DE3241134A1 - METHOD FOR PRODUCING 2,4-DIAMINO-5-BENZYLPYRIMIDINE AND NEW INTERMEDIATE PRODUCTS OF THE METHOD - Google Patents

Description

Attorney's file; 32 472

Be scription

The invention relates to a process for the preparation of a group of substituted 2 _/ 4-diamino-5-benzylpyrimidines.

German patent application 2,443,682 includes compounds of the general formula I

(I)

1 2 and their salts are known, in which R and R are the same or different and each is a C, ₃ -alkyl radical, C ₁ -.-. oxy, C ₂ _ ₃ alkenyl or C ₂ _ ₃ alkenyloxy and Z represents an amino group or an alkyl-substituted amino group. According to the description, these compounds have an antibacterial activity and the compound 2,4-diamino-5- (4-amino-3,5-dirnethoxy-benzyl) pyrimidine has a good diurecic activity as described below.

From the German patent application 2,634,358 are among others Compounds of the general formula II

324113

and their salts are known in which R represents a halogen atom and Z represents an amino group or an alkyl-substituted amino group. These compounds have according to the description an antibacterial effect.

A new synthesis of these compounds of formulas I and II has now been researched.

The invention provides a process for the preparation of 2,4-diamino-5-benzylpyrimidines of the general formula III

(III)

4 4a or their salts, in which R and R are identical or different and each represents a hydrogen atom or a C._ _A -alkyl-

5. ι «

represent radical, and R, represents a halogen atom a C ₁ _ ₄ -alkyl radical or a C,.-alkoxy radical, and R represents a halogen atom, a C,. alkyl group or a C.-alkoxy radical, wherein a compound of the general formula IV

, 5

- / If '

in which R, R and R have the meaning given at the beginning, with

(i) 2 _/ 4-diamino-5-hydroxymethylpyrimidine or a corresponding C._ ₄ ether is reacted,

(ii) formaldehyde and a secondary amine of the formula

7 8 R R NH to a compound of the general formula V

CH ₂ NR ⁷ R ⁸

(V)

is reacted, which then with a compound of the general formula VI

(VI)

to a compound of the general formula VII

(VII)

9 is implemented and then reductively the radical R, provided this is something other than a hydrogen atom

4 5 6 is split off, wherein R, R and R

7 8 have the meanings given above, R and R

7 8 each denote a C, «-alkyl radical or R R NH represents a morpholino or piperidino group

G
and R denotes a hydrogen atom, a hydroxyl group, a C., -alkylthio or -mercapto radical, or

(iii) 5-Dimethylaminomethyluraoil is reacted under if appropriate subsequent alkylation of the amino radical, halogenation and amination which takes place of the uracil derivative of the formula VIII obtained

(VIII)

and thereafter in any variant (i), (ii) or (iii) optionally a connection of the all- '

4a common formula III, in which R is a hydrogen atom means is alkylated, and so a compound of

4 a general formula III, in which R is a C 1, 4 -alkyl radical means is produced.

This process is particularly suitable for the preparation of those compounds in which R is a hydrogen atom. Preferred are compounds in which R and R are identical and are each a methoxy group, a chlorine atom or a Cj_ mean ₄ alkyl radical.

Variant (i) of the process is expediently carried out in a solvent which can dissolve the two reactants. Polar, non-phenolic solvents are particularly suitable. The reaction temperature should not be too high and should be between 25 ^° C. and 175 ^° C., preferably between 50 ^° C. and 150 ^° C., for example. The reaction is preferably carried out in the presence of an acid, for example in the presence of hydrochloric acid, acetic acid, methanesulfonic acid or p-toluenesulfonic acid. A preferred solvent is acetic acid.

The preparation of the compound according to formula V according to variant (ii) of the process is carried out under the conditions which have been described for the preparation of Mannich bases by Miocque and Vierfond (Bull. Soc. Chem. France 1970, 1896). The reaction is conveniently carried out in the presence of 0.5 mole of an acid, such as acetic acid, to 1 mole of each of the other additives. The compound of the formula VI is then reacted with a slight excess of a compound of the formula V in the presence of an acid such as, for example, p-toluenesulfonic acid. The reaction is normally at elevated temperature, suitably between 100 and 200 ⁰ C, in a solvent having a suitably high boiling point, for example, in a glycol such as ethylene glycol, performed. The dethiation is expediently carried out by hydrogenolysis in the presence of a transition metal catalyst. Raney nickel is particularly suitable for this process. This reaction is usually carried out in a polar solvent, for example in a C «alkanol, such as methanol or ethanol.

In variant (iii) the reaction of a compound of Formula IV with 5-dimethylaminomethyluracil normally in

an inert high-boiling polar solvent, for example in a high-boiling C ₂ _ _ß- alkanol, such as ethylene glycol, at temperatures between 100 and 200 ⁰ C, for example between 130 and 160 ⁰ C, carried out. The reaction is normally carried out under acidic conditions, for example in the presence of hydrochloric acid. The halogenation of the compound of the formula VIII and the subsequent amination can conveniently be carried out by the methods known to the person skilled in the art, for example using the reaction conditions described in GB-PS 875 562 or GB-PS 1 132 082 or DE-OS 22 58 238 have been described.

The alkylation of the amino group in variant (iii) of the process is carried out under conditions known to those skilled in the art performed that do not affect the uracil part of the molecule, such as, for example, by reacting the amine with formic acid and the corresponding aldehyde. Preferably the reaction is a methylation, the aldehyde in this case being formaldehyde. The free

Asked alkylation of the amino group NR H is under conditions carried out, which does not affect the amino group on the pyrimidine ring. Here, too, the suitable conditions are known to the person skilled in the art, such as, for example the reaction with formic acid and the corresponding aldehyde.

The compounds of the formulas VII and VIII are new intermediate compounds and as such form an essential part of the invention. The compound of the general formula IX

. 3 2.4 U 34

Cl

(IX)

4 5 6
in which R, R and R have the meaning given at the beginning is also a new intermediate compound and forms an essential part of the invention.

Example 1_ Preparation of _{2/6-diisopropyl-4-piperidinomethylanilin}

According to the conditions described by Miocque and Vierfond (Bull. Soc. Chim. France 1970, 1896), 17.73 g (0.10 mol) of 2,6-diisopropylaniline, 8.1 ml (0.10 mol) of a 37% -igen aqueous formaldehyde solution, 8.52 g (0.10 mol) of piperidine, 3.00 g (0.05 mol) of acetic acid and 25 ml of ethanol were heated together to the boil until the temperature of the solution reached 92 ^° C. The solution was then refluxed for 24 hours. The product was distilled under reduced pressure (122 to 140 ^° C. at 0.7 to 0.8 mm) and gave 17.57 g (64%) of the title compound.

H NMR (CDCl ₃ ):

cfi, 25 (d, 12, CH ₃ ), 1.50 (m, 6, ₂₃

2.35 (m, 4, N (CH ₂ ) ₂ ), 2.95 (m, 2, CH), 3.35 (s, 2, Ar-CH ₂ ), 3.70 (broad s, x 2 , NH ₀ ), 7.0 (s, 2, Ar-H)

Example 2 Preparation of 2, G-diethyl ^ -plperidinomethylaniline

A solution of 29.85 g (0.20 mol) of 2,6-diethylaniline, 16.2 ml

BATH ORIGINAL

(0.20 mol) of a 37% aqueous formaldehyde solution, 17.03 g (0.20 mol) of piperidine, 6.00 g (0.10 mol) of acetic acid and 25 ml of ethanol were under similar conditions, as indicated in Example 1, implemented.

28.49 g (57.8%) of the title compound were obtained by distillation under reduced pressure (115 to 125 ° C at 0.05 mm) isolated.

¹ HNMR (CDCl ₃ ): # 1.25 (t, 6, CH ₃ ), 1.50 (m, 6, (CH ₂ J ₃ ),

2.35 (m, 4, N (CH ₂ ) ₂ ), 2.55 (q, 4, CH ₃ Me),

3.45 (s, 2, ArCH ₂ ), 3.55 (broad S, 2, NH ₂ )

6.90 (s, 2, ArH).

Example 3

Production of 2,6-diisopropyl-4- (Ν, Ν-dimethylaminomethyl) aniline

A solution of 35.45 g (0.20 mol) of 2,6-diisopropylaniline, 16.2 ml (0.20 mol) of a 37% strength aqueous formaldehyde solution, .9.02 g (0.20 mol) Ν, Ν-dimethylamine, 6.00 g (0.10 mol) Acetic acid and 25 ml of ethanol were reacted under conditions similar to those of Example 1.

12.05 g (26%) of the title compound were ^{isolated by distillation under reduced pressure (112 to 120 °} C., 0.2 mm),

¹ HNMR (CDCl ₃ ): <fi, 25 (d, 12, CH ₃ ), 2.20 (s, 6, NMe ₃ ),

2.95 (m, 2, CH), 3.35 (s, 2, ArCH ₂ ), 3.70 (broad s, 2, NH ₂ ), 7.0 (s, 2, ArH).

. 3 2Λ U 3

Example 4

j Preparation of _{2/6-diisopropyl-4-morpholinomethylanilin}

A solution of 35.45 g (0.20 mol) of 2, 6-Diisopropy aniline, j 16.2 ml (0.20 mol) of a 37% aqueous formaldehyde!

solution, 17.42 g (0.20 mol) of morpholine, 6.00 g (0.10 mol) of acetic acid and 25 ml of ethanol were made under similar conditions implemented as in Example 1. After concentration in a rotary evaporator, the residue obtained was dissolved in diethyl ether dissolved and washed with aqueous sodium bicarbonate and water. After drying the ethereal solution was a solution of 0.20 moles of hydrochloric acid in ethanol added. Filtration and drying gave 47.58 g (76%) of the hydrochloride salt of the title compound. 20.0 g (0.6 mol) of the salt was dissolved in acetone and treated with solid potassium bicarbonate. After filtering off and evaporation of the solvent gave 16.27 g (92.2%) of the title compound.

analysis for ^C 17 ^H 2i 3 ^N 2 ° ': H 1 0 N 3 C. , 21 1 0 /1 7th ber .: 73 / 87 1 0 , 31 /1 found : 74 , 04 1 0

Example 5

Preparation of 2,4-diamino-5- (4-amino-3 _/ 5-diisopropylbenzyl) -6-methylthiopyrimidine

1.56 g (10.0 mmol) of 2,4-diamino-6-methylthiopyrimidine in 50 ml of ethylene glycol were treated at 114 ° C. with a solution of 3.32 g (12.0 mmol) of a compound of the formula V (R ₄ = H, R ₅ = R ₆ = CHMe ₂ , NR ₇ R ₈ = morpholino) in 25 ml of ethylene glycol

- 10 -

and 0.19 g (1.0 µmol) of p-toluenesulfonic acid monohydrate were added. The temperature was maintained for 3 1/4 hours between 125 ° C and 140 ⁰ C. The solvent was distilled off under reduced pressure, and 20 ml of 3N hydrochloric acid was added to the residue. 3.44 g (90%) of the crude hydrochloride salt of the title compound were dissolved in methanol, treated with activated charcoal, filtered off and evaporated until crystallization began. The slurry was diluted with isopropanol, filtered and dried to give 2.58 g (68%) of the purified hydrochloride salt of the title compound.

The title compound was obtained by adding 6 ml of concentrated ammonium hydroxide to an aqueous solution of 1.67 g (4.37 mmol) of the hydrochloride salt were obtained. Filtration and drying gave 1.38 g (91.4%) of the title compound obtain.

¹ H NMR (CDCl ₃ ): <$ 1.30 (d, 12, CH ₃ ), 2.60 (s, 3 SCH ₃ ),

3.0 (m, 2, CH), 3.6 (broad s, 2, ArNH ₃ ), 3.35 (s, 2, ArCH ₀ ), 4.7 (broad s, 4, NH ₉ ), 7 , 0 (s, 2, ArH)

In a similar way, a compound of the formula VI (Rq = SCH ₃ , 1.56 g, 10.0 mmol) was combined with a compound of the formula V (R ₄ = H, R ₅ = R ₆ = CHMe ₃ , NR ₇ R ₈ = Piperidino, 3.29 g, 12.0 mmol) and 1.41 g (41%) of the title compound were obtained.

Under similar conditions, a compound of the formula VI (R _g = SCH ₃ , 1.56 g, 10.0 mmol) with a compound of the formula V (R ₄ = H, R ₅ = R ₅ = CHMe ₃ , R ₇ = R _Q = CH ₃ , 2.81 g, 12.0 mmol) reacted to give 0.97 g (28.4%) of the title compound.

- 11 -

BATH ORIGINAL

-tz-

example

Preparation of 2,4-DIaInJnO-S- (4-amino-3, 5-diisopropylbenzyl) pyrimidine

A solution of a compound of the formula VII (R. = H, R ₅ = R ₆ = CHMe ₂ , R ₉ = SCH ₃ , 0.50 g, 1.45 mmol) in 10 ml of methylcellusolve and 0.5 ml of water was 6 Hours of reflux with 3 g of T-1 Raney nickel. The solution was filtered and evaporated. The residue was triturated with hot hexane and gave 0.36 g (84%) of the title compound with a melting point of 177 to 180 ^° C.

example

Preparation of 2,4-diamino-5- (4-amino-3,5-diisopropyl- . Benzyl) -6-hydroxypyrimidine

A solution of a compound of the formula VI ¹ H ₃ O (R_ = OH, 1.44 g, 10.0 mmol) a compound of the formula V (R ₄ = H, R ₅ = R ₆ = CHMe ₂ , NR ₇ R ₈ = Morpholine, 3.32 g, 12.0 mmol) and p-toluenesulfonic acid monohydrate (0.1.9 g, 1.0 mmol) in 75 ml of ethylene glycol was heated to 133 to 138 ° C. for 4 1/2 hours . The solvent was distilled off under reduced pressure, and 20 ml of hydrochloric acid was added to the residue. The hydrochloride salt obtained was isolated, dissolved in water and neutralized by adding concentrated ammonium hydroxide. 2.36 g (74.9%) of the title compound were obtained. The title compound was purified by recrystallization from ethanol (1.44 g, 45.7%).

¹ HNMR (DMSO-d ₆ ): <f1.05 (d, 6, CH ₃ ), 2.90 (m, 2, CH),

3.30 (s, 2 ArCH ₂ ), 4.15 (broad s, 2, ArNH ₂ ), 5.45 (broad s, 2, NH ₃ ), 4.15 (broad s, 2 NH ₃ ), 6 .80 (s, 2, ArH), 9.90 (s, 1, OH).

- 12 -

. . , J-I 34

The title compound can be converted into a compound of the formula VII (Rn = H) by successive reaction with methanesulfonyl chloride to give a compound of the formula VII (R _g = OSO ₂ Me) and subsequent catalytic hydrogenation with palladium to give a compound of the formula VII (R _Q = H), as for example in GB-PS 1 542 804.

Example 8

Preparation of 2,4-diamino-5- (4-amino-3,5-diisopropylbenzyl) pyrimidine

A solution of a compound of the formula VI (R_ = H, 1.10 g, 10.0 mmol), a compound of the formula V (R = H, R ₅ = R, = CHMe ₂ , NR ₇ Rg = morpholino, 3 , 32 g, 12.0 mmol) and p-toluenesulfonic acid monohydrate (0.19 g, 1.0 mmol) in 50 ml Äthyleriglykol was heated for 5 1/2 hours at 150 to 160 ⁰ C. The solvent was evaporated off under reduced pressure and the residue obtained was added with 20 ml of 3N hydrochloric acid. The resulting solution was washed with methylene chloride and evaporated to an oil which crystallized on standing. The crystals were triturated with isopropanol, filtered and dried. 1.51 g (45%) of the hydrochloride salt of the title compound were obtained, which was recrystallized from ethanol (1.04 g, 68.9%).

By adding 3N sodium hydroxide to an aqueous solution of the hydrochloride salt (0.74 g, 2.20 mmol), 0.50 g (76%) of the title compound was obtained.

¹ H NMR (DMSO-dg): 6 1.15 (d, 12, CH ₃ ), 2.95 (m, 2, CH),

3.50 (s, 2, ArCH ₂ ), 4.50 (broad s, 2, ArNH ₂ ), 6.15 (broad s, 2, NH ₃ ),

- 13 -

6.55 (broad s, 2, NH ₂ ), 6.80 (s, 2, ArH), 7.40 (s, 1, pyrimidine 5-H). Melting point 179 to 182 ⁰ C.

example Production of 5-dimethylaminomethylura'cil hydrochloride

56.05 g (0.50 mol) of uracil were mixed with 81.55 g (1.0 mol) of dimethylamine hydrochloride and 61 ml (1.0 mol) of a 37% aqueous formaldehyde solution in 100 ml of water for two days Heated to reflux. The solvent was evaporated and the product triturated with methanol. After filtering and drying, 80.6 g (78.3%) of the title compound were isolated.

¹ H NMR (DMSO-dg + D ₃ O): d 2.90 (s, 6, NMe ₃ ), 4.10 (s, 2,

NCH-), 7.95 (s, 1, uracil 6-H).

Example 10 Preparation of 5- (4-amino-3,5-diisopropylbenzyl) uracil

A mixture of 10.28 g (50.0 mmol) of 5-Dimethylaminomethyluracil hydrochloride and 10.64 g (60.0 mmol) of 2,6-diisopropylaniline in 75 ml ethylene glycol was 4 1/2 hours at 134 to 137 ⁰ C. heated. After cooling, the title compound was filtered off, washed with ethanol and dried (5.55 g, 37%). A second crop was obtained from the mother liquor after standing (3.24 g, 21.5%). The two crops were combined and recrystallized from methanol. 5.84 g (38.8%) of the purified title compound were obtained.

- 14 -

- 3-2-4 11 3A

analysis for ^C 17 ^H 2: Y ^N 3 ° 2 ^: 1 3 N C. H 1 3 , 94 ber .: 67 , 75 7th , 69 , 88 found : 67 , 59 7th , 75

The title compound can be converted into a compound of the formula VII (R ₄ = H, R ₅ = R ₅ = CHMe ₂ , R ₉ = H) via successive halogenation and amination, as described, for example, in GB-PS 875 562, of GB-PS 1 132 and DE-OS 22 58 238 is described.

Example 11

Preparation of 2,4-diamino-5- (4-amino-3,5-dimethoxybenzyl) pyrimidine

A mixture of 4.30 g (30.0 mmol) of 2,4-diamino-5-hydroxymethylpyrimidine, which had been prepared from 2,4-diamino-5-cyanopyrimidine according to GB-PS 1,413,472, 5.05 g (33.0 mmol) 2,6-dimethoxyaniline, 60 ml acetic acid and 4.2 ml concentrated hydrochloric acid were refluxed for 4 1/2 hours heated, cooled and filtered. 7.13 g (76.2%) dos Hydrochlori tlsalzos the T Hol verb received in du ng. That Salt was dissolved in water and the solution was made basic with concentrated ammonium hydroxide. The accruing Precipitate was filtered, washed with water and dried. 5.18 g (62.7%) of the title compound were obtained obtain.

analysis for ^C 13 ^H r 7 ^N 5 ° 2 ^: 25th N C. H 25th , 44 ber .: 56 ; 72 6th , 22 , 39 found: 56 , 63 6th , 29

- 15 -

• 16

Other compounds of formula III according to the variant (i) of the process are given in Table I as examples.

^R 5 ^R 6 yield
% TABEL I. C. 8th H 23 N ' found C. 8th H 23 N CHMe ₂ CHMe ₂ 55.1 68.19 7th , 42 25th , 39 68.08 8th , 49 25th , 17th ^R 4 Et Et 61.4 66.39 7th , 80 28 , 81 66.14 6th , 03 28 , 71 H Me Me 70.7 calculated 64.17 7th , 05 27 , 78 63.94 7th ', 97 27 , 79 H Me Et 63.3 65.34 7th , 44 25th , 21 65.03 7th , 49 25th , 11 H Me CHMe ₂ 54.5 66.39 8th , 80 23 , 81 66.07 8th , 77 23 , 57 H Et CHMeEt 66.2 68.20 8th , 42 23 , 39 68.11 8th , 54 23 , 37 H Me CMe 43.0 65.67 3 , 27 24 , 64 65.72 3 , 34 24 , 60 ' H Cl Cl 28.6 46.50 3 , 90 18th , 65 46.15 3 , 99 18th , 31 H Br Br 39.4 34.42 5 , 20 26th , 24 34.15 5 , 27 26th , 12 * H Cl Me 60.1 54.65 7th , 35 25th , 55 54.45 7th , 32 25th , 33 H Me Me 42.9 66.39 , 80 , 81 66.15 , 86 , 72 H Et

calculated for C H _O _N _1C · 0.25 H ₀ OO 20 MeOH. The NMR spectrum confirms the presence and the amount of MeOH. Analysis according to Karl Fischer: 1.49% HO

Calculated for C..H Br, N. 0., 6 ^H 9 ^ * Analysis according to Karl Fischer: 2.9% H ₀ O.

- 16 -

5- (4-Amino-3,5-dimethoxybenzyl) -2,4- (1H, 3H) -pyrimidinedione

A mixture of 10.04 g (49 mmol) of 5 - / "(dimethylamino) methyl./-uracil hydrochloride (B. Roth, JZ Strelitz and BS Hauckman, J. Med. Chem. Z3, 379 (1980)) and 7.48 g (49 mmol) of 2,6-dimethoxyaniline (melting point 73 to 74.5 ° C., prepared from 2,6-dimethoxybenzoic acid by the method according to the procedure from Org. Reactions 3_, 330 (1946) in 50 ml of ethylene glycol was heated for 5 hours at 145 ° C. "the mixture was cooled and the precipitated solid was collected, suspended in 300 ml of boiling ethanol and collected. It was 3.91 g (29%) of the title compound having a melting point of 243-245 ⁰ C. (Decomposition) obtained.

analysis for ^C 13 ^H 1i 5 ^N 3 ° 4 ■ 1/4 H ₂ O : N C. H , 91 ber .: 55 , 41 5 , 54 1 4th , 94 found : 55 , 46 5 , 54 1 4th

A second crop of 2.0 g (15%) was obtained by concentration obtained from the ethanol extract.

5- (3,5-Dimethoxy-4-dimethylaminobenzyl) -2,4- (1H, 3H) -pyrimidinedione

A solution of 5- (4-amino-3,5-dimethoxybenzyl) -2,4- (1H, 3H) -pyrimidinedione (5.4 g, 19.5 mmol) in 70 ml of 88% formic acid was treated with 1 , 75 g of a 37% formaldehyde solution are added. The solution was refluxed for 18 hours, the reaction mixture was then cooled and 2 ml of concentrated hydrochloric acid were added. The solution was evaporated and the residue was dissolved in 200 ml of water. The neutralization of this solution with 5N sodium hydroxide gave 5.25 g (89%) of the title compound with a melting point of 228 to 230 ⁰ C (decomposition).

- 17 -

analysis for ^C. 15 ^H. 19th N 3 ° 4th • 0 / 1 I. 1 ^l: N C. H 1 , 68 ber .: 58 / 66 6th I. 30th 3 / 69 found: 58 55 6th I. 30th 3

2,4-dichloro-5- (3,5-dlittethoxy-4-dimethylaminobenzyl) pyrimidine

A mixture of 5.02 g (16.4 mmol) of 5- (3,5-dimethoxy-4-dimethylaminobenzyl) -2,4- (1H, 3H) -pyrimidinedione in 100 ml of phosphoryl chloride was heated under reflux for 90 minutes. The excess POC1-. was removed under reduced pressure and the residue was dissolved in dichloromethane and then with aqueous sodium bicarbonate solution up to Washed neutrality and then washed with water. The solution was over MgSO. dried and then through a silica gel column with the eluent dichloromethane : Methanol / 19: 1 sent. The fractions containing the product were combined and given an oil in one Amount of 3.75 g (67%) concentrated. The structure was confirmed by NMR spectroscopy.

2,4-diamino-5- (3,5-dimethoxy-4-dimethylaminobenzyl) pyrimidine

A solution of 3.47 g (10.1 mmol) of 2,4-dichloro-5- (3,5-dimethoxy-4-dimethylaminobenzyl) pyrimidine in 200 ml of ethanol saturated with ammonia was heated to 150 ^° C. in an autoclave for 8 hours heated. The solvent was removed under reduced pressure and the remaining residue was triturated with water and collected. The residue was then dissolved in dichloromethane: methanol / 4: 1, absorbed onto silica gel and placed on top of a silica gel column. Elution with the same solvent gave 2.27 g (74%) of the title compound. A part was recrystallized from 95% ethanol with concentrated hydrochloric acid in the

Dihydrochloride with a melting point of 228 to 230 ⁰ C (decomposition) transferred.

Analysis for ^C ₁₅ ^H 21 ^N 5 ° 2 * ^{2 HC1-H} ₂ ^0:

C H N Cl

calc .: 45.69 6.39 17.76 17.98

• found: 45.70 6.40 17.77 17.86

Claims (1)

BERG · STARF -.-. "SCHWABE · SAN-LJ'MAIR" '~ MAUERKIRCHEBSTRASSE 45 8000 MUNICH 80 Lawyer files: 32 4 72 November 8, 1982 THE WELLCOME FOUNDATION LIMITED London NW1 2BP / England Process for the preparation of 2,4-diamino-5-benzylpyrimidines and new intermediates in the process Claims M ·) Process for the preparation of 2 ^ -Diamino-S-benzylpyrimidines of the general formula III R ⁴ R ^4a N (III) ί (089) 98 82 72-74 Telex: 05 24 560 BERG.d ΤηΙοΙη ^, ο, ο, - flΓιΒΟ \ QR ΊΠ ΛΟ . .Bank accounts: Bayer. Vereinsbank Munich 453100 (BLZ 700202 70) Uunn-Donl M.rr ^ hon Λ Λ 1Π 10O imn / Rl 7 7ηΠ9ηηΐ1 * Swlfl Γπίΐρ- MVPO DF MM 4 4a
in which R and R are identical or different and are each a hydrogen atom or a C _1. -alkyl radical 5 6 ~ and R and R each represent a halogen atom, a C._ ₄ -alkyl radical or a C, .- alkoxy radical, characterized / that a compound of the general formula IV , 5 R ⁴ HN (IV) 4 5 6
in which R, R and R have the meaning given at the beginning, with a) a 2,4-diamino-5-hydroxymethylpyrimidine or a corresponding C ₁ .ether is reacted or b) formaldehyde and a secondary amine of the formula 7 ft 7 r RR NH, in which R and R are each a C ₁ , -alkyl radical 7 8 ~ " or R R NH is a morpholino or piperidino group represents, to a compound of the general formula V CH ₂ NR ⁷ R ⁸ (V) is implemented, which is then connected to a connection the general formula. VI (VI) in which R is a hydrogen atom, a hydroxyl group, a C ^ alkylthio or mercapto radical, is converted to a compound of the general formula VII (VII) and then the radical R reductively, provided this is something represents other than a hydrogen atom, is split off, or c) 5-Dimethylaminomethyluracil is reacted under, if appropriate subsequent alkylation of the amino radical and halogenation and amination taking place the connection obtained. 2. The method according to claim 1 for the preparation of a compound of the general formula III BATH ORIGINAL marked that through this 4th
R is a hydrogen atom or a C ₁ ,, - alkyl radical 5 6 ~~ and R and R each represent a halogen atom / a C, ₄ -alkyl radical or a C. ^ - alkoxy radical, where a compound of the general formula IV (VI) reacted with 2, -l-diamino-S-hydroxymethylpyrimidine will. 3. The method of claim 1 for producing a compound of the general formula III characterized in that R is hydrogen or an atom means a C ... alkyl group, and R and R represents a halogen atom, a C.. Alkyl group or a C representing ₄ alkoxy, wherein a compound of the general formula IV (IV) 7 8 with formaldehyde and a secondary amine R R NH 7 8
is set, wherein R and R are each a C _{1 4} alkyl 7 8 ~ radical or R R NH mean a morpholino or piperidino group, whereby a compound of the general Formula V CH ₂ NR ⁷ R ⁸ R ⁴ IIN (V) is formed, which then with a compound of the general formula VI (VI) is reacted, in which R is a hydrogen atom, a hydroxyl group, a C, - alkylthio or mercapto radical means, whereby a compound of the general formula VII r, 5 (VII) is formed and then the group R, provided 9
R means something different from a hydrogen atom, which is split off by reduction. 4. The method of claim 1 for producing a compound of the general formula III, 5 R ^-1 HN ( () V-CH _O - (( )> --NH ₀ (III) characterized in that 4th
R is a hydrogen atom or a C ₁ _ ₄ alkyl loading and R and R each represent a halogen atom, a C, ₄ -alkyl radical or a C -.- alkoxy radical, where a compound of the general formula IV (IV) is reacted with 5-dimethylaminomethyluracil and the compound obtained is subsequently halogenated and is aminated. 5. The method according to claim 2, characterized in that the reaction is in the presence an acid. 6. The method according to claim 5, characterized that the acid from the group of hydrochloric acid, acetic acid, methanesulfonic acid and p-toluenesulfonic acid is selected. 7. The method according to claim 5, characterized in that the acid is hydrochloric acid. Process according to Claim 5, characterized in that the acid is methanesulphonic acid or p-toluenesulfonic acid. Process according to claim 1 for the preparation of a compound according to general formula III marked that through this R is a hydrogen atom or a C _1. -Alkyl radical beer fi ι "~ τ> and R and R each represent a halogen atom, a C., -alkyl radical or a C ₁ , -alkoxy radical, where a compound of the general formula IV (IV) 7 8 reacted with formaldehyde and a secondary amine R R NH 7 8
is set, in which R and R each have a C ₁ - alkyl 7 8 "~ radical or R R NH is a morpholino or piperadino group, whereby a compound of the general Formula V CH ₂ NR ⁷ R ⁸ (V) is obtained, which is then obtained with a compound of the general formula VI NH (VI) N ^X R ' is implemented, in which R is a hydrogen atom,
represents a hydroxyl group or a C1-alkylthio radical, whereby a compound of the general formula VII (VII) 9 9 is formed, and then the group R, provided that R represents something other than a hydrogen atom, is split off reductively. 10. Compound of the general formula VII characterized in that R
denotes a hydrogen atom or a C ₁ , -alkyl radical, C fr I - ^ R and R each represent a halogen atom, a C ₁ , -alkyl radical 9 or a C, ₄ ~ alkoxy radical and R a Hydroxyl group, a C,. -Alkylthio or a -Mercaptorest represents, and their acid addition salts, 11. Compound of the general formula VIII (VIII) characterized in that 4th
R is a hydrogen atom or a C, -alkyl radical 5 6
and R and R each represent a halogen atom, a C 1 -C alkyl radical or a C -C alkoxy radical, and their acid addition salts. 12. Compound of the general formula IX , 5 (IX) 4 characterized in that R represents a hydrogen atom or a C _1. Alkyl group, and R and R each represent a halogen atom, a C.-Alkyl radical or a C ₁ _-- alkoxy group, and their acid addition salts. 13. The method according to claim 3, characterized in that the implementation of a - 10 - bond of the general formula V with a compound of the general formula VI in the presence of an acid is carried out. 14. The method according to claim 13, characterized that the acid used is p-toluenesulfonic acid. 15. The method according to claim 4, characterized that the reaction is carried out in the presence of an acid. 16. The method according to claim 15, characterized that hydrochloric acid is used as the acid. 17. A method for preparing a compound of formula III as defined in claim 1, characterized in that a Compound of the general formula V is reacted with a compound of the general formula VI and the remainder R if it is something other than hydrogen represents, is split off reductively, where the formulas V and VI and the radical R are those in claim 1 have a defined meaning. 18. Process for the preparation of a compound according to formula III according to the definition in claim 1, characterized in that a Compound of formula - 11 - RR Ιί , 4 "4a , 6 _ "_. in which R "*, Κ * ^Λ , R ^D and R ^{b have} the meaning given in claim 1, is aminated.