GB2369359A - N-Phenyl-4-(4-pyridyl)-2-pyrimidinamines - Google Patents
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
A process for the preparation of N-phenyl-4-(pyridin-4-yl)-2-pyrimidinamines of the formula I <EMI ID=1.1 HE=45 WI=74 LX=511 LY=694 TI=CF> <PC>wherein<BR> <DL TSIZE=3> <DT>R<SB>1</SB><DD>is fluorine or chlorine <DT>R<SB>2</SB><DD>is C<SB>1</SB>-C<SB>6</SB>alkyl, C<SB>1</SB>-C<SB>3</SB>alkoxy, fluorine, chlorine, bromine, iodine, halo-C<SB>1</SB>-C<SB>6</SB>alkyl, halo-C<SB>1</SB>-C<SB>3</SB>alkoxy, hydroxy, phenyl, amino, C<SB>1</SB>-C<SB>3</SB>alkylamino, di(C<SB>1</SB>-C<SB>3</SB>alkyl)amino, C<SB>2</SB>-C<SB>4</SB>alkanoyl, propenyloxy, carboxy, carboxymethoxy, ethoxycarbonylmethoxy, sulfanilamido, N,N-di-(C<SB>1</SB>-C<SB>3</SB>alkyl)sulfanilamido, N-methylpiperazinyl, piperidinyl, 1H-imidazol-1-yl, 1H-triazol-1-yl, 1H-benzimidazol-2-yl, 1-naphthyl, cyclopentyl, 3,4-dimethylbenzyl or a radical of one of the formulae: -CO<SB>2</SB>R<SB>3</SB>, -NH-CO-R<SB>3</SB>, -N(R<SB>3</SB>)-CO-R<SB>4</SB>, -O-(CH<SB>2</SB>)<SB>n</SB>-N(R<SB>3</SB>)R<SB>4</SB>, -CO-NH-(CH<SB>2</SB>)<SB>n</SB>-R<SB>4</SB><SP>a</SP>, -CO-NH-(CH<SB>2</SB>)<SB>n</SB>-N(R<SB>3</SB>)R<SB>4</SB>, -CH(CH<SB>3</SB>)-NH-CHO, -C(CH<SB>3</SB>)=N-OH, -C(CH<SB>3</SB>)=N-OCH<SB>3</SB>, - CH(CH<SB>3</SB>)-NH<SB>2</SB>, -NH-CH<SB>2</SB>-CO-N(R<SB>3</SB>)R<SB>4</SB>, -(CH<SB>2</SB>)<SB>m</SB>-R<SB>6</SB>-X-(CH<SB>2</SB>)<SB>m</SB>-R<SB>6</SB>, -X-(CH<SB>2</SB>)<SB>m</SB>-R<SB>6</SB>-X-(CH<SB>2</SB>)<SB>m</SB>-R<SB>6</SB> <EMI ID=1.2 HE=15 WI=99 LX=406 LY=1991 TI=CF> wherein R<SB>3</SB> and R<SB>4</SB> are each independently of the other C<SB>1</SB>-C<SB>3</SB>alkyl, R<SB>4</SB><SP>a</SP> is hydroxy, amino or imidazolyl, X is oxygen or sulfur, m is 1, 2 or 3, n is 1, 2, or 3, R<SB>5</SB> is hydrogen, C<SB>1</SB>-C<SB>3</SB>alkyl, C<SB>1</SB>-C<SB>3</SB>alkoxy, chlorine, bromine, iodine or trifluoromethyl, R<SB>6</SB> is 1H-imidazolyl or morpholinyl, and R<SB>7</SB> is C<SB>1</SB>-C<SB>3</SB>alkyl or is phenyl that is unsubstituted or mono- substituted by C<SB>1</SB>-C<SB>3</SB>alkyl, halogen or trifluoromethyl; <DT>R<SB>0</SB><DD>is hydrogen, halogen, lower alkoxy or lower alkyl, and the salts thereof, is disclosed. </DL> The N-phenyl-4-(pyridin-4-yl)-pyrimidine-2-amines of the formula I are novel compounds when R<SB>1</SB> is fluorine and are valuable intermediates for the preparation of pharmacologically active compounds.
Description
Process for Preparation of N-phenyl-4-(4-pyridyl)2-pyrimidinamines
The present invention relates to a process for the preparation of N-phenyl-4- (4-pyridyl)-2- pyrimidinamines and to novel compounds prepared by that process.
The N-phenyl-4- (4-pyridyl)-2-pyrimidinamines which can be prepared by the process according to the present invention correspond to the formula I
wherein
Ri is fluorine or chlorine
R2 is Ci-C6alkyl, C1-C3alkoxy, fluorine, chlorine, bromine, iodine, halo-C1-C6alkyl, halo-C1-C3alkoxy, hydroxy, phenyl, amino, C1-C3alkylamino, di (C1-C3alkyl) amino,
C2-C4alkanoyl, propenyloxy, carboxy, carboxymethoxy, ethoxycarbonylmethoxy, sulfanilamido, N, N-Di-(C1-C3alkyl)sulfanilamido, N-methyliperazinyl, piperidinyl, 1 H-imidazol-1-yl, 1 H-triazol-1-yl, 1 H-benzimidazol-2-yl, 1-naphthyl, cyclopentyl, 3, 4-dimethylbenzyl or a radical of one of the formulae :
a - C02R3,-NH-CO-R3,-N (R3)-CO-R4,-0- (CH2) n-N (R3) R4,-CO-NH- (CH2) n-R4, - CO-NH- (CHz) n-N (R3) R4,-CH (CH3)-NH-CHO,-C (CH3) =N-OH,-C (CH3) =N-OCH3,
CH (CH3)-NH2,-NH-CH2-CO-N (R3) R4,- (CH-Re-XCH-Re, -X-(CH2)m-R6-X-(CH2)m-R6
wherein R3 and R4 are each independently of the other C1-C3alkyl, R4a is hydroxy, amino or imidazolyl, X is oxygen or sulfur, m is 1,2 or 3, n is 1,2, or 3, As is hydrogen, Ci-C3alkyl, C1-C3alkoxy, chlorine, bromine, iodine or trifluoromethyl, R6 is 1 H-imidazolyl or morpholinyl, and R7 is C1-C3alkyl or is phenyl that is unsubstituted or mono-substituted by C1-C3alkyl, halogen or trifluoroemthyl ;
Ro is hydrogen, halogen, lower alkoxy or lower alkyl, and the salts thereof.
The N-phenyl-4- (4-pyridyl)-2-pyrimidinamines of the formula I are valuable intermediates for the preparation of pharmacologically active compounds which inhibit protein kinase C with a high degree of selectivity. These active substances may be obtained from the N-phenyl-4 (4-pyridyl)-2-pyrimidinamines of the formula I by reaction with various amino compounds, for example alkylamines, hydroxyalkylamines, morpholine, piperazine etc. Such active compounds are described, for example, in WO 95/09851 and, in particular, in WO 95/09853.
As described in WO 95/09853, compounds of the formula 1, wherein Ri is chlorine, may be prepared by converting 4-acetylpyridine (1) with m-chloro-perbenzoic acid (mCPBA) or hydrogen peroxide into the corresponding N-oxide (2), reacting the N-oxide (2) with phosphorus oxychloride to form 4-acetyl-2-chloropyridine (3), which is further reacted with a dialkylformamide dialkylacetal (4), preferably dimethylformamide diethylacetal, to form a 3-dialkylamino-1- (2-chloro-4-pyridyl)-2-propen-1-one (5), which is further reacted with a 1- (substphenyl)-guanidine (6) to form the N-phenyl-4- (2-chloro-4-pyridyl)-2-pyrimidineamine (6) according to the following reaction sequence:
Alternatively, the N-phenyl-4- (2-chloro-4-pyridyl)-2-pyrimidinamine (6) can be obtained by
reacting the N-oxide (2) with a dialkylformamide dialkylacetal (4) to form a 3-dialkylamino-1 (4-pyridyl)-2-propen-1-one (5a) which is unsubstituted in the 2-position of the pyridine ring, and further reacting the 3-dialkylamino-1- (4-pyridyl)-2-propen-1-one (5a) with a 1- (substphenyl)-guanidine (6) to form a N-phenyl-4- (4-pyridyl)-pyrimidine-2-amine which is unsubstituted in the 2-position of the pyridine ring, and finally introducing the chlorine atom into the 2-position of the pyridine ring by reaction with phosphorus oxychloride.
The methods known from the prior art are disadvantageous in two aspects. First, the methods do not allow the preparation of the compounds of the formula I wherein Ri is fluorine which in comparison to chlorine is more appropriate as leaving group in the reaction with various amines to produce the active final compounds. Second, the 2-chloropyridine compounds prepared by reaction of the pyridine-N-oxides with phosphorus oxychloride are usually obtained only in poor yield of about 60 to 65% of the theory which detrimentally affects the overall yield obtainable by the known method.
It is the object of the present invention to overcome the disadvantages of the prior art and to provide a process according to which the N-phenyl-4- (2-chloro-4-pyridyl)-2-pyrimidinamines of the formula I can be prepared from easily accessible starting materials in good yield and
which process apart from the preparation of the compounds of the formula I in which Ri is chlorine also allows the preparation of compounds of the formula I in which Ri is fluorine.
ktxlo According to the present invention it is suggested to prepare the N-phenyl-4- (2-chro-4
According to
pyridyl)-2-pyrimidinamines of the formula 1, as defined above, by a process which comprises reacting a pyridylpyrimidine of the formula 11
wherein Ri is as defined for formula 1, in the presence of an inert solvent with an aniline of the formula III
wherein R2 and Ro are as defined for formula 1.
The reaction of a pyridylpyrimidine of the formula 11 with an aniline of the formula III may be carried out in an acidic aqueous reaction medium. Suitable aqueous reaction media are water or a mixture of water with a water-miscible organic solvent, such as a lower alkanol, glyme, digylme, tetrahydrofuran, dioxane or acetone. Suitable acids are Lewis acids such as hydrochloric acid, sulfonic acids (R-SO3H) or BF3 : C2Hs-OHs. Preferably the reaction is carried out in aqueous hydrochloric acid as reaction medium in which the hydrochloric acid is present in an amount 0.8-1. 2 equivalents and preferably in equimolar amount calculated on the amount of pyridylpyrimidine of the formula 11. The pyridylpyrimidine of the formula 11 and the aniline of the formula III are advantageously used in equimolar amount or with a slight excess of aniline. Preferably equivalent amounts of pyridylpyrimidine of the formula 11 and the aniline of the formula III are used. Advantageously the reaction is carried out at elevated temperature, preferably at the reflux temperature of the reaction mixture. When the reaction of the pyridylpyrimidine of the formula 11 and the aniline of the formulais carried out in water in the presence of an equimolar amount of hydrogen chloride the hydrochlorides of the N-phenyl-4- (2-chloro-4-pyridyl)-2-pyrimidinamines of the formula I are formed which can be isolated as such or, after addition of a base, such as an alkali metal hydroxide, an tertiary amine or an alkali metal carbonate or bicarbonate, the free N-phenyl 4- (2-chloro-4-pyridyl)-2-pyrimidineamines of the formula I can be obtained. Suitable bases are, for example, sodium or potassium hydroxide, triethylamine, ethyl-diisopropylamine and sodium or potassium carbonate and sodium and potassium bicarbonate. A preferred base is sodium bicarbonate.
Further, the reaction of the pyridylpyrimidine of the formula 11 with the aniline of the formula
III may be carried out in an anhydrous reaction medium either in the presence of a strong base or in the presence of a strong acid. Suitable anhydrous reaction media are anhydrous organic solvents such as dichloroethane, benzene, toluene, xylene, and even more preferably anhydrous tetrahydrofuran, dioxane, dimethylformamide, dichloromethane, and anhydrous acetonitril.
Suitable strong bases are, for example, lithium alkyl compounds such as n-butyl lithium, and alkali metal hydrides, such as sodium hydride. When the reaction of a pyridylpyrimidine of the formula it with a aniline of the formula III is carried out in the presence of a strong base the aniline of the formula ttt is used in equimolar amount or in a slight excess. Preferably, the aniline of the formulais used in equimolar amount. The reaction of a pyridylpyrimidine of the formula 11 with an aniline of the formula III is advantageously carried out at elevated temperature, preferably at a temperature of from + 75OC to the reflux temperature of the reaction medium. After completion of the reaction the N-phenyl-4- (2-chloro-4-pyridyl)-2pyrimidinamines of the formula I may be isolated from the reaction mixture by removing the solvent by distillation and purifying the crude product obtained by column chromatography.
Suitable strong acids are, for example, organic sulfonic acids, such as methanesulfonic acid, benzenesulfonic acid, phosphorus acid, polyphosphorus acid, trifluoroacetic acid and, preferably, p-toluenesulfonic acid. The acid is advantageously used in an amount of 0.6 to 1.1 equivalents with respect to the amount of pyridylpyrimidine of the formula 11. Preferably 0.8 to 0.9 equivalents of acid are used calculated on the amount of pyridylpyrimidine of the formula 11. When the reaction of a pyridylpyrimidine of the formula it with a aniline of the formulais carried out in the presence of a strong acid the aniline of the formula III is used in equimolar amount or in a slight excess. Preferably, the aniline of the formula III is used in an amount of 1.25 to 2 equivalents and most preferably in an amount of 1.4 to 1.6 equivalents. Preferred anhydrous solvents for the reaction in the presence of a strong acid are tetrahydrofuran and dioxane. The reaction of a pyridylpyrimidine of the formula 11 with a aniline of the formula III in an anhydrous reaction medium in the presence of a strong acid is advantageously carried out at elevated temperature, preferably at the reflux temperature of the reaction medium. After completion of the reaction the N-phenyl-4- (2-chloro-4-pyridyl)-2- pyrimidinamines of the formula I can be isolated after concentrating the reaction mixture by distilling off a part of the solvent, precipitating the reaction product by addition of water, addition of a base to neutralize the acid and filtration.
The pyridylpyrimidines of the formula 11 can be obtained by reacting a iodopyridine (7) with n-butyllithium to form the corresponding 4-Li-pyridine (8) and further reacting this intermediate either with a trialkylstannyl chloride, preferably tributylstannyl chloride to form the corresponding 4-trialkylstannylpyridine (9a) or with zinc chloride to form the corresponding 4-pyridyl-zinc chloride (9b) which is then reacted with 2, 4-dichloropyrimidine (10) to obtain a pyridylpyrimidine of the formula it according to the following reaction scheme:
The 4-iodopyridine (7) can be obtained according to the procedure of P. Rocca et al. J. Org.
Chem. 58,7832 (1993) by reacting the corresponding 3-iodopyridine in anhydrous tetrahydrofuran with Li-diisopropylamine (LDA) in order to move the iodine atom from the 3-position to the 4-position of the pyridine ring. The 3-iodopyridine in turn can be obtained according to the procedure of L. Estel et al., J. Org. Chem. 53,2740 (1988) by reacting a corresponding 2-Ri-pyridine in the presence of Li-diisopropylamine (LDA) in anhydrous tetrahydrofuran with iodine.
According to the present invention the N-phenyl-4- (4-pyridyl)-2-pyrimidinamines of the formula I are advantageously prepared by reacting a pyridylpyrimidine of the formula 11 with an aniline of the formula III, as defined above, wherein the pyridylpyrimidine of the formula 11
wherein Ri is as defined for formula 1, is prepared by reacting a compound of the formula V
wherein Ri is as defined for formula 1, and As represents-ZnCl or-Sn (alkyl, in the presence of a palladium catalyst and in the presence of an inert solvent at elevated temperature with 2, 4-dichloropyrimidine to form a compound of the formula 11.
Suitable palladium catalysts are palladium (0) complex compounds. A preferred palladium (0) complex compound is tetrakis- (triphenylphosphin) palladium (0). The palladium catalyst is preferably used in an amount of 0.03-0. 1 equivalents based on 2, 4-dichloropyri- midine. Most preferably the palladium catalyst is used in an amount of 0.05 equivalents based on 2, 4-dichloropyrimidine.
Among the compounds of the formula V the 4-pyridyl zinc chlorides of the formula Va
in which Ri is as defined for formula 1, are preferred.
The reaction of a compound of the formula V with 2, 4-dichloropyrimidine is advantageously carried out at a temperature of from +50oC to reflux temperature of the reaction mixture.
The 2, 4-dichloropyrimidine is advantageously used in an amount of 0.75-1. 25 equivalents based on compound of the formula V. Preferably, the 2, 4-dichlorpyrimidine and the compound of the formula V are used in equimolar amounts.
According to the present invention the N-phenyl-4- (4-pyridyl)-2-pyrimidinamines of the formula I are advantageously prepared by reacting a pyridylpyrimidine of the formula 11 with an aniline of the formula III, as defined above, wherein the pyridylpyrimidine of the formula 11 as defined above is prepared by a process which comprises a) reacting a 4-iodopyridine of the formula IV
wherein Ri is as defined for formula I, in an inert solvent at a temperature of-50"C to-80 C with a lithium alkyl compound to form a 4-Li-pyridine of the formula V
b) further reacting the 4-Li-pyridine of the formula V formed in step a), without isolation, with anhydrous zinc chloride to form the corresponding 4-pyridyl-zinc chloride of the formula
Va
and c) further reacting the 4-pyridyl zinc chloride of the formula formed in step b), without
isolation, in the presence of a palladium catalyst at elevated temperature with 2, 4-dichloropyrimidine of the formula VII
to obtain a compound of the formula 11.
The preparation of a pyridylprimidine of the formula 11 according to the afore-mentioned process is advantageously carried out in anhydrous tetrahydrofuran as inert solvent. The lithium alkyl compound used in step a) of the afore-mentioned process is advantageously
used in an amount of 1 to1 5 equivalents, preferably 1. 03 tol. 1 equivalents, based on the
compound of the formula and, preferably, the lithium alkyl compound is n-butyl lithium. In step b) of the afore-mentioned process the reaction of the 4-Li-pyridine of the formula V, V
with anhydrous zinc chloride is advantageously carried out under nitrogen at a temperature of-50 C to-90 C, preferabty-65 C to-75 C.
In step c) of the afore-mentioned process the palladium catalyst is advantageously used in an amount of 0.001 to 0.01 equivalents based on the 4-pyridyl zinc chloride of the formula
Va. Preferably, the palladium catalyst is tetrakis (triphenylposphin) palladium (O).
Further, in step c) the 2, 4-dichloropyridine of the formula VII is used in an amount of 0.65 to 1 equivalent based on 4-pyridyl zinc chloride of the formula Va.
Further, in step c) the reaction of a 4-pyridyl zinc chloride of the formula Va with a 2, 4-dichloropyrimidine of the formula VII is advantageously carried out at a temperature of from +50 C to reflux temperature of the reaction mixture.
The generic expressions used for the definition of formula I have the following meanings:
Ro as halogen is fluorine, chlorine, bromine and iodine, preferably chlorine.
Ro as lower alkoxy is preferably methoxy.
Ro as lower alkyl is preferably methyl.
In the R2 C1-C6alkyl and the hato-Ci-Ce-atkyi groups the alkyl group is preferably a C1-C3alkyl group. More preferably, the alkyl group in the R2 C1-C6alkyl and the halo d-C6alkyl groups is a methyl group. C1-C3-alkyl groups include methyl, ethyl, n-propyl and isopropyl.
In the R2 halo-C1-C6alkyl and halo-Cl-C. 3alkoxy groups halo is fluorine, chlorine or bromine, and up to 3 haloatoms can be present in these haloalkyl and haloalkoxy groups. Preferably the haloalkyl group is a trifluormethyl group and the haloalkoxy group is a trifluoromethoxy group.
Within the scope of this text the term"lower"denotes radicals having up to and including 6, preferably up to and including 3 carbon atoms. Unless otherwise indicated in the context concerned, lower alkyl is preferably methyl or ethyl.
The compounds of the formula I can form acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulfuric acid, or a phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example aliphatic mono-or di-carboxylic acids, such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid, oxalic acid, or amino acids, such as arginine or lysine, aromatic carboxylic acids, such as benzoic acid, 2-phenoxy-benzoic acid, 2-acetoxy-benzoic acid, salicyclic acid, 4-aminosalicylic acid, aromatic aliphatic carboxylic acids, such as mandelic acid or cinnamic acid, heteroaromatic carboxylic acids, such as nicotinic acid or isonicotinic acid, aliphatic sulfonic acids, such as methane-, ethane or hydroxyethane-sulfonic acid, or aromatic sulfonic acids, for example benzene-, p-toluene-or naphthalene-2-sulfonic acid. Mono-, di-or, if other basic groups, such as amino groups are present in the radical R2, poly-acid addition salts can be formed.
Compounds of the formula I that possess both basic and acidic groups may form intramolecular salts.
Preferred compounds of formula I correspond to formula la
wherein
Ri is as defined for formula 1, R2 is C1-C6alkyl, Ci-C3alkoxy, chlorine, bromine, iodine, halo-C1-C6alkyl, halo-Ci-C3alkoxy, hydroxy, phenyl, amino, mono (C1-C3alkyl) amino, di (Ci-C3alkyl) amino, C2-C4alkanoyl, propenyloxy, carboxy, carboxymethoxy, ethoxycarbonyl-methoxy. sulfanilamido,
N, N-di (Ci-C3alkyl) sulfanilamido, N-methyl-piperazinyl, piperidinyl, 1 H-imidazol-1-yl, 1 H-triazol-t-yl, 1 H-benzimidazol-2-yl, t-naphthyl. cyclopentyl, 3, 4-dimethyl-benzyl or a radical of one of the formulae :-CO2R3,-NH-CO-R3,-N (R3)-CO-R4,-0- (CH2) n-N (R3)-R4, - CO-NH-CH2) n-N (R3)-R4,-CH (CH3)-NH-CHO,-C (CH3) =N-OH,-C (CH3) =N-O-CH3, - C (CH3)-NH2,-NH-CH2-CO-N (R3)-R4,- (CH2) mR6,-X- (CH2) m-R6,
wherein R3 and R4 are each independently of the other C1-C3alkyl, X is oxygen or sulfur, m is 1,2 or 3, n is 2 or 3, R5 is hydrogen, Ci-Csatkyt, C1-C3alkoxy, chlorine, bromine, iodine or trifluoromethyl, R6 is 1 H-imidazol-t-yl or morpholinyl and R7 is C1-C3alkyl or is phenyl that is unsubstituted or mono-substituted by CrC3alkyl, halogen or by trifluoromethyl, and the salts thereof.
Preferred are compounds of the formula I in which Ri is fluorine.
A preferred group comprises compounds of formula I wherein
Ro is hydrogen, halogen, lower alkoxy or lower alkyl,
R2 is chlorine, trifluoroemthyl, carboxy, a radical of the formula -CO2R3 wherein R3 is
C1-C3alkyl or a radical of the formula -CO-NH-(CH2)n-R4a wherein n is 2 or 3 and R4a is hydroxy, amino or imidazolyl, and the salts thereof.
A further preferred group comprises compounds of formula I wherein
Ro is hydrogen, and R2 is chlorine or trifluoroemthyl and the salts thereof.
Preferred are compounds of formula I wherein
Ro is hydrogen, chlorine, lower alkyl or lower alkoxy,
R2 is chlorine, trifluoromethyl, carboxy, a radical of the formula-CO2R3 wherein R3 is C1-C3alkyl, or a radical of the formula -CO-NH-(CH2)n-R4a wherein n is 2 or 3 and R is hydroxy, amino or imidazolyl, and the salts thereof.
Especially preferred are compounds of formula I wherein
Ro is hydrogen, chlorine, methyl or methoxy,
R2 is chlorine, trifluoroemthyl, carboxy, a radical of the formula-CO2R3 wherein R3 is methyl, or a radical of the formula-CO-NH- (CH2) n-R4 wherein n is 2 or 3 and R4ais hydroxy, amino or 1 H-imidazol-4-yl, and the salts thereof.
The compounds of the formula I wherein Ri is fluorine and Ro and R2 are as defined above for formula I are novel. These novel compounds which are also within the scope of the present invention correspond to the formula lb
wherein
R2 is d-Ceatky), C1-C3alkoxy, fluorine, chlorine, bromine, iodine, halo-C1-C6alkyl halo-Ci-C3alkoxy, hydroxy, phenyl, amino, C1-C3alkylamino, di (C1-C3alkyl) amino,
C2-C4alkanoyl, propenyloxy, carboxy, carboxymethoxy, ethoxycarbonylmethoxy, sulfanilamido, N, N-di-(C1-C3alkyl)sulfanilamido N-methylpiperazinyl, piperidinyl, 1 H-imidazol-1-yl, 1 H-triazol-1-yl, 1 H-benzimidazol-2-yl, 1-naphthyl, cyclopentyl, 3, 4-dimethylbenzyl or a radical of one of the formulae: -CO2R3, -NH-CO-R3, - N (R3)-CO-R4,-O- (CH2) n-N (R3) R4, -CO-NH-(CH2)n-R4a -CO-NH-(CH2)n-N (R3) R4, - CH (CH3) -NH-CHO, -C (CH3) =N-OH,-C =N-OH, -C(CH3) =N-OCH3,-CH (CH3)-NH2, -NH-CH2-CO-N (R3) R4, -(CH2)m-R6-X-(CH2)m-R6, -X-(CH2)m-R6-X-(CH2)m-R6
wherein R3 and R4 are each independently of the other C1-C3alkyl, R4 is hydroxy, amino or imidazolyl, X is oxygen or sulfur, m is 1,2 or 3, n is 1,2, or 3, Rs is hydrogen, C1-C3alkyl, Ci-C3alkoxy, chlorine, bromine, iodine or trifluoromethyl, R6 is
1 H-imidazolyl or morpholinyl, and R7 is C1-C3alkyl or is phenyl that is unsubstituted or mono-substituted by C1-C3alkyl, halogen or trifluormethyl ;
Ro is hydrogen, halogen, lower alkoxy or lower alkyl, and the salts thereof.
The preferred meanings of the radicals Ro and R2 of formula lb are the same as those defined above for formula 1.
The present invention is further illustrated by but by no means limited to the following examples.
Example 1
Preparation of N-phenyl-4- (2-fluoropyridin-4-yl)-pyrimidine-2-amine-hvdrochloride 1.50 g (7.16 mmoles) of 1.10 g of 2-chloro-4- (2-fluoropyridin-4-yl)-pyrimidine and 0.70 g (7.52 mmoles) of aniline are heated in an aqueous solution of 0.26 g (7.16 mmoles) of hydrogen chloride at reflux temperature. The reaction mixture is clear at the beginning, but after some time a voluminous yellow precipitate is formed. After a reaction time of 5 hours the reaction mixture is cooled to room temperature and the reaction product is separated by filtration. Yield : 1. 11 g (51 % of theory) of the title compound.
Example 2
Preparation of N- (3-chlorophenyl)-4- (2-fluoropyridin-4-yl)-pyrimidine-2-amine 1.10 g (5.25 mmoles) of 2-chloro-4- (2-fluoropyridin-4-yl)-pyrimidine and 0.7 g (5. 51 mmoles) 3-chloraniline are heated in an aqueous solution of 0.19 g hydrogen chloride for 6 hours at reflux temperature. Thereafter the reaction mixture is cooled to room temperature and basified by addition of a saturated aqueous solution of sodium bicarbonate. The precipitated product is separated by filtration and dried. The crude product thus obtained is purified by column chromatography (silica gel 20: 1, PE: EE = 5: 1). Yield : 0.94 g (53% of theory) of the title compound. m. p. 188-190oC.
Example 3
Preparation of N-phenyl-4- (2-fluoropyridin-4-yi)-pyrimidine-2-amine To a solution of 0.14 g (1.50 mmoles) of aniline in 20 ml of anhydrous tetrahydrofuran which is kept under an atmosphere of nitrogen 0.63 ml (1.50 mmoles) of n-butyllithium are added at a temperature of-35 C. After stirring at-35 C for 30 minutes a solution of 0.28 g (1.34 mmoles) of 2-chloro-4- (2-fluoropyridin-4-yl)-pyrimidine in 5 ml of anhydrous tetrahydrofuran is added drop-wise. Then, after warming up to room temperature, the reaction mixture is heated under reflux for 18 hours. Thereafter the solvent is removed by distillation and the solid residue is worked up by column chromatography (silica gel (20: 1, PE: EE = 5: 1). Yield : 0.16 g (44% of theory) of the title compound were obtained. m. p. 180-183 OC.
Example 4
0. 34 g (1. 62 mmoles) of 2-chloro-4- (2-fluoropyridin-4-yl)-pyrimidine, 0. 26 g (2. 04 mmoles) of 3-chloraniline and 0.26 g (1.37 mmoles) of anhydrous p-toluenesulfonic acid are refluxed in anhydrous dioxane for 5 hours. After concentrating the reaction mixture in a rotary evaporator, water is added and the reaction mixture is basified by addition of a saturated aqueous sodium bicarbonate solution. The precipitated product is separated by filtration and dried in vacuo at +50oC. Yield: 0.43 g (89% of theory) the title compound; m. p. 188-190oC.
Example 5
Preparation of the starting materials. a) 2-chloro-4- (2-fluoropyridin-4-yl)-pyrimidine 2.00 g (5.18 mmoles) of 2-fluoro-4-tributylstannylpyridine, 0.77 g (5.17 mmoles) of 2,4-dichloropyrimidine and 0.30 g (0.26 mmoles) of Pd (PPh3) 4 are heated in 15 mi of anhydrous dimethylformamide for 18 hours at reflux temperature. Thereafter the solvent is distilled off and the crude product thus obtained is purified by column chromatography (silica gel 20: 1,
PE: EE = 10: 1). Yield : 0.60 d (56% of theory); m. p.: 157-159OC.
Alternatively, 2-chloro-4- (2-fluoropyridin-4-yl)-pyrimidine is prepared according to the following procedure:
To a solution of 15.52 g (69.6 mmoles) 2-fluoro-4-iodopyridine in 300 mi of anhydrous tetrahydrofuran which is cooled to-70 C and kept under an atmosphere of nitrogen 36.35 g (83.24 mmoles) of n-butyllithium are added. After stirring for 20 minutes at-70 C a solution of 10. 44 g (76.61 mmoles) of anhydrous zinc chloride in anhydrous tetrahydrofuran is added drop-wise in a manner such that the temperature could be kept beiow-60 C. When the addition of the zinc chloride solution is completed the reaction mixture is warmed up to room temperature within a period of 1 hour and 0.40 g (0.35 mmoles) of Pd (PPh3) 4 and 7.62 g (48.73 mmoles) of 2, 4-dichloropyrimidine are added and the reaction mixture is refluxed until the reaction was completed. Then most of the solvent is removed in a rotary evaporator and the residue is poured on water. The precipitated product is separated by filtration and dried. The crude product thus obtained is purified by column chromatogrphy (silica gel, 100: 1, PE: EE = 10: 1). Yield: 9. 17 g (90% of theory) m. p.: 157-159OC. b) 4-Tributylstannyl-2-fluoropyridine To a solution of 7. 58 g (33.99 mmoles) 2-fluoro-4-iodopyridine in 50 ml of anhydrous tetra
hydrofuran which is cooled toc and kept under an atmosphere of nitrogen 14. 00 g (34.02 mmoles) of n-butyllithium are added in a manner such that the temperature could be kept at-75 C. Then, after stirring the reaction mixture for 15 minutes at-80 C, 13.28 g (40.80 mmoles) of tributylstannylchloride are slowly added. Thereafter the dark colored reaction mixture is warmed up and stirred over-night at room temperature. Subsequently, the reaction mixture is poured on water and extracted with ether. The combined extracts are dried over sodium sulfate and the ether solution is evaporated to dryness. The crude product thus obtained is purified by distillation. Yield : 10.50 g (80% of theory) of colorless liquid; b. p. 125OC/0. 02 mbar). c) 2-Fluoro-4-iodopyridine To a solution of 7.82 g (77.28 mmoles) of diisopropylamine in 200 ml of anhydrous tetrahydrofuran, after cooling to-20 C, a solution of 31.80 mi (77.27 mmoles) n-butyllithium in hexane is added. After stirring for 30 minutes and cooling toc a solution of 17.23 g (77.27 mmoles) of 2-fluoro-3-iodopyridine in 25 ml of anhydrous tetrahydrofuran is added drop-wise during 30 minutes. After 1 hour a mixture of 3 ml of water and 10 ml of tetrahydrofuran is added, and, after warming up to room temperature, additional 75 mi of water are added. Then the solution is extracted with ether and the extract is dried over sodium sulfate.
The crude product obtained after evaporating the extract to dryness is purified by vacuum distillation. Yield : 16.87 g (98% of theory) of colorless crystals ; m. p. 55-58OC, b. p. 80OC/0. 1 mbar). d) 2-Fluoro-3-iodopyridine To a solution of 10.42 g (103.0 mmoles) of diisopropylamine in 250 ml of anhydrous tetrahydrofuran, after cooling to-20 C, a solution of 42.90 mi (103.0 mmoles) n-butyllithium in hexane is added. After stirring for 30 minutes and cooling to-75 C 10.00 g (103.0 mmoles) of 2-fluoropyridine are added during 30 minutes. After stirring of the solution for 4 hours at-75 C a solution of 26.14 g (103.0 mmoles) of iodine in 50 ml of anhydrous tetrahydrofuran is added and the reaction mixture is stirred for an additional hour at-75 C. Then a mixture of 2 ml of water and 10 ml of tetrahydrofurane is added, and, after warming up to room temperature, additional 100 ml of water are added. The solution is decolorized by addition of NaHSO3 and extracted with ether. The extract is dried over sodium sulfate and the ether is distilled off. Yield : 20.7 g (90% of theory) of brown oil.
Claims (41)
1 H-imidazolyl or morpholinyl, and R7 is Ci-Caatkyf or is phenyl that is unsubstituted or mono-substituted by Ci-C3alkyl, halogen or trifluoroemthyl ;
Ro is hydrogen, halogen, lower alkoxy or lower alkyl, and the salts thereof, which process comprises reacting a pyridylpyrimidine of the formula 11
wherein Ri is as defined under formula 1, in the presence of an inert solvent with an aniline of the formula III
wherein R2 and R3 are as defined for formula 1.
2. A process according to claim 1 wherein the reaction of the pyridylpyrimidine of the formula 11 with the aniline of the formula III is carried in an aqueous reaction medium in the presence of an acid.
3. A process according to anyone of claims 1 or 2 wherein the reaction medium is aqueous hydrochloric acid.
4. A process according to claim 3, wherein hydrochloric acid is used in an amount of 0.75 to 1.25 equivalents based on the amount of pyridylpyrimidine of the formula 11.
5. A process according to claim 3, wherein hydrochloric acid is used in an amount of 0.9 to 1.1 equivalents based on the amount of pyridylpyrimidine of the formula 11
6. A process according to claim 1 wherein the reaction of the pyridylpyrimidine of the formula 11 with the aniline of the formula III is carried in an anhydrous organic solvent in the presence of an organic sulfonic acid.
7. A process according to claim 6, wherein the anhydrous organic solvent is selected from dichloromethane, dichloroethane. benzene, toluene, xylene, and preferably dimethylformamide, tetrahydrofuran, dioxane, and acetonitrile.
8. A process according to anyone of claims 5 to 7, wherein the organic sulfonic acid is used in an amount of 0.75 to1. 25 equivalents based on the amount of pyridylpyrimidine of the formula 11.
9. A process according to anyone of claims 5 to 8, wherein the organic sulfonic acid is used in an amount of 0.9 to 1. 1 equivalents based on the amount of pyridylpyrimidine of the , formula li.
10. A process according to claim 9, wherein the organic sulfonic acid is used in an amount of 0.8 to 0.9 equivalents based on the amount of pyridylpyrimidine of the formula
11 zu A process according to anyone of claims 5 to 10, wherein the organic sulfonic acid is pTtoluenesulfonic acid.
12. A process according to claim 6, wherein the reaction of the pyridylpyrimidine of the formula 11 with the aniline of the formula III is carried in anhydrous dioxane in the presence of p-toluene sulfonic acid.
13. A process according to anyone of claims 5 to 12, wherein the aniline of the formula III is used in an equimolar amount or in slight excess.
14. A process according to anyone of claims 5 to 13, wherein the aniline of the formula III is used in an amount of 1.25 to 2 moles per mole of pyridylpyrimidine of the formula 11.
15. A process according to claim 14, wherein the aniline of the formula III is used in an amount of 1.4 to 1.6 moles per mole of pyridylpyrimidine of the formula II.
16. A process according to claim 1, wherein the reaction of the pyridylpyrimidine of the formula 11 with the aniline of the formula III is carried in the presence of a strong base as activator.
17. A process according to claim 16, wherein the strong base is used in an amount of
0. 75 to 1. 25 equivalents based on the amount of pyridylpyrimidine of the formula 11.
18. A process according to anyone of claims 16 or 17, wherein the strong base is used in an amount of 0.9 to 1.1 equivalents based on the amount of pyridylpyrimidine of the formula li.
19. A process according to anyone of claims 16 to 18, wherein the strong base is a lithium alkyl compound.
20. A process according to anyone of claims 16 to 19, wherein the strong base is n-butyllithium.
21. A process according to anyone of claims 1-20, wherein the pyridylpyrimidine of the formula 11
wherein Ri is as defined for formula 1, is prepared by reacting a compound of the formula V
wherein Ri is as defined for formula 1, and As represents-ZnCl or-Sn (alkyl) 3, in the presence of a palladium catalyst and in the presence of an inert solvent at elevated temperature with 2, 4-dichloropyrimidine to form a compound of the formula II.
22. A process according to claim 21, wherein the palladium catalyst is tetrakis (triphenylphosphine) palladium (0) of the formula Pd (PPh3) 4.
23. A process according to anyone of claims 21 or 22, wherein the palladium catalyst is used in an amount of 0.03 toO. 1 equivalents based on 2, 4-dichloropyrimidine.
24. A process according to anyone of claims 21 to 23, wherein the palladium catalyst is used in an amount of 0.05 equivalents based on 2, 4-dichloropyrimidine.
25. A process according to anyone of claims 21 to 24, wherein the 2, 4-dichloropyrimidine is used in an amount of 0.75 to1. 25 equivalents based on compound of the formula V.
26. A process according to anyone of claims 21 to 25, wherein the 2, 4-dichloropyrimidine and the compound of the formula V are used in equimolar amount.
27. A process according to anyone of claims 21 to 26, wherein the compound of the formula V is a 4-pyridyl zinc chloride of the formula Va
in which Ri is as defined for formula 1.
28. A process according to claims 21 to 27, wherein the inert solvent is dimethylformamide.
29. A process according to anyone of claims 21 to 28, wherein the reaction of the compound of the formula V with the 2, 4-dichloropyrimidine is carried out at a temperature of from +50oC to reflux temperature of the reaction mixture.
30. A process according to anyone of claims 1-15, wherein the pyridinylpyrimidine of the formula 11 is prepared by a process which comprises a) reacting a 4-iodopyridine of the formula IV
wherein Ri is as defined for formula 1, in an inert solvent at a temperature of-50 C to-80 C with a lithium alkyl compound to form a 4-Li-pyridine of the formula V
b) further reacting the 4-Li-pyridine of the formula V formed in step a), without isolation, with anhydrous zinc chloride to form the corresponding 4-pridyl-zinc chloride of the formula
Va
and c) further reacting the 4-pyridyl-zinc chloride of the formula VI formed in step b), without isolation, in the presence of a palladium catalyst at elevated temperature with 2, 4-dichloropyrimidine of the formula VII
to obtain a compound of the formula 11.
31. A process according to claim 30, wherein the inert solvent is anhydrous tetrahydrofuran.
32. A process according to anyone of claims 30 or 31, wherein in step a) the lithium alkyl compound is used in an amount of 1 to 1.5 equivalents based on compound of the formula V.
33. A process according to anyone of claims 30 or 32, wherein in step a) the lithium alkyl . compound is used in an amount of 1.03 to 1.1 equivalents based on compound of the formula V.
34. A process according to anyone of claims 30 to 33, wherein in step a) the lithium alkyl compound is n-butyllithium.
35. A process according to claim 30, wherein in step b) the reaction of the 4-Li-pyridine of the formula @V with anhydrous zinc chloride is carried out under nitrogen at a temperature of -500C to-900C.
36. A process according to anyone of claims 30 to 35, wherein in step b) the reaction of the 4-Li-pyridine of the formula V with anhydrous zinc chloride is carried out under nitrogen at a temperature of -65 C to-7.. 5OC.
37. A process according to claim 30, wherein in step c) the palladium catalyst is used in an amount of 0.001-0. 01 equivalents based on 4-pyridyl zinc chloride of the formula Va.
38. A process according to anyone of claims 35 or 37, wherein the palladium catalyst used in step c) is tetrakis (triphenylposphine) palladium (0).
39., A process according to anyone of claims 30 and 37-38, wherein in step c) the
2, 4-dichloropyrimidine of formula VII is used in an amount of 0.65 to 1 equivalent based on
4-pyridyl-zinc chloride of the formula Va.
40. A process according to anyone of claims 30 and 37-39, wherein in step c) the reaction of a 4-pyridyl-zinc chloride of the formula Va with 2, 4-dichloropyrimidine of the formula Vil is carried out at a temperature of from +50oC to the reflux temperature of the reaction mixture.
41. N-Phenyl-4-(4-pyridyl)-2-pyrimidiamine of the formula b
wherein
R2 is C1-C6alkyl, C1-C3alkoxy, fluorine, chlorine, bromine, iodine, halo-CrC6alkyl, halo-Cl-C3alkoxy, hydroxy, phenyl, amino, C1-C3alkylamino, di (Ci-C3alkyl) amino,
C2-C4alkanoyl, propenyloxy, carboxy, carboxymethoxy, ethoxycarbonylmethoxy, sulfanilamido, N, N-di- (Ci-C3a) ky)) su) fani) amido N-methy) piperaziny !, piperidiny), 1 H-imidazol-1-yl, 1 H-triazol-1-yl, 1 H-benzimidazol-2-yl, 1-naphthyl, cyclopentyl, 3, 4-dimethylbenzyl or a radical of one of the formulae :-CO2R3,-NH-CO-R3, - N (R3)-CO-R4,-0- (CH2) n-N (R3) R4,-CO-NH- (CH2) n-R4',-CO-NH- (CH2) n-N (R3) R4, - CH (CH3)-NH-CHO,-C (CH3) =N-OH,-C (CH3) =N-OCH3,-CH (CH3)-NH2, - NH-CH2-CO-N (R3) R4,- (CH2) m-R6-X- (CH2),-R6,-X- (CH2),-R6-X- (CH2) m-R6
Ro wherein R3 and R4 are each independently of the other C1-C3alkyl, R4'is hydroxy, amino or imidazolyl, X is oxygen or sulfur, m is 1,2 or 3, n is 1,2, or 3, R5 is hydrogen, C1-C3alkyl, C-C3alkoxy, chlorine, bromine, iodine or trifluoromethyl, R6 is 1 H-imidazolyl or morpholinyl, and R7 is CrC3alkyl or is phenyl that is unsubstituted or mono-substituted by C1-C3alkyl, halogen or trifluoroemthyl ; is hydrogen, halogen, lower alkoxy or lower alkyl, and the salts thereof.
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| GB0025820A GB0025820D0 (en) | 2000-10-20 | 2000-10-20 | Organic compounds |
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| GB0121825A Withdrawn GB2369359A (en) | 2000-10-20 | 2001-09-10 | N-Phenyl-4-(4-pyridyl)-2-pyrimidinamines |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7655669B2 (en) | 2002-09-27 | 2010-02-02 | Novartis Ag | Pyrimidineamide derivatives and the use thereof |
| EP2161259A1 (en) | 2008-09-03 | 2010-03-10 | Bayer CropScience AG | 4-Haloalkyl substituted Diaminopyrimidine |
| WO2020168237A1 (en) * | 2019-02-14 | 2020-08-20 | Bridgene Biosciences, Inc. | Fgfr inhibitors for the treatment of cancer |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999035140A1 (en) * | 1998-01-12 | 1999-07-15 | Novartis Ag | PYRIDINYLPYRIMIDINE AMINES AS IMMUNOGLOBULINE E (IgE) SYNTHESIS INHIBITORS |
-
2000
- 2000-10-20 GB GB0025820A patent/GB0025820D0/en not_active Ceased
-
2001
- 2001-09-10 GB GB0121825A patent/GB2369359A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999035140A1 (en) * | 1998-01-12 | 1999-07-15 | Novartis Ag | PYRIDINYLPYRIMIDINE AMINES AS IMMUNOGLOBULINE E (IgE) SYNTHESIS INHIBITORS |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7655669B2 (en) | 2002-09-27 | 2010-02-02 | Novartis Ag | Pyrimidineamide derivatives and the use thereof |
| EP2161259A1 (en) | 2008-09-03 | 2010-03-10 | Bayer CropScience AG | 4-Haloalkyl substituted Diaminopyrimidine |
| WO2020168237A1 (en) * | 2019-02-14 | 2020-08-20 | Bridgene Biosciences, Inc. | Fgfr inhibitors for the treatment of cancer |
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| Publication number | Publication date |
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| GB0025820D0 (en) | 2000-12-06 |
| GB0121825D0 (en) | 2001-10-31 |
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