FI58638B - PROCEDURE FOR THE FRAMSTATION OF ANTIBACTERIALS VERKSAMMA 2,4-DIAMINO-5-BENZYLPYRIMIDINER OCH SALTER DAERAV - Google Patents

Description

rrTgwT-l Γβΐ m1vAdvertisement PUBLICATION CO fix ö 1 $ 3Γφ ^ '11 * UTLÄGCNI NGSSKRIFT ^ ° Ο ό Ο C Patent granted 10 03 1931 • * ^^ 5? (^ 5) Patent: i; edi? Lat (51) Kv.ik.Va.3 C 07 D 239A9 FINLAND —FINLAND (21) P »t * n« lh.k * mu * -I> »t.« * «F» eknlnj 2561/74 (22) Hakamispllvl — AMBknlngad «g 02.09.74 (23) ALkupUvS — GIMghttsd« c 02.09.7 ^ (41) Translators] ulklMk * l - BIMt offmtllg q, ^ 5

Patent ·) «Registry Board M Nftttuitaip ™ * j. month.publish.date.-

Patent and registration authorities Arastan uti «jd ocH utUkrifun pubiic« rad 26.11.60 (32) (33) (31) Claimed privilege - Begird prlorltet 12.09.7 3

Switzerland-Switzerland (CH) 13057/73 (71) F. Hoffmann-La Roche & Co. Aktiengesellschaft, Grenzacherstrasse 124-181, Basel, Switzerland (Switzerland) (72) Ivan Kompis, Oberwil, Gerald Rey-Bellet, Basel, Guido Zanetti, Fiillinsdorf, Switzerland (CH) (74) Oy Kolster Ab (54) Process for the preparation of antibacterial 2,4-diamino-5-benzylpyrimidines and their salts - Preparation of antibacterial agents with antibacterial properties 2,4- & iamino-5-benzylpyrimidines and their salts

The invention relates to a process for the preparation of antibacterial 2,4-diamino-5-benzylpyrimidines of the formula R 1.

V-N y- N

z1 - (/ y-ch2 — P y — nh2 i

R2 'H2N

1.2 wherein R and R 1 are independently C 1-4 alkyl or C 1-4 alkoxy, Z 1 is amino, pyrrolo, -NHr 1 -NiR ^ g or -NR 1 COOR 1 *; R 1 is C 1-6 alkyl; and to prepare salts of these compounds.

As used herein, the term "C 1-4" refers to groups having 1 to 3 carbon atoms. Alkyl and alkoxy groups can be straight-chain or branched.

2 58638

Examples of such groups include methyl, ethyl, propyl and isopropyl; methoxy, ethoxy, propoxy and isopropoxy.

Particularly preferred are compounds of formula I wherein 1. h / h \. k li 1 o h Z is amino, -NHR, -N (R) or -NR COOR and R, R and R are as defined above.

. . 1.2 Of these compounds, the most preferred are those in which R and R are C 1-4 alkoxy, in particular methoxy or ethoxy. Further preferred are those compounds wherein Z is amino.

The compounds of formula I and their salts can be prepared according to the invention a) by reacting na or R 1.

f- \ / CN

Z1 - ({\ -CH „- C 'f Ilb

2 ^ CHY

A compound of formula R2 wherein R1 is lower alkyl, or both R1 groups. 1 2. 1 together form lower alkylene; Y is a leaving group, and R, R and Z are as defined above, for the reaction with guanidine, or b) by reductive removal of the formula R1 (χ2χ) -v \ -

21-Λ-CH2-f \ -KHg IV

of the compound of formula r 2 y 3,58638, wherein X 1 is chlorine, bromine or hydroxy,. 121.. . . 1.

and R, R and Z are as defined above, the substituent X, or c) by reduction or hydrolysis to an amino group or ... 1; . 2 can be converted to a group -NHR by a group Z of formulas O-) - “z Va

R2 / V

~ C 7.2 R2 ^ Z2 'r1 \ z2 - CH2- ^ 11 ^ - Z2 Vc r2 // z2' •. In the compounds of formula 1 2, in which R and R have the same meaning as above,. . . .

and the groups Ζ may be different groups, the amino group or the group -NHR, or

O

d) alkylating the group Z of the formula R1 v Z3 - ^ \ - CH - ^ - NH2 Ia) = / R nh2

• R lt 1 2. U

in which Z is a group -NHCOOR, and R, R and R

denote a sauna as above, and converting the compound of formula I thus obtained into a salt, if desired.

According to process variant (a) according to the invention, the formula <11 58638 is condensed

A compound according to IIa or IIb with guanidine. In the compound of formula Hb, the symbol Y represents a leaving group. Representative examples of such leaving groups include ether residues, e.g., lower alkoxy groups such as methoxy, ethoxy, thioether residues such as lower alkylthio groups, or amino groups derived from primary or secondary amines. Examples of such amino groups are a) groups derived from primary aliphatic, arylaliphatic or aromatic amines, such as lower alkylamino, benzylamino, arylamino, such as halphenylamino, mono- or substituent alone, but especially phenylamino (or anilino), which may be phenylamino (anilino), alkoxy, or b) groups derived from secondary aliphatic, aromatic or heterocyclic amines, such as N, N-di-lower alkylamino, N-lower alkyl-N-arylamino, e.g. N-methyl-N-phenylamino (N-methylanilino), which the phenyl ring may be optionally substituted mono- or polysubstituted by halogen, lower alkyl or lower alkoxy, pyrrolidino, piperidino, piperazino, morpholino. A particularly preferred leaving amino group is the anilino group.

The reaction of a compound of formula IIa or IIb with guanidine can be carried out in a manner known per se (see e.g. BE patents 59-131, 671,982 and Jb6 8U6), e.g. in a solvent such as an alkanol, e.g. methanol, ethanol or dimethylformamide, dimethyl sulphoxide , In N-methylpyrazolone, at about 25 to 200 ° C, preferably 50 to 170 ° C.

Under these conditions, a compound of formula IIb may be formed in situ from the tautomeric compound R1) - / / Cli Z1-ft p-CH = C Ile W X ch2y R2 12 1.. . . wherein R, R, Z and Y are as defined above. The capped compounds of formulas IIb and Ile may exist as cis or trans isomers or as mixtures thereof.

Process variant (a) gives compounds of formula I in which 12.1. . .

R, R and Z have the same meaning as above.

Removal of a bromine or chlorine substituent from a compound of formula IV (process option b) can be accomplished by treatment with reducing agents such as hydrogen iodide or catalytically activated hydrogen, e.g. Pd in 5,586,838 alcohol, or Zn / glacial acetic acid or amalgamated Zn / NaOH. If X 1 is hydroxy, the compound of formula IV is reacted with, for example, 1-phenyl-5-chlorotetrazole, and the 1-phenyltetrazol-5-yl ether thus obtained is hydrogenated by means of Pä / C. Alternatively, the compound of formula IV is first reacted with bromocyanine in the presence of triethylamine, and the reaction product is hydrogenated with paliadium carbons. Then we get. 12-1- compounds of formula I wherein R, R and Z are as defined above.

2

Examples of groups Z which can be converted to the amino group by process variant c) are nitro, carbobenzoxyamino, -NH-NH-aryl and -N = N-aryl.

The conversion of such groups by reduction to the amino group can be carried out by catalytic hydrogenation, e.g. using H 2 and palladium on carbon in an alcohol, e.g. methanol at 10-50 ° C, preferably at room temperature.

... 1+

Groups 7 which can be hydrolytically converted to an amino group or a group -NHR, respectively? are, for example, the groups -NHR '', -N = CHR ^, -N = C (R ^) and -N = CHOr \ -NHC00r \ 1 k, 1 5.. . .... 7.

-NR COOR, -N (R, R) and phthalimido, wherein R represents alkyl, alkenyl or aryl.

The hydrolysis of these groups is conveniently carried out in an acidic medium, e.g. aqueous or aqueous-alcoholic mineral acids such as hydrochloric acid. Alkali hydrolyzable groups Z are U U U. . . ...

-NR COOR, -NHCOOR and -NHCHO. Alkaline hydrolysis can take place with aqueous or aqueous-alcoholic (methanolic) alkali. Most preferably, the phthalimido group can be converted to an amino group by hydrazinolysis.

2 .....

The groups Z which are a substituent on the pyrimide ring are suitably hydrolyzable groups such as acetamino or formylamino; phthalimido or carbobenzoxyamino groups.

Process option c) thus provides compounds of formula I,

.. 1. . U. 1 2 · U

wherein Z is amino or -NHR, and R, R and R are as defined above.

The alkylation according to process variant d) can be carried out with alkyl halides, such as methyl iodide in the presence of a base, such as sodium hydroxide. Examples of suitable solvents are dimethylformamide or dimethylsulfoxide. Process variant d) gives compounds of formula I. . 1 _ b b. T 2. b compounds wherein Z is -NR COOR, and R, R and R are as defined above.

The starting materials used in the various process alternatives, when their preparation is not known or described below, can be prepared analogously to the methods described in the examples or by the methods described below.

6,58638 Starting material Prepared Reaction From jtv e Condensation BE patent publications R \ strongly alkali 59 ** 131 »7 ** 6 8 ^ 6

In the medium Z1-V \ - CHO + CHo \ / ^ ch2y R2

Ha Ilb Alcohol addition 1 1) Condensation with gua-DE application ^ \ CN nidin in a publication \ -λ / medium 2 003 578 UI z1 — y CH2CH 2) Hydroxyl substitution with Br or 2 / Cl with phosphorus (oxy) 2 halides

Inorganic acids commonly used for this purpose, such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., or organic acids, such as formic acid, acetic acid, succinic acid, citric acid, citric acid, citric acid, are suitable for the preparation of acid addition salts, in particular for the preparation of salts suitable for pharmaceutical preparations. methanesulfonic acid, p-toluenesulfonic acid, etc.

The compounds of formula I and their salts are antibacterially effective. They inhibit bacterial dihydrofolate reductase and potentiate the antibacterial effect of sulfonamides, such as sulfaisoxazole, sulfadimethoxine, sulfamethoxazole, U-sulfanilamido-5,6-dimethoxypyrimidine, 2-sulfanilamido-U, 5-dimethylpyrimidine, sulfacinoxalamine, or sulfaquinoxamine. - * +, 5-dimethylisoxazole, and other enzyme inhibitors involved in folic acid biosynthesis, such as pteridine derivatives.

The antibacterial potentiating properties of the sulfonamides of the compounds of the formula I-G were studied by examining the effect of said compounds on sulfamethoxazole (SMZ) and using trimethoprim (TMP) known from DE 2 023 977 as a reference. The experimental results obtained in the study of mice are shown in the following table.

7 58638

Table CD50 (mg / kg)

Infectious agent Diplococcus Escherichia Klebsiella - pneumoniae coli pneumoniae

Combination 1 + 2.2 + 81 +, 6 2.8 + 2.8 1+, 8 + 9.6 TMP + SMZ 19.7 + 98.8 1.3 + 2.5 2.7 + 13.7 0.75 + 3.75 9.9 + 19.8 2.8 + 2.8 1.9 + 3.8

A + SMZ 11.7 + 58.3 1.5 + 3.9 0.95+ M

1.1 + 5.1 * 16.7 + 33.1 * 3.9 + 3.9 0.9 + 1, 8 B + SMZ 1U, 1 + 70.9 1 +, 1 + 8.3 0.7 + 3, 1+ 2.1 + 10.3 10.7 + 21.1+ 1.8 + 1.8 0.8 + 1.7 C + SMZ 8.8 + 1 + 1 +, 1 1.9 + 3.9 0.1 +8+ 2.1+ 0.8 + 1+, 1 33.1+ + 61.9 3.3 + 3.3 1, 5 + D + SMZ 11.6 + 58.3 1.7 + 3, 3 0.56 + 2.8 1.3 + 6.6 ϊ + 2 + ”" 81+ 3.3 + 3.3 0.9 + ΪΤ8 E + SMZ 21.8 +108.8 2.0 + 1 +, 13 0.6 + 2.9 1.2 + 5.6 18 +35.9 42.9 + C2.9 0.8 + 1.6 F + SMZ 10.2 + 50.9 2.1 + 1+ , 1 0.95 + l +, 8 1 + 5 l + 7.3 + 9U, 7 1.9 + 1.9 htk + 8.8 G + SMZ 21+ +120 2.7 + 5.1+ 1, 5 + 7.1+ 0.95 + 1+, 8

The following 2,1 + -diamino-5-benzylpyrimidines were used in the experiment: A = 2,1 + -diamino-5- (1 + -amino-3,5-dimethoxybenzyl) -pyrimidine (2HCl) B = 2,1 + -diamino- 5- (1 + -amino-3,5-dimethylbenzyl) -pyrimidine C = 2,1 + -diamino-5- (1 + -methylamino-3,5-dimethoxybenzyl) -pyrimidine D = 2,1 + -diamino-5 '(1 + -pyrrolo-3,5 (dimethoxybenzyl) -pyrimidine E = 2,1 + -diamino-5- (1 + -ethylamino-3,5-dimethoxybenzyl) -pyrimidine F = 2,1 + -diamino-5- (1 + -dimethylamino) 3,5-dimethoxybenzyl) -pyrimidine G = 2,1 + -diamino-5- [1- (ethoxycarbonyl) -methylamino-3,5-dimethoxybenzyl] -7-pyrimidine.

Such combinations of one or more compounds of formula I and sulfonamides may be used in human medicine orally, rectally or parenterally. The ratio of Compound I to sulfonamide can vary within wide limits; it may be, for example, between 1: UO (parts by weight) -5: 1 (parts by weight); preferably this ratio is 1: 1 to 1: 5.

Thus one tablet may contain, for example, 80 mg of a compound of formula I prepared according to the invention and 100 mg of sulfamethoxazole, a pediatric tablet of 20 mg of a compound of formula I and 100 mg of sulfamethoxazole; the syrup (per 5 ml) may contain 1 + 0 mg of the compound of formula I and 200 mg of sulfamethoxazole.

The compounds of the formula I are characterized by a high antibacterial activity as well as a clear synergistic effect together with sulfonamides and good tolerability.

The following examples illustrate the invention. Temperatures are given in degrees Celsius. DMSO means dimethyl sulfoxide, THF tetrahydrofuran.

Example 1

To a solution of 1.16 g of sodium in 300 ml of absolute ethanol were added 9 * 1 g of guanidine carbonate and 5 * 9 g of N- (3-anilino-2-cyanoallyl) -2 ', 6'-dimethoxyacetanilide, and the mixture was refluxed for 18 hours. The mixture was diluted with 100 mL of water and the alcohol was removed in vacuo.

The precipitated o <- (2, U-diamino-5-pyrimidinyl) -2 ', 6'-dimethoxy-β-acetotoluide was filtered off with suction, washed with water and recrystallized from methanol-ethyl acetate. Mp 278-279 ° C. The starting material was prepared as follows: 9,58638

To a solution of 31 * 5 g of 4-acetamido-3,5-dimethoxytoluene in 2 liters of a pyridine-water mixture (1: 1) was added 142 g of potassium permanganate portionwise over 30 minutes with stirring. The mixture was refluxed for 11/2 hours. The runestone was filtered off with suction and washed with 500 ml of hot water. The filtrate was evaporated to dryness in vacuo at 60 °, the residue was dissolved in water, 2-N sodium hydroxide was added to the solution until strongly alkaline, then extracted twice with 500 ml of ethyl acetate. The vinegar ester phases were discarded and the aqueous solution was adjusted to pH 1 with concentrated hydrochloric acid. The precipitated 4-acetamido-3,5-dimethoxybenzoic acid was filtered off with suction, washed with water and recrystallized from methanol-ethyl acetate. Mp

237-238 °.

A solution of 20.4 g of 4-acetamido-3,5-dimethoxybenzoic acid in 500 ml of abs. methanol, saturated with dry hydrogen chloride. After standing for 18 hours at room temperature, the solvent was removed in vacuo. Ice water and 2-n sodium hydroxide were added to the residue until strongly alkaline. The resulting emulsion was extracted twice with 500 ml of ethyl acetate. The vinegar ester phases were washed twice with 200 ml of water, combined, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was dissolved in 400 ml of abs. tetrahydrofuran. To the solution were added 40 ml of pyridine and 40 ml of acetic anhydride, stirred for 20 hours at room temperature, and then evaporated to dryness in vacuo. To the residue was added 300 ml of water, then extracted twice with 600 ml of ethyl acetate. The ethyl acetate phases were washed twice with 200 ml of water, combined, dried over magnesium sulphate and evaporated to dryness in vacuo. The residual 4-acetamido-3,5-dimethoxybenzoic acid methyl ester was recrystallized from ethyl acetate. Mp 183 - 184 ° ·

A suspension of 30.1 g of dimethyl sulfone and 11.5 g of sodium hydride ($ 50 dispersion in oil) in 80 ml of dimethyl sulfoxide was stirred for 3 hours at 50 ° excluding moisture. Then 20.3 S was added

4-Acetamido-3,5-dimethoxy-benzoic acid methyl ether, and the mixture was stirred at room temperature for 20 hours. The solution was diluted with 1 liter of water and extracted 3 times with 1 liter of ethyl acetate. The ethyl acetate phases were washed twice with 300 ml of water, combined, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was recrystallized from ethyl acetate to give 2'-e'-dimethoxy-4'-dimethylsulfonyl-acetyl] -ethananilide, m.p. 206-207 ° ·

A suspension of 10.1 g of 2- (2'-dimethoxy-4'-dimethylsulfonyl) acetyl] acetanilide and 4.85 g of sodium borohydride in 400 ml of ethanol was stirred for 18 hours at room temperature. To the solution was added 100 ml of water, 10,58638 and the alcohol was removed in vacuo. The precipitated 4 '- [1-hydroxy-2- (methylsulfonyl) ethyl] -2', 6'-dimethoxyacetanilide was filtered off with suction and recrystallized from methanol-ethyl acetate. Mp 193 - 195 ·

A mixture of 3.78 g of sodium methylate, 5 x 1 g of β-anilinopropionitrile and 9.8 g of 4 '- [1-hydroxy-2- (methylsulfonyl) ethyl] -2', 6'-dimethoxyacetanilide In 40 ml of dimethyl sulfoxide, was stirred to exclude moisture for 4 hours at 50 °. The mixture was poured into 400 ml of water, and the resulting emulsion was extracted 3 times with 500 ml of ethyl acetate. The ethyl acetate phases were washed twice with 200 ml of water, combined, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was recrystallized from ethyl acetate: 4 '- (3-anilino-2-cyanoallyl) -2', 6'-dimethoxyacetanilide, m.p.

165-167 °.

Example 2

A solution of 10.1 g of α- (2,4-diamino-5-pyrimidinyl) -2 ', 6'-dimethoxyl * p * acetotoluidide in 600 ml of 1N hydrochloric acid was refluxed for 5 hours, and then the solution was evaporated to dryness in vacuo. The residue was recrystallized from methanol-ethanol to give 2,4-diamino-5- (4-amino-3,5-dimethoxybenzyl) -pyrimidine dihydrochloride, m.p. 286 ° (decomposes).

Example 3

To a solution of 1.38 g of sodium in 300 ml of absolute ethanol were added 10.8 g of guanidine carbonate and 7.5 g of 4 '- (3-anilino-2-cyanoallyl) -2', 6 • -dimethoxy-N- methylacetanilide, and the mixture was refluxed for 20 hours. The alcohol was removed in vacuo, and 100 ml of water and 20 ml of ethyl acetate were added to the residue. After stirring for 1 hour at room temperature, the precipitated α- (2,4-diamino-5-pyrimidinyl) -2 ', ε-dimethoxy-N-methyl-β-acetotoluide was filtered off with suction, washed with water, dried and recrystallized from methanol-ethyl acetate. , sul.p. 262-264 °.

Preparation of starting material:

To a suspension of 12.0 g of sodium hydride (50-6 dispersion in oil) in 50 ml of absolute dimethylformamide was added, with stirring and excluding moisture, a solution of 46.0 g of 4-acetamido-3,5 "dimethoxytoluene over 30 minutes. In 200 ml of absolute dimethylformamide. After stirring for 4 hours at room temperature, 31.2 ml of methyl iodide were added dropwise to the mixture under stirring and ice-cooling over 20 minutes. The mixture was stirred for 70 hours at room temperature, so it was evaporated to dryness in vacuo. To the residue was added 300 ml of water, and the resulting suspension was extracted twice with 500 ml of ethyl acetate. The vinegar ester extract was washed with 300 ml of water, dried over magnesium sulfate and 11,58638 was evaporated to dryness in vacuo. Recrystallization of the residue from ethyl acetate gave 3,5-dimethoxy-4- (U-methylacetamido) toluene, m.p.

160-161 °.

To a solution of 42.4 g of 5,5-dimethoxy-4- (N-methylacetamido) toluene in 2 liters of an aqueous pyridine mixture (1: 1) was added portionwise 180 g of potassium permanganate with stirring at 80 ° for one hour. The mixture was refluxed for one hour. The runestone was filtered off and washed with 1 liter of hot water. The filtrate was evaporated to dryness in vacuo. The residue was dissolved in 300 ml of water and the solution was extracted with 230 ml of ethyl acetate. The ethyl acetate extract was discarded, and concentrated hydrochloric acid was added to the aqueous phase until strongly acidic. The precipitated 3,5-dimethoxy-4- (H-diethylacetamido) -benzoic acid was filtered off with suction, washed with water and recrystallized from methanol. Mp 293 ° 295 ° ·

A suspension of 35.8 g of 3 ', 5'-dimethoxy-4- (N-methylacetamido) -benzoic acid in 300 ml of absolute methanol was saturated with dry hydrogen chloride to gradually give a solution. After standing for 20 hours at room temperature, the solution was evaporated to dryness in vacuo. To the residue were added 200 ml of ice water and concentrated sodium hydroxide solution until a strongly alkaline reaction, and the resulting emulsion was extracted twice with 300 ml of ethyl acetate. The ethyl acetate phases were washed twice with 100 ml of water, combined, dried over magnesium sulphate, filtered and evaporated to dryness in vacuo. The residue was recrystallized from ethyl acetate-cyclohexane to give 3,5-dimethoxy-4- (N-methylacetamido) -benzoic acid methyl ester, m.p. 115-116 °.

A suspension of 33> 7 g of dimethyl sulfone and 12.0 g of sodium hydride ($ 50 dispersion in oil) in 100 ml of absolute dimethyl sulfoxide was stirred to exclude moisture for 3 hours at 50 °, then 34.0 g of 3 "5-dimethoxy-4- (n-methylacetamido) -benteoehappo-metyylieeteriä. After stirring for 2 l / 4 hours at room temperature, it was diluted with 1 liter of water. The solution was acidified with 3 ~ b hydrochloric acid and extracted twice with 1 liter of ethyl acetate. The ethyl acetate phases were washed twice with 200 ml of water, combined, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was recrystallized from ethyl acetate to give 2,6,6-dimethoxy-N-methyl-4 * - [(methylsulfonyl) acetyl] acetanilide, m.p. 141 * 142 °.

A suspension of 20.9 g of 2,6,6-dimethoxy-N-methyl-4 '- [(methylsulfonyl) acetyl] acetanilide and 9.5 g of sodium borohydride in 300 ml of ethanol was stirred at room temperature for 20 hours. The solution was diluted with 300 mL of water and the alcohol was removed in vacuo. The resulting suspension is extracted- I? 5 8638 was added twice with 1 liter of ethyl acetate. The ethyl acetate phase was washed twice with 200 ml of water, combined, dried over magnesium sulphate and evaporated to dryness in vacuo. Recrystallization of the residue from ethyl acetate gave 4, - [1 'hydroxy-2- (methylsulfonyl) ethyl] -2,6,6'-dimethoxy-N-methylacetanilide, m.p. 175 - 177 ° ·

A mixture of 5.24 g of sodium methylate, 8.75 g of β-anilinopropiononitrile and 14.9 g of 4, - [1-hydroxy-2- (methylsulfonyl) ethyl] -2 ', 6'-dimethoxy-N -methylacetanilide in 60 ml of absolute dimethyl sulfoxide was stirred for 4 hours at 50 ° to prevent moisture from entering the mixture. The solution was poured into 600 any water, and the resulting emulsion was extracted twice with 400 ml of ethyl acetate. The ethyl acetate phase was washed twice with 150 ml of water, combined, dried over magnesium sulphate and evaporated to dryness. The residue was recrystallized from ethyl acetate to give 4 '- (3' anilino-2-cyanoallyl) -2 ', 6'-dimethoxy-N-methylethanilide, m.p.

202-204 °.

Example 4

To a solution of 6.9 g of sodium in 1 liter of absolute ethanol were added 54 g of guanidine carbonate and 31 → 6 6 4-amino-o- (anilinomethylene) -3,5-dimethoxyhydrocinnamic acid nitrile, and the mixture was refluxed for 20 hours. 500 ml of water were added and the alcohol was removed in vacuo.

After standing for 2 hours at room temperature, the 2,4-diamino-5- (4-amino-3,5-dimethoxybenzyl) -pyrimidine separated as a crystal was filtered off with suction, washed with water and recrystallized from methanol, m.p. 215-216 °.

Preparation of starting material: 13.8 g of sodium were dissolved in 900 ml of CH 2 OH. To this solution was added 46.8 g of 3-hydroxy-5-keto-3-cyclohexenecarboxylic acid. This mixture was stirred, the temperature was kept between -4 ° and -8 ° by means of a cold bath, and 27.9 g of aniline were added to the mixture over 30 minutes. A solution of phenyldiazonium chloride prepared from 450 ml of water, 72 ml of concentrated HCl and 21.0 g of sodium nitrite in 90 ml of water. Stirring was continued for another hour at -5 to -10 °. The precipitated red reaction product was filtered off with suction and washed with about 1000 ml of water, m.p. 218 °.

60 g of the 3-hydroxy-5-keto-4-phenylazo-3-cyclohexenecarboxylic acid thus obtained, 200 ml of methanol, 1200 ml of benzene and 5 g of p-toluenesulfonic acid were boiled together for 18 hours under reflux and using a water separator. After cooling, the solution was washed with 500 ml of 5 * sodium bicarbonate solution, then with water, the solution was dried and evaporated to gold. The residue was dissolved in ethyl acetate and purified on an alumina column (500 g alumina, activity grade I). Evaporation of the ethyl acetate gave 58638 as a solid, m.p. 144 ° (from benzene-petroleum ether).

54.8 g of the 3'-hydroxy-5-keto-4-phenylazo-3-cyclohexene carboxylic acid methyl ester thus obtained, 12.0 g of acetamide and 2.0 g of bromosuccinimide were mixed with 600 ml of chloroform, and 32.0 g of the mixture was added dropwise to the mixture. bromine (dissolved in 400 ml of chloroform). The reaction temperature was kept below 35 ° sun. Soon acetamide began to separate.HBr. Stirring was continued for a further 30 minutes at room temperature, the acetamide.HBr was filtered off and the filtrate was evaporated to dryness. The residue was taken up in a small amount of ethanol, filtered off with suction and washed with ethanol. Mp 216-218 °.

To a mixture of 27.2 g of 3,5-dihydroxy-4-phenylazobenzoic acid methyl ester obtained as described above, 150 ml of methanol and 64 g of dimethyl sulfate were added with stirring over 45 minutes a solution of 23 g of NaOH in 50 ml of water. By cooling in a cooling bath, care was taken to ensure that the temperature did not rise above 55 °. Stirred for a further hour at room temperature, cooled with ice water, filtered off with suction and recrystallized from 400 ml of ethanol. Red crystals were obtained, m.p.

I30 - I320.

12 g of 3,5-dimethoxy-4-phenylazobenzoic acid methyl ester thus obtained were dissolved in 400 ml of ethanol and, after the addition of Pd / carbon catalyst (0.80 g), hydrogenated under normal pressure and at room temperature. With slight warming of the solution, 2 moles of hydrogen were bound over 1 l / 2 hours. The catalyst was separated and the filtrate was evaporated in vacuo. The aniline formed was removed by steam distillation. After cooling, the remaining 4 ** amino-3,5-'-dimethoxybenzoic acid methyl ester remaining as an aqueous suspension was filtered off with suction, dried and recrystallized from cyclohexane. Mp

115-116 °.

A suspension of 214 L of dimethyl sulfone and 78.2 g of sodium hydride (50 # oil diepereio) in 400 mL of absolute dimethyl sulfoxide was stirred under a nitrogen atmosphere and 137 8 4-amino acids were added to the mixture cooled to 50 ° for 3 hours to prevent moisture from entering. 3,5-Dimethoxybenzoic acid methyl ester, raising the temperature to 50 °. Thus, after stirring for 1 hour under a nitrogen atmosphere at room temperature, a slurry formed which, after standing for 3 hours, dissolved when ice was added in 2 liters of water. The pH of the solution was adjusted to 6-7 with ice vinegar. After stirring for 1 hour under ice-cooling, the separated crystalline 4'-amino-3 *, 5 * -dimethoxy-2- (methylsulfonyl) -acetophenone was filtered off with suction, washed with water, dried and recrystallized from ethyl acetate. Mp 166 - 167 ° ·

A suspension of 123 8 4'-amino-3 ', 5'-dimethoxy-2- (methylsulfonyl) acetophenone and 68 e of sodium borohydride in 1.5 liters of alcohol was stirred for 20 hours at room temperature. The suspension was diluted with 1.5 liters of water. The alcohol was evaporated in vacuo and 4-amino-3,5-dimethoxy-α - [(methylsulfonyl) methyl] benzyl alcohol was filtered off with suction, washed with water and dried. Melting Point, 178 - 179 ° ·

A mixture of 8.64 g of sodium methylate, 14.6 g of β-anilinopropionitrile and 22.0 g of 4-amino-3,5-dimethoxy-α - [(methylsulfonyl) methyl] benzyl alcohol in 50 ml of absolute dimethyl sulfoxide, stirred for 1 hour at 50 ° under a nitrogen atmosphere and preventing moisture from entering.

The solution was poured into 500 ml of any ice water, and the resulting emulsion was extracted twice with 500 ml of ethyl acetate. The vinegar ester phases were washed twice with 250 ml of water, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was dissolved in 60 any ethyl acetate. After standing for 20 hours at room temperature, the crystalline 4-amino-α- (anilinomethylene) -3,5-dimethoxyhydrocinnamic acid nitrile separated by suction was filtered off, washed with a small amount of ethyl acetate and dried. Mp 150 - 151 ° ·

Example 8

To a solution of 36 mg of sodium in 100 ml of absolute ethanol were added 2.8 g of guanidine carbonate and 2.0 g of 4- (3-anilino-2-cyanoallyl) -2,6-dimethoxycarbanilic acid ethyl ether, and the mixture was refluxed for 20 hours. The solution was diluted with 100 mL of water and the alcohol was removed in vacuo. After standing for one hour at room temperature, the precipitate was filtered off with suction, washed with water and dissolved in about 200 parts of any boiling ethanol. The solution was chromatographed on 100 g of silica gel (Merck) with ethanol-acetic acid ester (iti) to give 4 - [(2,4-diamino-5-pyrimidinyl) -methyl] -2,6-dimethoxycarbanic acid ethyl ester, m.p. 228 ° (decomposes, from ethanol). Preparation of starting material: To a cooled solution of 12.0 g of 4'-amino-3 ', 5'-dimethoxy-2- (methylsulfonyl) acetophenone in 100 ml of absolute pyridine is added, with stirring, 5.06 ml of ethyl formic acid chloroformate. After stirring for 20 hours at room temperature, the pyridine was removed and the residue was dissolved in 100 ml of water. The precipitated 2,6-dimethoxy-4 - [(methylsulfonyl) acetyl] carboxylic acid ethyl ether was filtered off with suction, washed with water and recrystallized from ethanol. Mp 192 · 193 ° ·

A suspension of 12.1 g of 2,6-dimethoxy-4 - [(methylsulfonyl) -acetyl] -carbanic acid ethyl ester and 5 * 3 g of sodium borohydride in 150 ml of ethanol was stirred for 70 hours at room temperature. The alcohol was evaporated in vacuo and 150 ml of water were added to the residue. After standing for 1 hour at room temperature, the separated 4- [1-hydroxy-2- (methylsulfonyl) -ethyl] -2,6-dimethoxycarbanilic acid ethyl ester was filtered off with suction, washed with water and recrystallized from ethanol. Mp

168-170 °.

A mixture of 4.42 g of sodium ethylate, 5.1 g of β-anilinopropionitrile and 10.0 g of 4- [1-hydroxy-2- (methylsulfonyl) ethyl] -2,6-dimethoxycarboxylic acid ethyl ester in 150 ml of dimethyl sulfoxide , was stirred for 2 hours at 50 °, preventing the effect of moisture. The solution was poured into 1.5 liters of water, and the resulting emulsion was extracted twice with 1 liter of ethyl acetate. The ethyl acetate phases were washed twice with 500 ml of water, combined, dried over magnesium sulphate and evaporated to dryness. The residue was chromatographed on 800 g of 11a silica gel (Merck) with methylene chloride-ethyl acetate (3 * 1). 4- (3-Anilino-2-cyanoallyl) -2,6-dimethoxycarbanilic acid ethyl ester was obtained. Mp 150-151 ° (alcoholic).

Example 6

A suspension of 1.04 g of 4 - [(2,4-diamin-5-pyrimidinyl) methyl] -2,6-dimethoxycarbanilic acid ethyl ester in a mixture of 4N sodium hydroxide (50 ml) and ethanol (50 ml) was boiled under reflux. hours, during which time a solution was gradually obtained. The alcohol was removed in vacuo. After filtration for 1 hour at room temperature, the crystallized 2,4-diamino-5- (4-amino-3,5-dimethoxybenzyl) -pyrimidine was filtered off with suction, washed with water and recrystallized from methanol. Mp 215-216 °.

Example 7

To a solution of 1.5 g of 2,4-diamino-5- (4-amino-3,5-dimethoxybenzyl) -6-chloropyrimidine in 15.5 ml of glacial acetic acid was added 0.1 g of mercuric chloride II in 1 ml of water and 1.5 g of zinc powder, and the mixture was stirred and refluxed overnight. The next day the mixture was filtered hot, the zinc powder was washed with 5 ml of glacial acetic acid and the combined filtrates were added dropwise with stirring at 20 ° to 40 ml of concentrated ammonia. After stirring for a further hour at 20 °, the solid was filtered off with suction, washed with water, dried and crystallized from methanol. The melting point of 2,4-diamino-5- (4-amino-3,5-dimethoxybenzyl) pyridine was 214 ° · The starting material was subsequently prepared in 158 g of 4-amino-3,5-dimethoxy-α - [(methylsulfonyl) methyl] Benzyl alcohol in 250 ml of dimethyl sulfoxide, 9.75 g of sodium amide were added. The reaction mixture was stirred for 1 1/4 hours at room temperature, then poured into 2 liters of water. The resulting precipitate was extracted with 2 liters of ethyl acetate, the aqueous phase was extracted with 2 liters of ethyl acetate, the ethyl acetate phases were washed twice with 1 liter of water until deionized, dried over magnesium sulphate, filtered and evaporated to dryness in vacuo at 40 ° C. 58638 alcohol, 150 ml of water was added to the solution, and it was allowed to stand at 4 ° for 18 hours. The crystallized 4-amino-3,5-dimethoxybenzaldehyde was filtered off with suction, washed deionized with a mixture of methyl alcohol (40 ml) and water (20 ml) and dried in vacuo at 50 ° C. Melting point 90-93 °.

A mixture of 18.1 4-amino-3,5-dimethoxybenzaldehyde, 11.3 g of cyanoacetic acid ethyl ether and 3 drops of piperidine was heated in an open vessel for 120 hours at which time the resulting water evaporated. The residue was crystallized from ethyl acetate-petroleum ether. 4-Amino-α-cyano-3β-diaethoxy-quadric acid ethyl ester melted at 134-136 °.

13.8 g of 4-amino-n-cyano-3,5-dimethoxycinnamic acid ethyl ester were hydrogenated in 300 ml of ethanol in the presence of palladium on carbon (3 g) at room temperature under 1 atmosphere. When the theoretical amount of hydrogen was bound, the reaction was stopped. The catalyst was removed, the filtrate was evaporated to dryness in vacuo and the residue was purified by chromatography to give 10.8 g of 4-amino-α-cyano-3,3-dimethoxyhydrocinnamic acid ethyl ester which, recrystallized from ethyl acetate-petroleum ether, melted at 77-78 °.

To a solution of 1.13 g of sodium in 30 ml of ethanol were added 13 * 9 g of 4-amino-α-cyano-3,5-dimethoxyhydrocinnamic acid ethyl ether and 1.13 g of sodium in 30 ml of ethanol and 3 g of * guanidine hydrochloride. prepared guanidine solution. Stirred and refluxed for 1 hour, evaporated to dryness, and the residue was dissolved in a small amount of water, the solution was filtered, weakly acidified with acetic acid and made alkaline with sodium bicarbonate. The precipitated 2,6-diamino-5- (4-amino-3,5-dimethoxybenzyl) -4-pyrimidinol was filtered off with suction and recrystallized from ethanol-water. Mp 267-269 °.

To a suspension of 2.9 g of 2,6-diamino-3- (4-amino-3,3-dimethoxybenzyl) -4-pyrimidinol in 13 ml of phosphorus oxychloride was added dropwise with stirring 2.3 g of dimethylaniline. The mixture was then heated to reflux for 1 hour and refluxed for 4 hours. 8-9 ml of phosphorus oxychloride was distilled off from the mixture under reduced pressure, and the residue was poured into 80 g of ice with stirring. The mixture was allowed to stand for 6 days at room temperature, then 35 ml of concentrated ammonia were added portionwise.

After standing for 2 hours, the solid was filtered off with suction, dried and recrystallized from dimethylformamide ether. 2,4-Diamino-5- (4-amino-3,5-dimethoxybenzyl) -6-chloropyrimidine melted at 222-224 ° * SBa.

Example 8

To a solution of 0.33 g of sodium in 36 ml of absolute ethanol were added 2.16 g of guanidine hydrochloride and 3.4 g of α- (anilinomethylene) -3,5-dimethoxy-4- (pyrrol-1-yl) hydrocinnamic acid nitrile, and the mixture was boiled at 58638 with stirring under nitrogen for 20 hours. The ethanol was removed under reduced pressure, the residue was dissolved in water, the insoluble was filtered off with suction, washed with water and crystallized from ethanol. 2,4-diamino-5- [3,5-dimethoxy-4- (pyrrole) -1-yl) benzyl] pyrimidine melted at 220 °.

The starting material was prepared as follows:

To a solution of 10.5 g of 4-amino-3,5-ethoxybenzoic acid ethyl ester in 50 ml of glacial acetic acid was added dropwise at room temperature, with stirring, a mixture of 9 g of diethoxytetrahydrofuran and 5 ml of glacial acetic acid. Stirred for an additional 30 minutes at 100 °, cooled with ice, filtered off with suction, dried and recrystallized from cyclohexane. 3,5-Dimethoxy-4- (pyrrol-1-yl) -benzoic acid methyl ester melted at 145-146 ° C.

A suspension of 2.9 g of sodium hydride (50 # dispersion in oil) and 3.8 g of dimethyl sulfone in 20 ml of absolute dimethyl sulfoxide was stirred for 2 hours under a nitrogen atmosphere at 50 ° and preventing the ingress of moisture. The heating was stopped, and 5.2 g of 3 * 5-dimethoxy-4 '(pyrrol-1-yl) benzoic acid methyl ester was added to the mixture, raising the temperature to 67 °. After stirring for a further 2 hours, the mixture was diluted with 200 ml of ice, the aqueous solution was shaken with ethyl acetate (50 ml), filtered through charcoal, acidified with glacial acetic acid and left in the refrigerator overnight. The precipitated 3 ', 5, "dimethoxy-2- (methylsulfonyl) -4' - (pyrrol-1-yl) acetophenone melted after recrystallization from ethyl acetate-petroleum ether at 180 °.

To a suspension of 1.54 8 3 '(S'-dimethoxy (4-methylsulfonyl)) - (pyrrol-1-yl) acetophenone in 20 ml of ethanol and 20 ml of water was added a solution of 0.4 g of sodium borohydride in 5 ml of water (while adding 0.1 g of sodium hydroxide). Stirred for an additional 3 hours at room temperature, cooled with ice, diluted with 50 mL of water and filtered off with suction. Recrystallization from ethanol gave 3,5-dimethoxy-α - [(methylsulfonyl) methyl] -4- (pyrrol-1-yl) benzyl alcohol, melting at 192 °.

A mixture of 2.45 g of sodium methylmethylate, 9.75 g of 3,5-dimethoxy-α - [(methylsulfonyl) methyl] -4- (pyrrol-1-yl) benzyl alcohol and 6.6 g of β-anilinopropionitrile in 75 ml: absolute dimethyl sulfoxide, stirred for 1 hour under nitrogen at room temperature and preventing the effect of moisture, the mixture was poured into 250 ml of ice-cold water, extracted 3 times with 200 [mu] l of ethyl acetate, the ethyl acetate was washed with water, dried and evaporated to dryness. Purification was performed with alumina and recrystallized from ethanol to give α- (anilinomethylene) -3,5-dimethoxy-4- (pyrrol-1-yl) hydrocyanic acid nitrile, m.p. 182-184 °.

18 58638

Kwlmarlrki Q

To a solution of 0.53 g of sodium in 36 ml of ethanol were added 2.16 g of guanidine hydrochloride and 3.2 g of 4-amino-α- (anilinomethylene) -3,5-diethoxyhydrocinnamic acid nitrile, and the mixture was boiled for 20 hours under a nitrogen atmosphere. while stirring. The ethanol was removed under reduced pressure, the residue was dissolved in water, the precipitate was filtered off with suction, washed with water and crystallized from methanol. 2.4 "diamino-5- (4-amino-3,5" diethoxybenzyl) pyrimidine melted at 200-202 °.

The starting material was prepared as follows:

To a mixture of 54.4 g of 3,5-dihydroxy-4- (phenylteo) -benzoic acid methyl ester, 400 ml of metanol and 86 g of diethyl sulphate was added dropwise a solution of 50 g of sodium hydroxide in 200 ml of water, maintaining the temperature at 40 ° C. - 45 ° c. Stirring was continued for a further 2 hours at room temperature, even evaporated to dryness, the residue shaken with water and ethyl acetate, the organic phase separated, washed with sodium carbonate solution and then with water, dried and evaporated to dryness.

3,5-Diethoxy-4- (phenylazo) benzoic acid methyl ester was isolated by chromatography and recrystallization from methanol. Mp 92 °.

6.56 g of 3,5-diethoxy-4- (phenylazo) -benzoic acid methyl ester was dissolved in 100 ml of ethanol and, after the addition of Pd / carbon (0.4 g), was hydrogenated under normal pressure and at room temperature. As the solution warmed slightly, 2 moles of hydrogen bound. The catalyst was separated and the filtrate was concentrated in vacuo. The aniline formed was removed by steam distillation. After cooling, the remaining 4-amino-3,5-diethoxybenzoic acid methyl ester was filtered off with suction as an aqueous suspension, dried and recrystallized from cyclohexane. Melting point * 90-92 °.

A suspension of 3 to 76 g of dimethyl sulfone and 2.88 g of sodium hydride ($ 50 dispersion in oil in 20 ml of absolute dimethyl sulfoxide was stirred at 50 ° for 2 hours under a nitrogen atmosphere and preventing the ingress of moisture. Heating was stopped and 4 * 78 g of 4-amino-3,5-diethoxybenzoic acid methyl ester The mixture was heated at 90 ° for one minute, then stirred for 1 l / 2 hours at room temperature, diluted to 100 ml without ice, the aqueous solution was shaken with ethyl acetate (50 ml), the solution was filtered through charcoal, acidified with glacial acetic acid, filtered off with suction, and 4, -amino-3 ', 5, -diethoxy-2- (methylsulfonyl) acetophenone was recrystallized from ethyl acetate * mp 116-163 °.

To a suspension of 26 g of 4, -amino-3 ', 5, -diethoxy-2- (methylsulfonyl) -acetophenone in 350 ml of water was added a solution of 7.0 g of sodium boron-9,58638 hydride in 90 ml of water. (at the same time 0.5 g of sodium hydroxide was added). Stirring was continued at room temperature for 17 hours, then cooled with ice, diluted with 500 ml of water and filtered off with suction. After recrystallization from methanol, k-amino-3,5-diethoxy-o- [(methylsulfonyl) methyl] benzyl alcohol melted at 166-168 ° C.

A mixture of 0.82 g of sodium methylate, 3.0 g of 1-amino-3,5-diethoxy-N - ((methylsilfonyl) methyl / benzyl alcohol and 2.2 g of N, N-anilopropionitrile 12, In 5 ml of absolute dimethyl sulfoxide, stirred for 5 hours under a nitrogen atmosphere at 55 ° and preventing the ingress of moisture, the mixture was poured into 100 ml of water, extracted 3 times with 100 ml of ethyl acetate, the ethyl acetate was washed with water, dried and evaporated to dryness. recrystallized from ethyl acetate-petroleum ether, U-amino-oL- (anilinomethylene) -3.5 ° diethoxyhydrocinnamic acid nitrile melted at 179-118 °.

Example 10

A mixture of 6.5 g of sodium methylate, 21.6 g of guanidine carbonate and 12.8 g of o- (N-amino-3,5-dimethoxybenzyl) -N-morpholinoacrylonitrile in 120 ml of abs. DMSO, was stirred for 60 hours at 120 °. It was then diluted with 1.2 liters of water and extracted with 2x2 liters of ethyl acetate. The ethyl acetate phases were washed with 2 x 1 liter of water, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was recrystallized from 58638 by crystallization from methanol of 2,4-diamino-5- (4-amino-3,5-dimethoxybenzyl) pyrimidine, m.p. 215-216 °.

Preparation of starting material:

To a solution of 8.1 g (0.15 mol) of sodium methylate and 21.0 g (0.15 mol) of β-morpholinopropionitrile in 100 ml of abs * DMSO was added with stirring at 60 ° for 10 minutes, with 18.1 g (0.1 mol) of 4-amino-3,5-dimethoxybenzaldehyde in 50 ml of abs. LMS0 added. After stirring for 30 minutes at 60 °, the reaction mixture was poured into 1.5 liters of water, and the precipitated product was extracted with 2x1 liter of ethyl acetate. The ethyl acetate phases were washed with 2 x 500 ml of water, dried over magnesium sulphate and evaporated to dryness in vacuo. The crystalline residue (35 g) was triturated with alcohol (40 ml), and after standing for 2 hours at 4 °, the? - (4-amino-3,5-dimethoxybenzyl) -4-morpholinoacrylonitrile was filtered off with suction, washed with a small amount of ice-cold alcohol and dried. . Mp 128-129 °.

Example 11

To a solution of 1.3 g of sodium in 200 ml of abs. alcohol, 10.3 g of guanidine carbonate and 5 g of 4-amino-3,5-dimethoxy-α- (ethoxymethyl) -cinnamic acid nitrile were added, and the mixture was refluxed for 46 hours. 200 ml of water were added and the alcohol was removed in vacuo * then extracted with 2 x 500 ml of ethyl acetate. The insoluble matter was separated and discarded. 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 ethyl acetate-methanol (3 * 1) with 90 g of silica gel (Merck) to give 2,4-diamino-5- (4-amino-3,5-dimethoxybenzyl) pyrimidine, m.p. 215-216 ° (from methanol).

Preparation of starting material:

To a solution of 4 to 6 g of sodium in 400 ml of abs. alcohol, 18.1 g of 4-amino-3,5-dimethoxybenzaldehyde and 19.8 g of β-ethoxypropiononitrile were added and the mixture was refluxed for 20 hours, then evaporated to dryness in vacuo. The residue was dissolved by shaking in a mixture of 1.2 liters of ethyl acetate in 300 ml of water. After separation of the phases, the ethyl acetate extract was washed with 300 ml of water, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was chromatographed on ethyl acetate-methylene chloride (1: 9) on 1 kg of silica gel (Merck) to give 4-amino-3,5-dimethoxy-α- (ethoxymethyl) -cinnamic acid nitrile, m.p. 54-55 ° (alcohol-water). ).

Example 12

To a solution of 1.84 g of sodium in 200 ml of abs. alcohol, 14.4 g of guanidine carbonate and 8.9 g of 4 '- (5-anilino-2-cyanoallyl) -2', 6'-dimethocaiformanilide were added, and the mixture was refluxed for 20 hours.

21 58638

200 ml of water were added and the alcohol was removed in vacuo. After standing for 2 hours at room temperature, the crystalline 2,1-diamino-5- (1 + -amino-3,5-dimethoxybenzyl) -pyrimidine was filtered off with suction, washed with water and recrystallized from methanol. Mp 215-216 °.

Preparation of starting material: To a solution cooled to 10 ° of 18.1 g (0.1 mol) of U-amino-3,5-methoxybenzaldehyde in 210 ml of formic acid (98%) was added dropwise TO ml of acetic anhydride so that the reaction mixture the temperature did not rise above 15 °. The solution was then stirred for a further 2 hours at room temperature, 80 ml of water were added and the mixture was evaporated to dryness in vacuo. The 2 ', 6'-dimethoxy-N-formylformanilide thus obtained was washed with water and crystallized from alcohol. Mp 159-160 °.

A mixture of 2.7 g of sodium methylate, 3> 65 g of N-anilinopropiononitrile and 1.2 g of 2 ', 6'-dimethoxy-1' '- formylformanilide in 30 ml of abs.

DMSO, stirred at 50 ° for 30 minutes. The solution was poured into 500 ml of water and the resulting emulsion was extracted with 2 x 500 ml of ethyl acetate. The ethyl acetate phases were washed with 2 x 300 ml of water, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was obtained by recrystallization from ethyl acetate of U '- (3-anilino-2-cyanoallyl) -2', 6'-dimethoxyformanilide, m.p. 186-1870.

Example 13

To a solution of 2.75 g of 2,1 + -diamino-5- (1 + -amino-3,5-dimethoxybenzyl) -pyrimidine in 50 ml of methanol was added 10 ml of 1N hydrochloric acid. The resulting precipitate was dissolved by heating and the solution was evaporated in vacuo at 60 ° to about 20 ml. After standing for 2 hours at room temperature, the precipitated 2,1-diamino-5- (N- (amino-3,5-dimethoxybenzyl) pyrimidine hydrochloride was filtered off with suction, washed with methanol and dried. Mp 296 ° (decomposes).

Example 1 ^

A mixture of 8.7 g of (+ (1,2,1-diamino-5-pyrimidinyl) methyl] -2,6-dimethoxycarbanilic acid ethyl ester and 1.1 + 1 * g of sodium hydride (50% dispersion in oil) at 75 ral abs. dimethylformamide, stirred for 1 hour at room temperature, then 1.6 g of methyl iodide was added to the mixture.

After stirring for 3 hours at room temperature, the dimethylformamide was removed in vacuo at 60 ° and the residue was dissolved in a mixture of ethyl acetate (500 ml) and water (150 ml). After separation of the phases, the aqueous phase was extracted with 500 ml of ethyl acetate. The combined ethyl acetate phases were washed with 300 ml of water, dried over magnesium sulphate and evaporated to dryness in vacuo. Recrystallization of the residue from alcohol gave 1 '- ["(2, h-diamino-5-pyrimidinyl) methyl] -2,6-dimethoxy-N-methylcarbanic acid ethyl ester, mp 187-188 °.

22 5 86 38

Example 15

A mixture of 12 g of U- [T [2,2-diamino-5 '(pyrimidinyl) methyl] -2,6-dimethoxycarbanilic acid ethyl ester and 2 g of sodium hydride (50% dispersion in oil) in 100 ml of abs. dimethylformamide, stirred for k hours at room temperature, then 6.5 g of ethyl iodide was added to the mixture. After stirring for 30 minutes at room temperature, the dimethylformamide was removed in vacuo at 60 °. The residue was dissolved in 250 ml of water and the precipitated product was extracted with 2 x 600 ml of ethyl acetate. The ethyl acetate phases were washed with 2 x 300 ml of water, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was chromatographed with ethyl acetate (3: 1) on 350 g of silica gel (Merck) to give N-ethyl-4 - [(2,1-diamino-5-pyrimidinyl) -methyl] -2,6-dimethoxycarbanilic acid ethyl ester, m.p. p. 165 ~ 167 ° (from ethyl acetate).

Example 16

To a solution of 1 * 11 + mg sodium in 100 ml abs. alcohol, 3.2 g of guanidine carbonate and 2 g of o- (anilinomethylene) -1 + - (dimethylamino) -3,5-d-methoxyhydrocyanic acid nitrile were added, and the mixture was refluxed for 20 hours. 50 ml of water were added and the alcohol was removed in vacuo. The precipitated 2, U-diamino-5- [N- (dimethylamino) -3,5-dimethoxybenzyl] pyrimidine was filtered off with suction, washed with water and recrystallized from methanol.

Mp 218-219 ° · Preparation of starting material:

A suspension of 10 g of amino-3,5-dimethoxybenzoic acid methyl ester and 130 g of anhydrous potassium carbonate in 1.7 liters of anhydrous tetrahydrofuran was added dropwise with stirring at room temperature over 30 minutes to 1 x 8 g of dimethyl sulfate. The reaction mixture was stirred and refluxed for 18 hours. The tetrahydrofuran was evaporated in vacuo, 600 ml of water were added to the residue and the precipitated product was extracted with 2 x 600 ml of ethyl acetate. The ethyl acetate phases were washed with 2 x 300 ml of water, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was chromatographed on methylene chloride-ethyl acetate (9: 1) on 1.5 kg of silica gel (Merck) to give 1- (dimethylamino) -3,5-dimethoxybenzoic acid methyl ester, m.p. 71 ~ 72 ° (from cyclohexane).

A suspension of 21.6 g of dimethyl sulfone and 7.7 g of sodium hydride (50 # dispersion in oil) in 80 ml of abs. DMSO, was stirred for 3 hours under a nitrogen atmosphere at 50 ° and preventing moisture from entering. To the reaction mixture cooled to 30 ° was added 15.6 g of U- (dimethylamino) -3,5-dimethoxybenzoic acid methyl ester. After stirring for k hours at room temperature, 500 ml of water were added and the solution was adjusted to neutral with glacial acetic acid. The precipitated N- (dimethylamino) -3 *, 5'-dimethoxy-2-methylsulfonyl) acetophenone was filtered off with suction, washed with water, dried and recrystallized from ethyl acetate-cyclohexane. Mp 111-112 °.

23 58638

A suspension of 2 g of 1 +, - (dimethylamino) -3,5,5'-dimethoxy-2- (methylsulfonyl) acetophenone and 12.1 g of sodium borohydride in 260 ml of alcohol was stirred at room temperature for 16 hours, to give a solution. 260 ml of water were added and the alcohol was evaporated in vacuo. The precipitated h- (dimethylamino) -3,5-dimethoxy-O - [(methylsulfonyl) methyl] 7-benzyl alcohol was filtered off with suction, washed with water and recrystallized from ethyl acetate. Mp 11 * 7-1U8 °.

A mixture of 3.3 g of sodium methylate, 8.9 g of n-anilinopropionitrile and 15.7 g of * - (dimethylamino) -3,5-dimethoxy-N-methyl (methylsulfonyl) methyl] benzyl alcohol a UO in ml abs. DMSO, stirred for 2 hours at 50 °. The reaction mixture was poured into 1 * 00 ml of water, and the resulting emulsion was extracted with 2 x 1 * 00 ml of ethyl acetate. The ethyl acetate phases were washed with 2 x 200 ml of water, dried over magnesium sulphate and evaporated to dryness in vacuo. Recrystallization of the residue from the ethyl acetate gave o <- (anilinomethylene) -1 * - (dimethylamino) -3,5-dimethoxyhydrocinnamic acid nitrile, m.p. 130-132 °.

Example 17

To a solution of 1.29 g (56 mmol) of sodium in 200 mL of abs. alcohol, 10 g (56 mmol) of guanidine carbonate and 6 g (18.6 mmol) of - (anilinomethylene) -3,5-dimethoxy-U- (methylamino) -hydrocinnamic acid nitrile were added, and the mixture was refluxed for 20 hours. 200 ml of water were then added and the alcohol was evaporated in vacuo. After standing for 2 hours at room temperature, the precipitated 2,1'-diamino-5- (3,5'-dimethoxy) -1- (methylamino) -benzyl] pyrimidine was filtered off with suction, washed with water and recrystallized from alcohol. Mp 20L °.

Preparation of starting material:

To a solution of 50.6 g of U-amino-3,5-dimethoxybenzoic acid methyl ester in 1 liter of abs. pyridine, 82 g of carbobenzoxychloride were added under stirring and ice-cooling over 30 minutes, and the mixture was stirred for 20 hours at room temperature. The pyridine was evaporated in vacuo, and 1 liter of water and 3N hydrochloric acid were added to the residue until a strongly acidic reaction. The resulting emulsion was extracted with 2 x 1.5 liters of ethyl acetate. The ethyl acetate extract was washed with 2 x 800 ml of water, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was recrystallized from ethyl acetate to give 2,6-dimethoxy-L- (methoxycarbonyl) -carboxylic acid benzyl ester, m.p. 132-133 °.

A suspension of 3.2 g of 2,6-dimethoxy-U- (methoxycarbonyl) carbanyl acid benzyl ester and 5 * 8 g of sodium hydride (50% dispersion in oil) in 300 ml of abs. dimethylformamide, stirred for U hours at room temperature. To the resulting solution was added 17 g of methyl iodide under stirring and ice-cooling. After stirring for 1 hour at room temperature, the dimethylformamide was removed in vacuo at 60 °. To the residue was added 1 liter of water and the emulsion was extracted with 2x2 liters of ethyl acetate. The organic phases were washed with 2 x 1 liter of water, dried for 2 h 58638 over magnesium sulphate and evaporated to dryness in vacuo. The residue was obtained by recrystallization from alcohol of 2,6-dimethoxy-U- (methoxycarbonyl) -N-methylcarbanilic acid benzyl ester, m.p. 130-131 ° ·

A suspension of 33.5 g of 2,6-dimethoxy-1- + - (methoxycarbonyl) -N-methyl-carbanilic acid benzyl ester in 1 liter of methanol was hydrogenated in the presence of 5 "palladium on carbon (1.5 g) until hydrogen the commitment ceased. The suspension was heated to boiling point and filtered. The filtrate was evaporated in vacuo and the residue recrystallized from cyclohexane to give 3,5-dimethoxy-L- (methylamino) -benzoic acid methyl ester, m.p. 1 + 9-51 °.

A suspension of bb, 2 g of dimethyl sulfone and 16 g of sodium hydride (50% dispersion in oil) in 150 ml of abs. DMSO, was stirred for k hours under a nitrogen atmosphere at 50 ° and preventing moisture from entering. 30.1 g of 3,5-dimethoxy-L- (methylamino) -benzoic acid methyl ester were added, and the reaction mixture was stirred for 10 minutes at 80 ° and 30 minutes at 25 °, then dissolved in 600 ml of water. The solution was adjusted to neutral by the addition of glacial acetic acid. The precipitated 3 ', 5'-dimethoxy-1' - (methylamino) -2- (methylsulfonyl) acetophenome was filtered off with suction, washed with water, dried and recrystallized from ethyl acetate. Mp 98-99 ° ·

A suspension of 31 g of 3 ', 5'-dimethoxy-1' - (methylamino) -2- (methylsulfonyl) acetophenone and 16.3 g of sodium borohydride in 600 ml of ethanol was stirred at room temperature for 16 hours. The solution was diluted with 600 ml of water and the alcohol was distilled off in vacuo. The crystallized 3,5-dimethoxy-L- (methylamino) - [* - [(methylsulfonyl) methyl] 7-benzyl alcohol was filtered off with suction, washed with water and dried. Mp 11 + 1 - 11 + 2 °.

A mixture of 2.7 g of sodium methylate, 7.3 g of β-anilinopropionitrile and 12 g of 3,5-dimethoxy-L- (methylamino) - [(methylsulfonyl) methyl] 7-benzyl alcohol in 100 ml of abs. The DMSO was stirred for 30 minutes under a nitrogen atmosphere at 50 DEG C., then the mixture was poured into 1 liter of water, the resulting emulsion was extracted with 2 x 1 liter of ethyl acetate. <* E - (anilinomethylene) -3,5-dimethoxy-1 + - (methylamino) -hydrocannelic acid nitrile, mp 150-152 °.

Example 18

To a solution of L, 3 g of sodium in 1 liter of abs. alcohol, 33.6 g of guanidine carbonate and 21 g of α- (anilinomethylene) -H- (ethylamino) -3,5-dimethoxyhydrocinnamic acid nitrile were added, and the mixture was refluxed for 20 hours. After cooling, 1 liter of water was added and the alcohol was removed in vacuo. The precipitated 2,4-diamino-5- [4- (ethylamino) -3,5-dimethoxybenzyl)] pyrimidine was filtered off with suction, washed with water and recrystallized from alcohol, m.p. 186-188 °.

Preparation of starting material:

A suspension of 103 8 2,6-dimethoxy-4- (n-ethoxycarbonyl) -carboxylic acid benzyl ester and 17 → 3 8 sodium hydride (50 # dispersion in oil) in 1 liter of abs. dimethylformamide, was stirred for 4 hours at room temperature, and then 56 * 2 g of ethyl iodide was added thereto under stirring and ice-cooling. After stirring for 30 minutes at room temperature, the dimethylformamide was removed in vacuo at 60O. To the residue was added 1 liter of water, and then extracted with 2 x 1.5 liters of ethyl acetate. The ethyl acetate extract was washed with 2 x 700 ml of water, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was obtained by recrystallization from alcohol of N-ethyl-2,6-dimethoxy-4- (phthethoxycarbonyl) -carbanic acid benzyl ester, m.p. 85-86 °.

A suspension of 77.5 g of N-ethyl-2,6-dimethoxy-4- (methoxycarbonyl) -carboxylic acid benzyl ester in 1 liter of methanol was hydrogenated in the presence of $ 5 palladium on carbon (2 g) until hydrogen bonding ceased. The suspension was heated to the point and filtered. The filtrate was evaporated to dryness in vacuo. Filling the residue from cyclohexane gave 4- (ethylamino) -3,5-dimethoxybenzoic acid methyl ester, m.p. 50-51 °.

A suspension of 50.4 g of dimethyl sulfone and 21.2 g of sodium hydride ($ 50 dispersion in oil) in 200 ml of abs. DMSO, was stirred for 4 hours under a nitrogen atmosphere at 50 ° to prevent the ingress of moisture. 42.6 g of 4- (ethylamino) -3,5-dimethoxybenzoic acid methyl ester were added, the reaction mixture was stirred for 10 minutes at 80 °, then dissolved in 1 liter of water. The solution was adjusted to neutral with glacial acetic acid. The precipitated 4 '- (ethylamino) -3', 5, -dimethoxy-2- (methylsulfonyl) -acetophenone was filtered off with suction, dried and refilled from ethyl acetate. Mp 129-130 °.

A suspension of 4β g of 4 '- (ethylamino) -3', 5'-dimethoxy-2- (methylsulfonyl) acetophenone and 23.8 g of sodium borohydride in 1 liter of alcohol was stirred for 20 hours at room temperature, at which point everything dissolved. 1 liter of water was added, the alcohol was evaporated in vacuo. The crystalline separated 4- (ethylamino) -3,5-dimethoxy-α - [(methylsulfonyl) methyl] -benzyl alcohol was filtered off with suction, washed with water and dried. Mp

121-122 °.

26 5 8 6 3 8

A mixture of 8.9 g of sodium methylate, 24.1 g of β-anilinopropiononitrile and 41.5 g of 4- (ethylamino) -3,5-dimethoxy- [x - [(methylsulfonyl) methyl] benzyl alcohol in 200 ml: ssa abs. DMSO, was stirred for 20 minutes under a nitrogen atmosphere at 50 °. The reaction mixture was poured into 2 liters of water, and the resulting emulsion was washed with 2x1 liters of water, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was recrystallized from ethyl acetate to give? - (anilinomethylene) -4- (ethylamino) -3,5-dimethoxyhydrocinnamic acid nitrile, m.p. 128-130 °.

Example 19

To a solution of 1.95 g of sodium in 500 ml of abs. alcohol, 15.3 g of guanidine carbonate and 9-3 g of 4-amino-α- (anilinomethylene) -3,5-dimethylhydrocinnamic acid nitrile were added, and the mixture was refluxed for 40 hours. To this was added 500 ml of water and the alcohol was removed in vacuo. The precipitated 2,4-diamino-5- (4-amino-3,5-dimethylbenzyl) pyrimidine was filtered off with suction, washed with water and recrystallized from methanol.

Mp 258-260 °.

Starting material preparations

A suspension of 33 g of dimethyl sulfone and 11 g of sodium hydride ($ 50 dispersion in oil) in 160 ml of abs. DMSO, was stirred for 3 hours under a nitrogen atmosphere at 50 ° evenly, preventing the effect of moisture. Then 18 g of 4-amino-3,5-dimethylbenzoic acid methyl ester was added. The reaction mixture was stirred for 30 minutes at 80 ° and for one hour at room temperature, then dissolved in 400 ml of water. The solution was adjusted to neutral with glacial acetic acid, and the precipitated 4, -amino-3'-dimethyl-2- (methylsulfonyl) -acetophenone was filtered off with suction, washed with water, dried and recrystallized from ethyl acetate, m.p. 179-180 °.

A suspension of 16.5 g of 4 * -amino-3,5,5-dimethyl-2- (methylsulfonyl) acetophenone and 10.6 g of sodium hydride in 500 ml of alcohol was stirred for 20 hours at room temperature to give a solution. 500 ml of water were added and the alcohol was evaporated in vacuo, then extracted with 2x1 liter of ethyl acetate. The ethyl acetate phases were washed with 2 x 500 ml of water, dried over magnesium sulphate and evaporated to dryness in vacuo. By crystallizing the residue from ether to east, 4-amino-3,5-dimethyl-α - [(methylsulfonyl) methyl] benzyl alcohol, m.p. 146-148 °.

To a solution of 14t6 g of 4-amino-3,5-dimethyl-α - [(methylsulfonyl) methyl] -benzyl alcohol in 50 ml of abs. DMSO, 1.17 g of sodium amide were added, the solution was stirred for 2 hours at room temperature, diluted with 500 ml of water and extracted with 2 x 500 ml of ethyl acetate. The vinegar ester phases were washed with 2 x 200 ml of water and evaporated to dryness in vacuo. Recrystallization of the residue from cyclohexane gave 4-amino-3,5-dimethylbenzaldehyde, m.p. 75-76 °.

To a mixture of 1.38 g of sodium methylate and 3.8 g of 4-amino-3,5-dimethylbenzaldehyde in 30 ml of abs. DMSOs, a solution of 3.72 g of β-anilinopropionitrile in 30 ml of abs was added over 10 minutes under a nitrogen atmosphere at 55 °. DMSO, and the mixture was stirred for one hour at 70 °. The solution was poured into 1 liter of water, and the resulting emulsion was extracted with 2 x 500 ml of ethyl acetate. The ethyl acetate phases were washed with 2 x 300 ml of water, dried over magnesium sulphate and evaporated in vacuo. The residue was recrystallized from ethyl acetate to give 4-amino-α- (anilinomethylene) -3,5-dimethylhydrocinnamic acid nitrile, m.p. 165-167 °.

Example 20

To a solution of 0.69 g of sodium in 100 ml of abs. alcohol, 5.4 g of guanidine carbonate and 3 g of α- (anilinomethylene) -4- (dimethylamino) -3,5-cyanomethylhydrocinnamic acid nitrile were added, and the mixture was refluxed for 20 hours. 200 ml of water were added and the alcohol was evaporated in vacuo. The crystalline 2,4-diamino-5- [4- (dimethylamino) -3,5-dimethylbenzyl] pyrimidine was filtered off with suction, washed with water and recrystallized from alcohol, m.p. 162 - I630.

Preparation of starting material:

To a suspension of 18 g of 4-amino-3,5-dimethylbenzoic acid methyl ester and 69 g of potassium carbonate in 1 liter of abs. tetrahydrofuran, 50.4 g (0.4 mol) of dimethyl sulfate were added dropwise over 20 minutes at room temperature. The reaction mixture was stirred and refluxed for 1 hour, filtered and the filtrate evaporated to dryness in vacuo. To the residue was added 500 ml of water, and then 2 x 300 ml of ethyl acetate were extracted. The ethyl acetate phases were washed with 2 x 150 ml of water, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was chromatographed on methylene chloride on 500 g of silica gel (Merck) to give 4- (dimethylamino) -3,5 ′ dimethylbenzoic acid methyl ester as a colorless oil.

To a suspension of 24.5 g of dimethyl sulfone and 9.1 g of sodium hydride (50 .mu.m dispersion in oil) in 50 ml of abs. DMSOs, stirred for 3 hours under a nitrogen atmosphere at 50 ° and preventing moisture from entering, then 16 g of 4- (dimethylamino) -3,5-dimethylbenzoic acid methyl ester were added to the mixture. The reaction mixture was stirred for 45 minutes at 80 °, cooled to 28,58638 and dissolved in 300% water. The solution was adjusted to neutral with glacial acetic acid. The precipitated k '- (dimethylamino) ~ 3', 5'-dimethyl-2- (methylsulfonyl) -acetophenone was filtered off with suction, washed with water and recrystallized from alcohol, m.p. 132-133 °.

A suspension of 12 g of k '- (dimethylanino) -3', 5'-dimethyl-2- (methylsulfonyl) acetophenone and 6.6 g of sodium borohydride in 300 ml of alcohol was stirred for 20 hours at room temperature to give a solution. 300 ml of water were added and the alcohol was evaporated in vacuo. The crystalline separated N- (dimethylamino) -3,5-dimethyl-o - [(methylsulfonyl) methyl] 7-benzyl alcohol was filtered off with suction, washed with water and dried. Mp 133-13 ° ^ ·

A mixture of 1.3 g of sodium methylate, 3.5 g of / Vanilinopropionitrile and U, 8 g of 1- (dimethylamino) -3,5-dimethyl-O- (E-methylsulfonyl) methyl] benzyl alcohol in 30 ml abs. DMSO, stirred for 30 minutes at 50 °. The reaction solution was poured into 1 liter of water and extracted with 2 x 500 ml of ethyl acetate. The ethyl acetate phases were washed with 2 x 300 ml of water, dried over magnesium sulphate and evaporated to dryness in vacuo. Recrystallization of the residue from ethyl acetate gave et- (anilinomethylene) -U- (dimethylamino) -3,5-dimethylhydrocinnamic acid nitrile, m.p. 195-1960.

Example 21 Using 3.5 g of β- (anilinomethylene) -3,5'-diethoxy-H- (pyrrol-1-yl) -hydrocinnamic acid nitrile in analogy to the procedure described in Example 8, 2-diamino-5- [3,5] -diethoxy -U- (pyrrol-1-yl) benzyl-pyrimidine-view. Mp 173-175 °, crystallization: ethanol / water. Yield 78%.

Example 22 Using 3.3 g of N - (anilinomethylene) -3-ethoxy-5-methoxy-N- (pyrrol-1-yl) hydrocyanic acid nitrile in analogy to the procedure described in Example 8, 2, U-diamino-5- / 3 -ethoxy-5-methoxy - * - (pyrrol-1-yl) benzyl-7-pyrimidine. Mp 160-162 ° C, crystallization: methanol. Yield 72%.

Claims (1)

29 58638 Claim: Process for the preparation of antibacterial 2, U-diamino-5-benzylpyrimidines of the formula R1 v_z1- (\ -CH2- / \ -NH2 I y = J) = N R2 / H2N 1.2. . wherein R and R are independently C 1-4 alkyl or C 1-4 alkoxy; 1. h / ks k1 -3 k k 1 -3. . Z is amino, pyrrolo, -NHR, -N (R) 2 or -NR COOR; R is N-alkyl; and for the preparation of salts of these compounds, characterized in that a) of the formula R1 \ / - ^? N z1 - {/ \ -CH_ - CH At36 Ha \ / 2 IV— / CIH b2 / " - a compound according to the formula wherein R 1 is lower alkyl, or both R 1 groups 1 1, 2 together form a lower alkylene *, Y is a leaving group, and Z, R and R are as defined above, is reacted with guanidine or b) a compound of formula R1 NH2 z1-8-CH2- ^ y-NH2 IV yj y, wherein R1 is chlorine, bromine or hydroxy, and 12 1. and Z are as defined above, the substituent x 1 is removed by reduction or c) the group Z which can be converted into the amino group or the group i + 2 -NHR by reduction or hydrolysis with the formulas z2- ^ -ch2 -— NHi? Va H2 H2N z1- / \ - CH2-y- Z2 Vb,.) = 7 ,,> z 0H2_ <r - zo r2 / Z2 / 1 · 2, in which the formulas R and R have the same meaning as above 2. ... and the groups Z can be different from each other , converted to an amino group or a k group -NHR, or d) alkylating a group Z of formula R 1 Z 3 -N-CK 2 -N 2 -NH 2 Ia R 2 NH 2 3. h. 1 2. In the compound of formula U wherein Z is -NHCOOR, and R, R and R are as defined above, the compound of formula I thus obtained is, if desired, converted into a salt. 31 58638 For use in the preparation of antibacterial compounds 2, U-diamino-5-benzylpyrimidines with the formula R1 z1- ^ -CH2-- NHg I R2 H2N 1 2 color R and R are prepared from a variant C-alkyl or C. -alkoxy; 1 k, k U U Z 'star for amino, pyrrolo, -NHR, -N (R) 2 or -? IR COOR; R 1 is C 1-6 alkyl; (a) the guanidine content of the compounds of formula z2H2'f / ° R6 y or R1. \ 71 CN 71-ft \ - CH- - C ^ IIb Z V_ / 2 ^ CHY R2 color R1r is alkyl or bearer R1 but the same is alkylene; Y är o 112 ·. in which the group, and Z, R and R are somewhat defective, or b) a reductive source of the substituents X1 and a derivative of the formula R \ V —— v y N Z1— / —ch2- / -nh2 IV J X1 / R ^ X