Patent GB-1121922-A (GB)
Title: Pyrimidine derivatives
Inventor: HEPWORTH WALTER
IPC: C07D239/26
Filed: 1966-06-17
Abstract: Novel pyrimidines (and salts thereof, such a alkali metal, alkaline earth metal, aluminium, ammonium and organic base salts) of the general formula <FORM:1121922/C2/1> wherein W is H or an alkyl radical of not more than 4 carbons, X is H, an alkyl or alkoxy radical of not more than 4 carbons, or a halogen atom, Y is a phenyl or benzyl radical, either of which may optionally be substituted by one or two halogen atoms or by the -CF3 radical, and Z represents a radical of formula -CR1R2R3, wherein R1 is H, an alkyl radical of not more than 3 carbons or a Cl or Br atom, R2 is H, an alkyl radical of not more than 3 carbons, an alkoxycarbonyl radical or a Cl or Br atom, and R3 represents a radical of formula -CO2R4 or -CONHR5, wherein R4 is H or an alkyl, dialkylaminoalkyl or benzyl radical and R5 is H or an amino, dialkylaminoalkyl, alkoxycarbonylalkyl or carboxyalkyl radical provided that the Y and Z radicals are not linked to adjacent carbon atoms in the pyrimidine nucleus and excluding ethyl 4 - chloro - 2 - phenylpyrimid - 5 - ylacetate, ethyl 2 - phenylpyrimid - 5 - ylacetate, 2-phenylpyrimid-5-ylacetic acid, ethyl 2-benzyl-pyrimid - 5 - ylacetate, ethyl 2 - benzyl - 4 - chloropyrimid - 5 - ylacetate and ethyl 4-methyl - 2 - phenylpyrimid - 5 - ylacetate, are prepared:  (i) by halogenation of a 2-, 4- or 6-hydroxypyrimidine (i.e. X is -OH and W, Y and Z are as above defined provided that neither R1 nor R2 is Cl or Br) to give the corresponding 2-, 4- or 6-halopyrimidine which may be further converted to the corresponding 2-, 4- or 6-alkoxypyrimidine by treatment with an alkali metal alkoxide; (ii) by reacting a 2-, 4-, 5- or 6-hydroxypyrimidine (W, Y and Z as defined above provided that neither R1 nor R2 is Cl or Br) with a diazoalkane to give the corresponding 2-, 4-, 5- or 6-alkoxypyrimidine; (iii) by dehalogenation of a 2-, 4-, 5- or 6-halopyrimidine (W, Y and Z as defined above provided that neither R1 nor R2 is Cl or Br), thus affording a pyrimidine as defined above, wherein X is H; (iv) a compound wherein Z is -CR1R2.CO2H (W, X, Y, R1 and R2 as defined above provided that R1 is not Cl or Br and R2 is not Cl or Br or an alkoxycarbonyl radical) is prepared by hydrolysing a corresponding compound, wherein Z is -CR1R2CN or -CR1R2CONH2 or -CR1R2.CO2R6, wherein R6 is an alkyl, phenyl or benzyl radical; (v) a compound wherein Z is -C.Alk.R2.CO2R4 (W, X, Y, R2 and R4 as defined above provided that R2 is not Cl or Br and Alk is an alkyl radical of not more than 3 carbons) is prepared by a -alkylation of the corresponding pyrimidine, wherein Z is -CH.R2.CO2R4; (vi) a compound wherein Z is -CR1R2.CONHR5 (W, X and Y as defined above, R1 and R2 stand for H or an alkyl radical of not more than 3 carbons and R5 is H or an amino or dialkylaminoalkyl radical and salts thereof) is prepared by reacting the corresponding pyrimidine wherein Z is -CR1R2.CO2R6 (R6 as defined in iv) with an amine, R5NH2 (R5 as defined above); (vii) a compound wherein Z is -CR1R2.CONHR5 (W, X, Y, R1 and R2\h as defined above provided that neither R1 nor R2 is Cl or Br, and R5 is an alkoxycarbonylalkyl or dialkylaminoalkyl radical, and salts thereof) is prepared by reacting the corresponding pyrimidine wherein Z is -CR1R2.CO2H with an amine, R5.NH2 in the presence of dicyclohexylcarbodiimide, the products in which R5 is an alkoxycarbonylalkyl radical may be hydrolysed to give compounds wherein R5 is the carboxyalkyl radical; (viii) esters wherein Z is -CR1R2.CO2R4 (W, X and Y as defined above, R1 and R2 stand for H or an alkyl radical of not more than 3 carbons and R4 is an alkyl, dialkylaminoalkyl or benzyl radical) are prepared by reacting the corresponding pyrimidine wherein Z is -CR1R2.CO2M (M is a metal atom) with a halide R4Hal, or by reacting the appropriate carboxylic acid with a compound of formula R4OH in the presence of an inorganic acid or dicyclohexylcarbodiimide, or by interaction of the appropriate compound wherein Z is -CR1R2.CO2(CH2)nCH3 (n is 0 o 1) and an aluminium derivative, AlOR4, wherein R4 is an alkyl radical of more than 2 carbon atoms, or a dialkylaminoalkyl or benzyl radical; (ix) chlorination or bromination of compounds wherein R1 or R1 and R2 stands or stand for hydrogen produces corresponding compounds, wherein R1 is Cl or Br and R2 is H, an alkyl radical of not more than 3 carbons, or an alkoxycarbonyl radical or wherein R1 and R2 are selected from Cl and Br atoms; (x) hydrolysis of a nitrile (Z is -CR1R2.CN) yields the corresponding amide wherein W, X and Y are as defined above and R1 and R2 stand for H or an alkyl radical of not more than 3 carbons and the nitrile or amide may be converted to the corresponding ester wherein Z is -CR1R2.CO2R4 (R4 is an alkyl or benzyl radical) by reacting under anhydrous and acidic conditions, with a compound of formula R4OH; (xi) a dicarboxylate compound wherein Z is -CR1(CO2R4)2 (W, X and Y as defined above, R1 is H or an alkyl radical of not more than 3 carbons and R4 is an alkyl radical) and not linked to the 5-position of the pyrimidine nucleus is prepared by reacting Na or K, or a hydride, amide or alkoxide thereof with a carbonate, CO.(OR4)2 and the corresponding pyrimidine compound wherein Z is -CH2R1; (xii) heating the previous dicarboxylate with an inorganic base in the presence of water yields the corresponding compound wherein Z is -CHR1.CO2H (and salts thereof) and (xiii) a compound wherein W and X are hydrogen, Y is as defined above and attached at the 5 - position and Z is -CHR1CONH2, attached at the 2-position of the pyrimidine nucleus, and wherein R1 is H or an alkyl radical of not more than 3 carbons, is obtained by the interaction of an appropriate amidine, H2NCO.CHR1.C=NH.(NH)2 and an acrolein, OCH.CY=CH.NR72 (R7 is an alkyl radical).  Pharmaceutical compositions contain as the active ingredient the above novel compounds, have anti-inflammatory, analgesic and anti-pyretic activity and may be administered in the form of tablets, pills, capsules, solutions, suspensions, injectable solutions or suspensions, creams, lotions or ointments.  2 - Amino - 6 - p - chlorophenyl - 4 - methylpyrimidine is obtained by the interaction of guanidine carbonate and p-chlorobenzoyl acetone and is converted in successive steps to the corresponding 2-hydroxy compound (by heating under reflux with concentrated HCl and neutralizing), 2-chloro compound and 2-ethoxy compound.  Ethyl 6 - hydroxy - 2 - phenylpyrimid - 4 - ylacetate is obtained by the interaction of benzamidine hydrochloride, and diethyl acetone-dicarboxylate.  2 - p - Chlorophenyl - 4 - methylpyrimidine, obtainable from p-chlorobenzamidine hydrochloride and formyl acetone dimethyl acetal, is converted to ethyl 2 - p - chlorophenylpyrimid-4-ylpyruvate, by treatment with diethyl oxalate and KOEt, which in turn is converted to the corresponding oxime ethyl ester using NH2OH.HCl, which is hydrolysed to the oximino free acid, which acid is heated with acetic anhydride to yield 2 - p - chlorophenyl - 4 - cyanomethylpyrimidine; 4 - p - chlorophenyl - 2 - cyanomethylpyrimidine is obtained using an identical reaction sequence and the corresponding intermediates are described; 4-p-chlorophenyl - 2 - methylpyrimidine, however, is obtained from acetamidine hydrochloride, NaOEt and p-chlorophenyl-b -chlorovinylketone.  4 - Chloro - 2 - p - chlorophenyl - 5,6 -dimethylpyrimidine is prepared by the interaction of p-chlorobenzamidine hydrochloride and ethyl 2-methylacetoacetate followed by treatment of the resulting 4-hydroxy compound with POCl3; dehalogenation of the 4-chloro compound using Zn dust affords 2-p-chlorophenyl-5,6-dimethylpyrimidine. p-Trifluoromethylbenzamidine hydrochloride, prepared by ammonolysis of the corresponding nitrile, is reacted with diethyl acetonedicarboxylate to yield ethyl 6-hydroxy-2-p-trifluoromethylphenylpyrimid-4-ylacetate.  2 - p - Chlorophenyl - 4,6 - dimethylpyrimidine is prepared by the interaction of p-chlorobenzamidine hydrochloride and acetyl acetone. 2 - p - Chlorophenyl - 4 - methoxy - 6 - methylpyrimidine is obtained by treating the corresponding 4-chloro compound with NaOMe/MeOH.  a - p - Chlorophenyl - b  - dimethylaminoacrolein is obtained by the interaction of dimethyl formamide and p-chlorophenylacetic acid in the presence of POCl3.  Ethyl 2 - p - Chlorophenyl - 6 - hydroxy - 4 - methylpyrimid-5-ylacetate is prepared from p-chlorobenzamidine hydrochloride and diethylacetylsuccinate.  Ethyl 2 - p - chlorophenyl - 6 - hydroxypyrimid-4-ylacetate is obtained from p-chlorobenzamidine hydrochloride and diethyl acetonedicarboxylate; the corresponding methyl ester is obtained using dimethyl acetone-dicarboxylate instead of diethyl acetonedicarboxylate.  Ethyl 2 - m - chlorophenyl-, ethyl 2-p-bromophenyl- and ethyl 3,4-dichlorophenyl-6-hydroxy-pyrimid-4-ylacetates are also described. Ethyl 2 - p - chlorophenyl - 4 - hydroxy-pyrimid-5-ylacetate is obtained from diethyl formyl succinate and p-chlorobenzamidine hydrochloride.  Ethyl 2 - p - chlorobenzyl - 4 - hydroxy-pyrimid-5-ylacetate is prepared by the interaction of diethyl formyl succinate and a -4-chlorophenylacetamidine hydrochloride. Ethyl 6 - chloro - 2 - m - chlorophenylpyrimid-4-ylacetate is obtained from the corresponding 6-hydroxy compound using POCl3.