DE2435934A1 - NEW BENZYL PYRIMIDINE - Google Patents

Description

Dr. Ing, A. τοπ <to W «i Dr. Franz Leder * 2 5 _t July 1974

FATENTANWÄktt

RAN 4440/131

F. Hoffmann-La Roche & Co. Aktiengesellschaft, Basel / Switzerland

New benzylpyrimidines

The present invention "relates to new benzylpyrimidines, namely 2,4-diamino-5-benzy! pyrimidines of the general formula

1 2
where R and R are alkyl or alkenyl ", Z is an oxygen atom bonded to one of the ring nitrogen atoms, η = 0 or 1 and A is trifluoromethyl or one of the groups

509807/1 UI

R ⁶

(a) or _ _c - _R 9

ι. ^(b)

R ¹⁰

represents

r rj

wherein R is oxo and R 'is hydrogen, alkyl, or alkoxy; or R hydroxyimino and R '

c 7 r

Alkyl; or R together with R nitrilo; Around

Q TO '

R ^ is hydrogen or alkyl and R is hydroxy, alkoxy, or -K (R ⁵ , R ⁴ ); or R ⁹ and R ^{10 are} alkoxy

Q in

or alkylthio; or R together with R alkylene

dioxy or alkylenedithio; and R ^ and R ^ hydrogen, Represent alkyl or alkanoyl; and acid addition salts of such compounds.

The term "alkyl" in the context of this description denotes straight-chain or branched saturated aliphatic ^ Hydrocarbon groups with a maximum of 4 carbon atoms, such as methyl, ethyl and propyl .. The term "alkenyl" relates refer to straight-chain or branched, olefinically unsaturated hydrocarbon radicals with up to 3 carbon atoms, such as Allyl.

The term "alkanoyl" refers to straight-chain or branched alkanecarboxylic acid radicals with up to 4 carbon atoms, such as formyl and acetyl.

The term "alkylenedioxy" or "alkylenedithio" refers to groups having 2 or 3 carbon atoms.

Group (a) includes in particular the radicals cyano, alkoxy carbonyl, ÜT-hydroxyiminoalkyl, pormyl and alkylcarbonyl.

609807/1141

Group (b) includes in particular the radicals alkyl-dialkoxymethyl, alkyl-alkylenedioxymethyl, alkyldialkylthiomethyl, alkyl-alkylenedithiomethyl, optionally C-mono- or -dialkylated hydroxymethyl _1, optionally C-mono- or -dialkylated alkoxymethyl, optionally C-mono- or dialkylated aminomethyl, optionally C mono- or dialkylated alkylaminomethyl, optionally C mono- or dialkylated dialkylaminomethyl.

One in particular within the scope of the present invention

preferred subgroup of compounds of formula I are

1 2

those in which R and R are alkyl, in particular methyl or ethyl. Such compounds are also preferred of the formula I in which A is C-mono- or di-alkylated hydroxymethyl or optionally C-mono- or -di-alkylated Alkoxymethyl; or is alkylcarbonyl.

The benzylpyrimidines of the formula I and their salts can be obtained according to the invention by

a) a combination of the formulas

Ha

509807/1 14 1

or

Man

in which formulas Ir alkyl; Y an outgoing group

gang group and A trifluoromethyl or a

r "

(c) represent nrter> q ^ 9 (ή ),

¹² |

U 12

wherein R 'is oxo and R is alkoxy; or R 'together

with R ¹² nitrilo; R ^{15 is} hydroxy, alkoxy or -N (R ³ , R ⁴ );

9

or R together with R alkylenedioxy or alkylenedithio

represent and R ¹ , R ² , R ⁵ , R ⁴ , R ⁸ and R ^{9 have} the above meaning, reacted with guanidine, or that one

b) a compound of the formula

III

1 in which R and R have the above meaning,

dehydrated to nitrile, or that one

509807/1

c) a compound of the formula

wherein X ^{1 is} chlorine, bromine, alkylthio or alkylsulfonyl and kr trifluoromethyl or one of the groups

(c) or

\ _R 12

C ff

(e)

11 represents 12 wherein R is oxo and R is alkoxy; or

11 12 14

R together with R nitrile, and R- alkoxy

or -N (R ⁵ , R ⁴ ); or R ⁹ together with R ^{14 represent} alkylenedioxy, and R, R, R, R,

8 9
R and R have the above meaning ",

with ammonia, or that one

d) the substituents X ¹ , ¹ in a compound of

formula

NH ₂

12 ¹ ^

where R, R and A have the above meanings, and X "represents chlorine, bromine or hydroxy,

509807/1141

replaced by a hydrogen atom, or that one

e) in a compound of the formula

VI

where A is the groups

p8

R p8

-GO-GH-SO ₉ CH ,, -CO-CH-

SO ₂ -

Is phenyl or -CO-CH-SO-CH-, and r \ R ²

8 ^

and R have the above meaning

the group A reductively cleaves to the acetophenone grouping, or that one

f) a compound of the formula I in which η = 0, subject to N-oxidation,

or that one

g) the amino protective groups in a compound of the formula

V = N '

NHX

VII

wherein X is H or an amino protecting group and at least one X is a protecting group, and R,

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2 1 R and A have the above meaning

split off hydrolytically or hydrogenolytically, or that one h) in a compound of the formula

HOOC

NH2

1 2

where Il, R, Z and η have the above meaning

to have,

the carboxyl group is esterified or reduced to the aldehyde group; or that one

i) in a compound of the formula I in which A is a

1 2

Represents alkylcarbonyl group and R, R, Z and η are those given Have meaning that the carbonyl group condenses with hydroxylamine to form the hydroximino group; "or reductively aminated; or reduced to alcohol; or ketalized or thioketalized; or with a Grignard compound to a homologous one Converts alcohol; or that one

j) in a compound of the formula I in which A is a

1 2

Represents alkoxycarbonyl group and R, R, Z and η are those given Have meaning, the alkoxycarbonyl group with

converting a Grignard compound to the ketone or to the secondary or tertiary alcohol; or reduced to alcohol; or that one

k) in a compound of the formula I an alcohol function contained in the substituent A is alkylated or to form a carbonyl group

509807/114 1

oxidized; or that one

1) in a compound of the formula I a nitrile group A reduced to the amino group or to the aldehyde group; or that he

m) in a compound of the formula I cleaves a ketal or thioketal group contained in the substituent A; or that one

n) in a compound of the formula I in which A represents a group ⁵ , the acyl radical is hydrolyzed,

and optionally converting a base obtained into an acid addition salt.

According to variant (a) of the process according to the invention becomes a compound of the formula Ha or Hb with guanidine condensed. In the compound of the formula Hb, the symbol Y represents a leaving group. Representative examples for such leaving groups are ether radicals, e.g. alkoxy groups such as methoxy, ethoxy, propoxy etc., thioether radicals such as alkylthio groups, or aliphatic, aromatic or heterocyclic amino groups such as alkylamino, benzylamino, Arylamino (e.g. optionally substituted anilino, or naph thylamino), dialkylamino, pyrrolidino, piperidino, piperazino, morpholine. Particularly preferred is anilino, its phenyl ring may optionally be substituted one or more times by halogen, alkyl or alkoxy.

The reaction of the compound Ha or Hb with guanidine can be carried out according to methods known per se (see e.g. Belgian patent specifications No. 594 131 » 671 982 and 746 846), for example in a solvent such as a

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Alkanol, for example methanol, ethanol, or in dimethylformamide, dimethylsulfoxide, N-methylpyrazolone, at about 25 ° to 200 °, preferably 50 ° to 170 ⁰ C.

The compound of the formula Hb can be formed from the tautomeric compound under these reaction conditions

lic

12 2

where R, R, A and Y have the above meaning,

form in situ.

The compounds obtainable according to variant (a) can be represented by the formula

. NH2

12 2
where R, R and A have the above meaning,

be circumscribed.

The dehydration of an acid amide of the formula III (variant b) can be achieved by treatment with dehydrating agents such as POCl ,, SOCIp, P ₂ O ₁ - or polyphosphoric acid. Inert organic solvents, for example pyridine, can be used as solvents, but the dehydrating agent ch itself can serve as the solvent.

50980.7 / 1141

The variant (b) thus leads to compounds of the formula

According to process variant (c), a compound of the formula IV is reacted with ammonia, the substituent X ¹ in the pyrimidine radical of the molecule being replaced by an amino group. The reaction is expediently carried out in an alkaline, in particular methanolic solution, for example methanolic ammonia is used as the reactant. The reaction temperature conveniently lies between about 80 ° and 200 ⁰ C, in particular between about 100 ° and 150 ⁰ C. As these temperatures are above the boiling point of methanol, the reaction is then carried out in a closed system, for example in an autoclave.

So obtained compounds of the formula R ¹ Q

Id

wherein A, R and R have the above meaning.

The exchange of bromine or chlorine in the compound V 509807/1141

by a hydrogen atom (process variant (d)) can by treatment with reducing agents such as hydrogen iodide or catalytically excited hydrogen, e.g. Pd in alcohol; or with Zn / glacial acetic acid. If X "= hydroxyl, the reaction product is first reacted with BrCN in the presence of triethylamine and the reaction product is hydrogenated in the presence of Pd / C. This gives compounds of the above formula Id.

The cleavage of the sulfonyl or sulfoxide group in a compound of the formula VI can be achieved by treatment with Al amalgam in Tetrahydrofuran / water, optionally with heating or by means of Zinc / acetic acid can be achieved.

The variant (e) thus leads to compounds of the formula R ¹ Q

Ie CH ₃ CO.

The N-oxidation (variant f) can be carried out according to known methods Methods carried out using common N-oxidizing agents will. Perbenzoic acids are particularly preferred, and very specifically m-chloro-perbenzoic acid.

The N-oxidation can e.g. in inert solvents, such as chlorinated hydrocarbons, e.g. chloroform, methylene chloride, or in alcohols, such as methanol or ethanol, or in dimethylformamide, dimethyl sulfoxide, water or in Dioxane can be carried out.

The reaction temperature is expediently in a range between room temperature and the boiling point of the solvent, expediently between approximately 10 and approximately 60 ^° C. The range from approximately 10 to approximately is preferred

509807/1 141

The N-oxides obtained can be isolated from the reaction mixture in a customary manner. When using m-chloroperbenzoic acid or perbenzoic acid as N-oxidizing agent it has proven to be useful to wash the reaction solution with a weakly alkaline aqueous solution (e.g. shake out with aqueous sodium bicarbonate solution) and first to acidify the aqueous extract obtained in order to precipitate the excess acid and then filter it off the latter to make the filtrate neutral or weakly basic.

The N-oxidation usually leads to mixtures of EL and F ^ oxides of the formulas

respectively.

NH ₂

The separation and purification of these isomeric reaction products can be carried out by chromatography, e.g. column chromatography,

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and / or recrystallization, preferably from polar solution. agents, such as alcohols, water, etc., can be accomplished.

In the compound of the formula VII, which is used as starting material in variant (g) the symbol X represents an amino protecting group; those by hydrolysis or hydrogenolysis can be converted into a free amino group. Representative examples of the former category of Protective groups are acyl groups, for example alkanoyl groups such as formyl, acetyl, propionyl, etc., or aroyl groups such as Benzoyl, or tert. Butyloxycarbonyl. A group which can be converted into a free amino group by hydrogenolysis, is for example the carbobenzoxy group. The preferred amino protecting groups are acyl groups, especially the acetyl group.

The hydrogenolysis of an amino protective group X can for example catalytically, e.g. by means of palladium on carbon and in a solvent e.g. an alcohol such as methanol 10-50 ° are preferably carried out at room temperature.

The hydrolysis of a compound VII can be alkaline, for example with aqueous or aqueous alcoholic (methanolic) alkali; or acidic, e.g. with aqueous or aqueous alcoholic mineral acids (e.g. hydrochloric acid) '.

The esterification of the carboxyl group in a compound of the formula Ia can be carried out in a manner known per se by reaction a reactive acid derivative with an alkanol in the presence of a condensing agent such as an alkali alkoxide, or a strong acid, such as HcI. The reduction of the carboxyl group to the aldehyde group can e.g. complex metal hydride take place via the acid chloride (process variant h).

509807 / 1U1

The reduction of a carbonyl group according to variant i) can be carried out using complex metal hydrides, such as HaBH. in watery Alkanol. The reductive amination can be carried out with an amine and Raney nickel in an inert solvent, e.g. Ethanol.

The reduction of an alkoxycarbonyl group to the hydroxymethyl group according to variant j) can be carried out with diisobutylaluminum hydride in dioxane.

The oxidation of an alcohol group according to variant k) can take place, for example, with oxidizing agents such as CrO ₅ in pyridine. The reduction of a nitrile group according to variant 1) can be carried out using complex metal hydrides such as LiAlH. in ether (for the preparation of compounds of the formula I with A = -CH ^ M ^) or by means of diisobutylaluminum hydride in dioxane (for the preparation of compounds of the formula I with A = -CHO).

The (thio) etal cleavage according to variant m) can be carried out with aqueous Acids, if necessary with heating, accomplished

2+, the thioketal plating is preferably done by means of Hg executed.

The starting materials used in process variants a) to e) can, if they are not known or in the are described below, in analogy to the methods described in the examples or in accordance with the methods below specified methods.

For the hydrolysis according to variant n), preference is given to aqueous and aqueous-alcoholic mineral acids.

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Tabel

Starting material

Man

made of

CN

reaction

Alkanol and

Alfcali-

metal alkoxide

literature

Belgian patent specification No. 671 982

Ha

Hc

lib

.CHO

+ cprr alcohol addition

Eondensation.in
strongly alkaline
milieu

Belgian Patent Specification No. 594 131, 746 846

CO

cn co

CO

cn O co oo ο

—N
'J-HH ₂

^ COOR ⁵

Halogenation

Belgian patent specification
Uo. 565 002

1) condensation
with guanidine in
alkaline environment

DOS 2003578

2) Replacement of the HydroxyIs
against Br or Gl with
Phosphorus (oxyhalides

Pur the production of acid addition salts, in particular of salts "useful in pharmaceutical preparations" come the inorganic salts commonly used for this purpose Acids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc. or organic acids such as formic acid, acetic acid, Succinic acid, lactic acid, citric acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid eto. into consideration.

The compounds of the formula I and their salts have an antibacterial effect. They inhibit the bacterial dihydrofolate reductase and potentiate the antibacterial effect of sulfoiiamides, such as sulfisoxazole, sulfadimethoxin, sulfamethoxazole, 4-sulfanilamido-5,6-dimeth.oxy-pyrimidine, 2-sulfanilamido-4> 5-dimethyl-pyrimidine or sulfachinoxaline, sulfadiazine, sulfamonomethoxine, Isosulfisoxazole and other inhibitors for Enzymes involved in poly acid biosynthesis, such as pteridine derivatives.

Only such combinations of one or more of the inventive Compounds I with sulfonamides are used in human medicine for oral, rectal and parenteral administration in embossing. The ratio of compound I to sulfonamide can vary within a wide range; it is e.g. between 1:40 (weight parts) and 5: 1 (weight parts), preferred Ratios are 1: 1 to 1: 5.

For example, a tablet can contain 80 mg of a compound I according to the invention and 400 mg sulfamethoxazole, a children's tablet ' 20 mg of a compound I according to the invention and 100 mg sulfamethoxazole; Syrup (per 5 ml) 40 mg of compound I and 200 mg Contain sulfamethoxazole.

The following examples illustrate the invention. DMSO will

as an abbreviation for dimethyl sulfoxide; THP used for tetrahydrofuran .

509807 / 1U1

example 1

Stir in a 2 liter flask with a magnet and a reflux condenser 8 g of sodium metal in 200 ml. Abs. Dissolved methanol.

24.7 g of guanidine.HCl were added to this solution and the suspension was stirred at room temperature for 30 minutes. The sodium chloride was filtered off with suction and mixed with approx. 10 ml of cold abs. Methanol washed. The filtrate was washed with 46 g of 4- (3 ~ anilino-2-cyanoallyl) heated -2 6-dimethoxybenzoesäuremethylester and 1000 ml of isopropanol was added and the suspension under stirring, 50 hours at reflux. The reaction mixture was concentrated and cooled, and the precipitated crystals were suction filtered.

Make crystallization from approx. 4 l of methanol with the addition approx. 1 g of charcoal was converted into methyl a- (2,4-diamino-5-pyrimidinyl) -2,6-dimethoxy-p-toluate obtained from m.p. 250-251 °.

The starting material was produced as follows:

A mixture of 271 g of 2,6-dimethoxyterephthalic acid monomethyl ester, 1.2 1 abs. Benzene, 100 ml of thionyl chloride and 30 ml of dimethylformamide were removed with the exclusion of moisture Boiled under reflux for 2 hours. The solution was evaporated to dryness in vacuo and the residue in approx. 100 ml twice Section. Benzene dissolved and the solvent removed again in vacuo. After recrystallization from 7, the residue yielded hot n-heptane 260 g of acid chloride with a melting point of 100-101 ° C. After concentrating the mother liquors, a further 20 g of acid chloride were obtained (M.p. 90-95 °).

40 g of acid chloride were dissolved in 400 ml of xylene dried over sodium. 4 g

509807/1141

5% Pd / BaSO. and 0.4 ml of quinoline-sulfur regulator added, 4th

the suspension is blown out for a further 10 minutes with N "and then, was passed through with stirring at 110 ° hydrogen. The course of the reaction was through. Titrate the resulting HCl pursued. After about 2 hours ($ 90 of the theoretical Amount of HCl released) the reaction was terminated, the suspension was cooled under N "and the catalyst was suction filtered. The filtrate was concentrated to dryness in vacuo, the residue was taken up in -150 ml of benzene and 500 ml of approx. 37% Sodium bisulfite solution shaken for 2 hours. The benzene phase was separated off and the aqueous phase washed with 100 ml of benzene.

The remaining aqueous solution was cooled to 5 ° and then with approx. 20 $ NaOH solution to approx. pH 10 set. The precipitated aldehyde (and inorganic salts) was filtered off with suction. The solid material was in 400 ml Benzene and 700 ml of water were added, the benzene solution was separated off and the aqueous phase was added twice with 100 ml of benzene each time extracted. The combined benzene extracts were 2 × 50 ml Washed water, over MgSO. dried and evaporated to dryness in vacuo; 2,6-dimethoxy-4-formylbenzoic acid methyl ester, 113-114 °.

From a solution of 0.9 g of sodium metal in 15 ml of abs. MeOH, the solvent was evaporated off under N with exclusion of moisture. The remaining sodium methylate was in a solution of 25.2 g of ß-morpholinopropionitrile in 28 ml Suspended dimethyl sulfoxide dried over molecular sieve and heated to 70 °. At this temperature it became a solution of 30 g of 2,6-dimethoxy-4-formyl-benzoic acid methyl ester in 45 ml of anhydrous dimethyl sulfoxide were added dropwise over the course of 30 minutes and the mixture was then stirred for a further 30 minutes at 75 °. After this time, practically no more aldehyde could be detected. The solution was cooled to + 5 ° and drop-

509807/1 141

30-40 ml of water are added, inoculated and approx. Stirred for another 3 hours. The crystalline product was sucked off, washed with about 15 ml of methanol cooled to 0 ° and recrystallized from methanol.

The 4 ~ (2-cyano ~ 3-morpholinoallyl), 2,6-dimethoxybenzoic acid methyl ester has a m.p. of 137-138 °.

8.6 g of aniline were concentrated with 7.6 ml with cooling. HCl offset. Then 32 g of 4- (2-Gyano-3-morpholinoallyl) -2,6-dimethoxybenzoic acid methyl ester were added and 100 ml of isopropanol are added. The suspension was taking 30 minutes Stir heated to reflux. About 1/3 to half of the solvent was evaporated, 20 ml of water added, the crystalline product filtered off with suction, washed with a little cold methanol and dried. Recrystallization from methanol provided 4- (3-anilino-2-cyanoallyl) -2,6-dimethoxybenzoic acid methyl ester from m.p. 193-194 °.

Example 2

A solution of 30 mg of sodium metal in 3 ml of abs. Methanol 0.12 g of guanidine.HCl was added and the suspension was stirred for 15 minutes. Thereafter, 0.29 g of methyl 4- (3,3-dimethoxy-2-cyanopropyl) -2,6-dimethoxybenzoate was obtained added and the mixture heated to reflux for 18 hours. Then the methanol was evaporated in vacuo and the basic products dissolved in acetic acid. The solution was filtered, while cooling with conc. Ammonia made alkaline, the α- (2,4-diamino-5-pyrimidinyl) -2,6-dimethoxy-p-toluic acid ethyl ester suction filtered and recrystallized from methanol. M.p. 247-248 °.

The starting material was prepared as follows: To a solution, cooled to 5 °, of 3.45 g of sodium

509807/1 UI

Metal in 47 ml abs. Methanol was 11.2 g under nitrogen 2,6-Dimethoxy-4-formylbenzoic acid methyl ester was added. Under vigorous stirring then a solution of 6.6 ml of acrylonitrile (0.1 M) in 3 ml of metha ιοί was added dropwise (in about 20 minutes), so that the temperature did not rise above 20 °. The reaction mixture was stirred for 17 hours at room temperature and to dryness evaporated. The residue was dissolved in 200 ml of water and 200 ml Aether added. The water phase was extracted several times with ether. The ether extracts were dried and concentrated (10 g). Column chromatography (400 g of silica gel; eluent; ether) yielded ethyl 4- (3,3-dimethoxy-2-cyanopropyl) -2,6-dimethoxybenzoate. M.p. 90-92 ° (from methanol).

Example 3

To a solution of 0.7 g of sodium metal in 9 ml of abs. Methanol was added 5.4 g of guanidine carbonate under ITp. The suspension was stirred for 30 minutes at 80 ° and, after cooling to room temperature, a solution of 3.5 g of A- (2-cyano-3-morphqlinoallyl)-2,6-dimethoxybenzoic acid methyl ester in 12 ml of DMSO was added.

The mixture was stirred for 3 hours at 145 ° and 2 hours at 175 ° under N-. After this time, the mixture was cooled and poured onto a little ice, filtered (Na ₂ CO-) and the filtrate was evaporated to dryness in a high vacuum (temperature <6O ^{0 O).} The residue was suspended in ethanol with heating and suction filtered: a- (2,4-diamino-5-pyrimidinyl) -2,6-dimethoxy-p-toluic acid, sodium salt, mp> 300 ° '.

Example 4

A suspension of 12.7 g of ct- (2,4-diamino-5-pyrimidinyl) -2,6-dimethoxy-p-tolylbenzoic acid methyl ester in a solution of 1.7 g of NaOH in 80 ml of water and 20 ml of ethanol was under

B09807 / 1U1

Stirring at reflux for 16 hours. The resulting solution was filtered warm and adjusted to pH 6 with approx. 40 ml IN HCl. The suspension was diluted with 300 ml of water and filtered: α- (2,4 ~ diamino-5-pyrimidinyl) -2,6 ~ dimethoxy-p-toluy1-acid, mp. 264-267 ⁰ G (from methanol / water) .

Example 5

To a solution of 20 mg of sodium metal in 200 ml of abs. Isopropanol was 1.2 g of methyl a «- (2,4-diamino-5-pyrimidinyl) -2,6-dimethoxy-p-toluylbenzoate given.

The suspension was in the pressure tube at 150 ° for 72 hours (5 atm.) Warmed. The solution was cooled and evaporated. The remaining substance was suspended in a little water, filtered off with suction and recrystallized from isopropanol: α- (2,4-Diamino-5-pyrimidinyl) -2,6-dimethoxy-p-toluic acid isopropyl ester, M.p. 209-213 °.

Example 6

A solution of 0.4 g of sodium metal (17.4 mM) in 20 ml Section. Isopropanol was evaporated to dryness. The residue was dissolved in 10 ml of dimethyl sulfoxide. 2 g of a- (2,4-diamino-5-pyrimidinyl) -2,6-dimethoxy-p-toluic acid methyl ester were added and the reaction mixture stirred for 24 hours under nitrogen and with exclusion of moisture. After adding The precipitated α- (2,4-diamino-5-pyrimidinyl) -2,6-dimethoxy-p-toluic acid isopropyl ester became 30 ml of water suctioned off and recrystallized from isopropanol.

Example 7

In a solution of 20 mg of sodium metal in 250 ml anhydrous butanol- (l) were 1.6 g of a- (2,4 ~ diamino-5-pyrimi-

509807/1141

dinyl) -2,6-diinethoxy-p-toluic acid methyl ester dissolved.

The reaction mixture was left with exclusion of moisture

Boiled under reflux for 12 hours and then hot

filtered. The filtrate was evaporated and the residue was recrystallized from butanol- (l): a- (2,4-diamino-5-pyrimidinyl) -

2,6-dimethoxy-p-toluic acid butyl ester. 186-188 °.

Example 8

'To a solution of approx. 100 mg sodium metal in 200 ml Section. Ethanol were 2.0 g of a- (2,4-diamino-5-pyrimidinyl) -2,6-dimethoxy-p-toluic acid methyl ester given. The solution was refluxed for 48 hours and filtered. The hasty council was concentrated to 1/4 and cooled. The precipitated α- (2,4-diamino-5-pyrimidinyl) -2,6-dimethoxy-p-toluic acid ethyl ester was filtered off with suction and recrystallized from ethanol; M.p. 201-202 °.

Example 9

To a solution of 4 »45 g of a- (2,4-diamino-5-pyrimidinyl) -2,6-dimethoxy-p-toluic acid methyl ester in 400 ml of abs. Dioxane were taking ^{at 50 0 C.} Nitrogen and moisture exclusion 135 ml of approx. 15 $ diisobutylaluminum hydride solution in dioxane were added dropwise over the course of 30 minutes. The resulting suspension was stirred at 50 ° for 1 hour. After cooling to 30 ⁰ C was used as a reaction mixture with a mixture of 25 ml of methanol, 5 ml of water and 50 ml of dioxane and stirred at 50 ° for a further 2 hours. The solid material was separated and discarded. The filtrate was evaporated to dryness. After recrystallization from approx. 20 ml of methanol, the residue gave 4 - [(2,4-diamino-5-pyrimidinyl) methyl] -2,6-dimethoxybenzyl alcohol with a melting point of 227-228 °.

509807/1 141

-2A-

Example 10

2.4 g of 3-chloroperbenzoic acid were added to a suspension of 3 »18 S a- (2,4-diamino-5-pyrimidinyl) -2,6-d3jaiethoxy-p-toluic acid methyl ester in 50 ml of dioxane, while stirring. After 5 minutes (no more oxidizing agent can be detected) a further 1.2 g of 3-chloroperbenzoic acid were added. After 30 minutes, the brown-colored solution (no peroxides; no oxidizing agent) was evaporated to dryness and the residue was treated with 200 ml of a mixture of chloroform-propanol-concentrated ammonia (80: 20: 2). The precipitated ammonium salt of chlorobenzoic acid (approx. 3.5 g) was separated off, washed with chloroform and the solvents removed in vacuo. The residue (approx. 3.0 g) was chromatographed on 90 g of silica gel using the above-mentioned system. The more rapidly migrating a- (2 ', 4'-diamino-5'-pyrimidinyl) -2,6-dimethoxy-p-toluic acid methyl ester 3'-oxide was recrystallized from methanol. M.p. 251-253 °.

The slower moving α- (2 ', 4'-diamino-5'-pyrimidinyl) -2,6-dimethoxy-p-toluic acid methyl ester-l'-oxide (Rf 0.1) was recrystallized from methanol. M.p. 258-259 ° (dec.).

Example 11

A solution of 735 mg of sodium in 100 ml of absolute alcohol was mixed with 5.8 g of guanidine carbonate and 4.2 g of ethyl 4- (3-anilino-2-cyanoallyl) -2,6-diethoxybenzoate added and refluxed for 20 hours. The alcohol was evaporated in vacuo. 50 ml of water were added to the residue and then added Stirring at 25 ° for 3 hours became the a- (2,4-diamino-5-pyrimidinyl) ~ 2,6-diethoxy-p-toluyl-acid ethyl ester suctioned off, with water washed and recrystallized from alcohol. 197-199 °.

B09807 / 1H1

Production of the raw material:

A mixture of 29.7 g of 2,6 ~ dihydroxyterephthalic acid 228 g of potassium carbonate and 234 g of ethyl iodide in 500 ml of absolute dimethylformamide were dried for 18 hours with the exclusion of moisture. "Stirred at 60 °. The solvent was, in vacuo at 60 ° removed and the residue mixed with 750 ml of water. the The resulting emulsion was extracted with 2 × 700 ml of ethyl acetate. The ethyl acetate phases were washed with 600 ml of water, dried over magnesium sulfate and evaporated in vacuo. Recrystallize the residue from cyclohexane gave 2,6-diethoxyterephthalic acid diethyl ester of m.p. 104-105 °.

A solution of 24.8 g of 2,6-diethoxyterephthalic acid diethyl ester 84 ml of Uf sodium hydroxide solution were added in 700 ml of alcohol at 25 ° with stirring over the course of 3 hours. the The solution was stirred for 70 hours at 25 ° and then in vacuo evaporated to dryness at 40 °. The residue was dissolved in 400 ml of water and the aqueous solution extracted with 300 ml of ether. The ether phase was discarded and the water phase with conc. Acidified hydrochloric acid. The unusual 2,6-diethoxy ~ 1-monoethyl terephthalate was filtered off with suction, with water washed, dried and recrystallized from ethyl acetate-cyclohexane. 142-144 °.

A solution of 20.9 g of 2,6-diethoxyterephthalic acid 1-monoethyl ester in 100 ml of thionyl chloride, the mixture was refluxed for 3 hours with exclusion of moisture and then evaporated to dryness in vacuo. The residue was in 300 ml suspended in boiling petroleum ether (low boiling). After 2 hours Standing at 25 ° was the ethyl 4- (chloroformyl) -2,6-diethoxybenzoate suctioned off, washed with petroleum ether and dried. M.p. 73-74 °.

A mixture of 12 g of 4- (chloroformyl) -2,6-diethoxy-

60 9 807./1141

ethyl benzoate 1.4 g of Pd-BaSO.-catalyst (5 %) and 0.2 ml of quinoline-sulfur regulator were heated to 120 ° while gassing with nitrogen and stirring. Hydrogen was then passed through the reaction mixture at 120 ° until 90 % of the theoretical amount of hydrochloric acid had been released. The reduction was stopped and the suspension was cooled to 25 ° while gassing with nitrogen. The catalyst was separated off and the piltrate was evaporated to dryness in vacuo, crude ethyl 2,6-diethoxy-4-formylbenzoate being obtained as a colorless oil 45-46 °.

A solution of 10.2 g of 2,6 - diethQxy - 4 ~ formylbenzoe ~ · acid ethyl ester, 8.4 g of ß-morpholinopropionitrile and 4.1 g Sodium ethylate in 40 ml of absolute dimethyl sulfoxide was 20 hours. stirred at 25 °. 600 ml of water were added to the solution and the mixture was extracted with 2 × 500 ml of ethyl acetate. The ethyl acetate phases were washed twice with 200 ml of water each time, over magnesium sulfate dried and evaporated in vacuo «, the residue was dissolved in 40 ml of alcohol. After standing at 4 ° for 20 hours, the crystallized 4- (2-cyano-3-morpholinoallyl) -2,6-diethoxybenzoic acid ethyl ester became suctioned off, washed with alcohol and dried. 117-119 °.

A solution of 3> 7 g of ethyl 4- (2-cyano-3-morpholinoallyl) -2,6-diethoxybenzoate 1.4 g of aniline and 1.5 ml conc. Hydrochloric acid in 100 ml of alcohol was refluxed for 1 hour and then evaporated to dryness in vacuo. 50 ml of water were added to the residue. Stirring at 25 ° was the ethyl 4- (3-anilino ~ 2 ~ cyanoallyl) -2,6-diethoxybenzoate Sucked off, washed with water, dried and recrystallized from methylene chloride-alcohol. 178-179 °.

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Example 12

A mixture of 1.94 g of ethyl 4- (2-cyano-3-morpholinoallyl) -2,6-diethoxybenzoate, 3.6g guanidine carbonate and 1.36 g of sodium ethylate in 20 ml of absolute dimethyl sulfoxide was Stirred at 120 ° for 20 hours. After adding 200 ml of water, the mixture was extracted with 2 × 200 ml of ethyl acetate. The ethyl acetate phases were washed twice with 50 ml of water each time, over magnesium sulfate dried and evaporated in vacuo. The residue was with ethyl acetate-methanol (4: 1) on 40 g silica gel (Merck) chromatographed, wherein a- (2,4-diamino-5-pyrimidinyl) -2, -6-diethoxy-p-toluic acid ethyl ester of m.p. 197-199 °.

Example 13

The from 53.5 g of magnesium and 284 g of methyl iodide in 500 ml of absolute ether produced Grignard reagent was with stirring and ice cooling in the course of 2 hours. With a Solution of 36 g of a- (2,4-diamino-5-pyrimidiny.l) -2,6-diethoxyp-toluic acid ethyl ester in 2 liters of absolute "tetrahydrofuran. The resulting suspension was 20 hours under Boiled under reflux. The reaction mixture, cooled to 25 °, was carefully decomposed with ice; then 3 liters of water and 2N sodium hydroxide solution was added until the reaction was strongly alkaline. The resulting precipitate was filtered off and the The filtrate was extracted with 2 × 51 ethyl acetate. The ethyl acetate phases were washed with 2 × 21 water, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was dissolved in 2 1 of absolute tetrahydrofuran and how described above, prepared again with the Grignard reagent from 26.7 g magnesium, 142 g methyl iodide and 250 ml absolute Aether, implemented. The reaction product obtained after work-up was treated with ethyl acetate-methanol (3: 1) on 400 g of silica gel

B09807 / 1U1

(Merck), using 4 - [(2,4-diamino-5-pyrimidinyl) methyl] -2,6-diethoxy-α, α-dimethylbenzyl alcohol was obtained. Mp. 217-218 ° after recrystallization from methanol.

Example 14

A suspension of 8.0 g of a- (2,4-diamino-5-pyrimidinyl) - ' 2,6-dimethoxy-p-toluamide in 25 ml of dry pyridine was mixed with 4.0 g of phosphorus oxychloride are added dropwise at 20-30 °. To After stirring for 3 hours at room temperature, the mixture was poured into 150 ml of water, the precipitated a- (2,4-diamino-5-pyrimidinyl) -2,6-dimethoxy-p-tolunitrile Sucked off, washed with water and recrystallized from dimethylformamide-methanol. M.p. 270-272 °.

The starting material was prepared as follows:

A solution of 195 g of 2,6-dimethoxy-4-methylbenzamide in 2.5 1 of water and 1.7 1 of pyridine was stirred at 80 ° over the course of one hour in portions with 63O g of potassium permanganate offset. The mixture was refluxed for 2 hours. The brownstone was separated off and washed with 1 liter of hot water and the piltrate evaporated to dryness in vacuo. The residue was taken up in 1 l of water, and the starting material was filtered off with suction and the Piltrat with conc. Hydrochloric acid is added until it becomes strongly acidic. The precipitated 3,5-dimethoxy-terephthalamic acid was separated, washed with water and dried. M.p.> 300 °,

A solution of 50 g of 3 t 5-dimethoxy-terephthalamic acid in 500 ml of methanol was saturated with hydrochloric acid gas, boiled for 3 hours under reflux and further introduction of hydrochloric acid and evaporated to dryness in vacuo. The residue was treated with 200 ml of a sodium bicarbonate solution followed by 5 shaken vigorously suction filtered, the solid product washed with water and recrystallized from methanol. The 3,5-dimethoxy-terephthalic acid methyl ester

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melts at 259-261 °.

A suspension of 2.4 g of sodium hydride (50% dispersion in oil) and 7.05 g of dimethyl sulfone in 18 ml of absolute prostitute Ethyl sulfoxide was removed under exclusion of pressure and nitrogen Stirred for 2 hours at 50 °. The heating was interrupted and 5.95 g of methyl 3,5-dimethoxy-terephthalamic acid were added, whereupon the temperature rose to 65 °. It was another hour stirred at room temperature, diluted with 100 ml of water, the aqueous solution shaken twice with 50 ml of ethyl acetate each time, over Filtered charcoal and adjusted to pH = 6-7 with glacial acetic acid. The precipitated 2,6-dimethoxy-4- ((methylsulfonyl) acetyl-benzamide was sucked off, washed with water and made of dimethylformamide- Aether re-crystallized. 228-230 °.

A suspension of 37 g of 2,6-dimethoxy-4- <£ (methylsulfonyl) acetyl ^ benzamide in 50 ml of ethanol and 155 ml of water was with a solution of 1.55 g of sodium borohydride in 30 ml of water (under Added 0.1 g of sodium hydroxide). There were two more " Stirred for hours at room temperature, cooled with ice and sucked off the pest. After recrystallization from dimethylformamide-ethanol melted the 4-O-hydroxy-2- (methylsulfonyl aethyl ^ -2,6-dimethoxybenzamide at 258 ° with decomposition.

A mixture of 3.1 g of sodium methylate, 16 g of 4-C-hydroxy-2- (methylsulfonyl) ethyl > -2,6-dimethoxybenzamide and 8.2 g of ß-anilinopropionitrile in 35 ml of absolute dimethyl sulfoxide stirred under nitrogen and exclusion of humidity for 5 hours at 50 °. The solution was poured into 400 ml of water and the resulting emulsion extracted with 3 x 200 ml of ethyl acetate.

The ethyl acetate phases were washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was recrystallized from dimethylformamide-water. The 4- (3-anilino-2-cyanoallyl) -2,6-dimethoxybenzamide melted at 226-228 °.

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A solution of 0.83 g of sodium in 55 ml of absolute ethanol was mixed with 3 »52 g of g-uanidine hydrochloride and 4.1 g of 4 ^l - (3-anilino ~ 2 ~ cyanoallyl) ~ 2,6-dimethoxybenzamide and reduced for 20 hours Nitrogen and boiled with stirring. The mixture was diluted with 100 ml of water and the ethanol was removed under vacuum. The precipitated a- (2,4-diamino-5-pyrimidinyl) -2,6-dimethyloxy-p ™ toluamide was filtered off with suction, washed with water and recrystallized from dimethylformamide-methanol. M.p. 288-290 °.

Example 15 '

A suspension of 1.0 g of N-C4 "- (2,4-diamino-5-pyrimidinyl) -2,6-dimethoxybenzy ! ^ - acetamide in 30 ml IH hydrochloric acid Heated for 15 hours at 100 °, a clear solution being formed, and then evaporated to dryness in vacuo. Of the The residue was dissolved in a little water, the solution with potassium carbonate made alkaline and the precipitated 2,4-diamino-5- (4 ~ aminomethyl-3f5 ~ dimethoxybenzyl) pyrimidine transferred to the maleate. 176-178 ° (dec.) °

■ Example 15 a

A solution of 0.53 g of sodium in 36 ml of absolute ethanol was mixed with 2.6 g of guanidine hydrochloride and 3A S N- (4- (3-Anilino ™ 2 ™ cyanoallyl) -2,6 »dimethoxybenzyl) acetamide and 20 Boiled for hours under nitrogen and with stirring. The ethanol was removed under reduced pressure, the residue was taken up in water, suction filtered, washed with water and recrystallized from methanol «, Das Ki-4.4- (2,4-diamino-5-pyrimidinyl) -2,6-dimethoxybenzyl) acetamide melted at 218-220 °.

509807/1141

The starting material was prepared as follows:

A mixture of 20 g of 3,5-dimethoxy-terephthalamic acid and 100 ml of thionyl chloride was refluxed for one hour, a clear solution being formed. The reaction mixture was used under reduced pressure. Evaporated dry, the residue dissolved in benzene, the benzene distilled off, the residue was redissolved in benzene and this solution was added dropwise to 400 ml of methanol. The whole was refluxed for 1 hour. Boiled cooler, evaporated to dryness, the residue dissolved in benzene, the benzene solution with water and sodium bicarbonate and water, dried and evaporated. The 4-cyano-3,5-dimethoxy-benzoic acid methyl ester was obtained by recrystallizing the residue from methanol obtain. M.p. 151-153 °

30 g of methyl 4-cyano-3,5-dimethoxy-benzoate in 1500 ml of methanol and 150 ml of 1N hydrochloric acid were hydrogenated in the presence of 10 g of palladium-carbon at room temperature and under atmospheric pressure. 2 mols of hydrogen were absorbed in about 5 hours. The solution was filtered off the catalyst, evaporated to dryness, the residue taken up in a little water, the solution filtered, saturated with solid potassium carbonate and shaken with benzene. The methyl 4- (aminomethyl) -3,5-dimethoxy-benzoate was obtained from the benzene layer, which after recrystallization from high-boiling petroleum ether at 81-83. ⁰ C melted.

9.0 g of methyl 4- (aminomethyl) -3,5-dimethoxy-benzoate, dissolved in 30 ml of acetic acid, were treated dropwise with 4 »1 g of acetic anhydride and the whole was heated on the steam bath for 30 minutes. The acetic acid was distilled off and the residue was recrystallized from methanol. The 4- (acetylaminomethyl) -3,5-dimethoxy-benzoic acid methyl ester melted at 184 ^° C.

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A suspension of 2.9 g Natfiumhydrid (50 follow dispersion in oil) and 3.8 g of dimethylsulfone in 20 ml of absolute dimethyl sulfoxide was stirred under exclusion of moisture and nitrogen for 2 hours at 50 ⁰ C. The heating was discontinued and 5.34 g of 4 ~ (acetylaminomethyl) -3,5-dimethoxybenzoesäuremethylester added, whereupon the temperature rose to 63 ⁰ G. The mixture was stirred for a further two hours at room temperature and diluted with 200 ml of water. The aqueous solution is shaken twice with 50 ml of ethyl acetate each time, filtered through charcoal, adjusted to pH = 6-7 with glacial acetic acid and placed in the refrigerator overnight. The precipitated N- / 2,6-dimethoxy-4- (methylsulfonyl) acetylbenzyl / acetamide was filtered off with suction, washed with water and recrystallized from methanol-water (50:50). M.p. 233-5 °.

A suspension of 9.5 g of N- / 2,6-dimethoxy-4 - ^ (methyl ~ · sulfonyl) acetyl ^ benzyl / acetamide in 120 ml of ethanol and 120 ml of ethanol and 120 ml of water was with a solution of 2.4 g sodium borohydride in 30 ml water (with the addition of 0.1 g sodium hydroxide). The mixture was stirred for a further 3 hours at room temperature, cooled with ice, poured into 150 ml of water and the solid material was filtered off with suction. After recrystallization from methanol, the N- / p- (l-hydroxy-2 - '(methylsulfonyl) ethyl} -2,6-dimethoxybenzyl / acetamide melted at 19O ⁰ G.

A mix of 0.82. g sodium methylate, 3.28 g N- / p- (l ~ hydroxy-2- (methylsulfonyl) ethyl ^ -2,6-dimethoxybenzyl / acetamide and 2.2 g of ß-anilinopropionitrile in 13 ml of absolute Dimethyl sulfoxide was stirred for 5 hours at 50 ° under nitrogen and with exclusion of moisture. After cooling, it was the solution was poured into 60 ml of water and the resulting emulsion was shaken with ethyl acetate. The ethyl acetate was washed with water, dried over sodium sulfate and evaporated. The residue was recrystallized from methanol. The N- (4- (3-anilino-2-cyanoallyl) -2,6-dimethoxybenzyl ^ -acetamide melted at 216 °.

B09807 / 1U1

Example 16 '

To a solution of 4.5 g of dimethyl sulfone in 10 ml of abs. DMSO was added 4.6 g (ca. 50 follow suspension) of sodium hydride (96 mM) and the mixture 2 h. Stirred at 60 °. Then 5.8 g of a- (2,4-diamino-5-pyrimidinyl) -2,6-diethoxyp-toluy / benzoic acid ethyl ester were added in 3 portions, the temperature rising to 65 °.

The reaction mixture was stirred for a further 15 minutes at 60 ° and after cooling (cooling with ice water) with approx. 150 ml Water added. The cloudy solution was washed 3 times with 50 ml of benzene and the benzene extracts discarded. The aqueous phase was washed with conc. HCl (10 ml) adjusted to pH 7-8, the precipitated 4 '- [(2,4-diamino-5-pyrimidinyl) methyl] -2', 6'-diethoxy-2- (methylsulfonyl) acetophenone suction filtered and dried at 50 ° in a high vacuum. Snip, after crystallization from water 206-207 °

Example 17

A suspension of 5.8 g of 4 '- [(2,4-diamino-5-pyrimidinyl) methyl] -2', 6'-diethoxy-2- (methylsulfonyl) acetophenone in 50 ml of 20 lean aqueous tetrahydrofuran was mixed with 1 g amalgamated aluminum reduced for 4 hours at 65 °. (Aluminum shavings were immersed for 2 min. In a 2 % HgOl solution, rinsed with methanol and used immediately for the reduction.) The reaction mixture was filtered hot, the filtrate was concentrated, adjusted to pH 9 with 5% NaOH and 5 × 50 ml of ethyl acetate shaken out. A crude product was obtained which, after column chromatography (200 g of silica gel, eluent CHCl: n-propanol: conc. EH.OH / 80: 20: 1) 4 '- [(2,4-diamino-5-pyrimidinyl) methyl] - 2 ', 6'-diethoxyacetophenone of melting point 229-231 ° (from ethanol) resulted.

509807/1141

Example 18

To a solution of 8.8 g of dimethylsulfone in 20 ml of sieve-dried dimethyl sulfoxide were added 11.5 g of NaH (ca. 50 rim suspension, 25 mM) and the mixture stirred under nitrogen for 2 hrs. At 6O ^0th At this temperature (the heating bath removed), 10 g of a- (2,4-diamino-5-pyrimidinyl) -2,6-dimethoxy-p-toluic acid methyl ester were added in portions, the temperature rising to 70-75 ° . The reaction mixture was stirred for a further 15 minutes at 60 ° and then cooled. 250 ml of water were then added to the mixture with cooling (and with a current of IL). The cloudy solution was washed with 3% 50 ml benzene (the benzene extracts were discarded), with conc. HGl adjusted to pH 7-8 and extracted 6 χ with 200 ml of ethyl acetate each time. The combined extracts were over MgSO. dried, concentrated and the residue kept in a high vacuum for 5 hours. 4 '- [(2,4-Diamino-5-pyrimidinyl) methyl] -2', 6'-dimethoxy-2 »(methylsulfonyl) acetophenone were obtained. M.p. 225-225 °.

A sample dissolved in water and treated with conc. Acidified HCl, after recrystallization from methanol gave 4 - [(2,4 ~ diamino-5-pyrimidinyl) methyl] ~ 2 ', 6'-dimethoxy ~ 2 ~ (methylsulfonyl) acetophenone hydrochloride of melting point> 300 °.

Example 19

A solution of 7.0 g of 4 '- [2,4-diamino-5-pyrimidinyl) methyl] -2', 6 '~ dimethoxy-2- (methylsulfonyl) acetophenone in 80 ml of 20% aqueous tetrahydrofuran was garnished with 1 g of ama! Aluminum reduced for 1 hour at 40 °. The reaction mixture was filtered, the filtrate concentrated to about 1/3 and washed with 4N NaOH adjusted to pH 9. The precipitated product was taken up in ethyl acetate. The ethyl acetate extract was over MgSO. dried and evaporated. The residue was recrystallized from methanol

509807 / 1U1

and gave 4 '- [(2,4-diamino-5-pyrimidinyl) methyl] -2', 6'-dimethoxyacetophenone of m.p. 282-285 ° (decomp.)

Example 20

To a suspension of 1 g of 4 '- [' (2,4-diamino-5-pyrimidinyl) methyl] -2 ', 6'-diethoxy-2- (methylsulfonyl) acetophenone, in a mixture of 25 ml of ethanol and 10 ml of water, were added in portions with stirring within 30 min. 500 mg NaBH. given. First a clear solution resulted; after a further 30 minutes of stirring, the 4 - [(2,4-diainino ~ 5-pyriniidinyl) methyl] ~ 2,6-diethoxy-a- [ (methylsulfonyl) methyl] benzyl alcohol. M.p. 205-206 ° after recrystallization from methanol.

Example 21

A solution of 302 mg of 4 '- [(2,4-diamino-5-pyrimidinyl) methyl] -2', 6'-dimethoxyacetophenone in 30 ml of methanol was diluted with 6 ml of water and 1 drop of IN NaOH was added. Thereafter were at 40 ° for 3 hours in 50 mg portions in total 200 mg NaBH. admitted. About half of the solvent was distilled off in vacuo. The precipitated 4 - [(2,4-diamino-5- pyrimidinyl) methyl] -2,6-dimethoxy-α-methylbenzyl alcohol was suction filtered and then recrystallized from methanol. M.p. 280-285 ° (dec.).

Example 22

To a g-uanidine solution in methanol, made from 0.34 g of sodium metal in 40 ml of methanol and 1.38 g of guanidine hydrochloride, 4.0 g of 4- (1-hydroxyethyl) -3,5-dimethoxy-ct- (methoxymethylene) hydrocinnamonitrile given and the mixture refluxed for 18 hours. The solvent was at evaporated under normal pressure and the (semi-solid) residue through

609807/1141

purified by column chromatography. (100 g silica gel, with Chloroform: n-propanol: conc. HE.OH / 80: 20: 1 as eluent.) After concentration of the fractions containing the product and recrystallization of the residue from methanol, the product was obtained 4 - [(2,4-diamino-5-pyrimidinyl) methyl] -2,6-dimethoxy-α-methylbenzyl alcohol.

The starting material was prepared as follows:

To a solution of 8.5 g of dimethyl sulfone in 15 ml of dimethyl sulfoxide, 3 g of approx. 50 consecutive suspension of sodium hydride (0.06 M) were added and the mixture was stirred for 2 hours under nitrogen at 60 ° g of 2,6-dimethoxy-4- (diethoxymethyl) benzoic acid methyl ester in 5 ml of DMSO were added dropwise and the mixture was stirred for a further 30 minutes at 65 °. After cooling, the reaction mixture was quenched with 100 ml × water while cooling and extracted with 5 × 50 ml ether. The combined ether extracts were dried (MgSO.), Evaporated to dryness and the residue, 2,6-dimethoxy-4- (diethoxymethyl) methylsulfonyl acetophenone, processed further directly.

A solution of 8.8 g of sulfon in 80 ml of 10 t aqueous THF was reduced with 0.8 g of amalgamated aluminum shavings for 2 hours at. After this time, no more suIfon was detectable. The suspension was filtered and the filtrate was concentrated to about 2/3 and shaken out with 5 x 50 ml of ether. After drying the ether extracts and evaporation of the solvent obtained one 4- (diethoxymethyl) -2,6-dimethoxyacetophenone.

To a solution of 4 g of 4- (diethoxymethyl) ^ 2,6-dimethoxyacetophenone in 20 ml of 30 tiger methanol and 1 drop of 4N NaOH was at room temperature with stirring in several portions within 4 hours. 1 g of NaBH. given. The reaction mixture Was stirred for a further 1 hour, concentrated to about 1/3 and diluted with 30 ml of water. The resulting suspension was

509807/1141

acidified with 2N HCl (pH 1), covered with 50 ml of ether and stirred for 1 hour "at room temperature. Then the ether phase separated, dried (MgSO.) and evaporated. After crystallization from ether, the residue gave 4- (1-hydroxyethyl) -3,5-dimethoxybenzaldehyde of m.p. 95-96 °.

1.94 g of β-methoxypropionitrile and 4.0 g of 4- (1-hydroxyethyl) -3,5-dimethoxybenzaldehyde were added to a solution of 0.45 g of sodium in 20 ml of methanol dissolved and refluxed for 24 hours. After evaporating the solvent, the residue was dissolved in 50 ml Benzene and 10 ml of water were added. The benzene phase was separated off and washed several times with water. The 4- (l-hydroxyethyl) ~ 3,5-dimethoxy-a- (methoxymethylene) -hydrozinnonitrile obtained (yellowish ool) was used directly after the benzene had been evaporated off.

A sample, purified by preparative thin-layer chromatography, gave 4 ~ (1-hydroxyethyl) -3j.5-dimethoxy ~ α- (methoxy ~ methylene) -hydrocinnamonitrile as a colorless oil (crystalline with time) with a melting point of <30 ° _e

Beis piel 23

From 3 »5 ga ~ (dimethoxymethyl) -3s5 ~ dimethoxy-4- (1-hydroxypropyl) hydrocinnamonitrile, 2.29 g (24 mM) guanidine hydrochloride, 0.56 g sodium and 35 ml methanol were obtained in analogy to Example 22 4 - [(2,4 ~ Diamino ~ 5-pyrimidinyl) methyl] -a-ethyl-2 _? 6-dimethoxybenzyl alcohol, m.p. 235-238 ° (from methanol).

The starting material was prepared as follows:

In a solution of 0.18 g of sodium metal in 50 ml of abs. Methanol were 2.74 g of β-methoxypropionitrile and 4- (1-hydroxypropyl) -3,5-dimethoxybenzaldehyde solved and 48 hours on

609807/1141

Boiled under reflux. The mixture was evaporated and the residue was taken up in 50 ml of benzene and 10 ml of water. The aqueous phase was χ 2 with 20 ml of benzene washed. The combined benzene extracts were dried and evaporated. The residue (yellowish oil) was used further in this form.

A sample purified by preparative thin layer chromatography (silica gel, ether as eluant) gave '- (dimethoxymethyl) -3, 5-dimethoxy-4- (1-hydroxypropyl) -hydrozimtsäurenitril as a colorless oil. ■ '

To a solution of 0.62 g of sodium metal in 50 ml of methanol was added 2 g _f 3 G-uanidin hydrochloride and the suspension stirred for 30 min. " The NaGl was filtered off with suction and washed with a little cold methanol. A solution of 5.0 g of a- (dimethoxymethyl) -5.5- "dimethoxy-4- (niethoxymethyl) hydrocinnamic acid in 20 ml of methanol was added to the piltrate and Then a water separator was attached and methanol was distilled off (with increasing internal temperature up to 80 °). 25 ml of isopropanol were added to the remainder and this was also evaporated off for 2 hours. The residue was directly subjected to chromatography (100 g Silica gel, eluent chloroform: n-propanol: ammoniac / 80: 20: 1), with 2,4-diamine. 5- [3 jr 5-dimethoxy = -4- (methoxymethyl) benzyl] pyrimidine from Mp »221-223 ° (from methanol) was obtained.

The starting material was prepared as follows:

A solution of 29 * 8 g of 2,6-dimethoxy ~ 4 ~ (a, a-diethoxy ~ methyl) benzoic acid methyl ester was dissolved in 250 ml of abs »benzene and at 25-40 ° with 230 ml of a (^ 20%) solution of diisobutylaluminum hydride in toluene. The homo-

509807/1141

The reaction mixture was stirred at room temperature for 3 hours and then quenched with a solution of 10 ml of water, 25 ml of methanol and approx. 10 ml of benzene while cooling, so that the temperature does not exceed 40 °. The suspension the stirring was continued for 30 minutes, the aluminum hydroxide was filtered off with suction, washed with benzene and the filtrate evaporated to dryness. 2,6-Dimethoxy-4 ~ (α, α-diethoxybenzyl alcohol was obtained as a colorless, viscous oil.

• After treatment of the oil with 20 ml IN HGl and crystallization benzene became the crystalline α-hydroxy-3 »5-Ä.imethoxyp-tolualdehyde obtain. M.p. 128-129 ° (sub.).

A solution of 20 g of 2,6-dimethoxy-4- (α, α-diethoxybenzyl alcohol in 40 ml of absolute ether became a suspension of 2.35 g of NaH (55% , 0.07 M) in 40 ml of absolute ether The mixture was stirred for 1 hour at room temperature under nitrogen, then reacted with 40 g (0.28 M) methyl iodide and stirred at reflux for 22 hours.

The solvent and excess methyl iodide were removed distilled off, the residue with 100 ml of IN HCl for 15 minutes at 25 ° treated and the aldehyde taken up in ether. Recrystallization from benzene-n-pentane gave a, 3,5-trimethoxy-p ~ tolualdehyde, M.p. 72-76 °.

In a solution of 0.25 g of sodium metal in 20 ml of abs. Methanol were 2.45 g of β-methoxypropionitrile and 5 g of cCj3 »5-trimethoxytolualdehyde dissolved and the solution was refluxed for 48 hours. After this time, no more aldehyde was detectable. After evaporation of the solvent, the residue was dissolved in 50 ml Benzene and 15 ml of water / water taken up, the benzene phase separated and washed several times with water / water, over MgSO. dried and evaporated. A yellowish oil was obtained, which "in the next stage.

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The purified by chromatography (silica gel, 'eluent ether) sample for analysis, yielded α- (dimethoxymethyl) -3,5-dimethoxy-4- (methoxymethylhydrozimtsäurenitril as a colorless, crystalline substance from the substance of mp. ^ - o ^ ⁰ °.

Example 25

A suspension of 11.3 g of N- [2-amino-5- ^ 4- (1-hydroxy-imethylethyl) ~ 3,5-dimethoxybenzyl ^ -4-pyrimidinyl] acetamide in 40 ml of 10 tiger methanolic EOH was refluxed for 1 hour, then cooled to approx. 10 °. The crystals were suction filtered and washed with a little methanol. After crystallization from Methanol gave 4 - [(2,4-diamino-5-pyrimidinyl) -methyl] -2,6-dimethoxy-α, α-dimethylbenzyl alcohol from m.p. 248-250 °.

The starting material was prepared as follows:

Acetic anhydride (10 ml) at 95 ° was added in portions 5 g of a- (2,4-diamino-5-pyrim3dynyl) ~ 2,6-dimethozy-p-toluic acid methyl ester given. The resulting solution was stirred for a further 30 minutes at this temperature and then with 30 ml Toluene added and cooled. The suction filtered cc- (2,4 ~ diacetamido-5-pyrimidinyl) -2,6-dimethoxy ~ p-toluic acid methyl ester was recrystallized from methanol. 183-185 °.

To a methylmagnesium iodide solution, 'made' from 2.4 g of magnesium and 14.5 g of methyl iodide in 100 ml of ether became a solution of 2.5 g of a- (2,4-diacetamido-5-pyrimidinyl) -2,6- dimethoxy-p-toluic acid methyl ester in 200 ml of abs. Tetrahydrofuran was added dropwise over the course of 30 minutes and the resulting suspension was stirred at 40 ° for 24 hours. The reaction mixture was with 20 ml Water is added, the organic phase is separated off and washed with a little 4N NaOH and water, dried (MgSO.) And evaporated. The crude product thus obtained (yellowish oil) was used directly in the next stage.

50 9807/1 HI

After chromatographic purification (silica gel, CHCl “: n-propanol: conc. Ammonia / 80: 20: 1), a sample yielded N- [2-amino-5- ^ 4- (1-hydroxy-1-methylethyl) -3, 5-dimethoxy-benzyl ^ -4-pyrimidinyl] acetamide of m.p. 214-216 ° (from methanol).

Example 26

A solution of 5.1 g of sodium metal in 300 ml of abs. 21.1 g of g-uanidine hydrochloride were added to methanol and the The suspension was heated to reflux for 15 min. After cooling, the NaCl was filtered off with suction and washed with a little cold methanol. 51.4 g of 4- (1-hydroxy-1-methylethyl) -3,5- <iimethoxy-α- (methoxymethylene) hydrocinnamonitrile were found in the filtrate dissolved and refluxed for 18 hours. After cooling, the mixture was concentrated in vacuo and the residue in approx. 50 ml of methanol

suspended with heating, cooled again, the solid material sucked off and washed with cold methanol. Crystallization from methanol gave 4 - [(2,4 ~ diamino-5 ~ pyrimidinyl) methyl] ~ 2,6-dimethoxy-a, a-dimethylbenzyl alcohol. M.p. 248-250 °.

The starting material was prepared as follows:

A solution of 22.4 g of methyl 2,6-dimethoxy-4-formylbenzoate, 17.8 g of ethyl orthoformate and 0.5 ml of conc. HCl in 100 ml of abs. Ethanol was 2 hours on Boiled under reflux. The reaction mixture was concentrated under reduced pressure and yielded methyl 2,6-dimethoxy-4- (oc, a-diethoxymethyl) benzoate. ,

From 21.6 g of magnesium and 62 ml of methyl iodide in 800 ml Aether was made of methyl magnesium;] 'odide. To this G-rignard solution was 90 g of 2-, 6-dimethoxy-4- (α, α-diethoxymethyl) benzoic acid methyl ester at room temperature added dropwise in 150 ml of ether. After the reaction had subsided, the mixture was refluxed for a further 3 hours; After cooling down

509807/1141

50 ml of water were added to the suspension, 50 ml of 4M ITaOH were added, the ether phase was separated off and washed with 10 ml of 4 ITaOH. The alkaline aqueous solution was extracted with 5 × 200 ml of ether and the combined ether extracts over Fa ₂ SO. dried and evaporated. The residue was shaken well with 250 ml of 1H HCl for 10 minutes and taken up in about 250 ml of ether. The ether solution was washed with water, dried (MgSO.) And concentrated. Crystallization from ether-petroleum ether gave 4- (1-hydroxy ~ l ~ methylethyl) -3.5 ~ dimethoxybenzaldehyde, melting point 52-53 °.

From 1.5 g of sodium in 500 ml of methanol, 20.8 g of ß-methoxypropionitrile and 50.0 g of 4 ~ (1-hydroxy ~ 1-methylethyl) -3,5-dimethoxybenzaldehyde, by refluxing for 48 hours after work-up, 4- (1-Hydroxy-1-methylethyl) -3 , 5-dimethoxy-α-(methoxymethylene) -hydrocinnamonitrile obtained as a yellow oil.

The analysis sample was chromatographed (silica gel, Eluent ether) purified. M.p.rv55 °

Example 27

A solution of 0.73 S Na metal in 45 ml of methanol 2.96 g of g-uanidine hydrochloride were added and the suspension Boiled under reflux for 15 min. After cooling, the ITaCl was suction filtered and 8 g of 4- (1-hydroxy-1-ethylpropyl) -3,5-dimethoxy-a- (methoxymethylene) -hydrocinnonitrile were in the piltrate solved. The mixture was refluxed for 24 hours, the solvent was evaporated off under normal pressure and the residue «^ Min. Heated at 110 °. The semi-solid mixture was purified by column chromatography (200 g silica gel, Eluent chloroform: n-propanol: conc. Ammonia / 80: 20: 1) and gave, after recrystallization from methanol, 4 - [(2,4-diamino-5-pyrimidinyl) methyl] ~ a, a-diethyl-2,6-dimethoxybenzyl alcohol, 160-161 °.

509807 / 1U1

The starting material was prepared as follows:

From 2.16 g of magnesium turnings and 10.3 ml of ethyl iodide in 280 ml abs. Aether, the Grignard reagent was made. 9 g of methyl 2, e-dimethoxy - ^ - diethoxy-methylbenzoate were added to this solution added dropwise, the temperature rising to about 32 °. The reaction mixture was refluxed for 2 hours boiled and then mixed with 15 ml of water and 50 ml of 4N NaOH. The aqueous phase was separated and 5 times with 15 ml Aether .washed. The combined ether extracts were with Washed water and concentrated to 100 ml. The ether solution was stirred with 25 ml IN HCl overnight at room temperature. The ether phase was separated off, washed with water, dried (MgSO.) And concentrated. The residue, "a colorless one OeI (7.7 g) j was a mixture of 2 substances which by Column chromatography (650 g silica gel, eluent benzene: ether / 3: 1) were separated.

The substance with R “0.45 (in the above system), a colorless one OeI was obtained as 4- (1-hydroxy-1-ethylpropyl) ~ 3> 5-dimethoxybenzaldehyde identified.

The slower running connection (R "0.30) was identified as colorless oil isolated and as 4 - (1 ~ hydroxypropyl) -3,5 ~ dimethoxybenzaldehyde characterized.

To a solution of 0.44 g of sodium metal in 40 ml of abs. 8 g of 4- (l-hydroxy-l-ethylpropyl) -3,5-dimethoxybenzaldehyde and 5.4 g of β-methoxypropionitrile were added to methanol. The yellow-brown one Solution was refluxed for 18 hours. The reaction mixture was then concentrated and the residue was dissolved in 250 ml of ether and added 100 ml of water. The ether phase was 3 times with Washed 50 ml of water each time, dried (MgSO.), evaporated and dried for 8 hours at 40 ° in a high vacuum. The crude product obtained in this way was used in the further reaction.

509807/1141

-η

A sample, by, preparative thin layer chromatography purified, gave 4- (l-hydroxy-l-ethylpropyl) -3,5-dimethoxy-a: - (meth.oxymethylene) hydrocinnamonitrile as a colorless oil.

Example 28

A solution of 40 mg HgCl _? in 1 ml of water and 700 mg of zinc powder and refluxed and stirred the whole thing overnight. The reaction mixture was filtered hot, the zinc powder was washed on the filter with 6 ml of 90% acetic acid and the combined filtrates were made alkaline with 20 ml of constant M.OH while cooling. The precipitated methyl a- (2,4-diamino-5-pyrimidinyl) -2,6-dimethoxy-p-tolylbenzoate was filtered off with suction and recrystallized from methanol, melting point 250-251 °.

The starting material was produced as follows '

A mixture of 11.2 g of 2,6 «dimethoxy-4-formylbenzoic acid methyl ester, 6.3 g of ethyl cyanoacetate and 3 drops of piperidine were heated to 120 ° in an open vessel with stirring heated and stirred at this temperature for 15 minutes. The residue, recrystallized from ethyl acetate, gave a ~ cyano ~ 3,5 ~ dimethoxy-4- (methoxycarbonyl) ethyl cinnamate, m.p. 142-144 °.

A solution of 10.6 g of a-cyano-3> 5 ~ dimethoxy-4- (methoxycarbonyl) -cinnamic acid ethyl ester in 500 ml of ethanol was hydrogenated in the presence of 0.5 g of 5 ^ Pd / C at room temperature and 760 torr. After uptake of one equivalent of hydrogen (810 ml), the reaction was terminated. The catalyst and partially precipitated product were filtered off with suction and washed on the filter with benzene. The filtrate was evaporated to dryness. The residue, recrystallized from ethyl acetate, gave a-cyano-3 , 5-

B09807 / 1U1

ethyl dimethoxy-4- (methoxycarbonyl) dihydrocinnamate from 119-121 °.

In a solution of 0.7 g of sodium metal in 80 ml of abs. Ethanol were 8 g of a-cyano-3,5-dimethoxy-4 ~ (methoxycarbonyl) -dihydro2imtsäureäthylester dissolved and the mixture with an ethanolic solution of guanidine [made from 0.7 g Sodium in 100 ml of ethanol and 2.7 g of guanidine hydrochloride (0.028 M)] added. The reaction mixture was refluxed for 2 hours and evaporated to dryness. The residue was dissolved in 90 ml of hot water, filtered and adjusted to pH 4 with glacial acetic acid. The precipitated product resulted after recrystallization from methanol, a- (2,4-diamino-6-hydroxy-5-pyrimidinyl) -2,6-dimethoxy-p-toluic acid methyl ester, M.p. 224-226 °.

To a suspension of 3.4 g of cc- (2,4-diamino-6-hydroxy- '5-pyrimidinyl) -2,6-dimethoxy-p-toluic acid methyl ester in 25.6 g of POOL, 2.4 G N, N-dimethyl aniline added, the mixture brought to the boiling point in the course of an hour and then refluxed for 4 hours. About 2/3 of the POCl ^ were then distilled off under reduced pressure, the remainder was poured onto 80 g of ice with stirring and left to stand for 2 days at room temperature. 38 ml of 25 ° aqueous ammonia were added to the suspension (the temperature not exceeding 20 °). After 2 hours, the solid was filtered off with suction, rinsed into a flask with a little water and separated from the dimethylaniline with steam. After cooling, the suspended compound was filtered off with suction and taken up in ethyl acetate. The solution was dried over MgSO. And the solvent was evaporated dark residue, purified by column chromatography (60 g silica gel Merck, eluent chloroform: n-propanol: ammonia 25 ^ / 80: 20: 1), gave a - (- 2,4-diamino ~, 6 ~ chloro ~ 5-pyrimidinyl) -2,6-dimethoxy-p-toluic acid methyl ester, melting point 228-229 ° (from methanol).

509807/1141

Claims (17)

A process for the preparation of compounds of the general formula -CV- 1 2 in which R and R are alkyl or alkenyl, Z is an oxygen atom bonded to one of the ring nitrogen atoms, η = 0 or I and A is trifluoromethyl or one of the groups R6 * 8C (a) or CR (bj 1.0, where R is oxo and R 'is hydrogen, alkyl, or r rj alkoxy: or R is hydroxyimi.no and RG 7 8 alkyl; or R together with R is nitrilo; R and q -in R ^ hydrogen or alkyl and R hydroxy, alkoxy, or -IT (R ^, R4); or R ^ and R10 alkoxy 9 10 or alkylthioj or R together with R alkylenedioxy or alkylenedithioj and R and R represent hydrogen, ΑΙΙςτΊ or alkanoyl, 609807 / 1U1 and acid addition salts of such compounds, characterized in that a) a compound of the formulas o & r Hb CHY 5 in which formulas R is alkyl; Y is a leaving group and A is trifluoromethyl or a (c) or -. C-R ^ (cL). represent, R12 - wherein R is oxo and R is alkoxy; or R together with R12 nitrilo; R15 hydroxy, alkoxy or -N (R5, R4); 9 17) or R together with R represent alkylenedioxy or alkylenedithio and R1, R2, R5, R4, R8 and R9 have the above meaning, reacted with guanidine, or that B09807 / 1U1 b) a compound of the formula HoNCO III 1 2 in which R and R have the above meaning, dehydrated to the nitrile, or that c) a compound of the formula IV wherein X! ChIOr3, bromine, alkylthio or alkylsulfonyl and kJ trifluorometloyl or one of the G groups .C ^ (c) or r_r9 ^ R14 11, -wherein R is oxo and R is alkoxy; or R11 together with R12 nitrilo; and R14 alkoxy or -N (R ^, R4); or R9 together with R14 alkylenedioxy, and R, R, R, R, 8 9 R and R have the above meaning, with ammonia, or that one 509807 / 1U1 -19. d) the substituent X ″ in a compound of the formula NH2 in which R, R and kJ have the above indication and X ″ represents chlorine, bromine or hydroxy, replaced by a hydrogen atom, or that e) in a compound of the formula VI wherein A ^ represents the groups -CO-CH-SO2CH5, -CO-CH-SO2- phenyl or -CO-CH-SO-CH, and R, RR and R have the above meaning, the group A ^ cleaves the group reductively to the acetophenone group , or that f) a compound of the formula I in which η = 0 is subjected to N-ozidation, or that B09807 / 1U1 g) the amino protective groups in a compound of the \ —κι / NHX VII in which XH or an amino protective group represents and at least one X represents a protective group, and R, 2 1 R and A have the above meaning, cleaved hydrolytically or hydrogenolytically, or that h) in a compound of the formula HOOC CH2 fl \ NH2 NH2 Ia 1 2 wherein R, R , Z and η have the above meaning, esterifies the carboxyl group or reduces it to the aldehyde group, or that m on i) in a compound of the formula I in which A represents a 1 2 alkylcarbonyl group and R, R, Z and η have the meaning given, the carbonyl group condenses with hydroxylamine to form the hydroximino group; or reductively aminated; odor reduced to alcohol; or ketalized or thioketalized 509807/1141; or reacted with a G-rignard compound to give a homologous alcohol; or that j) in a compound of the formula I in which A represents a 1 2 alkoxycarbonyl group and R, R, Z and η have the meaning given, the alkoxycarbonyl group is reacted with a G-rignard compound to give the ketone or the secondary or tertiary alcohol; or reduced to alcohol; or that k) in a compound of the formula I an alcohol function contained in the substituent A is alkylated. "'. · Or oxidized to the carbonyl group; or that one 1) in a compound of formula I a nitrile group A reduced to the amino group or to the aldehyde group; or that one ) in a compound of formula I one in the substituent A contained ketal or thioketal group cleaves; or that one n) in a compound of the formula I in which A is a group, the acyl radical is hydrolyzed, and optionally converting a base obtained into an acid addition salt. 2. The method according to claim 1, characterized in that a prebinding of the formula CH2 1 [\ -NH ₂ NH ₂ B09807 / 1U1 12 2 wherein R, R and A have the meaning given in claim 1,
according to process variant a). 3. The method according to claim 1, characterized in that that you can get a compound of the formula 12 3 wherein R, R and A ^ are those given in claim 1 Have meaning according to process variant c) or d) from compounds of the formulas IV or V in which X ¹ and X "are Cl or Br. 4. The method according to claim 1, characterized in that 11 2 a compound of the formula I in which A, R and R are the in 1 7 claim 1 have given meaning, where in the radical A, R is not -CH ₂ 30 ₂ CH ", B? and R ^{4 is} not alkanoyl and R ^{8 is} not methylsulfonyl, according to process variant f). 5. The method according to claim 1, characterized in that 11 2 that a compound of the formula I, in which A, R and R have the meaning given in claim 1 and η = 0, according to process variant g) from a compound of the formula VII produces, in which both residues X represent amino protective groups, 6, method according to claim 1, characterized in, 1 2 that a compound of the formula I in which R, R, Z and η have the meaning given in claim 1 and A is Represents alkoxycarbonyl or aldehyde group, according to process variant h). 509807/1141 7. The method according to claim 1, characterized in that that in a compound of the formula I in which A is a 1 2 Represents alkylcarbonyl group and R, R, Z and η are those given Have meaning that the carbonyl group condenses with hydroxylamine to form the hydroximino group; or reductively aminated; or reduced to alcohol; or ketalized or thioketalized; or with a G-rignard compound to a homologous one Converts alcohol. 8. The method according to claim 1, characterized in that 1 2 that in a compound of formula I in the R, R, η and Z have the meaning given and A represents an alkoxycarbonyl group, the alkoxycarbonyl group with a G-rignard compound converts to ketone, or reduced to alcohol. 9. The method according to claim 1, characterized in that a compound of formula I contains one in the A. substituent
oxidized. A contained alcohol function is alkylated or to the carbonyl group 10. The method according to claim 1, characterized in that a kitrile group in a compound of formula I A reduced to the amino group or to the aldehyde group. 11. The method according to claim 1, characterized in that in a compound of formula I one in the substituent A contained ketal or thioketal group cleaves. 12. The method according to claims 1-11, characterized in that compounds of the formula I are prepared in which 12 1 R and R alkyl and A G- mono- or di-alkylated hydroxymethyl; or optionally C ~ mono- or di-alkylated alkoxymethyl; or represent alkylcarbonyl. 509807/1 UI 13. Process for the production of antibacterially active preparations, characterized in that a compound of the formula I as defined in claim 1 or an acid addition salt thereof, optionally together with an antibacterially active sulfonamide, with non-toxic, inert, therapeutically acceptable solid or _r mixed liquid carriers. 14. Antibacterially active preparations containing a compound of the formula I as defined in claim 1 or an acid addition salt thereof, optionally together with "a antibacterial sulfonamide, with non-toxic, inert, therapeutically acceptable solid or liquid carriers. 5098Ö7 / 1U1 15. Compounds of the general formula - R ¹ O. -TV 1 2
wherein R and R are alkyl or alkenyl "mean, Z represents an oxygen atom bonded to one of the ring nitrogen atoms, η = O or 1 and A is trifluoromethyl or one of the groups R ⁸ * I 9 C (al or C-R (b) represents / T ty wherein R is oxo and R ^{1 is} hydrogen, alkyl, or fl V Alkoxy, or R hydroxyimino and R 'alkyl; or R together with R 'nitrilo; R 'and R ^{9 are} hydrogen or alkyl and R ^{1 is} hydroxy, alkoxy, or -N (R ⁵ , R ⁴ ); or R ⁹ and R ^{1 are} alkoxy or alkylthio; or R together with R alkylenedioxy or alkylenedithio, and R ^ and R ^ represent hydrogen, alkyl or alkanoyl, and acid permeation resins of such compounds'. 1 16. Compounds according to claim 15, wherein R, R and η 10 7 have the meaning given, R oxo and R hydrogen, Alkyl or alkoxy; or R is hydroxyimino and R is alkyl; or R 509807/1 UI 7 "5 4. and R together Nitriloj R and R hydrogen or alkyl; R and R hydrogen or alkyl and R hydroxy, alkoxy or -N (R ⁵ , R ⁴ )? or R ⁹ and R ^{10 are} alkoxy or alkylthio; or 9 10 R together with R represent alkylenedioxy or alkylenedithio; or A is trifluoromethyl. 1 2 17. Compounds according to claim 15, wherein R and R Alkyl and A C- mono- or dialkylated hydroxymethyl; or optionally "C- mono- or dialkylated alkoxymethyl; or Represent alkoxycarbonyl. 509807/1 U1