CA1059127A - Benzylpyrimidines - Google Patents
BenzylpyrimidinesInfo
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- CA1059127A CA1059127A CA242,038A CA242038A CA1059127A CA 1059127 A CA1059127 A CA 1059127A CA 242038 A CA242038 A CA 242038A CA 1059127 A CA1059127 A CA 1059127A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
- C07D207/327—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
- C07D239/49—Two nitrogen atoms with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Cosmetics (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Benzyl pyrimidine derivatives of the formula:
Benzyl pyrimidine derivatives of the formula:
Description
~OS912'7 - The present invention relates to ben7ylpyrimidine derivatives.
More particularly, the invention is concerned with benzylpyrimidine derivatives, a process for the manufacture thereof and antibacterial compositions containing same.
The benzylpyrimidine derivatives provided by the present invention are compounds of the general formula Rl N
wherein Rl and R2 each independently represent an amino, optionally Cl 3-alkyl-substituted pyrrolo, -NHR3, -N~R3)2, -NHR4 or -NtR3)(R4) group, R3 represents a Cl 4-alkyl group, R4 represents an acyl group derived from a lower aliphatic carboxylic or sulphonic acid, and Z represents a hydrogen, chlorine or bromine atom, a piperidino group or a group R3, -oR3 or -N(R3)2, and salts thereof.
The terms "Cl 4" and "C2 4" used in this specification denote -that the groups prefixed therewith contain 1-4 or 2-4 carbon atoms. The alkyl, alkoxy, alkenyl and alkenyloxy groups can be straight-chain or branched-chain and expediently contain a low number of carbon atoms.
Examples of such groups are methyl, ethyl, propyl, isopropyl and ~ -tert.butyl, methoxy, ethoxy, propoxy and isopropoxy, vinyl and allyl, and vinyloxy and allyloxy. The preferred acyl groups are derived from Cl 4-aliphatic monocarboxylic acids (e.g. formyl, acetyl, propionyl, butyryl and ethoxyacetyl) and from aliphatic sulphonic acids (e.g. mesyl).
A preferred group of compounds of formula I hereinbefore comprises those in which Rl and R2 each independently represent an amino, pyrrolo, -NHR3 or -N(R3)2 group, R3 represents a Cl 4-alkyl group and Z represents a chlorine or bromine atom or the group R3 or oR3.
According to the process provided by the present invention, ~. . ~.,.
the benzylpyrimidine derivatives aforesaid (i.e. the compounds of formula I
and their salts) are manufactured by (a) reacting a compound of the general formula R \
Z ~ CH2 CH/ oRS (~l8) or R
~12 C ~ (llb~
R
wherein R5 represents a lower alkyl group or both R 's together represent ~-a lower alkylene group, Y represents a leaving group and R , R , R3, R4 and z have the significance given earlier, with guanidine, or (b) converting the group denoted by R in a compound of the general formula --~3 ~N~-- ;
wherein R8 represents a group -NHR4 or -NR R4, an amino group or an -NHR3 group, R9 represents an amino, pyrrolo, -NHR , -N(R )2 or R group and R3 and R4 are as defined above, into the amino group or a group -NHR3, and, if desired, converting a compound of formula I obtained into a salt. .
lOS91Z7 Accordlng to embodlment (a) of the present process, a compound of formula IIa or IIb is reacted wlth guanldine. The symbol Y in a compound of formula IIb represent~ a leavlng group. Examples of such leavlng groups are ether groups (e.g. lower alkoxy groups such as methoxy and ethoxy), thlo-ether groups (e.g. lower alkylthio groups) or amino groups derived from primary or secondary amines. Example~ of such amino groups are 1) groups derived from prlmary aliphatlc, aryl-aliphatic or aromatic amines such as lower alkylamino, benzylamino and arylamino (e.g. naphthylamino), but especially phenylamino (anilino) whlch may carry in the phenyl ring one or more halogen, lower alkyl or lower alkoxy substituents, or ii) groups derlved from secondary aliphatlc, aromatic or heterocyclic amines such as N,N-di(lower alkyl)amino, N-(lower alkyl)-N-arylamino [e.g. N-methyl-N-phenylamino (N-methyl-anilino) which may carry in the phenyl ring one or more halo-gen, lower alkyl or lower alkoxy substituents], pyrrolidino, piperidino, piperazino and morpholino. An especially pre-ferred amino leaving group is the anilino group.
The reaction of a compound of formula IIa or IIb with guanidine can be carried out according to methods known per se, for example, as described in Belgian Patent Spec~fiza-tions Nos. 594 131, 671 982 and 746 846. For example, the reaction can be carried out in a solvent such as an alkanol (e.g. methanol or ethanol), dimethylformamide, dimethyl sulphoxide or N-methylpyrazolone at a temperature in the approximate range of from 25C to 200C, preferably at 50C to 170C.
B:i ~
,~
,, , , ,, , ~ , , . ~
lOS91Z7 The compounds of formula lIb can be formed in situ under the conditions of the reaction from the tautomeric compound of the general formula ; Rl / CN
Z ~ CH=C (IIc) R
wherein Rl, R2, Z and Y have the significance given earlier. The compounds of formulae IIb and IIc can occur as cis or trans isomers or as mixtures thereof.
Groups denoted by R8 which are convertible by hydrolysis into an amino group include the -NHR4 and -N(R3)tR ) groups. The hydrolysis of these groups is expediently carried out in an acidic medium (e.g. with aqueous or aqueous-alcoholic mineral acids such as hydrochloric acid).
Embodiment (b) of the present process leads to compounds of formula I in which R represents an amino or -NHR3 group, R represents an am-ino, pyrrolo, NHR3 or N(R3)2 group and Z and R have the significance given earlier.
The starting materials used in the present process insofar as they are not known or insofar as they are not described hereinafter, can be prepared in a manner analogous to that described in the Examples hereinafter or according to the following methods.
Starting compounds of formulæ IIb and IIc can be prepared by conden-sation of a compound of the formula:
Z ; ~3~o :~
with a compound of the formula CN
~"" ,, _5_ ,, , ~, ..
.
in a strongly alkaline medium (see Belgian Patents 594,131 and 746,846).
Compounds of formula IIa can be obtained by the addition of an alcohol to a compound of formula IIb.
, lOS9127 The compounds of formula I can be converted into acld addltlon salts, especlally those whlch are customary ln phar-maceutlcal preparatlons, by treatment wlth inorganic acids (e.g. hydrochloric acid, sulphuric acid, phosphoric acid etc) or organic acids (e.g. formic acid, acetic acid, succlnlc acid, lactic acld, cltrlc acld, malelc acld, fumarlc acid, tartarlc acld, methanesulphonlc acld, p-toluenesulphonlc acld etc).
The benzylpyrimidine derlvatlves provlded by thls lnven-tion (i.e. the compounds of formula I and thelr salts) possess antlbacterlal actlvlty. They lnhlblt the bacterlal dlhydro-folate reductase and potentlate the antlbacterlal actlon of tsulphonamldes such as, for example, sulphlsoxazole, sulpha-dlmethoxlne, ~ulphamethoxazole, 4-sulphanllamldo-5,6-dlmeth-oxy-pyrlmldlne, 2-sulphanllamldo-4,5-dlmethyl-pyrlmldlne, sulphaqulnoxallne, sulphadlazlne, sulphamonomethoxine, 2-sulphanllamldo-4,5-dimethyl-lsoxazole and other lnhibitors of enzymes whlch are involved in the folic acid biosynthesis such as, for example, pteridine derivatives.
A comblnation of one or more of the present benzyl-pyrimidlne derlvatives with sulphonamides can be used ln human medlclne ln a form adapted for oral, rectal or parenteral admlnlstratlon. The ratlo of a compound of formula I to a sulphonamlde can vary withln a wide range; for example, between 1:40 (parts by welght) and 5:1 (parts by weight), the preferred ratlo being between 1:1 to 1:5.
Thus, for example, a tablet can contain 80 mg of a com-pound of formula I and 400 mg of sulphamethoxazole, a tablet ,~ :
for children can contain 20 mg of a compound of formula I and 100 mg of sulphamethoxazole and a syrup can contaln (per 5 ml) ;; 40 mg of a compound of formula I and 200 mg of sulphamethox-azole.
The compounds of formula I possess a high antibacterlal actlvity and a pronounced synergi~tic effect in combination wlth ~ulphonamldes. They also have a good compatibility.
" ~
Y
.
~\ ~
The following Examples lllustrate the process provlded by the present lnventlon:
Example 1 A solution of 1.5 g of sodium ln 100 ml of absolute ethanol was treated with 6.33 g of guanidine hydrochloride and 7.35 g of a-(anllinomethylene)-3,5-bis(dimethylamlno)-4-methylhydrocinnamic acid nitrile and bolled under reflux for 20 hours. The mixture was dlluted with 180 ml of water and the ethanol removed in vacuo. The precipltated 2,4-dlamlno-5-t3,5-bls(dimethylamino)-4-methylbenzyl]-pyrimldine was fll-tered off under suctlon, washed with water and recrystallised from ethanol; melting point 191-192C.
The Qtarting material was prepared as follows:
A mixture of 27 g of methyl 3,5-diamlno-4-methylbenzo-ate, 75.6 g of dimethyl sulphate, 207 g of dry pota~slum car-bonate and 1000 ml of acetone was bolled under reflux for 20 hour~ with stlrring. After coollng, the inorganic salts were filtered off from the solution, the acetone removed in vacuo, the residue treated with 200 ml of water, the precipitated oil -~
extracted twice wlth 200 ml of ethyl acetate each tlme, the ethyl acetate solution washed wlth water, dried over sodium sulphate and evaporated. There was obtained an oil from whlch methyl 3,5-bis(dimethylamino)-4-methylbenzoate was iso-lated as an oil by column chromatography over silica gel with methylene chloride/ethyl acetate (9:1). The hydrochloride melted at 216C (from ethanol/ether).
--,a~ --~, ,,,, . , :
. .
.
.
~059lZ7 A suspenslon of 18.8 g of dlmethylsulphone and 3.6 g of sodlum hydrlde (50~ dlsperslon in oll) ln 80 ml of dlmethyl sulphoxlde was stirred with the exclu~ion of molsture for 2 hours at 50C. Thereupon, 23.6 g of methyl 3,5-bls(dlmethyl-amlno)-4-methylbenzoate were added and the mlxture was stlrred at room temperature for 1.5 hours. The solutlon was dlluted wlth 400 ml of water and extracted twlce wlth ethyl acetate.
The ethyl acetate phases were combined, washed wlth water, drled over sodlum sulphate and evaporated to dryness in vacuo.
After recrystalllsatlon of the resldue from methanol, there was obtalned 3',5'-bls(dlmethylamlno)-4'-methyl-2-methylsul-phonylacetophenone of meltlng polnt 161-163C.
A ~u~penslon of 4.75 g of 3',5'-bls(dlmethylamlno)-4'-methyl-2-methyl~ulphonylacetophenone and 0.20 g of sodlum borohydride ln 200 ml of ethanol was stlrred at room tempera-ture for 2 hours. The solution was dlluted wlth 100 ml of water, cooled, the preclpitated 3,5-bis(dlmethylamino)-4-methyl-alpha-t(methylsulphonyl)methyl]benzyl alcohol was fil-tered off under suction and recrystalllsed from ethanol;
melting polnt 163-164C.
A mixture of 1.8 g of sodium methylate, 4.8 g of ~-anllinoproplonltrlle and 9.0 g of 3,5-bls(dimethylamino)-4-methyl-alpha-t(methylsulphonyl)methyl]benzyl alcohol ln 20 ml of dimethyl sulphoxide was stlrred with the excluslon of moisture for 5 hours at 40C. The mixture was poured into 250 ml of water and the resulting emulsion extracted three tlme~ with 300 ml of ethyl acetate. The ethyl acetate phases were combined, washed wlth water, drled over sodium sulphate B~ ,~
, . ~
lOS9lZ7 and evaporated. The residue, alpha-(anlllnomethylene)-3,5-bls(dlmethylamino)-4-methylhydroclnnamic acid nltrile, was recrystallised from methanol and melted at 151-152C.
Example 2 S A solution of 1.7 g of sodlum in 110 ml of absolute ethanol was treated with 7.04 g of guanldlne hydrochloride and 9.2 g of 5'-(3-anilino-2-cyanoallyl)-3'-dimethylamino-2'-methoxy-N-methylacetanllide and bolled under reflux for 20 hours. The alcohol was removed in vacuo, the resldue taken up ln water, the solld material flltered off under suctlon and recrystalllsed from ethanol. The 5'-t(2,4-dlamlno-5-Pyrim-ldlnyl)methyl]-3'-dlmethylamlno-2'-methoxy-N-methylacetanlllde melted at 220-222C.
The startlng materlal was prepared as follows:
A mlxture of 29.4 g of methyl 3,5-dlamino-4-methoxy-benzoate, 57.3 ml of dimethyl sulphate, 207 g of dry potassium carbonate and 1000 ml of acetone was boiled under reflux for 16 hours wlth ~tlrrlng. After coollng, inorganic salts were flltered from the solution, the acetone was removed ln vacuo, the resldue treated wlth 200 ml of water, the preclpltated oll extracted twlce wlth 300 ml of ethyl acetate each time, the ethyl acetate solutlon washed wlth water, dried over sodium sulphate and evaporated. There was obtained an oil from whlch methyl 3-dlmethylamino-5-methylamino-p-anLsoate and methyl 3,5-bls~dlmethylamlno)-p-anisoate were isolated by column chromatography over sllica gel wlth methylene chloride/
ethyl acetate (9:1).
~, _ ,~ _ .
~059127 25 g of methyl 3-dimethylamino-5-methylamino-p-anisoate and lOo ml of acetic anhydride were heated on a steam-bath for 1 hour. The excess anhydride was removed in vacuo and the residue recrystallised from high-boiling petroleum ether. The methyl 3-dimethylamino-5-(N-methylacetamido)~p-anisoate melted at 88-89C.
A suspension of 7.05 g of dimethylsulphone and 2.4 g of sodium hydride (50% dispersion in oil) in 18 ml of dimethyl sulphoxide was stirred with the exclusion of moisture for 2 hours at 50C. Thereupon, 6.95 g of methyl 3-dimethylamino-5-(N-methylacetamido)-p-anisoate were added and the mixture was ~tlrred for 1 hour at room temperature. The solution was diluted with 100 ml of water, made acidic with acetic acid and extracted twice with ethyl acetate. The ethyl acetate phases were combined, washed with water, dried over sodium sulphate and evaporated to dryness in vacuo. After recrystallisation of the residue from methanol, the 3'-dimethylamino-2'-methoxy-N-methyl-5'-t(methyl~ulphonyl)acetyl]acetanilide melted at 174-176C.
A suspension of 10.9 g of 3'-dimethylamino-2'-methoxy-N- - -methyl-5'-t(methylsulphonyl)acetyl]acetanilide and 0.40 g of sodium borohydride in 50 ml of 85% aqueous ethanol was stirred for 1.5 hours at 20C, made neutral with acetic acid and con-centrated in vacuo. The precipitated oil was extracted with ethyl acetate, the ethyl acetate solution evaporated and the residue recrystallised from ethyl acetate/petroleum ether.
The 3'-dimethylamino-5'-[1-hydroxy-2-(methylsulphonyl)ethyl]-
More particularly, the invention is concerned with benzylpyrimidine derivatives, a process for the manufacture thereof and antibacterial compositions containing same.
The benzylpyrimidine derivatives provided by the present invention are compounds of the general formula Rl N
wherein Rl and R2 each independently represent an amino, optionally Cl 3-alkyl-substituted pyrrolo, -NHR3, -N~R3)2, -NHR4 or -NtR3)(R4) group, R3 represents a Cl 4-alkyl group, R4 represents an acyl group derived from a lower aliphatic carboxylic or sulphonic acid, and Z represents a hydrogen, chlorine or bromine atom, a piperidino group or a group R3, -oR3 or -N(R3)2, and salts thereof.
The terms "Cl 4" and "C2 4" used in this specification denote -that the groups prefixed therewith contain 1-4 or 2-4 carbon atoms. The alkyl, alkoxy, alkenyl and alkenyloxy groups can be straight-chain or branched-chain and expediently contain a low number of carbon atoms.
Examples of such groups are methyl, ethyl, propyl, isopropyl and ~ -tert.butyl, methoxy, ethoxy, propoxy and isopropoxy, vinyl and allyl, and vinyloxy and allyloxy. The preferred acyl groups are derived from Cl 4-aliphatic monocarboxylic acids (e.g. formyl, acetyl, propionyl, butyryl and ethoxyacetyl) and from aliphatic sulphonic acids (e.g. mesyl).
A preferred group of compounds of formula I hereinbefore comprises those in which Rl and R2 each independently represent an amino, pyrrolo, -NHR3 or -N(R3)2 group, R3 represents a Cl 4-alkyl group and Z represents a chlorine or bromine atom or the group R3 or oR3.
According to the process provided by the present invention, ~. . ~.,.
the benzylpyrimidine derivatives aforesaid (i.e. the compounds of formula I
and their salts) are manufactured by (a) reacting a compound of the general formula R \
Z ~ CH2 CH/ oRS (~l8) or R
~12 C ~ (llb~
R
wherein R5 represents a lower alkyl group or both R 's together represent ~-a lower alkylene group, Y represents a leaving group and R , R , R3, R4 and z have the significance given earlier, with guanidine, or (b) converting the group denoted by R in a compound of the general formula --~3 ~N~-- ;
wherein R8 represents a group -NHR4 or -NR R4, an amino group or an -NHR3 group, R9 represents an amino, pyrrolo, -NHR , -N(R )2 or R group and R3 and R4 are as defined above, into the amino group or a group -NHR3, and, if desired, converting a compound of formula I obtained into a salt. .
lOS91Z7 Accordlng to embodlment (a) of the present process, a compound of formula IIa or IIb is reacted wlth guanldine. The symbol Y in a compound of formula IIb represent~ a leavlng group. Examples of such leavlng groups are ether groups (e.g. lower alkoxy groups such as methoxy and ethoxy), thlo-ether groups (e.g. lower alkylthio groups) or amino groups derived from primary or secondary amines. Example~ of such amino groups are 1) groups derived from prlmary aliphatlc, aryl-aliphatic or aromatic amines such as lower alkylamino, benzylamino and arylamino (e.g. naphthylamino), but especially phenylamino (anilino) whlch may carry in the phenyl ring one or more halogen, lower alkyl or lower alkoxy substituents, or ii) groups derlved from secondary aliphatlc, aromatic or heterocyclic amines such as N,N-di(lower alkyl)amino, N-(lower alkyl)-N-arylamino [e.g. N-methyl-N-phenylamino (N-methyl-anilino) which may carry in the phenyl ring one or more halo-gen, lower alkyl or lower alkoxy substituents], pyrrolidino, piperidino, piperazino and morpholino. An especially pre-ferred amino leaving group is the anilino group.
The reaction of a compound of formula IIa or IIb with guanidine can be carried out according to methods known per se, for example, as described in Belgian Patent Spec~fiza-tions Nos. 594 131, 671 982 and 746 846. For example, the reaction can be carried out in a solvent such as an alkanol (e.g. methanol or ethanol), dimethylformamide, dimethyl sulphoxide or N-methylpyrazolone at a temperature in the approximate range of from 25C to 200C, preferably at 50C to 170C.
B:i ~
,~
,, , , ,, , ~ , , . ~
lOS91Z7 The compounds of formula lIb can be formed in situ under the conditions of the reaction from the tautomeric compound of the general formula ; Rl / CN
Z ~ CH=C (IIc) R
wherein Rl, R2, Z and Y have the significance given earlier. The compounds of formulae IIb and IIc can occur as cis or trans isomers or as mixtures thereof.
Groups denoted by R8 which are convertible by hydrolysis into an amino group include the -NHR4 and -N(R3)tR ) groups. The hydrolysis of these groups is expediently carried out in an acidic medium (e.g. with aqueous or aqueous-alcoholic mineral acids such as hydrochloric acid).
Embodiment (b) of the present process leads to compounds of formula I in which R represents an amino or -NHR3 group, R represents an am-ino, pyrrolo, NHR3 or N(R3)2 group and Z and R have the significance given earlier.
The starting materials used in the present process insofar as they are not known or insofar as they are not described hereinafter, can be prepared in a manner analogous to that described in the Examples hereinafter or according to the following methods.
Starting compounds of formulæ IIb and IIc can be prepared by conden-sation of a compound of the formula:
Z ; ~3~o :~
with a compound of the formula CN
~"" ,, _5_ ,, , ~, ..
.
in a strongly alkaline medium (see Belgian Patents 594,131 and 746,846).
Compounds of formula IIa can be obtained by the addition of an alcohol to a compound of formula IIb.
, lOS9127 The compounds of formula I can be converted into acld addltlon salts, especlally those whlch are customary ln phar-maceutlcal preparatlons, by treatment wlth inorganic acids (e.g. hydrochloric acid, sulphuric acid, phosphoric acid etc) or organic acids (e.g. formic acid, acetic acid, succlnlc acid, lactic acld, cltrlc acld, malelc acld, fumarlc acid, tartarlc acld, methanesulphonlc acld, p-toluenesulphonlc acld etc).
The benzylpyrimidine derlvatlves provlded by thls lnven-tion (i.e. the compounds of formula I and thelr salts) possess antlbacterlal actlvlty. They lnhlblt the bacterlal dlhydro-folate reductase and potentlate the antlbacterlal actlon of tsulphonamldes such as, for example, sulphlsoxazole, sulpha-dlmethoxlne, ~ulphamethoxazole, 4-sulphanllamldo-5,6-dlmeth-oxy-pyrlmldlne, 2-sulphanllamldo-4,5-dlmethyl-pyrlmldlne, sulphaqulnoxallne, sulphadlazlne, sulphamonomethoxine, 2-sulphanllamldo-4,5-dimethyl-lsoxazole and other lnhibitors of enzymes whlch are involved in the folic acid biosynthesis such as, for example, pteridine derivatives.
A comblnation of one or more of the present benzyl-pyrimidlne derlvatives with sulphonamides can be used ln human medlclne ln a form adapted for oral, rectal or parenteral admlnlstratlon. The ratlo of a compound of formula I to a sulphonamlde can vary withln a wide range; for example, between 1:40 (parts by welght) and 5:1 (parts by weight), the preferred ratlo being between 1:1 to 1:5.
Thus, for example, a tablet can contain 80 mg of a com-pound of formula I and 400 mg of sulphamethoxazole, a tablet ,~ :
for children can contain 20 mg of a compound of formula I and 100 mg of sulphamethoxazole and a syrup can contaln (per 5 ml) ;; 40 mg of a compound of formula I and 200 mg of sulphamethox-azole.
The compounds of formula I possess a high antibacterlal actlvity and a pronounced synergi~tic effect in combination wlth ~ulphonamldes. They also have a good compatibility.
" ~
Y
.
~\ ~
The following Examples lllustrate the process provlded by the present lnventlon:
Example 1 A solution of 1.5 g of sodium ln 100 ml of absolute ethanol was treated with 6.33 g of guanidine hydrochloride and 7.35 g of a-(anllinomethylene)-3,5-bis(dimethylamlno)-4-methylhydrocinnamic acid nitrile and bolled under reflux for 20 hours. The mixture was dlluted with 180 ml of water and the ethanol removed in vacuo. The precipltated 2,4-dlamlno-5-t3,5-bls(dimethylamino)-4-methylbenzyl]-pyrimldine was fll-tered off under suctlon, washed with water and recrystallised from ethanol; melting point 191-192C.
The Qtarting material was prepared as follows:
A mixture of 27 g of methyl 3,5-diamlno-4-methylbenzo-ate, 75.6 g of dimethyl sulphate, 207 g of dry pota~slum car-bonate and 1000 ml of acetone was bolled under reflux for 20 hour~ with stlrring. After coollng, the inorganic salts were filtered off from the solution, the acetone removed in vacuo, the residue treated with 200 ml of water, the precipitated oil -~
extracted twice wlth 200 ml of ethyl acetate each tlme, the ethyl acetate solution washed wlth water, dried over sodium sulphate and evaporated. There was obtained an oil from whlch methyl 3,5-bis(dimethylamino)-4-methylbenzoate was iso-lated as an oil by column chromatography over silica gel with methylene chloride/ethyl acetate (9:1). The hydrochloride melted at 216C (from ethanol/ether).
--,a~ --~, ,,,, . , :
. .
.
.
~059lZ7 A suspenslon of 18.8 g of dlmethylsulphone and 3.6 g of sodlum hydrlde (50~ dlsperslon in oll) ln 80 ml of dlmethyl sulphoxlde was stirred with the exclu~ion of molsture for 2 hours at 50C. Thereupon, 23.6 g of methyl 3,5-bls(dlmethyl-amlno)-4-methylbenzoate were added and the mlxture was stlrred at room temperature for 1.5 hours. The solutlon was dlluted wlth 400 ml of water and extracted twlce wlth ethyl acetate.
The ethyl acetate phases were combined, washed wlth water, drled over sodlum sulphate and evaporated to dryness in vacuo.
After recrystalllsatlon of the resldue from methanol, there was obtalned 3',5'-bls(dlmethylamlno)-4'-methyl-2-methylsul-phonylacetophenone of meltlng polnt 161-163C.
A ~u~penslon of 4.75 g of 3',5'-bls(dlmethylamlno)-4'-methyl-2-methyl~ulphonylacetophenone and 0.20 g of sodlum borohydride ln 200 ml of ethanol was stlrred at room tempera-ture for 2 hours. The solution was dlluted wlth 100 ml of water, cooled, the preclpitated 3,5-bis(dlmethylamino)-4-methyl-alpha-t(methylsulphonyl)methyl]benzyl alcohol was fil-tered off under suction and recrystalllsed from ethanol;
melting polnt 163-164C.
A mixture of 1.8 g of sodium methylate, 4.8 g of ~-anllinoproplonltrlle and 9.0 g of 3,5-bls(dimethylamino)-4-methyl-alpha-t(methylsulphonyl)methyl]benzyl alcohol ln 20 ml of dimethyl sulphoxide was stlrred with the excluslon of moisture for 5 hours at 40C. The mixture was poured into 250 ml of water and the resulting emulsion extracted three tlme~ with 300 ml of ethyl acetate. The ethyl acetate phases were combined, washed wlth water, drled over sodium sulphate B~ ,~
, . ~
lOS9lZ7 and evaporated. The residue, alpha-(anlllnomethylene)-3,5-bls(dlmethylamino)-4-methylhydroclnnamic acid nltrile, was recrystallised from methanol and melted at 151-152C.
Example 2 S A solution of 1.7 g of sodlum in 110 ml of absolute ethanol was treated with 7.04 g of guanldlne hydrochloride and 9.2 g of 5'-(3-anilino-2-cyanoallyl)-3'-dimethylamino-2'-methoxy-N-methylacetanllide and bolled under reflux for 20 hours. The alcohol was removed in vacuo, the resldue taken up ln water, the solld material flltered off under suctlon and recrystalllsed from ethanol. The 5'-t(2,4-dlamlno-5-Pyrim-ldlnyl)methyl]-3'-dlmethylamlno-2'-methoxy-N-methylacetanlllde melted at 220-222C.
The startlng materlal was prepared as follows:
A mlxture of 29.4 g of methyl 3,5-dlamino-4-methoxy-benzoate, 57.3 ml of dimethyl sulphate, 207 g of dry potassium carbonate and 1000 ml of acetone was boiled under reflux for 16 hours wlth ~tlrrlng. After coollng, inorganic salts were flltered from the solution, the acetone was removed ln vacuo, the resldue treated wlth 200 ml of water, the preclpltated oll extracted twlce wlth 300 ml of ethyl acetate each time, the ethyl acetate solutlon washed wlth water, dried over sodium sulphate and evaporated. There was obtained an oil from whlch methyl 3-dlmethylamino-5-methylamino-p-anLsoate and methyl 3,5-bls~dlmethylamlno)-p-anisoate were isolated by column chromatography over sllica gel wlth methylene chloride/
ethyl acetate (9:1).
~, _ ,~ _ .
~059127 25 g of methyl 3-dimethylamino-5-methylamino-p-anisoate and lOo ml of acetic anhydride were heated on a steam-bath for 1 hour. The excess anhydride was removed in vacuo and the residue recrystallised from high-boiling petroleum ether. The methyl 3-dimethylamino-5-(N-methylacetamido)~p-anisoate melted at 88-89C.
A suspension of 7.05 g of dimethylsulphone and 2.4 g of sodium hydride (50% dispersion in oil) in 18 ml of dimethyl sulphoxide was stirred with the exclusion of moisture for 2 hours at 50C. Thereupon, 6.95 g of methyl 3-dimethylamino-5-(N-methylacetamido)-p-anisoate were added and the mixture was ~tlrred for 1 hour at room temperature. The solution was diluted with 100 ml of water, made acidic with acetic acid and extracted twice with ethyl acetate. The ethyl acetate phases were combined, washed with water, dried over sodium sulphate and evaporated to dryness in vacuo. After recrystallisation of the residue from methanol, the 3'-dimethylamino-2'-methoxy-N-methyl-5'-t(methyl~ulphonyl)acetyl]acetanilide melted at 174-176C.
A suspension of 10.9 g of 3'-dimethylamino-2'-methoxy-N- - -methyl-5'-t(methylsulphonyl)acetyl]acetanilide and 0.40 g of sodium borohydride in 50 ml of 85% aqueous ethanol was stirred for 1.5 hours at 20C, made neutral with acetic acid and con-centrated in vacuo. The precipitated oil was extracted with ethyl acetate, the ethyl acetate solution evaporated and the residue recrystallised from ethyl acetate/petroleum ether.
The 3'-dimethylamino-5'-[1-hydroxy-2-(methylsulphonyl)ethyl]-
2'-methoxy-N-methylacetanilide melted at 118-119C.
IZ
_ ~ _ lOS9~27 A mixture of 10.6 g of 3'-dlmethylamino-5'-tl-hydroxy-2-(methylsulphonyl)ethyl]-2'-methoxy-N-methylacetanllide, 1.8 g of sodium methylate and 4.8 g of ~-anllinopropionitrlle in 20 ml of dimethyl sulphoxide was stirred with the excluslon of 6 molsture for 5 hours at 50C. The mlxture was poured lnto 250 ml of water, the preclpi~ated oil extracted with ethyl acetate, the ethyl acetate ~olutlon drled over sodlum sulphate and evaporated. By purlflcatlon of the resldue over alumln-lum oxlde wlth benzene and recrystalllsatlon from ethyl acetate/petroleum ether, there was obtained the 5'-(3-anlllno-2-cyanoallyl)-3'-dimethylamlno-2'-methoxy-N-methylacetanlllde of meltlng polnt 176-178C.
Example 3 4.0 g of 5'-t(2,4-dlamlno-5-pyrimldlnyl)methyl]-3'-dimethylamino-2'-methoxy-N-methylacetanlllde, (prepared as descrlbed ln the flrst paragraph of Example 2), and 100 ml of l-N hydrochlorlc acld were bolled under reflux for 2 hours.
After neutrallsatlon and evaporatlon ln vacuo, purification of the residue over silica gel with methylene chloride/propanol (8:2) and recrystallisation from ethanol, there was obtained 2,4-dlamino-5-t3-dimethylamlno-4-methoxy-5-(methylamlno)-benzyl]pyrimidine of melting point 183C.
Example 4 A solution of 1.7 g of sodlum ln 110 ml of absolute ethanol was treated with 7.04 g of guanidine hydrochloride and 8.5 g of alpha-(anilinomethylene)-3,5-bls(dimethylamino)-4-, ,~ , . i, , . " , ,,, , ~ ,. .. .
~OS9~Z7 methoxyhydroclnnamonltrile and boiled under reflux for 20hours. The alcohol was removed ln vacuo, the resldue taken up ln water, the solld materlal flltered off under ~uctlon and recrystallised from ethanol. The 2,4-diamino-5-[3,5-bis-(dimethylamino~-4-methoxybenzyl]pyrimidlne melted at 207-208C.
The startlng material wa~ prepared as follows:
A suspenslon of 3.6 g of sodium hydride (50% dispersion in oll) and 9.4 g of dlmethylsulphone ln 40 ml of dlmethyl sulphoxlde was stlrred with the excluslon of molsture for 2 hours at 50C. Thereupon, 12.6 g of methyl 3,5-bls(dlmethyl-amlno)-p-anlsoate (obtained as descrlbed ln Example 2) were ~dded and the mlxture was stlrred for 2 hours at room tem-perature. The solutlon was dlluted wlth 200 ml of water, extracted wlth ethyl acetate, the ethyl acetate solution washed wlth water, dried over sodium sulphate and evaporated.
After recrystallisation of the resldue from ethyl acetate/
petroleum ether, the 3',5'-bls(dlmethylamlno)-4'-methoxy-2-methylsulphonylacetophenone meltlng at 103-104C.
A suspenslon of 5.04 g of 3',5'-bis(dimethylamino)-4'-methoxy-2-methylsulphonylacetophenone and 0.20 g of sodium borohydrlde in 10 ml of 70% aqueous ethanol was stirred at room temperature for 1.5 hours, cooled, the solid material f~ltered off under suction and recrystallised from methanol.
The 3,5-bl~(dimethylamlno)-4-methoxy-alpha-[(methyl~ulphonyl)-methyl]benzyl alcohol melted at 161-162C.
A mixture of 9.76 g of 3,5-bis(dimethylamino)-4-methoxy-.., 1~
_ ,~ _ lOS9~27 alpha-[(methylsulphonyl)methyl]benzyl alcohol, 1.8 g of sodium methylate and 4.8 g of ~-anilinopropionitrile ln 20 ml of dimethyl sulphoxide was stirred with the exclusion of moi~ture for S hours at 50C. The mixture was poured into 250 ml of water, the precipitated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulphate and evapor-ated. By recrystallisation of the residue from high-boillng petroleum ether, there was obtained alpha-(anilinomethylene)-
IZ
_ ~ _ lOS9~27 A mixture of 10.6 g of 3'-dlmethylamino-5'-tl-hydroxy-2-(methylsulphonyl)ethyl]-2'-methoxy-N-methylacetanllide, 1.8 g of sodium methylate and 4.8 g of ~-anllinopropionitrlle in 20 ml of dimethyl sulphoxide was stirred with the excluslon of 6 molsture for 5 hours at 50C. The mlxture was poured lnto 250 ml of water, the preclpi~ated oil extracted with ethyl acetate, the ethyl acetate ~olutlon drled over sodlum sulphate and evaporated. By purlflcatlon of the resldue over alumln-lum oxlde wlth benzene and recrystalllsatlon from ethyl acetate/petroleum ether, there was obtained the 5'-(3-anlllno-2-cyanoallyl)-3'-dimethylamlno-2'-methoxy-N-methylacetanlllde of meltlng polnt 176-178C.
Example 3 4.0 g of 5'-t(2,4-dlamlno-5-pyrimldlnyl)methyl]-3'-dimethylamino-2'-methoxy-N-methylacetanlllde, (prepared as descrlbed ln the flrst paragraph of Example 2), and 100 ml of l-N hydrochlorlc acld were bolled under reflux for 2 hours.
After neutrallsatlon and evaporatlon ln vacuo, purification of the residue over silica gel with methylene chloride/propanol (8:2) and recrystallisation from ethanol, there was obtained 2,4-dlamino-5-t3-dimethylamlno-4-methoxy-5-(methylamlno)-benzyl]pyrimidine of melting point 183C.
Example 4 A solution of 1.7 g of sodlum ln 110 ml of absolute ethanol was treated with 7.04 g of guanidine hydrochloride and 8.5 g of alpha-(anilinomethylene)-3,5-bls(dimethylamino)-4-, ,~ , . i, , . " , ,,, , ~ ,. .. .
~OS9~Z7 methoxyhydroclnnamonltrile and boiled under reflux for 20hours. The alcohol was removed ln vacuo, the resldue taken up ln water, the solld materlal flltered off under ~uctlon and recrystallised from ethanol. The 2,4-diamino-5-[3,5-bis-(dimethylamino~-4-methoxybenzyl]pyrimidlne melted at 207-208C.
The startlng material wa~ prepared as follows:
A suspenslon of 3.6 g of sodium hydride (50% dispersion in oll) and 9.4 g of dlmethylsulphone ln 40 ml of dlmethyl sulphoxlde was stlrred with the excluslon of molsture for 2 hours at 50C. Thereupon, 12.6 g of methyl 3,5-bls(dlmethyl-amlno)-p-anlsoate (obtained as descrlbed ln Example 2) were ~dded and the mlxture was stlrred for 2 hours at room tem-perature. The solutlon was dlluted wlth 200 ml of water, extracted wlth ethyl acetate, the ethyl acetate solution washed wlth water, dried over sodium sulphate and evaporated.
After recrystallisation of the resldue from ethyl acetate/
petroleum ether, the 3',5'-bls(dlmethylamlno)-4'-methoxy-2-methylsulphonylacetophenone meltlng at 103-104C.
A suspenslon of 5.04 g of 3',5'-bis(dimethylamino)-4'-methoxy-2-methylsulphonylacetophenone and 0.20 g of sodium borohydrlde in 10 ml of 70% aqueous ethanol was stirred at room temperature for 1.5 hours, cooled, the solid material f~ltered off under suction and recrystallised from methanol.
The 3,5-bl~(dimethylamlno)-4-methoxy-alpha-[(methyl~ulphonyl)-methyl]benzyl alcohol melted at 161-162C.
A mixture of 9.76 g of 3,5-bis(dimethylamino)-4-methoxy-.., 1~
_ ,~ _ lOS9~27 alpha-[(methylsulphonyl)methyl]benzyl alcohol, 1.8 g of sodium methylate and 4.8 g of ~-anilinopropionitrile ln 20 ml of dimethyl sulphoxide was stirred with the exclusion of moi~ture for S hours at 50C. The mixture was poured into 250 ml of water, the precipitated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulphate and evapor-ated. By recrystallisation of the residue from high-boillng petroleum ether, there was obtained alpha-(anilinomethylene)-
3,5-bis(dimethylamino)-4-methoxyhydrocinnamonitrlle of melting polnt 103-105C.
Example 5 A solutlon of 1.7 g of sodium ln 110 ml of absolute ethanol was treated with 7.04 g of guanidlne hydrochloride and 8.6 g of alpha-(anillnomethylene)-4-chloro-3,5-bis(dimethyl-amlno)hydroclnnamonitrlle and boiled under reflux for 20hours. The ethanol was removed in vacuo, the residue taken up ln water, filtered off under suction and recrystallised from ethanol. The 2,4-diamino-5-~4-chloro-3,5-bis(dimethyl-amlno)benzyl]pyrlmldlne melted at 202-203C.
The startln~ materlal was prepared as follows:
A mlxture of 22.5 g of methyl 3,5-dlamino-4-chloro-benzoate, 50 ml of dimethyl sulphate, 155 g of dry potassium carbonate and 750 ml of acetone was boiled under reflux for 16 hours with stlrring. After cooling, the inorganic salts were filtered off, the acetone removed in vacuo, the residue taken up in ethyl acetate, the ethyl acetate solution washed wlth ,. : , . ..
water, dried over sodium sulphate and evaporated. By column chromatography of the product over silica gel with methylene chloride/ethyl acetate (9:1), there were obtained methyl 4-chloro-3,5-bis(dimethylamino)benzoate of boiling point 0.01/
S 100C and methyl 4-chloro-3-dimethylamino-5-methylaminobenz-oate of boiling point 0.01/110C.
A suspension of 7.05 g of dimethylsulphone and 2.4 g of sodium hydride (50% dispersion in oil) in 17 ml of dimethyl sulphoxide was stirred with the excluslon of moisture for 2 hours at 50C. Thereupon, 6.35 g of methyl 4-chloro-3,5-bis(dimethylamino)benzoate were added and the mixture was stirred for l.S hours at 20C. The solution was diluted with 200 ml of water and extracted twice with ethyl acetate. The ethyl acetate phases were combined, washed with water, dried over sodium sulphate and evaporated in vacuo. After recrys-tallisation of the residue from ethanol, the 4'-chloro-3',5'-bis(dimethylamino)-2-methylsulphonylacetophenone melted at 150C.
A su~pension of 25.45 g of 4'-chloro-3',5'-bis(dimethyl-amino)-2-methylsulphonylacetophenone and 1.0 g of sodium boro-hydrlde in 150 ml of 20% aqueous ethanol was stirred for 2 hours at room temperature and then cooled with ice. The precipitate was filtered off under suction and recrystallised from ethanol. The 4-chloro-3,5-bis(dimethylamino)-alpha-t(methylsulphonyl)methyl]benzyl alcohol melted at 168C.
A mixture of 15.7 g of 4-chloro-3,5-bis(dimethylamino)-alpha-t~methylsulphonyl)methyl]benzyl alcohol, 2.8 g of sodium methylate and 7.1 g of B-anilinopropionitrile ln 31 ml of L~J
l~S9lZ7 dimethyl sulphoxide was stirred with the exclusion of moisture for 5 hours at 50C. The mixture was poured lnto 200 ml of water, the precipitated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulphate and evapor-ated in vacuo. By purification of the residue over aluminlumoxide wlth benzene and recrystallisation from ethyl acetate/
petroleum ether, there was obtained alpha-(anilinomethylene)-
Example 5 A solutlon of 1.7 g of sodium ln 110 ml of absolute ethanol was treated with 7.04 g of guanidlne hydrochloride and 8.6 g of alpha-(anillnomethylene)-4-chloro-3,5-bis(dimethyl-amlno)hydroclnnamonitrlle and boiled under reflux for 20hours. The ethanol was removed in vacuo, the residue taken up ln water, filtered off under suction and recrystallised from ethanol. The 2,4-diamino-5-~4-chloro-3,5-bis(dimethyl-amlno)benzyl]pyrlmldlne melted at 202-203C.
The startln~ materlal was prepared as follows:
A mlxture of 22.5 g of methyl 3,5-dlamino-4-chloro-benzoate, 50 ml of dimethyl sulphate, 155 g of dry potassium carbonate and 750 ml of acetone was boiled under reflux for 16 hours with stlrring. After cooling, the inorganic salts were filtered off, the acetone removed in vacuo, the residue taken up in ethyl acetate, the ethyl acetate solution washed wlth ,. : , . ..
water, dried over sodium sulphate and evaporated. By column chromatography of the product over silica gel with methylene chloride/ethyl acetate (9:1), there were obtained methyl 4-chloro-3,5-bis(dimethylamino)benzoate of boiling point 0.01/
S 100C and methyl 4-chloro-3-dimethylamino-5-methylaminobenz-oate of boiling point 0.01/110C.
A suspension of 7.05 g of dimethylsulphone and 2.4 g of sodium hydride (50% dispersion in oil) in 17 ml of dimethyl sulphoxide was stirred with the excluslon of moisture for 2 hours at 50C. Thereupon, 6.35 g of methyl 4-chloro-3,5-bis(dimethylamino)benzoate were added and the mixture was stirred for l.S hours at 20C. The solution was diluted with 200 ml of water and extracted twice with ethyl acetate. The ethyl acetate phases were combined, washed with water, dried over sodium sulphate and evaporated in vacuo. After recrys-tallisation of the residue from ethanol, the 4'-chloro-3',5'-bis(dimethylamino)-2-methylsulphonylacetophenone melted at 150C.
A su~pension of 25.45 g of 4'-chloro-3',5'-bis(dimethyl-amino)-2-methylsulphonylacetophenone and 1.0 g of sodium boro-hydrlde in 150 ml of 20% aqueous ethanol was stirred for 2 hours at room temperature and then cooled with ice. The precipitate was filtered off under suction and recrystallised from ethanol. The 4-chloro-3,5-bis(dimethylamino)-alpha-t(methylsulphonyl)methyl]benzyl alcohol melted at 168C.
A mixture of 15.7 g of 4-chloro-3,5-bis(dimethylamino)-alpha-t~methylsulphonyl)methyl]benzyl alcohol, 2.8 g of sodium methylate and 7.1 g of B-anilinopropionitrile ln 31 ml of L~J
l~S9lZ7 dimethyl sulphoxide was stirred with the exclusion of moisture for 5 hours at 50C. The mixture was poured lnto 200 ml of water, the precipitated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulphate and evapor-ated in vacuo. By purification of the residue over aluminlumoxide wlth benzene and recrystallisation from ethyl acetate/
petroleum ether, there was obtained alpha-(anilinomethylene)-
4-chloro-3,5-bis(dimethylamino)hydrocinnamonltrile of meltlng polnt 168C.
Example 6 A solutlon of 0.9 g of sodium ln 60 ml of absolute ethanol was treated with 3.7 g of guanidine hydrochloride and 4.3 g of alpha-(anilinomethylene)-4-chloro-3-dimethylamlno-5-methylamlnohydroclnnamonltrlle and boiled under reflux for 20 hours. The alcohol was removed ln vacuo, the resldue taken up ln water, filtered off under suctlon and recrystallised from ethanol. The 2,4-diamino-5-[4-chloro-3-dimethylamlno-5-methylamlnobenzyl]pyrimldlne melted at 215-216C.
The startlng materlal was prepared as follows:
A suspenslon of 2.4 g of sodium hydride (50% dispersion ln oll) and 7.05 g of dimethylsulphone in 18 ml of dlmethyl sulphoxide was stirred wlth the excluslon of molsture for 2 hours at 50C. Thereupon, 5.77 g of methyl 4-chloro-3-dimethylamino-5-methylamlnobenzoate (obtained as described in Example S) were added and the mlxture was stlrred for 2 hours at room temperature. The solution was diluted with 100 ml of : /7 -- 2~--" ~ .
water, the aqueous solution washed with ethyl acetate and made slightly acidlc wlth ethyl acetate. After standing for 18 hours at 4C, the preclpltated 4-chloro-3-dimethylamino-5-methylamlno-2-methylsulphonylacetophenone was filtered off under suction and recrystalllsed from ethanol; melting point:
A suspenslon of 4.85 g of 4-chloro-3-dlmethylamlno-5-methylamlno-2-methylsulphonylacetophenone and 0.20 g of sodlum borohydrlde ln 30 ml of 20~ aqueous ethanol was stirred for 1 hour at 20C, cooled with lce and the 4-chloro-3-dimethyl-amlno-5-methylamino-alpha-[(methylsulphonyl)methyl]benzyl alcohol was filtered off under suctlon and recrystalllsed from ethanol; melting polnt: 147-148C.
A mixture of 9.48 g of 4-chloro-3-dimethylamlno-5-methylamino-alpha-~(methylsulphonyl)methyl]benzyl alcohol, 1.8 g of sodium methylate and 4.8 g of ~-anillnoproplonitrile in 20 ml of dimethyl sulphoxide was stirred with the exclusion of molsture for S hours at 50C. The mlxture was cooled, poured lnto 200 ml of water, the preclpitated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium ~ulphate and evaporated. By purlfication of the product over aluminium oxide with benzene and recrystallisation from ethanol, there was obtained alpha-(anilinomethylene)-4-chloro-3-dimethylamino-5-methylaminohydroclnnamonitrile of melting point 173-174C.
Example 7 A ~olutlon of 0.53 g of sodium in 36 ml of absolute ethanol was treated with 2.16 g of guanldine hydrochloride and 3.2 g of alpha-(anilinomethylene)-3,5-bis(2,5-dimethylpyrrol-l-yl)-4-methylhydrocinnamonitrile and boiled under reflux for 20 hours~ The alcohol was removed in vacuo, the residue taken up in water, filtered off under suction and recrystal-lised from methanol/water. The 2,4-diamino-5-[3,5-bls(2,5-dimethylpyrrol-l-yl)-4-methylbenzyl]pyrimidine melted at 205-206C.
The starting material was prepared as follows:
A mlxture of 10.8 g of methyl 3,5-diamino-4-methyl-benzoate and 30 g of acetonylacetone was heated under nitrogen at 200C for 17 hours. On the following day, the solid mass was dlssolved in benzene, the benzene solutlon purified over alumlnlum oxlde, evaporated and the residue recrystallised lS from methanol. The methyl 3,5-bis(2,5-dimethylpyrrol-1-yl)-4-methylbenzoate melted at 163-165C.
A suspension of 6.25 g of dimethylsulphone and 2.4 g of sodium hydride (50% dlspersion ln oil) in 30 ml of dimethyl ~ulphoxide was stirred with the exclusion of moisture for 2 hours at 50C. Thereupon, 11.2 g of methyl 3,5-bis(2,5-dimethylpyrrol-l-yl)-4-methylbenzoate were added and the mix-ture was stirred for 1.5 hours at 20C. The solution was diluted with 150 ml of water, the precipitated product extra-cted with ethyl acetate, the ethyl acetate solution dried over sodium sulphate and evaporated. 3',5'-Bis(2,5-dimethyl-pyrrol-l-yl)-4'-methyl-2-methylsulphonylacetophenone of mel-ting point 173C was lsolated from the residue by column ., Iq I _ ~y _ ", ' .
~OS9127 chromatography over sllica gel with methylene chloride/ethyl acetate (9:1).
A suspension of 1.9 g of 3',5'-bis(2,5-dimethylpyrrol-1-yl)-4'-methyl-2-methylsulphonylacetophenone and 0.40 g of sodium borohydride in 50 ml of 90~ aqueous ethanol was stirred for 3 hours at room temperature, cooled, the precipitate fil-tered off under suction and recrystallised from ethanol. The 3,5-bis(2,5-dimethylpyrrol-1-yl)-4-methyl-alpha-[(methyl-sulphonyl)methyl]benzyl alcohol melted at 207-208C.
A mixture of 4.95 g of 3,5-bis(2,5-dimethylpyrrol-1-yl)-4-methyl-alpha-[(methylsulphonyl)methyl]benzyl alcohol, 0.95 g of sodium methylate and 2.16 g of ~-anilinopropionitrile in 13 ml of dimethyl qulphoxide was stirred with the exclusion of moisture for 5 hours at 50C. The mixture was poured into 100 ml of water, the precipitated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulphate and evaporated. By purification of the residue over alumin-ium oxide with ethyl acetate and recrystallisation from ethyl acetate, there was obtained alpha-(anilinomethylene)-3,5-bis-(2,5-dlmethylpyrrol-1-yl)-4-methylhydrocinnamonitrile of meltlng polnt 252C.
Example 8 A solution of 0.94 g of sodium in 65 ml of absolute ethanol was treated with 3.85 g of guanidine hydrochloride and 6.6 g of 5'-(3-anllino-2-cyanoallyl)-3'-(pyrrol-1-yl)-o-aceto-toluidlde and bolled for 20 hours under reflux and under -- 3,0~ --lOS91Z7 nitrogen. The alcohol was removed ln vacuo, the resldue taken up ln water, flltered off under suctlon and recrystal-lised from methanol. The N-[alpha5-(2,4-diamino-5-pyrimidin-yl)-3-(pyrrol-1-yl)-2,5-xylyl]acetamide melted at 110C.
The starting material was preparèd as follows:
A mixture of 18 g of methyl 3,5-dlamlno-4-methylben-zoate, 0.7 g of p-toluenesulphonic acld, 8.2 g of sodium acetate, 32 q of diethoxytetrahydrofuran, 10 ml of glaclal acetic acid, 100 ml of ethanol and 100 ml of water was boiled at reflux for 3 hours. The alcohol was removed ln vacuo and the residue extracted with ethyl acetate. The ethyl acetate solution was washed with water, dried over sodium sulphate and evaporated. By purification of the residue over aluminium oxide with ethyl acetate and recrystallisation from hlgh-boiling petroleum ether, there was obtained methyl 3-amino-4-methyl-5-(pyrrol-1-yl)benzoate of melting point 112C. -A suspension of 4.6 g of methyl 3-amlno-4-methyl-5-(pyrrol-l-yl)benzoate in 15 ml of glaclal acetic acld was treated with 2.1 g of acetic anhydride. Wlth self-heating, -there re~ulted firstly a clear solution and soon afterwards crystals began to separate. The mixture was heated on a steam-bath for a further 30 minutes and then cooled. The crystals were filtered off under suctlon and recrystallised from methanol. The methyl 3-acetamldo-4-methyl-5-(pyrrol-1-yl)benzoate melted at 184-185C.
A suspension of 1.44 g of sodium hydride (50% disper-.. j. , --,a~ --~0591Z7 sion in oil) and 3.7 g of dimethylsulphone in 20 ml of dimeth-yl sulphoxide was stirred with the exclusion of moisture for 2 hours at 50C. Thereupon, 5.45 g of methyl 3-acetamido-4-methyl-5-(pyrrol-1-yl)benzoate were added and the mixture was stirred for 2 hours at room temperature. The solution was diluted with 200 ml of water, the aqueous solution washed with ethyl acetate, made slightly acidic with acetic acid and left to stand overnight in a refrigerator. On the following day, the precipltate was filtered off under suction and recrystal-lised from ethanol. The 5'-[(methylsulphonyl)acetyl]-3'-(pyrrol-l-yl)-o-acetotoluidide melted at 212-214C.
A suspension of 1.6 g of 5'-[(methylsulphonyl)acetyl]-3'-(pyrrol-1-yl)-o-acetotoluidide and 0.40 g of sodium boro-hydrlde in 50 ml of 50~ aqueous ethanol was stirred at room temperature for 30 minutes. The ethanol was removed in vacuo, the precipitate filtered off under suction, dried and recrystallised from ethyl acetate/petroleum ether. The 5'-tl-hydroxy-(2-methylsulphonyl)ethyl]-3'-(pyrrol-1-yl)-o-aceto-toluidlde melted at 167-168C.
A mixture of 1.35 g of 5'-[1-hydroxy-2-(methylsulphon-yl)ethyl]-3'-(pyrrol-1-yl)-o-acetotoluidide, 0.43 g of sodium methylate and 1.1 g of ~-anilinopropionitrile in 12 ml of dimethyl sulphoxide was stirred with the exclusion of moisture for 1 hour at room temperature. The mixture was poured into 100 ml of water, the precipitated oil extracted with ethyl acetate, the ethyl acetate solution washed with water, dried over sodlum sulphate and evaporated. By column chromatog-raphy over silica gel with methylene chlorlde/ethyl acetate el .~
(9:1) and recrystallisation from ethanol, there was obtained
Example 6 A solutlon of 0.9 g of sodium ln 60 ml of absolute ethanol was treated with 3.7 g of guanidine hydrochloride and 4.3 g of alpha-(anilinomethylene)-4-chloro-3-dimethylamlno-5-methylamlnohydroclnnamonltrlle and boiled under reflux for 20 hours. The alcohol was removed ln vacuo, the resldue taken up ln water, filtered off under suctlon and recrystallised from ethanol. The 2,4-diamino-5-[4-chloro-3-dimethylamlno-5-methylamlnobenzyl]pyrimldlne melted at 215-216C.
The startlng materlal was prepared as follows:
A suspenslon of 2.4 g of sodium hydride (50% dispersion ln oll) and 7.05 g of dimethylsulphone in 18 ml of dlmethyl sulphoxide was stirred wlth the excluslon of molsture for 2 hours at 50C. Thereupon, 5.77 g of methyl 4-chloro-3-dimethylamino-5-methylamlnobenzoate (obtained as described in Example S) were added and the mlxture was stlrred for 2 hours at room temperature. The solution was diluted with 100 ml of : /7 -- 2~--" ~ .
water, the aqueous solution washed with ethyl acetate and made slightly acidlc wlth ethyl acetate. After standing for 18 hours at 4C, the preclpltated 4-chloro-3-dimethylamino-5-methylamlno-2-methylsulphonylacetophenone was filtered off under suction and recrystalllsed from ethanol; melting point:
A suspenslon of 4.85 g of 4-chloro-3-dlmethylamlno-5-methylamlno-2-methylsulphonylacetophenone and 0.20 g of sodlum borohydrlde ln 30 ml of 20~ aqueous ethanol was stirred for 1 hour at 20C, cooled with lce and the 4-chloro-3-dimethyl-amlno-5-methylamino-alpha-[(methylsulphonyl)methyl]benzyl alcohol was filtered off under suctlon and recrystalllsed from ethanol; melting polnt: 147-148C.
A mixture of 9.48 g of 4-chloro-3-dimethylamlno-5-methylamino-alpha-~(methylsulphonyl)methyl]benzyl alcohol, 1.8 g of sodium methylate and 4.8 g of ~-anillnoproplonitrile in 20 ml of dimethyl sulphoxide was stirred with the exclusion of molsture for S hours at 50C. The mlxture was cooled, poured lnto 200 ml of water, the preclpitated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium ~ulphate and evaporated. By purlfication of the product over aluminium oxide with benzene and recrystallisation from ethanol, there was obtained alpha-(anilinomethylene)-4-chloro-3-dimethylamino-5-methylaminohydroclnnamonitrile of melting point 173-174C.
Example 7 A ~olutlon of 0.53 g of sodium in 36 ml of absolute ethanol was treated with 2.16 g of guanldine hydrochloride and 3.2 g of alpha-(anilinomethylene)-3,5-bis(2,5-dimethylpyrrol-l-yl)-4-methylhydrocinnamonitrile and boiled under reflux for 20 hours~ The alcohol was removed in vacuo, the residue taken up in water, filtered off under suction and recrystal-lised from methanol/water. The 2,4-diamino-5-[3,5-bls(2,5-dimethylpyrrol-l-yl)-4-methylbenzyl]pyrimidine melted at 205-206C.
The starting material was prepared as follows:
A mlxture of 10.8 g of methyl 3,5-diamino-4-methyl-benzoate and 30 g of acetonylacetone was heated under nitrogen at 200C for 17 hours. On the following day, the solid mass was dlssolved in benzene, the benzene solutlon purified over alumlnlum oxlde, evaporated and the residue recrystallised lS from methanol. The methyl 3,5-bis(2,5-dimethylpyrrol-1-yl)-4-methylbenzoate melted at 163-165C.
A suspension of 6.25 g of dimethylsulphone and 2.4 g of sodium hydride (50% dlspersion ln oil) in 30 ml of dimethyl ~ulphoxide was stirred with the exclusion of moisture for 2 hours at 50C. Thereupon, 11.2 g of methyl 3,5-bis(2,5-dimethylpyrrol-l-yl)-4-methylbenzoate were added and the mix-ture was stirred for 1.5 hours at 20C. The solution was diluted with 150 ml of water, the precipitated product extra-cted with ethyl acetate, the ethyl acetate solution dried over sodium sulphate and evaporated. 3',5'-Bis(2,5-dimethyl-pyrrol-l-yl)-4'-methyl-2-methylsulphonylacetophenone of mel-ting point 173C was lsolated from the residue by column ., Iq I _ ~y _ ", ' .
~OS9127 chromatography over sllica gel with methylene chloride/ethyl acetate (9:1).
A suspension of 1.9 g of 3',5'-bis(2,5-dimethylpyrrol-1-yl)-4'-methyl-2-methylsulphonylacetophenone and 0.40 g of sodium borohydride in 50 ml of 90~ aqueous ethanol was stirred for 3 hours at room temperature, cooled, the precipitate fil-tered off under suction and recrystallised from ethanol. The 3,5-bis(2,5-dimethylpyrrol-1-yl)-4-methyl-alpha-[(methyl-sulphonyl)methyl]benzyl alcohol melted at 207-208C.
A mixture of 4.95 g of 3,5-bis(2,5-dimethylpyrrol-1-yl)-4-methyl-alpha-[(methylsulphonyl)methyl]benzyl alcohol, 0.95 g of sodium methylate and 2.16 g of ~-anilinopropionitrile in 13 ml of dimethyl qulphoxide was stirred with the exclusion of moisture for 5 hours at 50C. The mixture was poured into 100 ml of water, the precipitated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulphate and evaporated. By purification of the residue over alumin-ium oxide with ethyl acetate and recrystallisation from ethyl acetate, there was obtained alpha-(anilinomethylene)-3,5-bis-(2,5-dlmethylpyrrol-1-yl)-4-methylhydrocinnamonitrile of meltlng polnt 252C.
Example 8 A solution of 0.94 g of sodium in 65 ml of absolute ethanol was treated with 3.85 g of guanidine hydrochloride and 6.6 g of 5'-(3-anllino-2-cyanoallyl)-3'-(pyrrol-1-yl)-o-aceto-toluidlde and bolled for 20 hours under reflux and under -- 3,0~ --lOS91Z7 nitrogen. The alcohol was removed ln vacuo, the resldue taken up ln water, flltered off under suctlon and recrystal-lised from methanol. The N-[alpha5-(2,4-diamino-5-pyrimidin-yl)-3-(pyrrol-1-yl)-2,5-xylyl]acetamide melted at 110C.
The starting material was preparèd as follows:
A mixture of 18 g of methyl 3,5-dlamlno-4-methylben-zoate, 0.7 g of p-toluenesulphonic acld, 8.2 g of sodium acetate, 32 q of diethoxytetrahydrofuran, 10 ml of glaclal acetic acid, 100 ml of ethanol and 100 ml of water was boiled at reflux for 3 hours. The alcohol was removed ln vacuo and the residue extracted with ethyl acetate. The ethyl acetate solution was washed with water, dried over sodium sulphate and evaporated. By purification of the residue over aluminium oxide with ethyl acetate and recrystallisation from hlgh-boiling petroleum ether, there was obtained methyl 3-amino-4-methyl-5-(pyrrol-1-yl)benzoate of melting point 112C. -A suspension of 4.6 g of methyl 3-amlno-4-methyl-5-(pyrrol-l-yl)benzoate in 15 ml of glaclal acetic acld was treated with 2.1 g of acetic anhydride. Wlth self-heating, -there re~ulted firstly a clear solution and soon afterwards crystals began to separate. The mixture was heated on a steam-bath for a further 30 minutes and then cooled. The crystals were filtered off under suctlon and recrystallised from methanol. The methyl 3-acetamldo-4-methyl-5-(pyrrol-1-yl)benzoate melted at 184-185C.
A suspension of 1.44 g of sodium hydride (50% disper-.. j. , --,a~ --~0591Z7 sion in oil) and 3.7 g of dimethylsulphone in 20 ml of dimeth-yl sulphoxide was stirred with the exclusion of moisture for 2 hours at 50C. Thereupon, 5.45 g of methyl 3-acetamido-4-methyl-5-(pyrrol-1-yl)benzoate were added and the mixture was stirred for 2 hours at room temperature. The solution was diluted with 200 ml of water, the aqueous solution washed with ethyl acetate, made slightly acidic with acetic acid and left to stand overnight in a refrigerator. On the following day, the precipltate was filtered off under suction and recrystal-lised from ethanol. The 5'-[(methylsulphonyl)acetyl]-3'-(pyrrol-l-yl)-o-acetotoluidide melted at 212-214C.
A suspension of 1.6 g of 5'-[(methylsulphonyl)acetyl]-3'-(pyrrol-1-yl)-o-acetotoluidide and 0.40 g of sodium boro-hydrlde in 50 ml of 50~ aqueous ethanol was stirred at room temperature for 30 minutes. The ethanol was removed in vacuo, the precipitate filtered off under suction, dried and recrystallised from ethyl acetate/petroleum ether. The 5'-tl-hydroxy-(2-methylsulphonyl)ethyl]-3'-(pyrrol-1-yl)-o-aceto-toluidlde melted at 167-168C.
A mixture of 1.35 g of 5'-[1-hydroxy-2-(methylsulphon-yl)ethyl]-3'-(pyrrol-1-yl)-o-acetotoluidide, 0.43 g of sodium methylate and 1.1 g of ~-anilinopropionitrile in 12 ml of dimethyl sulphoxide was stirred with the exclusion of moisture for 1 hour at room temperature. The mixture was poured into 100 ml of water, the precipitated oil extracted with ethyl acetate, the ethyl acetate solution washed with water, dried over sodlum sulphate and evaporated. By column chromatog-raphy over silica gel with methylene chlorlde/ethyl acetate el .~
(9:1) and recrystallisation from ethanol, there was obtained
5'-(3-anilino-2-cyanoallyl)-3'-(pyrrol-1-yl)-o-acetotoluldide of melting point 218-220C.
Example 9 2.0 g of N-[alpha5-(2,4-diamino-5-pyrlmidinyl)-3-(pyr-imldinyl)-3-(pyrrol-1-yl)-2,5-xylyl]-acetamide, (prepared as desc`ribed ln the flrst paragraph of Example 8), and 70 ml of l-N hydrochloric acld were heated on a steam-bath for 3 hours.
After cooling, the solution was made alkaline wlth potassium carbonate, the preclpltate filtered off in vacuo and recrys- -tallised from ethanol/petroleum ether. The 2,4-dlamino-5-[3-amlno-4-methyl-5-(pyrrol-1-yl)benzyl]pyrlmldine melted at 202-204C.
Exam~le 10 A solutlon of 0.33 g of sodium in 30 ml of absolute ethanol was treated with 1.43 g of guanidine hydrochloride and 1.9 g of alpha-(anlllnomethylene)-4-methoxy-3,5-dl(pyrrol-1-yl)hydrocinnamonitrile and boiled under reflux for 20 hours.
The alcohol was removed in vacuo, the residue taken up in water, filtered off under suction and recrystallised from -methanol. The 2,4-diamino-5-[4-methoxy-3,5-di(pyrrol-1-yl)-benzyl]-pyrimldlne melted at 182-183C.
The startlng materlal was prepared as follows:
A mixture of 19.6 g of methyl 3,5-diamino-4-methoxy-P . ~3 ~059127 benzoate, lOo ml of glaclal acetic acid and 36 g of diethoxy-tetrahydrofuran wa~ ~tirred for 30 mlnutes at 100C. The glaclal acetlc acid was removed ln vacuo. There was obtalned from the residue, after purificàtion over aluminlum oxlde with benzene and recrystallisation from methanol, methyl 4-methoxy-3,5-dl(pyrrol-1-yl)benzoate of melting polnt 55-57C.
A suspenslon of 5.8 g of sodium hydride (50% dlsperslon in oll) and 15 g of dlmethylsulphone in 80 ml of dimethyl sulphoxide was stirred with the exclusion of moisture for 2 hours at 50C. Thereupon, 23.6 g of methyl 4-methoxy-3,5-dl(pyrrol-l-yl)benzoate were added and the mixture was stirred for 2 hours at room temperature. The solution was dlluted wlth 300 ml of water, the aqueous solution made weakly acidic wlth acetlc acid, the precipltate filtered off under suctlon lS and recxystallised from ethanol. The 4'-methoxy-2-methyl-sulphonyl-3',5'-di(pyrrol-1-yl)acetophenone melted at 155-A suspension of 3.4 g of 4'-methoxy-2-methylsulphonyl-3',5'-di(pyrrol-1-yl)acetophenone and 0.8 g of sodlum boro-hydrlde in 70 ml of 90% ethanol was stlrred for 16 hours at room temperature. The alcohol was removed in vacuo, the residue taken up in water, filtered off under suction and recrystalllsed from methanol. The 4-methoxy-alpha-[(methyl-sulphonyl)methyl]-3,5-di(pyrrol-1-yl)benzyl alcohol melted at 185-186C.
A mixture of 1.8 g of 4-methoxy-alpha-[(methylsulphon-yl)methyl]-3,5-di(pyrrol-1-yl)benzyl alcohol, 0.41 g of sodium methylate and 1.1 g of ~-anlllnoproplonltrile ln 12 ml of ,,",, . ~?s~
_,~ _ ~059127 dimethyl sulphoxide was stirred with the exclusion of moisture for 3 hours at room temperature. The mixture was diluted with 100 ml of water, the precipitated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulphate and evaporated. ~y purification of the residue over aluminlum oxide with benzene and recrystallisation from ethyl acetate/petroleum ether, there was obtained alpha-(anlllno-methylene)-4-methoxy-3,5-di~pyrrol-1-yl)hydrocinnamonitrlle of melting point 152C.
Example 11 A solution of 690 mg of sodium in 100 ml of absolute ethanol was treated with 5.4 g of guanldine carbonate and 3.2 g of alpha-(anilinomethylene)-3,5-bis(dimethylamino)hydro-cinnamonitrile and boiled under reflux for 20 hours. After the addition of 50 ml of water, the alcohol was evaporated in vacuo. After standing for 1 hour at 25C, the preclpitated 2,4-diamino-5-t3,5-bis(dimethylamino)benzyl]pyrimidlne was flltered off under suctlon, washed with water and recrystal-lised from methanol/ethyl acetate; melting point: 198-199C.
The starting material was prepared as follows:
24.9 g of methyl 3,5-diaminobenzoate, 75.6 g of dimethyl sulphate and 207 g of anhydrous potassium carbonate were bolled for 20 hours in 1 litre of tetrahydrofuran under a reflux condenser while stirring and excluding moisture. After coollng, the mixture was filtered and the filtrate evaporated lOS91Z7 to dryness in vacuo. The residue was treated with 200 ml of water and the precipitated oil extracted with 400 ml of ethyl acetate. The ethyl acetate phases were washed with 200 ml of water, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was chromatographed on 500 g of silica gel with ethyl acetate/methylene chloride (1:9), there being obtained methyl 3,5-bis(dimethylamino)benzoate of melting point 86-88C.
A suspension of 3.6 g of sodium hydride (50% dispersion in oil) and 9.4 g of dimethylsulphone in 50 ml of absolute dimethyl sulphoxide was stirred with the exclusion of moisture for 2.5 hours at 50C and then treated with 11.1 g of methyl 3,5-bis(dimethylamino)benzoate. The mixture was stirred for 18 hours at room temperature, diluted with 500 ml of water and extracted with 600 ml of ethyl acetate. The ethyl acetate phases were washed wlth 300 ml of water, dried over magnesium sulphate and evaporated to dryness in vacuo. Recrystallisa-tion of the residue from ethyl acetate yielded 3',5'-bis-(dimethylamino)-2-methylsulphonylacetophenone of melting point 151-153C.
A suspenslon of 7.4 g of 3',5'-bis(dimethylamino)-2-methylsulphonylacetophenone and 3.8 g of sodium borohydride in 100 ml of ethanol was stirred for 20 hours at 25C. After the addition of 50 ml of water, the alcohol was removed in vacuo and the remaining aqueous suspension extracted with 400 ml of ethyl acetate. The ethyl acetate phases were washed with 50 ml of water, dried over magnesium sulphate and evap-orated to drynes~ in vacuo. ~ecrystallisation of the residue from ethanol gave 3,5-bis(dimethylamino)-a-[(methylsulphonyl)-methyl]benzyl alcohol of meltlng polnt 142-143C.
A mixture of 1.6 g of sodium methylate, 2.3 g of B-anilinopropionitrile and 4.3 g of 3,5-bis(dimethylamino)--~(methylsulphonyl)methyl]benzyl alcohol in 20 ml of absolutedimethyl sulphoxide was stirred with the exclusion of moisture for 4 hours at 50C. The solution was diluted with 250 ml of water and extracted with 500 ml of ethyl acetate. The ethyl acetate phases were washed wlth 100 ml of water, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was dissolved in 20 ml of ethanol. After standing for 20 hours at 4C, the crystallised a-(anilinomethylene)-3,5-bis(dimethylamino)hydrocinnamonitrile was filtered off under suction, washed with ethanol and dried; melting polnt:
128-130C.
Exarnple 12 A solution of 4.1 g of sodium in 600 ml of ethanol was treated wlth 32.4 g of guanldine carbonate and 17.8 g of a-(anilinomethylene)-3,5-bis(methylamino)hydrocinnamonitrile and bolled under reflux and under nitrogen gassing for 20 hours.
After the addition of 500 ml of water, the alcohol was evapor-ated in vacuo. After standing for 2 hours at 25C, the pre-cipitated 2,4-diarnino-S-[3,5-bis(methylamino)benzyl]pyrimidine was filtered off under suction, washed with water and recrys-talllsed from methanol; melting point: 209C.
~he startlng rnaterlal was prepared as follows:
~ i _, ~_ ~oss~27 A mixture of 134 g of methyl 3,5-dlaminobenzoate, 870 ml of acetic anhydride and 870 ml of absolute pyridine was stir-red for 20 hours at 25C and subsequently evaporated to dry-ness in vacuo. Recrystallisation of the residue from ethyl acetate yielded methyl 3,5-bis(acetamido)benzoate of melting point 220-221C.
A suspension of 88 g of sodium hydride (50~ dispersion in oil) in B00 ml of absolute dimethylformamide was treated with a solution of 191 g of methyl 3,5-bis(acetamido)benzoate in 800 ml of absolute dimethylformamide with stirring and ice-cooling. After stirrlng for 1 hour at 25C, 650 g of methyl iodide were added dropwise with ice-cooling. The mixture was stirred for S0 hours at 25C, treated with 4 litres of water and extracted 6 times with 5 litres of ethyl acetate each time. The ethyl acetate extract was washed with 3 litres of water, dried over magnesium sulphate and evaporated to dryness in vacuo. Recrystallisation of the residue from ethyl acetate/cyclohexane gave methyl 3,5-bis(N-methylacetamido)-benzoate of melting point 106C.
A suspension of 19.2 g of sodium hydride (50% dispersion in oil) and 56.1 g of dimethylsulphone in 200 ml of absolute dimethyl sulphoxide was stirred with the exclusion of moisture for 3 hours at 50C and then treated at 25C with 41.8 g of methyl 3,5-bis(N-methylacetamido)benzoate. The mixture was stirred for 18 hours at 25C, diluted with 2 litres of water, adjusted to pH 7 with glacial acetic acid and extracted with 9 litres of ethyl acetate. The ethyl acetate solution was washed with 3 litres of water, dried over magne~ium sulphate ,~ _ ,;~ _ ', ' ' ~ . , , 105912~7 and evaporated ln vacuo. Recrystalllsation of the re~ldue ; from ethanol ylelded 3',5'-bl~(methylamino)-2-methylsulphonyl-acetophenone of meltlng point 144-146C.
A suspenslon of 7.6 g of sodium borohydride and 12.8 g of 3',5'-bis(methylamino)-2-methylsulphonylacetophenone in 200 ml of ethanol was stlrred for 18 hours at 25C. After the addltlon of 50 ml of water, the solution was evaporated to dryness ln vacuo. The residue was heated to boiling ln 300 ml of ethyl acetate. The insoluble material was separated and the filtrate evaporated to dryness in vacuo. Recrystal-llsation of the resldue from ethanol gave 3,5-bls(methyl-amlno)-a-t(methylsulphonyl)methyl]benzyl alcohol of meltlng polnt 106C.
A mixture of 8.6 g of sodium methylate, 12.4 g of ~-anllinoproplonltrile and 20.4 g of 3,5-bls(methylamino)-a-t(methylsulphonyl)methyl]benzyl alcohol ln 100 ml of absolute dlmethyl sulphoxide wa~ stirred for 1 hour at 50C and then treated with 1 litre of water. The preclpitated product was extracted wlth 3 lltres of ethyl acetate. The ethyl acetate extract was washed wlth 1 lltre of water, dried over magnesium sulphate and evaporated in vacuo. The residue was chromato-graphed on 1 kg of silica gel with methylene chloride/ethyl acetate (3:1), there being obtained a-(anilinomethylene)-3,5-bis(methylamino)hydroclnnamonltrlle as a brownlsh-coloured oll.
Example 13 A ~olution of 8 g of sodlum in 300 ml of absolute ~`
,,, -~39' -lOS9127 ethanol was boiled under reflux wlth 62 g of guanldlne car-bonate and 40 g of 5'-(3-anllino-2-cyanoallyl)-N,2'-dlmethyl-3'-methylaminoacetanilide for 20 hours. After the addition of 500 ml of water, the alcohol was evaporated in vacuo. The crystalllsed a -(2,4-dlamino-5-pyrimidinyl)-N-methyl-3'-methylamino-2,5-acetoxylidide was filtered off under suction, washed with water and recrystallise* from alcohol; melting point: 237C.
The starting material was prepared as follows:
A solution of 36 g of methyl 3,5-diamino-p-toluate, in 600 ml of absolute pyridine, was treated dropwise with 200 ml of acetic anhydride while stirring. After stlrring for 5 t hours at 25C, the precipitated methyl 3,5-bis(acetamido)-p-toluate was filtered off under suction, washed with 300 ml of water and recrystallised from methanol; melting point above 260C.
A suspension of 28.8 g of sodium hydride (50~ dispersion in oil) ln 800 ml of absolute dimethylformamide was treated portionwise with 66 g of methyl 3,5-bis(acetamido)-p-toluate.
After stirring for 20 hours at 50C, the mixture was cooled with ice. 105 g of methyl iodide were added dropwise and the mixture was stirred for 20 hours at room temperature. The dimethylformamide was removed in vacuo at 60C and the residue treated with 500 ml of water. The precipitated product was extracted with 3 litres of ethyl acetate. The ethyl acetate solutlon was washed wlth 500 ml of water, dried over magnesium sulphate and evaporated in vacuo. The residue was,chromato-:
-graphed on 1 kg of silica gel with acetone, there being obtained methyl 3,5-bls(N-methylacetamido)-p-toluate of mel-ting point 163-164C.
A suspension of 3.8 g of sodium hydride (50~ dispersion in oil) and 11.2 g of dimethylsulphone in 40 ml of absolute dimethyl sulphoxide was stlrred for 3 hours at 50C. After cooling to 25C, 8.8 g of methyl 3,5-bis(N-methylacetamido)-p-toluate were added. The mlxture was stirred for 18 hours at 25C, diluted with 500 ml of ice-water, adjusted to pH 7 with glacial acetic acid, saturated with sodium chloride and ex-tracted with 2 litres of ethyl acetate. The ethyl acetate extract was washed with 200 ml of water, dried over magnesium sulphate and evaporated in vacuo. The residue was recrystal-lised from alcohol, there being obtained N-methyl-3'-methyl-amino-5'-t(methylsulphonyl)acetyl]-o-acetotoluidide of melting point 182C.
A suspension of 56 g of sodium borohydride and 116 g of N-methyl-3'-methylamino-5'-[(methylsulphonyl)acetyl]-o-aceto-toluidide in 1 litre of ethanol was stirred for 20 hours at 25C. The solvent was evaporated in vacuo, the residue treated with 2 litres of water and extracted with 9 litres of ethyl acetate. The ethyl acetate solution was washed with 1 -litre of water, dried over magnesium sulphate and evaporated in vacuo. Recrystallisation of the residue from ethanol yielded 5'-[1-hydroxy-2-(methylsulphonyl)ethyl]-N,2'-dimethyl-3'-methylaminoacetanilide of melting point 191-192C.
A mixture of 27 g of sodium methylate, 41 g o~ ~-anilinoproplonitrile and 79.5 g of 5'-tl-hydroxy-2-(methyl-~ 3 , sulphonyl)ethyl]-N,2'-dimethyl-3'-methylaminoacetanilide in 350 ml of absolute dimethyl sulphoxide was stirred for 1 hour at 50C, then diluted with 2 litres of water and extràcted with 6 litres of ethyl acetate. The ethyl acetate extract was washed with 1 litre of water, dried over magnesium sul-phate and evaporated in vacuo. The residue was chromato-graphed on 2 kg of silica gel with ethyl acetate/methylene chloride (1:1), there being obtained 5'-(3-anilino-2-cyano-allyl)-N,2'-dimethyl-3'-methylaminoacetanilide as an oil.
ExamPle 14 A solution of 0.53 g of sodium in 600 ml of absolute ethanol was treated with 2.16 g of guanidine hydrochloride and 3.95 g of a-(anilinomethylene)-4-tert.butyl-3,5-bis(dimethyl-amino)hydrocinnamonitrile and boiled under reflux for 20 hours. The ethanol was removed under reduced pressure, the residue taken up in watsr, the precipitated 2,4-diamino-5-[4-tert.butyl-3,5-bis(dimethylamino)benzyl]pyrimidine filtered off under suction, washed with water and recrystallised from ethanol; melting point: 266-267C.
The starting material was prepared as follows:
20 g of 4-tert.butyl-3,5-dinitrobenzoic acid [J. Org.
Chem. 19, 87-102 (1954)] and 100 ml of thionyl chloride were boiled under reflux for 2 hours. The excess thionyl chloride was removed in vacuo, the residue dissolved in 100 ml of acetone and the resulting solution added dropwise to 100 ml of methanol while stirring. The resulting mixture wa~ bolled 3~
. .
: ' ., :' l~S9127 under reflux for 30 minutes, the methanol dlstllled off, the residue dissolved in benzene, the benzene solutlon washed wlth sodium carbonate solutlon and then wlth water until neutral, drled over sodium sulphate and evaporated. After recrystal-lisation of the residue from methânol, there was obtainedmethyl 4-tert.butyl-3,5-dinitrobenzoate of melting point 115-117C.
28.2 g of methyl 4-tert.butyl-3,5-dinitrobenzoate dis-solved in 200 ml of methanol were hydrogenated under normal pressure and at room temperature in the presence of 2 g of palladium/carbon ~5~). After the uptake of the theoretical amount of hydrogen, the solution was flltered from the cat-alyst and evaporated. The residue was dissolved ln benzene and purified over alumlnlum oxlde, there belng obtained methyl 3,5-diamino-4-tert.butylbenzoate of melting point 71-73C
after recrystallisation from benzene/petroleum ether.
A mixture of 25 g of methyl 3,5-diamino-4-tert.butyl-benzoate, 50 ml of dimethyl sulphate, 155 g of dry potassium carbonate and 750 ml of acetone was boiled for 22 hours under reflux and while stirring. After cooling, the solution was filtered off from inorganic salts, the acetone removed in vacuo and the residue recrystallised from methanol/water, there being obtained methyl 4-tert.butyl-3,5-bis(dimethyl-amino)benzoate of melting point 80-82C.
A suspension of 2.4 g of sodium hydride (50% suspension in oil) and 7.05 g of dimethylsulphone in 17.5 ml of dimethyl sulphoxide was stirred with the exclusion of mois~u~e for 2 _ , lOS9~27 hours at 50C. 6.9 g of methyl 4-tert.butyl-3,5-bis(di-methylamino)benzoate were then added and the mixture was stlrred at room temperature for 1.5 hours. The solution was tdlluted with 150 ml of ice-water, the precipitated solld material filtered off, washed with water and recrystallised from methanol, there being obtained 4'-tert.butyl-3',5'-bis-(dimethylamino)-2-methylsulphonylacetophenone of melting point 177-179C.
A suspension of 8 g of 4'-tert.butyl-3',5'-bis(dimethyl-amino)-2-methylsulphonylacetophenone in 200 ml of ethanol was stirred at 20C for 4 hours with a solution of 2.3 g of sodium borohydride in 25 ml of water. After dilution with 250 ml of ice-water, the precipitated 4-tert.butyl-3,5-bis(dimethyl-amino)-a-[(methylsulphonyl)methyl]benzyl alcohol wa~ filtered off under suctlon and recrystallised from methanol; melting point: 202-204C.
A mixture of 4.66 g of 4-tert.butyl-3,5-bis(dimethyl-amino)-a-~(methylsulphonyl)methyl]benzyl alcohol, 1.28 g of sodium methylate and 3.3 g of ~-anilinopropionitrile in 35 ml of dimethyl sulphoxide was stirred at room temperature under nitrogen for 60 minutes. The mixture was poured into 200 ml of ice-water, the separated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulphate and then evaporated. By purification of the residue over aluminium oxide with benzene and recrystallisation from ethanol, there was obtained a-(anilinomethylene)-4-tert.butyl-3,5-bis(di-methylamino)hydrocinnamonitrile of melting point 150C.
_ ~_ Example 15 A solution of 0.53 g of sodium in 60 ml of absolute ethanol was treated with 2.16 g of guanidine hydrochloride and 3.8 g of a-(anilinomethylene)-3,4,5-trls(dimethylamino)hydro-cinnamonitrile and boiled under reflux for 20 hours. Theethanol was removed under reduced pressure, the residue taken up in water, the precipitated 2,4-diamino-5-~3,4,5-tris-(dimethylamino)benzyl]pyrimidine filtered off under suction, washed with water and recrystallised from ethanol; melting point: 203-204C.
The starting material was prepared as follows:
27 g of methyl 4-dlmethylamino-3,5-dinltrobenzoate [Rec.
trav. chim. 73, 68 (1954)] dissolved ln 300 ml of methanol were hydrogenated under normal pressure and at room tempera-ture in the presence of 3 g of palladium/carbon (5~). Afteruptake of the theoretical amount of hydrogen, the solution was filtered off from the catalyst and evaporated. The residue, methyl 3,5-diamino-4-dimethylaminobenzoate, was characterlsed as the monohydrochloride; melting point: 222-223C (from ethanol/ether).
A mixture of 37 g of methyl 3,5-diamino-4-dimethylamino-benzoate, 113 ml of dimethyl sulphate, 350 g of dry potassium carbonate and 14 ml of acetone was boiled under reflux while stirring for 18 hours. After coollng, the solution was fil-tered off from inorganic salts, the acetone removed in vacuo,the resldue dissolved ln benzene, purified over alu,minium _ ~_ lOS9127 oxide and recrystallised from methanol/water, there belng obtained methyl 3,4,5-trls(dimethylamino)benzoate of meltlng point 61-63C.
A suspension of 4.8 g of sodium hydride (50~ emulsion in oil) and 14.1 g of dimethylsulphone in 35 ml of dimethyl sulphoxide was stirred under nitrogen and with the exclusion of moisture for 2 hours at 50C. 13.2 g of methyl 3,4,5-tris(dlmethylamlno)benzoate were then added and the mixture was stirred at room temperature for 1.5 hours. The solution was diluted wlth 300 ml of ice-water, extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulphate and evaporated. The residue was treated with 30 ml of boiling methanol, cooled and filtered under suction. By recrystallisation of the solid material from ethyl acetate/
petroleum ether, there was obtained 3',4',5'-tris(dimethyl-amino)-2-methylsulphonylacetophenone of melting point 108C.
A suspension of 15 g of 3',4',5'-tris(dimethylamino)-2-methylsulphonylacetophenone in 400 ml of ethanol was treated with a solution of 4 g of sodium borohydride in 50 ml of water and stirred at room temperature for 7 hours. After dilution with 500 ml of water, the precipitated 3,4,5-tris(dimethyl-amino)--t(methylsulphonyl)methyl]benzyl alcohol was filtered off under suction, washed with water and recrystallised from methanol; melting point: 160-162C.
A mixture of 8.96 g of 3,4,5-tris(dimethylamino)-a-t(methylsulphonyl)methyl]benzyl alcohol, 2.56 g of sodium methylate and 6.6 g of ~-anilinopropionitrile in 70 ml of _ ~_ ,,, ~ , ", ": ",-, .
~059~27 dimethyl sulphoxide was stirred at room temperature under nitrogen for 50 minutes. The mlxture was poured lnto 500 ml of lce-water, the separated oll extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulphate and evaporated. By purlflcation of the residue over aluminium oxide with benzene and recrystallisation from ethanol, there was obtained a- (anilinomethylene)-3,4,5-tris(dimethylamino)-hydrocinnamonitrile of melting point 179-181C. , A solution of 1.22 g of sodium in 110 ml of absolute ethanol was treated with 5.26 g of guanidine hydrochloride and 7.0 g of a-(anilinomethylene)-3,5-bls(dimethylamino)-4-piperidinohydrocinnamonitrlle and boiled under nltrogen and under reflux for 24 hours. The ethanol was removed under reduced pressure, the residue taken up in water, the pre-cipitated 2,4-diamino-5-[3,5-bls(dlmethylamlno)-4-piperidino-benzyl]pyrimidine filtered off under suction, washed with water and recrystallised from ethanol; melting point: 216-218C.
The starting material was prepared as follows:
15.45 g of methyl 3,5-dinitro-4-piperidinobenzoate [Rec.
trav. chim. 73, 68 (1954)] dissolved in 200 ml of methanol were hydrogenated under normal pressure and at room tempera-ture in the presence of 1 g of palladium/carbon (5%). After uptake of the theoretlcal amount of hydrogen, the solution was flltered off from the catalyst and evaporated. By recrystal-~3'' 34~
lisation of the residue from ethyl acetate/petroleum ether, there was obtained methyl 3,5-diamino-4-piperidinobenzoate of melting point 133-134C.
A mlxture of 42 g of methyl 3,5-diamino-4-piperidino-benzoate, 75 ml of dlmethyl sulphate, 232.5 g of dry potasslum carbonate and 1125 ml of acetone was bolled under reflux and while stirrlng for 20 hours. After cooling, the solution was filtered off from lnorganic salts, the acetone removed in vacuo and the residue recrystallised from methanol, there being obtained methyl 3,5-bis(dimethylamino)-4-piperidino-benzoate of melting polnt 103-105C.
A suspenslon of 2.9 g of sodlum hydride (50% emulsion in oll) and 3.7 g of dlmethylsulphone ln 20 ml of dlmethyl sulphoxlde was stlrred with the exclusion of moisture for 2 hours at 50C. 6.1 g of methyl 3,5-bis(dimethylamino)-4-piperldinobenzoate were then added and the mixture was stirred at room temperature for 2 hours. The solution was diluted with 200 ml of ice-water, the precipitated material filtered off under suction, washed wlth water and recrystallised from methanol, there being obtained 3',5'-bis(dimethylamino)-2-methylsulphonyl-4-piperidinoacetophenone of melting point 165C.
A suspension of 8.9 g of 3',5'-bis(dimethylamino)-2-methylsulphonyl-4'-piperidinoacetophenone in 250 ml of ethanol was treated with a solution of 2 g of sodium borohydride in 50 ml of water and stlrred at 20C for 4 hours. After dilution with 350 ml of ice-water, the precipitated 3,5-bis(dimethyl-3~
_ ,g~ _ , , . . . .
amino)-a-[(methylsulphonyl)methyl]-4-plperidinobenzyl alcohol wa~ filtered off under suction and recrystalllsed from ethan-ol; melting point: 179-180C.
A mixture of 7.4 g of 3,5-bis(dimethylamino)-a-[(methyl-sulphonyl)methyl]-4-piperidinobenzyl alcohol, 1.64 g of sodium methylate and 4.4 g of ~-anilinopropionitrile in 40 ml of dimethyl sulphoxide was stirred for 2 hours at 50C under nitrogen. The mixture was poured into 250 ml of water, the precipitated product extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulphate and evaporated.
By purification of the residue over aluminium oxide with ben-zene and recrystallisation from ethyl acetate/petroleum ether, there was obtained a-(anilinomethylene)-3,5-bis(dimethyl-amino)-4-piperidinohydrocinnamonitrile of melting point 200-202C.
Example 17 A solution of 0.85 g of sodium in 55 ml of absoluteethanol was treated with 3.4 g of guanidine hydrochloride and 3.8 g of a-(anilinomethylene)-4-chloro-3,5-bis(methylamino)-hydrocinnamonitrile and boiled under reflux and under nitrogenfor 24 hours. The ethanol was removed under reduced pres-sure, the residue taken up in water, the precipitated 2,4-diamino-5-[4-chloro-3,5-bis(methylamino)benzyl]pyrimidine fil-tered off under suction, washed with water and recrystallised from ethanol; melting point: 230C.
The starting material was prepared as follows:
16 g of methyl 3,5-diamino-4-chlorobenzoate were dis-solved ~n 100 ml of dry pyridine and treated with 40 ml of acetic anhydrlde. After standing at room temperature for 2 hours and after a further 2 hours in a refrigerator, the pre-cipitated methyl 3,5-diacetamido-4-chlorobenzoate was filtered off under suction, washed wlth ethyl acetate and recrystal-lised from ethanol; melting point: 282C.
To a suspension of 4.4 g of sodium hydride (50% suspen-sion in oil) in 80 ml of dimethylformamide was added dropwlse at room temperature a solution of 21.7 g of methyl 3,5-diacet-amido-4-chlorobenzoate in 240 ml of dimethylformamide. After 1 hour, 65.1 g of methyl iodide were added dropwise and the resulting mixture was stirred at room temperature for 48 hours. The mixture was dlluted wlth 100 ml of water, the precipitated product extracted with ethyl acetate and the ethyl acetate solution evaporated. The residue was dissolved in ethyl acetate and purified over aluminium oxide, there being obtained methyl 4-chloro-3,5.bis(N-methylacetamido)-benzoate which melted at 162-164C after recrystallisation from ethyl acetate/petroleum ether.
A suspension of 3.8 g of sodium hydride (50% suspension in oil) and 11.2 g of dimethylsulphone in 40 ml of dimethyl sulphoxide was stirred with the exclusion of moisture for 2 hours at 50C. 9.4 g of methyl 4-chloro-3,5-bis(N-methyl-acetamido)benzoate were then added and the mixture was stirred at 80C for 3 hours. The solution was diluted with 200 ml of ice-water, the precipitated material extracted with ethyl acetate, the ethyl acetate solution purified over aluminium S~
-- 5~--.' 105912~7 oxide, evaporated and the residue recrystallised from meth-anol, there being obtained 4'-chloro-3',5'-bis(methylamino)-2-methylsulphonylacetophenone of melting point 165-167C.
A suspension of 1.4 g of 4'-chloro-3',5'-bis(methyl-5 amino)-2-methylsulphonylacetophenone in 50 ml of ethanol was treated with a solution of 0.40 g of sodium borahydride in 10 ml of water and stirred at 20C for 4 hours. The ethanol was removed under reduced pressure, the residue treated with 100 ml of lce-water, the insoluble 4-chloro-3,5-bis(methylamino)- -a-t(methylsulphonyl)methyl]benzyl alcohol filtered off under suction and recrystallised from ethanol; melting point: 180-182C.
A mixture of 13.2 g of 4-chloro-3,5-bis(methylamino)-a-t(methylsulphonyl)methyl]benzyl alcohol, 3.6 g of sodium methylate and 9.6 g of ~-anilinopropionitrile in 80 ml of dimethyl sulphoxide was stirred for 5 hours under nitrogen at 50C. The mixture was poured into 200 ml of iae-water, the separated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulphate and evaporated. By purification of the residue over aluminium oxide with benzene and recrystallisation from ethyl acetate/petroleum ether, there was obtained a-(anilinomethylene)-4-chloro-3,5-bis-(methylamino)hydrocinnamonitrile of melting point 142-147C.
Example 18 A solution of 0.33 g of sodium in 30 ml of absolute ethanol was treated wlth 1.43 g of guanidine hydrochlorlde and , .~
-~, `~ ~
~059127 2.2 g of 4'-(3-anilino-2-cyanoallyl)-2',4'-bis(dimethylamino)-N-methylacetanilide and boiled under reflux and under nitrogen for 24 hours. The ethanol was removed under reduced pres-sure, the residue taken up in water and the precipitated a-(2,4-diamino-S-pyrimidinyl)-2',6'-bis(dimethylamino)-N-methyl-acetotoluidide flltered off under suction, washed wlth water and recrystallised from methanol; melting point: 267C.
The starting material was prepared as follows:
A suspension of methyl 4-methylamino-3,5-dinitrobenzoate ln 50 ml of acetic anhydride was treated with 3 drops of con-centrated sulphuric acid. After a short time, the solld material dissolved completely and, after 30 mlnutes, the prod-uct began to crystalllse. The product was filtered off under suction and recrystallised from methanol. The methyl --lS 4-(N-methylacetamido)-3,5-dlnitrobenzoate melted at 156-157C.
9.7 g of methyl 4-(N-methylacetamido)-3,5-dinitrobenz-oate in lO0 ml of methanol were hydrogenated under normal pressure and at room temperature in the presence of l g of palladium/carbon. After uptake of the theoretical amount of hydrogen, the solution was filtered off from the catalyst and evaporated. The residue was recrystallised from methanol, there being obtained methyl 3,5-diamino-4-(N-methylacetamido)-benzoate of melting point 221-222C.
A mixture of 50 g of methyl 3,5-diamino-4-~N-methyl-acetamldo)benzoate, 720 g of dry sodium carbonate, lS00 ml of -.
acetone and 212 g of dimethyl sulphate was boiled under reflux while stirring for 24 hours. After cooling, the solution was filtered off from inorganic salts, the acetone evaporated in vacuo and methyl 3,5-bis(dimethylamino)-4-(N-methylacetamido)-benzoate of melting point 120C extracted from the residue byboiling with high-boiling petroleum ether.
A suspension of 0.77 g of sodium hydride (50~ suspension in oil) and 2.28 g of dimethylsulphone in 28 ml of dimethyl sulphoxide was stirred with the exclusion of moisture and under nitrogen for 2 hours at 50C. 2 g of methyl 3,5-bis-(dimethylamino)-4-(N-methylacetamido)benzoate were then added, the mixture heated to 70C for a short time and stirred for a further 2 hours without heating. The solution was diluted with 100 ml of ice-water, washed with 100 ml of low-boillng petroleum ether, the product extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulphate and evapor-ated. After purification of the residue over aluminium oxide with benzene and recrystallisation from ethyl acetate/petrol-eum ether, there was obtained 2',6'-bis(dimethylamino)-N-methyl-4'-[(methylsulphonyl)acetyl]acetanilide of melting point 130C.
A suspension of 1.4 g of 2',6'-bis(dimethylamino)-N-methyl-4'-t(methylsulphonyl)acetyl]acetanilide in 50 ml of ethanol was treated with a solution of 0.4 g of sodium boro-hydride in 10 ml of water and stirred at room temperature for4 hours. The ethanol was removed in vacuo, the residue treated with water, the precipitated 2',6'-bis(dimethylamino)-4~-tl-hydroxy-2-(methylsulphonyl)ethyl]-N-methylacetanilide 4!~
_,~ _ : -' 1~591Z7 flltered off under quctlon and recrystalllsed from ethyl acetate/petroleum ether; meltlng polnt: 120C.
A mlxture of 1.23 g of sodlum methylate, 5.31 g of 2',
Example 9 2.0 g of N-[alpha5-(2,4-diamino-5-pyrlmidinyl)-3-(pyr-imldinyl)-3-(pyrrol-1-yl)-2,5-xylyl]-acetamide, (prepared as desc`ribed ln the flrst paragraph of Example 8), and 70 ml of l-N hydrochloric acld were heated on a steam-bath for 3 hours.
After cooling, the solution was made alkaline wlth potassium carbonate, the preclpltate filtered off in vacuo and recrys- -tallised from ethanol/petroleum ether. The 2,4-dlamino-5-[3-amlno-4-methyl-5-(pyrrol-1-yl)benzyl]pyrlmldine melted at 202-204C.
Exam~le 10 A solutlon of 0.33 g of sodium in 30 ml of absolute ethanol was treated with 1.43 g of guanidine hydrochloride and 1.9 g of alpha-(anlllnomethylene)-4-methoxy-3,5-dl(pyrrol-1-yl)hydrocinnamonitrile and boiled under reflux for 20 hours.
The alcohol was removed in vacuo, the residue taken up in water, filtered off under suction and recrystallised from -methanol. The 2,4-diamino-5-[4-methoxy-3,5-di(pyrrol-1-yl)-benzyl]-pyrimldlne melted at 182-183C.
The startlng materlal was prepared as follows:
A mixture of 19.6 g of methyl 3,5-diamino-4-methoxy-P . ~3 ~059127 benzoate, lOo ml of glaclal acetic acid and 36 g of diethoxy-tetrahydrofuran wa~ ~tirred for 30 mlnutes at 100C. The glaclal acetlc acid was removed ln vacuo. There was obtalned from the residue, after purificàtion over aluminlum oxlde with benzene and recrystallisation from methanol, methyl 4-methoxy-3,5-dl(pyrrol-1-yl)benzoate of melting polnt 55-57C.
A suspenslon of 5.8 g of sodium hydride (50% dlsperslon in oll) and 15 g of dlmethylsulphone in 80 ml of dimethyl sulphoxide was stirred with the exclusion of moisture for 2 hours at 50C. Thereupon, 23.6 g of methyl 4-methoxy-3,5-dl(pyrrol-l-yl)benzoate were added and the mixture was stirred for 2 hours at room temperature. The solution was dlluted wlth 300 ml of water, the aqueous solution made weakly acidic wlth acetlc acid, the precipltate filtered off under suctlon lS and recxystallised from ethanol. The 4'-methoxy-2-methyl-sulphonyl-3',5'-di(pyrrol-1-yl)acetophenone melted at 155-A suspension of 3.4 g of 4'-methoxy-2-methylsulphonyl-3',5'-di(pyrrol-1-yl)acetophenone and 0.8 g of sodlum boro-hydrlde in 70 ml of 90% ethanol was stlrred for 16 hours at room temperature. The alcohol was removed in vacuo, the residue taken up in water, filtered off under suction and recrystalllsed from methanol. The 4-methoxy-alpha-[(methyl-sulphonyl)methyl]-3,5-di(pyrrol-1-yl)benzyl alcohol melted at 185-186C.
A mixture of 1.8 g of 4-methoxy-alpha-[(methylsulphon-yl)methyl]-3,5-di(pyrrol-1-yl)benzyl alcohol, 0.41 g of sodium methylate and 1.1 g of ~-anlllnoproplonltrile ln 12 ml of ,,",, . ~?s~
_,~ _ ~059127 dimethyl sulphoxide was stirred with the exclusion of moisture for 3 hours at room temperature. The mixture was diluted with 100 ml of water, the precipitated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulphate and evaporated. ~y purification of the residue over aluminlum oxide with benzene and recrystallisation from ethyl acetate/petroleum ether, there was obtained alpha-(anlllno-methylene)-4-methoxy-3,5-di~pyrrol-1-yl)hydrocinnamonitrlle of melting point 152C.
Example 11 A solution of 690 mg of sodium in 100 ml of absolute ethanol was treated with 5.4 g of guanldine carbonate and 3.2 g of alpha-(anilinomethylene)-3,5-bis(dimethylamino)hydro-cinnamonitrile and boiled under reflux for 20 hours. After the addition of 50 ml of water, the alcohol was evaporated in vacuo. After standing for 1 hour at 25C, the preclpitated 2,4-diamino-5-t3,5-bis(dimethylamino)benzyl]pyrimidlne was flltered off under suctlon, washed with water and recrystal-lised from methanol/ethyl acetate; melting point: 198-199C.
The starting material was prepared as follows:
24.9 g of methyl 3,5-diaminobenzoate, 75.6 g of dimethyl sulphate and 207 g of anhydrous potassium carbonate were bolled for 20 hours in 1 litre of tetrahydrofuran under a reflux condenser while stirring and excluding moisture. After coollng, the mixture was filtered and the filtrate evaporated lOS91Z7 to dryness in vacuo. The residue was treated with 200 ml of water and the precipitated oil extracted with 400 ml of ethyl acetate. The ethyl acetate phases were washed with 200 ml of water, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was chromatographed on 500 g of silica gel with ethyl acetate/methylene chloride (1:9), there being obtained methyl 3,5-bis(dimethylamino)benzoate of melting point 86-88C.
A suspension of 3.6 g of sodium hydride (50% dispersion in oil) and 9.4 g of dimethylsulphone in 50 ml of absolute dimethyl sulphoxide was stirred with the exclusion of moisture for 2.5 hours at 50C and then treated with 11.1 g of methyl 3,5-bis(dimethylamino)benzoate. The mixture was stirred for 18 hours at room temperature, diluted with 500 ml of water and extracted with 600 ml of ethyl acetate. The ethyl acetate phases were washed wlth 300 ml of water, dried over magnesium sulphate and evaporated to dryness in vacuo. Recrystallisa-tion of the residue from ethyl acetate yielded 3',5'-bis-(dimethylamino)-2-methylsulphonylacetophenone of melting point 151-153C.
A suspenslon of 7.4 g of 3',5'-bis(dimethylamino)-2-methylsulphonylacetophenone and 3.8 g of sodium borohydride in 100 ml of ethanol was stirred for 20 hours at 25C. After the addition of 50 ml of water, the alcohol was removed in vacuo and the remaining aqueous suspension extracted with 400 ml of ethyl acetate. The ethyl acetate phases were washed with 50 ml of water, dried over magnesium sulphate and evap-orated to drynes~ in vacuo. ~ecrystallisation of the residue from ethanol gave 3,5-bis(dimethylamino)-a-[(methylsulphonyl)-methyl]benzyl alcohol of meltlng polnt 142-143C.
A mixture of 1.6 g of sodium methylate, 2.3 g of B-anilinopropionitrile and 4.3 g of 3,5-bis(dimethylamino)--~(methylsulphonyl)methyl]benzyl alcohol in 20 ml of absolutedimethyl sulphoxide was stirred with the exclusion of moisture for 4 hours at 50C. The solution was diluted with 250 ml of water and extracted with 500 ml of ethyl acetate. The ethyl acetate phases were washed wlth 100 ml of water, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was dissolved in 20 ml of ethanol. After standing for 20 hours at 4C, the crystallised a-(anilinomethylene)-3,5-bis(dimethylamino)hydrocinnamonitrile was filtered off under suction, washed with ethanol and dried; melting polnt:
128-130C.
Exarnple 12 A solution of 4.1 g of sodium in 600 ml of ethanol was treated wlth 32.4 g of guanldine carbonate and 17.8 g of a-(anilinomethylene)-3,5-bis(methylamino)hydrocinnamonitrile and bolled under reflux and under nitrogen gassing for 20 hours.
After the addition of 500 ml of water, the alcohol was evapor-ated in vacuo. After standing for 2 hours at 25C, the pre-cipitated 2,4-diarnino-S-[3,5-bis(methylamino)benzyl]pyrimidine was filtered off under suction, washed with water and recrys-talllsed from methanol; melting point: 209C.
~he startlng rnaterlal was prepared as follows:
~ i _, ~_ ~oss~27 A mixture of 134 g of methyl 3,5-dlaminobenzoate, 870 ml of acetic anhydride and 870 ml of absolute pyridine was stir-red for 20 hours at 25C and subsequently evaporated to dry-ness in vacuo. Recrystallisation of the residue from ethyl acetate yielded methyl 3,5-bis(acetamido)benzoate of melting point 220-221C.
A suspension of 88 g of sodium hydride (50~ dispersion in oil) in B00 ml of absolute dimethylformamide was treated with a solution of 191 g of methyl 3,5-bis(acetamido)benzoate in 800 ml of absolute dimethylformamide with stirring and ice-cooling. After stirrlng for 1 hour at 25C, 650 g of methyl iodide were added dropwise with ice-cooling. The mixture was stirred for S0 hours at 25C, treated with 4 litres of water and extracted 6 times with 5 litres of ethyl acetate each time. The ethyl acetate extract was washed with 3 litres of water, dried over magnesium sulphate and evaporated to dryness in vacuo. Recrystallisation of the residue from ethyl acetate/cyclohexane gave methyl 3,5-bis(N-methylacetamido)-benzoate of melting point 106C.
A suspension of 19.2 g of sodium hydride (50% dispersion in oil) and 56.1 g of dimethylsulphone in 200 ml of absolute dimethyl sulphoxide was stirred with the exclusion of moisture for 3 hours at 50C and then treated at 25C with 41.8 g of methyl 3,5-bis(N-methylacetamido)benzoate. The mixture was stirred for 18 hours at 25C, diluted with 2 litres of water, adjusted to pH 7 with glacial acetic acid and extracted with 9 litres of ethyl acetate. The ethyl acetate solution was washed with 3 litres of water, dried over magne~ium sulphate ,~ _ ,;~ _ ', ' ' ~ . , , 105912~7 and evaporated ln vacuo. Recrystalllsation of the re~ldue ; from ethanol ylelded 3',5'-bl~(methylamino)-2-methylsulphonyl-acetophenone of meltlng point 144-146C.
A suspenslon of 7.6 g of sodium borohydride and 12.8 g of 3',5'-bis(methylamino)-2-methylsulphonylacetophenone in 200 ml of ethanol was stlrred for 18 hours at 25C. After the addltlon of 50 ml of water, the solution was evaporated to dryness ln vacuo. The residue was heated to boiling ln 300 ml of ethyl acetate. The insoluble material was separated and the filtrate evaporated to dryness in vacuo. Recrystal-llsation of the resldue from ethanol gave 3,5-bls(methyl-amlno)-a-t(methylsulphonyl)methyl]benzyl alcohol of meltlng polnt 106C.
A mixture of 8.6 g of sodium methylate, 12.4 g of ~-anllinoproplonltrile and 20.4 g of 3,5-bls(methylamino)-a-t(methylsulphonyl)methyl]benzyl alcohol ln 100 ml of absolute dlmethyl sulphoxide wa~ stirred for 1 hour at 50C and then treated with 1 litre of water. The preclpitated product was extracted wlth 3 lltres of ethyl acetate. The ethyl acetate extract was washed wlth 1 lltre of water, dried over magnesium sulphate and evaporated in vacuo. The residue was chromato-graphed on 1 kg of silica gel with methylene chloride/ethyl acetate (3:1), there being obtained a-(anilinomethylene)-3,5-bis(methylamino)hydroclnnamonltrlle as a brownlsh-coloured oll.
Example 13 A ~olution of 8 g of sodlum in 300 ml of absolute ~`
,,, -~39' -lOS9127 ethanol was boiled under reflux wlth 62 g of guanldlne car-bonate and 40 g of 5'-(3-anllino-2-cyanoallyl)-N,2'-dlmethyl-3'-methylaminoacetanilide for 20 hours. After the addition of 500 ml of water, the alcohol was evaporated in vacuo. The crystalllsed a -(2,4-dlamino-5-pyrimidinyl)-N-methyl-3'-methylamino-2,5-acetoxylidide was filtered off under suction, washed with water and recrystallise* from alcohol; melting point: 237C.
The starting material was prepared as follows:
A solution of 36 g of methyl 3,5-diamino-p-toluate, in 600 ml of absolute pyridine, was treated dropwise with 200 ml of acetic anhydride while stirring. After stlrring for 5 t hours at 25C, the precipitated methyl 3,5-bis(acetamido)-p-toluate was filtered off under suction, washed with 300 ml of water and recrystallised from methanol; melting point above 260C.
A suspension of 28.8 g of sodium hydride (50~ dispersion in oil) ln 800 ml of absolute dimethylformamide was treated portionwise with 66 g of methyl 3,5-bis(acetamido)-p-toluate.
After stirring for 20 hours at 50C, the mixture was cooled with ice. 105 g of methyl iodide were added dropwise and the mixture was stirred for 20 hours at room temperature. The dimethylformamide was removed in vacuo at 60C and the residue treated with 500 ml of water. The precipitated product was extracted with 3 litres of ethyl acetate. The ethyl acetate solutlon was washed wlth 500 ml of water, dried over magnesium sulphate and evaporated in vacuo. The residue was,chromato-:
-graphed on 1 kg of silica gel with acetone, there being obtained methyl 3,5-bls(N-methylacetamido)-p-toluate of mel-ting point 163-164C.
A suspension of 3.8 g of sodium hydride (50~ dispersion in oil) and 11.2 g of dimethylsulphone in 40 ml of absolute dimethyl sulphoxide was stlrred for 3 hours at 50C. After cooling to 25C, 8.8 g of methyl 3,5-bis(N-methylacetamido)-p-toluate were added. The mlxture was stirred for 18 hours at 25C, diluted with 500 ml of ice-water, adjusted to pH 7 with glacial acetic acid, saturated with sodium chloride and ex-tracted with 2 litres of ethyl acetate. The ethyl acetate extract was washed with 200 ml of water, dried over magnesium sulphate and evaporated in vacuo. The residue was recrystal-lised from alcohol, there being obtained N-methyl-3'-methyl-amino-5'-t(methylsulphonyl)acetyl]-o-acetotoluidide of melting point 182C.
A suspension of 56 g of sodium borohydride and 116 g of N-methyl-3'-methylamino-5'-[(methylsulphonyl)acetyl]-o-aceto-toluidide in 1 litre of ethanol was stirred for 20 hours at 25C. The solvent was evaporated in vacuo, the residue treated with 2 litres of water and extracted with 9 litres of ethyl acetate. The ethyl acetate solution was washed with 1 -litre of water, dried over magnesium sulphate and evaporated in vacuo. Recrystallisation of the residue from ethanol yielded 5'-[1-hydroxy-2-(methylsulphonyl)ethyl]-N,2'-dimethyl-3'-methylaminoacetanilide of melting point 191-192C.
A mixture of 27 g of sodium methylate, 41 g o~ ~-anilinoproplonitrile and 79.5 g of 5'-tl-hydroxy-2-(methyl-~ 3 , sulphonyl)ethyl]-N,2'-dimethyl-3'-methylaminoacetanilide in 350 ml of absolute dimethyl sulphoxide was stirred for 1 hour at 50C, then diluted with 2 litres of water and extràcted with 6 litres of ethyl acetate. The ethyl acetate extract was washed with 1 litre of water, dried over magnesium sul-phate and evaporated in vacuo. The residue was chromato-graphed on 2 kg of silica gel with ethyl acetate/methylene chloride (1:1), there being obtained 5'-(3-anilino-2-cyano-allyl)-N,2'-dimethyl-3'-methylaminoacetanilide as an oil.
ExamPle 14 A solution of 0.53 g of sodium in 600 ml of absolute ethanol was treated with 2.16 g of guanidine hydrochloride and 3.95 g of a-(anilinomethylene)-4-tert.butyl-3,5-bis(dimethyl-amino)hydrocinnamonitrile and boiled under reflux for 20 hours. The ethanol was removed under reduced pressure, the residue taken up in watsr, the precipitated 2,4-diamino-5-[4-tert.butyl-3,5-bis(dimethylamino)benzyl]pyrimidine filtered off under suction, washed with water and recrystallised from ethanol; melting point: 266-267C.
The starting material was prepared as follows:
20 g of 4-tert.butyl-3,5-dinitrobenzoic acid [J. Org.
Chem. 19, 87-102 (1954)] and 100 ml of thionyl chloride were boiled under reflux for 2 hours. The excess thionyl chloride was removed in vacuo, the residue dissolved in 100 ml of acetone and the resulting solution added dropwise to 100 ml of methanol while stirring. The resulting mixture wa~ bolled 3~
. .
: ' ., :' l~S9127 under reflux for 30 minutes, the methanol dlstllled off, the residue dissolved in benzene, the benzene solutlon washed wlth sodium carbonate solutlon and then wlth water until neutral, drled over sodium sulphate and evaporated. After recrystal-lisation of the residue from methânol, there was obtainedmethyl 4-tert.butyl-3,5-dinitrobenzoate of melting point 115-117C.
28.2 g of methyl 4-tert.butyl-3,5-dinitrobenzoate dis-solved in 200 ml of methanol were hydrogenated under normal pressure and at room temperature in the presence of 2 g of palladium/carbon ~5~). After the uptake of the theoretical amount of hydrogen, the solution was flltered from the cat-alyst and evaporated. The residue was dissolved ln benzene and purified over alumlnlum oxlde, there belng obtained methyl 3,5-diamino-4-tert.butylbenzoate of melting point 71-73C
after recrystallisation from benzene/petroleum ether.
A mixture of 25 g of methyl 3,5-diamino-4-tert.butyl-benzoate, 50 ml of dimethyl sulphate, 155 g of dry potassium carbonate and 750 ml of acetone was boiled for 22 hours under reflux and while stirring. After cooling, the solution was filtered off from inorganic salts, the acetone removed in vacuo and the residue recrystallised from methanol/water, there being obtained methyl 4-tert.butyl-3,5-bis(dimethyl-amino)benzoate of melting point 80-82C.
A suspension of 2.4 g of sodium hydride (50% suspension in oil) and 7.05 g of dimethylsulphone in 17.5 ml of dimethyl sulphoxide was stirred with the exclusion of mois~u~e for 2 _ , lOS9~27 hours at 50C. 6.9 g of methyl 4-tert.butyl-3,5-bis(di-methylamino)benzoate were then added and the mixture was stlrred at room temperature for 1.5 hours. The solution was tdlluted with 150 ml of ice-water, the precipitated solld material filtered off, washed with water and recrystallised from methanol, there being obtained 4'-tert.butyl-3',5'-bis-(dimethylamino)-2-methylsulphonylacetophenone of melting point 177-179C.
A suspension of 8 g of 4'-tert.butyl-3',5'-bis(dimethyl-amino)-2-methylsulphonylacetophenone in 200 ml of ethanol was stirred at 20C for 4 hours with a solution of 2.3 g of sodium borohydride in 25 ml of water. After dilution with 250 ml of ice-water, the precipitated 4-tert.butyl-3,5-bis(dimethyl-amino)-a-[(methylsulphonyl)methyl]benzyl alcohol wa~ filtered off under suctlon and recrystallised from methanol; melting point: 202-204C.
A mixture of 4.66 g of 4-tert.butyl-3,5-bis(dimethyl-amino)-a-~(methylsulphonyl)methyl]benzyl alcohol, 1.28 g of sodium methylate and 3.3 g of ~-anilinopropionitrile in 35 ml of dimethyl sulphoxide was stirred at room temperature under nitrogen for 60 minutes. The mixture was poured into 200 ml of ice-water, the separated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulphate and then evaporated. By purification of the residue over aluminium oxide with benzene and recrystallisation from ethanol, there was obtained a-(anilinomethylene)-4-tert.butyl-3,5-bis(di-methylamino)hydrocinnamonitrile of melting point 150C.
_ ~_ Example 15 A solution of 0.53 g of sodium in 60 ml of absolute ethanol was treated with 2.16 g of guanidine hydrochloride and 3.8 g of a-(anilinomethylene)-3,4,5-trls(dimethylamino)hydro-cinnamonitrile and boiled under reflux for 20 hours. Theethanol was removed under reduced pressure, the residue taken up in water, the precipitated 2,4-diamino-5-~3,4,5-tris-(dimethylamino)benzyl]pyrimidine filtered off under suction, washed with water and recrystallised from ethanol; melting point: 203-204C.
The starting material was prepared as follows:
27 g of methyl 4-dlmethylamino-3,5-dinltrobenzoate [Rec.
trav. chim. 73, 68 (1954)] dissolved ln 300 ml of methanol were hydrogenated under normal pressure and at room tempera-ture in the presence of 3 g of palladium/carbon (5~). Afteruptake of the theoretical amount of hydrogen, the solution was filtered off from the catalyst and evaporated. The residue, methyl 3,5-diamino-4-dimethylaminobenzoate, was characterlsed as the monohydrochloride; melting point: 222-223C (from ethanol/ether).
A mixture of 37 g of methyl 3,5-diamino-4-dimethylamino-benzoate, 113 ml of dimethyl sulphate, 350 g of dry potassium carbonate and 14 ml of acetone was boiled under reflux while stirring for 18 hours. After coollng, the solution was fil-tered off from inorganic salts, the acetone removed in vacuo,the resldue dissolved ln benzene, purified over alu,minium _ ~_ lOS9127 oxide and recrystallised from methanol/water, there belng obtained methyl 3,4,5-trls(dimethylamino)benzoate of meltlng point 61-63C.
A suspension of 4.8 g of sodium hydride (50~ emulsion in oil) and 14.1 g of dimethylsulphone in 35 ml of dimethyl sulphoxide was stirred under nitrogen and with the exclusion of moisture for 2 hours at 50C. 13.2 g of methyl 3,4,5-tris(dlmethylamlno)benzoate were then added and the mixture was stirred at room temperature for 1.5 hours. The solution was diluted wlth 300 ml of ice-water, extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulphate and evaporated. The residue was treated with 30 ml of boiling methanol, cooled and filtered under suction. By recrystallisation of the solid material from ethyl acetate/
petroleum ether, there was obtained 3',4',5'-tris(dimethyl-amino)-2-methylsulphonylacetophenone of melting point 108C.
A suspension of 15 g of 3',4',5'-tris(dimethylamino)-2-methylsulphonylacetophenone in 400 ml of ethanol was treated with a solution of 4 g of sodium borohydride in 50 ml of water and stirred at room temperature for 7 hours. After dilution with 500 ml of water, the precipitated 3,4,5-tris(dimethyl-amino)--t(methylsulphonyl)methyl]benzyl alcohol was filtered off under suction, washed with water and recrystallised from methanol; melting point: 160-162C.
A mixture of 8.96 g of 3,4,5-tris(dimethylamino)-a-t(methylsulphonyl)methyl]benzyl alcohol, 2.56 g of sodium methylate and 6.6 g of ~-anilinopropionitrile in 70 ml of _ ~_ ,,, ~ , ", ": ",-, .
~059~27 dimethyl sulphoxide was stirred at room temperature under nitrogen for 50 minutes. The mlxture was poured lnto 500 ml of lce-water, the separated oll extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulphate and evaporated. By purlflcation of the residue over aluminium oxide with benzene and recrystallisation from ethanol, there was obtained a- (anilinomethylene)-3,4,5-tris(dimethylamino)-hydrocinnamonitrile of melting point 179-181C. , A solution of 1.22 g of sodium in 110 ml of absolute ethanol was treated with 5.26 g of guanidine hydrochloride and 7.0 g of a-(anilinomethylene)-3,5-bls(dimethylamino)-4-piperidinohydrocinnamonitrlle and boiled under nltrogen and under reflux for 24 hours. The ethanol was removed under reduced pressure, the residue taken up in water, the pre-cipitated 2,4-diamino-5-[3,5-bls(dlmethylamlno)-4-piperidino-benzyl]pyrimidine filtered off under suction, washed with water and recrystallised from ethanol; melting point: 216-218C.
The starting material was prepared as follows:
15.45 g of methyl 3,5-dinitro-4-piperidinobenzoate [Rec.
trav. chim. 73, 68 (1954)] dissolved in 200 ml of methanol were hydrogenated under normal pressure and at room tempera-ture in the presence of 1 g of palladium/carbon (5%). After uptake of the theoretlcal amount of hydrogen, the solution was flltered off from the catalyst and evaporated. By recrystal-~3'' 34~
lisation of the residue from ethyl acetate/petroleum ether, there was obtained methyl 3,5-diamino-4-piperidinobenzoate of melting point 133-134C.
A mlxture of 42 g of methyl 3,5-diamino-4-piperidino-benzoate, 75 ml of dlmethyl sulphate, 232.5 g of dry potasslum carbonate and 1125 ml of acetone was bolled under reflux and while stirrlng for 20 hours. After cooling, the solution was filtered off from lnorganic salts, the acetone removed in vacuo and the residue recrystallised from methanol, there being obtained methyl 3,5-bis(dimethylamino)-4-piperidino-benzoate of melting polnt 103-105C.
A suspenslon of 2.9 g of sodlum hydride (50% emulsion in oll) and 3.7 g of dlmethylsulphone ln 20 ml of dlmethyl sulphoxlde was stlrred with the exclusion of moisture for 2 hours at 50C. 6.1 g of methyl 3,5-bis(dimethylamino)-4-piperldinobenzoate were then added and the mixture was stirred at room temperature for 2 hours. The solution was diluted with 200 ml of ice-water, the precipitated material filtered off under suction, washed wlth water and recrystallised from methanol, there being obtained 3',5'-bis(dimethylamino)-2-methylsulphonyl-4-piperidinoacetophenone of melting point 165C.
A suspension of 8.9 g of 3',5'-bis(dimethylamino)-2-methylsulphonyl-4'-piperidinoacetophenone in 250 ml of ethanol was treated with a solution of 2 g of sodium borohydride in 50 ml of water and stlrred at 20C for 4 hours. After dilution with 350 ml of ice-water, the precipitated 3,5-bis(dimethyl-3~
_ ,g~ _ , , . . . .
amino)-a-[(methylsulphonyl)methyl]-4-plperidinobenzyl alcohol wa~ filtered off under suction and recrystalllsed from ethan-ol; melting point: 179-180C.
A mixture of 7.4 g of 3,5-bis(dimethylamino)-a-[(methyl-sulphonyl)methyl]-4-piperidinobenzyl alcohol, 1.64 g of sodium methylate and 4.4 g of ~-anilinopropionitrile in 40 ml of dimethyl sulphoxide was stirred for 2 hours at 50C under nitrogen. The mixture was poured into 250 ml of water, the precipitated product extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulphate and evaporated.
By purification of the residue over aluminium oxide with ben-zene and recrystallisation from ethyl acetate/petroleum ether, there was obtained a-(anilinomethylene)-3,5-bis(dimethyl-amino)-4-piperidinohydrocinnamonitrile of melting point 200-202C.
Example 17 A solution of 0.85 g of sodium in 55 ml of absoluteethanol was treated with 3.4 g of guanidine hydrochloride and 3.8 g of a-(anilinomethylene)-4-chloro-3,5-bis(methylamino)-hydrocinnamonitrile and boiled under reflux and under nitrogenfor 24 hours. The ethanol was removed under reduced pres-sure, the residue taken up in water, the precipitated 2,4-diamino-5-[4-chloro-3,5-bis(methylamino)benzyl]pyrimidine fil-tered off under suction, washed with water and recrystallised from ethanol; melting point: 230C.
The starting material was prepared as follows:
16 g of methyl 3,5-diamino-4-chlorobenzoate were dis-solved ~n 100 ml of dry pyridine and treated with 40 ml of acetic anhydrlde. After standing at room temperature for 2 hours and after a further 2 hours in a refrigerator, the pre-cipitated methyl 3,5-diacetamido-4-chlorobenzoate was filtered off under suction, washed wlth ethyl acetate and recrystal-lised from ethanol; melting point: 282C.
To a suspension of 4.4 g of sodium hydride (50% suspen-sion in oil) in 80 ml of dimethylformamide was added dropwlse at room temperature a solution of 21.7 g of methyl 3,5-diacet-amido-4-chlorobenzoate in 240 ml of dimethylformamide. After 1 hour, 65.1 g of methyl iodide were added dropwise and the resulting mixture was stirred at room temperature for 48 hours. The mixture was dlluted wlth 100 ml of water, the precipitated product extracted with ethyl acetate and the ethyl acetate solution evaporated. The residue was dissolved in ethyl acetate and purified over aluminium oxide, there being obtained methyl 4-chloro-3,5.bis(N-methylacetamido)-benzoate which melted at 162-164C after recrystallisation from ethyl acetate/petroleum ether.
A suspension of 3.8 g of sodium hydride (50% suspension in oil) and 11.2 g of dimethylsulphone in 40 ml of dimethyl sulphoxide was stirred with the exclusion of moisture for 2 hours at 50C. 9.4 g of methyl 4-chloro-3,5-bis(N-methyl-acetamido)benzoate were then added and the mixture was stirred at 80C for 3 hours. The solution was diluted with 200 ml of ice-water, the precipitated material extracted with ethyl acetate, the ethyl acetate solution purified over aluminium S~
-- 5~--.' 105912~7 oxide, evaporated and the residue recrystallised from meth-anol, there being obtained 4'-chloro-3',5'-bis(methylamino)-2-methylsulphonylacetophenone of melting point 165-167C.
A suspension of 1.4 g of 4'-chloro-3',5'-bis(methyl-5 amino)-2-methylsulphonylacetophenone in 50 ml of ethanol was treated with a solution of 0.40 g of sodium borahydride in 10 ml of water and stirred at 20C for 4 hours. The ethanol was removed under reduced pressure, the residue treated with 100 ml of lce-water, the insoluble 4-chloro-3,5-bis(methylamino)- -a-t(methylsulphonyl)methyl]benzyl alcohol filtered off under suction and recrystallised from ethanol; melting point: 180-182C.
A mixture of 13.2 g of 4-chloro-3,5-bis(methylamino)-a-t(methylsulphonyl)methyl]benzyl alcohol, 3.6 g of sodium methylate and 9.6 g of ~-anilinopropionitrile in 80 ml of dimethyl sulphoxide was stirred for 5 hours under nitrogen at 50C. The mixture was poured into 200 ml of iae-water, the separated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulphate and evaporated. By purification of the residue over aluminium oxide with benzene and recrystallisation from ethyl acetate/petroleum ether, there was obtained a-(anilinomethylene)-4-chloro-3,5-bis-(methylamino)hydrocinnamonitrile of melting point 142-147C.
Example 18 A solution of 0.33 g of sodium in 30 ml of absolute ethanol was treated wlth 1.43 g of guanidine hydrochlorlde and , .~
-~, `~ ~
~059127 2.2 g of 4'-(3-anilino-2-cyanoallyl)-2',4'-bis(dimethylamino)-N-methylacetanilide and boiled under reflux and under nitrogen for 24 hours. The ethanol was removed under reduced pres-sure, the residue taken up in water and the precipitated a-(2,4-diamino-S-pyrimidinyl)-2',6'-bis(dimethylamino)-N-methyl-acetotoluidide flltered off under suction, washed wlth water and recrystallised from methanol; melting point: 267C.
The starting material was prepared as follows:
A suspension of methyl 4-methylamino-3,5-dinitrobenzoate ln 50 ml of acetic anhydride was treated with 3 drops of con-centrated sulphuric acid. After a short time, the solld material dissolved completely and, after 30 mlnutes, the prod-uct began to crystalllse. The product was filtered off under suction and recrystallised from methanol. The methyl --lS 4-(N-methylacetamido)-3,5-dlnitrobenzoate melted at 156-157C.
9.7 g of methyl 4-(N-methylacetamido)-3,5-dinitrobenz-oate in lO0 ml of methanol were hydrogenated under normal pressure and at room temperature in the presence of l g of palladium/carbon. After uptake of the theoretical amount of hydrogen, the solution was filtered off from the catalyst and evaporated. The residue was recrystallised from methanol, there being obtained methyl 3,5-diamino-4-(N-methylacetamido)-benzoate of melting point 221-222C.
A mixture of 50 g of methyl 3,5-diamino-4-~N-methyl-acetamldo)benzoate, 720 g of dry sodium carbonate, lS00 ml of -.
acetone and 212 g of dimethyl sulphate was boiled under reflux while stirring for 24 hours. After cooling, the solution was filtered off from inorganic salts, the acetone evaporated in vacuo and methyl 3,5-bis(dimethylamino)-4-(N-methylacetamido)-benzoate of melting point 120C extracted from the residue byboiling with high-boiling petroleum ether.
A suspension of 0.77 g of sodium hydride (50~ suspension in oil) and 2.28 g of dimethylsulphone in 28 ml of dimethyl sulphoxide was stirred with the exclusion of moisture and under nitrogen for 2 hours at 50C. 2 g of methyl 3,5-bis-(dimethylamino)-4-(N-methylacetamido)benzoate were then added, the mixture heated to 70C for a short time and stirred for a further 2 hours without heating. The solution was diluted with 100 ml of ice-water, washed with 100 ml of low-boillng petroleum ether, the product extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulphate and evapor-ated. After purification of the residue over aluminium oxide with benzene and recrystallisation from ethyl acetate/petrol-eum ether, there was obtained 2',6'-bis(dimethylamino)-N-methyl-4'-[(methylsulphonyl)acetyl]acetanilide of melting point 130C.
A suspension of 1.4 g of 2',6'-bis(dimethylamino)-N-methyl-4'-t(methylsulphonyl)acetyl]acetanilide in 50 ml of ethanol was treated with a solution of 0.4 g of sodium boro-hydride in 10 ml of water and stirred at room temperature for4 hours. The ethanol was removed in vacuo, the residue treated with water, the precipitated 2',6'-bis(dimethylamino)-4~-tl-hydroxy-2-(methylsulphonyl)ethyl]-N-methylacetanilide 4!~
_,~ _ : -' 1~591Z7 flltered off under quctlon and recrystalllsed from ethyl acetate/petroleum ether; meltlng polnt: 120C.
A mlxture of 1.23 g of sodlum methylate, 5.31 g of 2',
6'-bls(dimethylamino)-4'-tl-hydroxy-2-(methylsulphonyl)ethyl]-N-methylacetanilide and 3.3 g of ~-anillnoproplonltrlle ln 40 ml of dlmethyl sulphoxlde was stlrred at room temperature under nltrogen for 5 hours. The mlxture was poured lnto 200 ml of lce-water, the separated oll extracted with ethyl ace-tate, the ethyl acetate solution drled over sodlum sulphate and evaporated. After puriflcatlon of the resldue over alumlnlum oxlde wlth benzene and recrystalllsation from ethyl acetate/petroleum ether, there was obtalned 4'-(3-anllino-2-cyanoallyl)-2',6'-bls(dimethylamlno)-N-methylacetanilide of meltlng polnt 190-200C.
. ~ .
ExamPle 19 4.6 g of 3,5-bls(dimethylamlno)-4-plperldlnobenzaldehyde and 17 g of ~-methoxyproplonltrlle were added to a solutlon of 0.2 g of sodlum ln 10 ml of absolute methanol and the mlxture was bolled under reflux for 3 hours. Then, a solutlon of 1.23 g of ~odlum and 5.15 g of guanldlne hydrochlorlde was prepared, flltered and added to the mlxture. The resulting mlxture was boiled under reflux for 24 hours, whereby approx-imately half of the methanol was distllled off. After coollng, the preclpltated 2,4-diamlno-5-~3,5-bls(dimethyl-amlno)-4-plperldlnobenzyl]pyrlmidlne was flltered off under suctlon, wa~hed wlth water and recrystalllsed from ethanol;
meltlng polnt : 216-218C.
., ', . .
``
The startlng material was prepared as follows:
A solution of 25 g of methyl 3,5-bis(dimethylamino)-4-piperidinobenzoate in 150 ml of absolute tetrahydrofuran was added dropwise to a solutlon of lithlum alumlnium hydrlde in ~; 5 300 ml of absolute tetrahydrofuran and the mlxture was boiled under reflux for 3 hours. After cooling, the excess lithium alumlnlum hydrlde was cautlously decomposed with 100 ml of ; ethyl acetate and then with 3 ml of water and the solution evaporated to dryness. The residue was taken up in water, the oily product extracted with ethyl acetate and the ethyl ' acetate solutlon drled and evaporated. After recrystalllsa-i tlon from hlgh-boiling petroleum ether, there was obtained 3,5-bis(dimethylamlno)-4-piperldinobenzyl alcohol of melting polnt 90-92C.
12.9 g of 3,5-bls(dlmethylamino)-4-piperidinobenzyl alcohol, 17.1 g of activated manganese dioxlde and 80 ml of chloroform were mlxed together and stlrred at room temperature for 48 hours. The manganese dioxide was flltered off, washed wlth chloroform and the chloroform evaporated. After pur-lflcatlon over aluminium oxide with benzene and recrystallisa-tion from ethanol, there was obtained 3,5-bls(dimethylamino)-4-piperidlnobenzaldehyde of meltlng polnt 114-116C.
The followlng Example illustrates a typical pharma-ceutlcal preparation containing one of the benzylpyrlmldlne derlvatlves provided by the present invention:
B~ ~ t -lOS9127 Example A
: A tablet can contaln the followlng lngredient~:
2,4-Diamlno-5-(4-chloro-3-dimethylamino-5-methylamino-benzyl)pyrlmidine 60 mg Sulphamethoxazole 225 mg Malze starch 100 mg Talc 15 mg Magneslum stearate 5 mg Lactose 233 mg Gelatin 12 mg Total weight 650 mg --,S6 --
. ~ .
ExamPle 19 4.6 g of 3,5-bls(dimethylamlno)-4-plperldlnobenzaldehyde and 17 g of ~-methoxyproplonltrlle were added to a solutlon of 0.2 g of sodlum ln 10 ml of absolute methanol and the mlxture was bolled under reflux for 3 hours. Then, a solutlon of 1.23 g of ~odlum and 5.15 g of guanldlne hydrochlorlde was prepared, flltered and added to the mlxture. The resulting mlxture was boiled under reflux for 24 hours, whereby approx-imately half of the methanol was distllled off. After coollng, the preclpltated 2,4-diamlno-5-~3,5-bls(dimethyl-amlno)-4-plperldlnobenzyl]pyrlmidlne was flltered off under suctlon, wa~hed wlth water and recrystalllsed from ethanol;
meltlng polnt : 216-218C.
., ', . .
``
The startlng material was prepared as follows:
A solution of 25 g of methyl 3,5-bis(dimethylamino)-4-piperidinobenzoate in 150 ml of absolute tetrahydrofuran was added dropwise to a solutlon of lithlum alumlnium hydrlde in ~; 5 300 ml of absolute tetrahydrofuran and the mlxture was boiled under reflux for 3 hours. After cooling, the excess lithium alumlnlum hydrlde was cautlously decomposed with 100 ml of ; ethyl acetate and then with 3 ml of water and the solution evaporated to dryness. The residue was taken up in water, the oily product extracted with ethyl acetate and the ethyl ' acetate solutlon drled and evaporated. After recrystalllsa-i tlon from hlgh-boiling petroleum ether, there was obtained 3,5-bis(dimethylamlno)-4-piperldinobenzyl alcohol of melting polnt 90-92C.
12.9 g of 3,5-bls(dlmethylamino)-4-piperidinobenzyl alcohol, 17.1 g of activated manganese dioxlde and 80 ml of chloroform were mlxed together and stlrred at room temperature for 48 hours. The manganese dioxide was flltered off, washed wlth chloroform and the chloroform evaporated. After pur-lflcatlon over aluminium oxide with benzene and recrystallisa-tion from ethanol, there was obtained 3,5-bls(dimethylamino)-4-piperidlnobenzaldehyde of meltlng polnt 114-116C.
The followlng Example illustrates a typical pharma-ceutlcal preparation containing one of the benzylpyrlmldlne derlvatlves provided by the present invention:
B~ ~ t -lOS9127 Example A
: A tablet can contaln the followlng lngredient~:
2,4-Diamlno-5-(4-chloro-3-dimethylamino-5-methylamino-benzyl)pyrlmidine 60 mg Sulphamethoxazole 225 mg Malze starch 100 mg Talc 15 mg Magneslum stearate 5 mg Lactose 233 mg Gelatin 12 mg Total weight 650 mg --,S6 --
Claims (8)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the manufacture of benzylpyrimidine derivatives of the general formula (I) wherein R1 and R2 each independently represent an amino, optionally C1-3-alkyl-substituted pyrrolo, -NHR3, -N(R3)2, -NHR4 or -N(R3)(R4) group, R3 represents a C1-4-alkyl group, R4 represents an acyl group, derived from a lower aliphatic carboxylic or sulphonic acid, and Z represents a hydrogen, chlorine or bromine atom, a piperidino group or a group R3, OR3 or -N(R3)2, and of salts thereof, which process comprises: (a) reacting a compound of the general formula (IIa) and (IIb) wherein R5 represents a lower alkyl group or both R5's together represent a lower alkylene group, Y represents a leaving group and R1, R2, R3, R4 and Z
have the significance given above, with guanidine or (b)converting the group denoted by R8 in a compound of the general formula (Va) wherein R8 represents -NHR4 or -NR3R4, an amino group or a -NHR3 group, R9 represents an amino, pyrrolo, -NHR3, -N(R3)2 or R8 group and R3 and R4 are as defined above, into the amino group or a group -NHR3, and, if desired, converting a compound of formula I obtained into a salt.
have the significance given above, with guanidine or (b)converting the group denoted by R8 in a compound of the general formula (Va) wherein R8 represents -NHR4 or -NR3R4, an amino group or a -NHR3 group, R9 represents an amino, pyrrolo, -NHR3, -N(R3)2 or R8 group and R3 and R4 are as defined above, into the amino group or a group -NHR3, and, if desired, converting a compound of formula I obtained into a salt.
2. A process as claimed in claim 1, wherein .alpha.-anilinomethylene-4-chloro-3,5-bis-(dimethylamino)-hydrocinnamonitrile is reacted with guanidine hydrochloride to give 2,4-diamino-5-[4-chloro-3,5-bis(dimethyl-amino)-benzyl]-pyrimidine.
3. A process as claimed in claim 1, wherein .alpha.-anilinomethylene-4-chloro-3-dimethylamino-5-methylamino-hydrocinnamonitrile is reacted with guanidine hydrochloride to give 2,4-diamino-5-[4-chloro-3-dimethylamino-5-methylamino-benzyl]-pyrimidine.
4. A process as claimed in claim 1, wherein .alpha.-anilinomethylene-4-chloro-3,5-bis-(methylamino)-hydrocinnamonitrile is reacted with guanidine hydrochloride to give 2,4-diamino-5-[4-chloro-3,5-bis-(methylamino)-benzyl]-pyrimidine.
5. Compounds of the general formula I
wherein R1 and R2 each independently represent an amino, optionally C1-3-alkyl-substituted pyrrolo, -NHR3, -N(R3)2, -NHR4 or -N(R3)(R4) group, R3 represents a C1-4-alkyl group, R4 represents an acyl group and Z represents a hydrogen, chlorine or bromine atom, a piperidino group or a group R3, OR3 or -N(R3)2 and salts thereof, whenever prepared by the process claimed in claim 1 or by an obvious chemical equivalent thereof.
wherein R1 and R2 each independently represent an amino, optionally C1-3-alkyl-substituted pyrrolo, -NHR3, -N(R3)2, -NHR4 or -N(R3)(R4) group, R3 represents a C1-4-alkyl group, R4 represents an acyl group and Z represents a hydrogen, chlorine or bromine atom, a piperidino group or a group R3, OR3 or -N(R3)2 and salts thereof, whenever prepared by the process claimed in claim 1 or by an obvious chemical equivalent thereof.
6. 2,4-Diamino-5-[4-chloro-3,5-bis-(dimethylamino)-benzyl]-pyrimidine, whenever prepared according to the process claimed in claim 2, or by an obvious chemical equivalent thereof.
7. 2,4-Diamino-5-<4-chloro-3-dimethylamino-5-methylaminobenzyl>-pyrimi-dine, whenever prepared according to the process claimed in claim 3, or by an obvious chemical equivalent thereof.
8. 2,4-Diamino-5-<4-chloro-3,5-bis-(methylamino)-benzyl>-pyrimidine, whenever prepared according to the process claimed in claim 4, or by an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1728774A CH605828A5 (en) | 1974-12-24 | 1974-12-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1059127A true CA1059127A (en) | 1979-07-24 |
Family
ID=4424233
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA242,038A Expired CA1059127A (en) | 1974-12-24 | 1975-12-18 | Benzylpyrimidines |
Country Status (25)
| Country | Link |
|---|---|
| JP (1) | JPS5191273A (en) |
| AT (1) | AT344704B (en) |
| AU (1) | AU500102B2 (en) |
| BE (1) | BE836996A (en) |
| BR (1) | BR7508534A (en) |
| CA (1) | CA1059127A (en) |
| CH (2) | CH605828A5 (en) |
| CU (1) | CU34406A (en) |
| DD (1) | DD123603A5 (en) |
| DE (1) | DE2558150A1 (en) |
| DK (1) | DK137797B (en) |
| ES (1) | ES443790A1 (en) |
| FI (1) | FI753312A (en) |
| FR (1) | FR2295750A1 (en) |
| GB (1) | GB1492140A (en) |
| HU (1) | HU174324B (en) |
| IL (1) | IL48416A (en) |
| LU (1) | LU73971A1 (en) |
| NL (1) | NL7514269A (en) |
| NO (1) | NO141408C (en) |
| PH (1) | PH12314A (en) |
| PL (1) | PL101046B1 (en) |
| SE (1) | SE417607B (en) |
| SU (1) | SU612629A3 (en) |
| ZA (1) | ZA756964B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GR71725B (en) * | 1977-11-10 | 1983-06-22 | Hoffmann La Roche | |
| US9567318B2 (en) | 2009-08-17 | 2017-02-14 | Memorial Sloan-Kettering Cancer Center | Substituted pyrimidine compounds and uses thereof |
| KR102461419B1 (en) | 2014-05-13 | 2022-11-02 | 메모리얼 슬로안 케터링 캔서 센터 | Hsp70 MODULATORS AND METHODS FOR MAKING AND USING THE SAME |
-
1974
- 1974-12-24 CH CH1728774A patent/CH605828A5/xx not_active IP Right Cessation
-
1975
- 1975-11-04 IL IL48416A patent/IL48416A/en unknown
- 1975-11-05 ZA ZA00756964A patent/ZA756964B/en unknown
- 1975-11-07 AU AU86433/75A patent/AU500102B2/en not_active Expired
- 1975-11-25 FI FI753312A patent/FI753312A/fi not_active Application Discontinuation
- 1975-11-29 CU CU7534406A patent/CU34406A/en unknown
- 1975-12-08 NL NL7514269A patent/NL7514269A/en not_active Application Discontinuation
- 1975-12-09 LU LU73971A patent/LU73971A1/xx unknown
- 1975-12-18 CA CA242,038A patent/CA1059127A/en not_active Expired
- 1975-12-19 HU HU75HO1864A patent/HU174324B/en unknown
- 1975-12-22 JP JP50152026A patent/JPS5191273A/ja active Pending
- 1975-12-22 FR FR7539341A patent/FR2295750A1/en active Granted
- 1975-12-22 AT AT975975A patent/AT344704B/en not_active IP Right Cessation
- 1975-12-22 BR BR8534/75A patent/BR7508534A/en unknown
- 1975-12-22 SU SU752301512A patent/SU612629A3/en active
- 1975-12-22 PH PH7517896A patent/PH12314A/en unknown
- 1975-12-23 NO NO754372A patent/NO141408C/en unknown
- 1975-12-23 DD DD190511A patent/DD123603A5/xx unknown
- 1975-12-23 SE SE7514642A patent/SE417607B/en unknown
- 1975-12-23 DE DE19752558150 patent/DE2558150A1/en not_active Ceased
- 1975-12-23 GB GB52604/75A patent/GB1492140A/en not_active Expired
- 1975-12-23 PL PL1975185924A patent/PL101046B1/en unknown
- 1975-12-23 ES ES443790A patent/ES443790A1/en not_active Expired
- 1975-12-23 BE BE163041A patent/BE836996A/en unknown
- 1975-12-23 DK DK589675AA patent/DK137797B/en unknown
-
1977
- 1977-12-07 CH CH1499977A patent/CH617191A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DE2558150A1 (en) | 1976-07-01 |
| NO141408C (en) | 1980-03-05 |
| DK137797B (en) | 1978-05-08 |
| DK137797C (en) | 1978-10-16 |
| BR7508534A (en) | 1976-12-21 |
| DK589675A (en) | 1976-06-25 |
| AU500102B2 (en) | 1979-05-10 |
| NO141408B (en) | 1979-11-26 |
| FR2295750B1 (en) | 1980-06-20 |
| IL48416A (en) | 1980-02-29 |
| PH12314A (en) | 1979-01-16 |
| ES443790A1 (en) | 1977-12-16 |
| PL101046B1 (en) | 1978-11-30 |
| BE836996A (en) | 1976-06-23 |
| NO754372L (en) | 1976-06-25 |
| DD123603A5 (en) | 1977-01-05 |
| AU8643375A (en) | 1977-05-12 |
| FI753312A (en) | 1976-06-25 |
| SE417607B (en) | 1981-03-30 |
| IL48416A0 (en) | 1976-01-30 |
| ZA756964B (en) | 1976-10-27 |
| FR2295750A1 (en) | 1976-07-23 |
| AT344704B (en) | 1978-08-10 |
| ATA975975A (en) | 1977-12-15 |
| HU174324B (en) | 1979-12-28 |
| CH617191A5 (en) | 1980-05-14 |
| CU34406A (en) | 1978-09-08 |
| CH605828A5 (en) | 1978-10-13 |
| JPS5191273A (en) | 1976-08-10 |
| GB1492140A (en) | 1977-11-16 |
| SE7514642L (en) | 1976-06-28 |
| SU612629A3 (en) | 1978-06-25 |
| LU73971A1 (en) | 1977-07-01 |
| NL7514269A (en) | 1976-06-28 |
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