethylamine solution (40%) were used. It was thus possible to isolate 28.1 g (62%) of product. Example 4 Preparation of 5-ethoxy-3-hydroxy-2-phenyl-3-trifluoromethyl-pent-4-enenitrile as Cyclisierungsvorstufe

500 ml of THF were cooled to -72 ° C and at this temperature, first with 31.9 g of diisopropylamine and then at the same temperature with 126 ml of n-BuLi (2.5 molar in hexane). Subsequently, 35.1 g of benzyl cyanide dissolved in a further 250 ml of THF were added dropwise within 1 h. Stirring was continued for an additional 2 hours to complete the formation of the anion. Subsequently, at -72 ° C within 2 h with a solution of 50 g of 1,1,1-trifluoro-but-3-en-2-one was added and then allowed to stir for 1 h at this temperature. The mixture was then warmed to 0 ° C and added to neutralize with a solution of 16.1 g of sulfuric acid (96%) in 50 ml of water. Subsequently, 500 ml of toluene were added, the phases were separated and the aqueous phase was counter-extracted twice with a further 100 ml of toluene. The combined organic phases were dried with sodium sulfate and then concentrated on a rotary evaporator. It was thus obtained about 77 g of a crude product, which was used in the next step. Example 5: Preparation of 3-phenyl-4-trifluoromethyl-pyridin-2-ylamine by cyclization of 5-ethoxy-3-hydroxy-2-phenyl-3-trifluoromethyl-pent-4-enenitrile with ammonia water

It were 50 g of 5-ethoxy-3-hydroxy-2-phenyl-3-trifluoromethyl-pent-4-enenitrile mixed with 600 g of aqueous ammonia (25%) and the resulting mixture was placed in an autoclave at 125 ° C for 24 h heated. Subsequently, the reaction mixture was cooled and the resulting biphasic mixture several times with dichloromethane extracted. The combined organic phases were evaporated and then the product recrystallized from heptane. It was thus 24.1 g of 3-phenyl-4-trifluoromethyl-pyridin-2-ylamine (52% over both levels).

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• - DE 374291 B [0003]
• - WO 2007/000249 [0009, 0012]
• EP 0228846 [0010]

Cited non-patent literature

• - Chem. Ber. 1936, 69, 2593 for the reaction of 3-amino-2-chloropyridine to 2,3-diaminopyridine [0003]
• - Org. Lett. 2001, 3, 3417 [0004]
• - Dunn et al. in J. Fluor. Chem 1999, page 153 [0010]
• - Chem. Ber. 1989, 122, 1179-1186 [0032]
• AD Dunn et al. in J. Fluorine Chem. 1999, 93, 153-157 [0034]

Claims (9)

Process for the preparation of 2-aminopyridine derivative of general formula II, characterized in that an open-chain nitrile precursor I or III is reacted with a nitrogen compound in a cyclization reaction:

wherein the substituents R ¹ to R ⁶ and R ^{f have} the following meanings: R _f : C _n H _{(2n + 1-m)} X _m X: F, Cl, Br, where for m> 1 X is identical or different n : positive integer between 1 and 8 m: positive integer between 1 and 2n + 1 R ¹ : hydrogen, C 1 -C 8 -alkyl, C 6 -C 14 -aryl, C ₁ -C -heteroaryl, COOR, CN, SO ₂ R, SOR, PO (OR) ₂ , where these alkyl, aryl, heteroaryl, -COOR, -CN, -SO ₂ R, -SOR and -PO (OR) ₂ radicals are unsubstituted or monosubstituted or polysubstituted, R ² : hydrogen or a protecting group for alcohols R ³ , R ⁶ : C 1 -C 8 alkyl, C 1 -C 8 acyl, C 6 -C 14 aryl, R ₃ silyl, wherein the alkyl, acyl and aryl radicals are unsubstituted or mono- or polysubstituted, R ⁴ , R ⁵ : hydrogen, C 1 -C 8 -alkyl, C 6 -C 14 -aryl, C 1 -C -heteroaryl, C 1 -C 8 -acyl, -CONR ₂ , where these are alkyl, aryl -, heteroaryl, acyl and -CONR2 radicals are unsubstituted or mono- or polysubstituted, or R ⁴ and R ⁵ together form a C4-C8-alkylene chain, wherein also a CH ₂ Group can be replaced by NH or O and wherein this C4-C8 chain is unsubstituted or mono- or polysubstituted R: C1-C8-alkyl, C6-C14-aryl, C1-C13-heteroaryl. The process of claim 1, wherein the cyclization is carried out starting from the enol ether I. Process according to Claim 2, characterized in that the enol ether I is obtained starting from ketone IV by reaction with metallated acetonitrile or a metallated acetonitrile derivative according to the following reaction scheme:

where M is Li, Na, K, MgY, Mg _0.5 , CaY, Ca _0.5 , ZnY, Zn _0.5 , CdY, Cd _0.5 , Cu, TiY ₃ and Y for X or I, OR, O-CO-R stands. Process according to claim 1, wherein the cyclization starting from the acetal III is carried out. Method according to. Claim 4, characterized in that acetal III is reacted starting from ketone V by reaction with metallated acetonitrile or a metalated acetonitrile derivative in the sense of the following reaction scheme.

where M is Li, Na, K, MgY, Mg _0.5 , CaY, Ca _0.5 , ZnY, Zn _0.5 , CdY, Cd _0.5 , Cu, TiY ₃ and Y for X or I, OR, O-CO-R stands. Method according to one of claims 1 to 5, characterized in that R ² = hydrogen. Method according to one of claims 1 to 6, characterized in that the radical R _f is trifluoromethyl. Method according to one of claims 1 to 7, characterized in that it is in the nitrogen compound is an amine. Method according to one of claims 1 to 8, characterized in that it is in the nitrogen compound is ammonia.