DE1248055B - Process for the preparation of 6- (p-aminobenzenesulfonamido) -2- (methoxymethyl) -4-methoxypyrimidine - Google Patents

Description

GERMAN JMWWt PATENT OFFICE

EDITORIAL DEVELOPMENT German Cl .: 12 ρ-7/01

Number: 1248 055

File number: C 31632 IV d / 12 ρ

j [248 055 filing date: December 10, 1963

Opened on: August 24, 1967

The invention relates to processes for the preparation of the new 6- (p-aminobenzene sulfonamido) - 2 - (methoxymethyl) - 4 - methoxypyrimidines of the formula I

CH ₂ -O-CH ₃

OCH ₃ process for the preparation of 6- (p-aminobenzenesulfonamido) -2- (methoxymethyl) -4-methoxypyrimidine

Applicant:

CIBA Aktiengesellschaft, Basel (Switzerland) Representative:

Dr.-Ing. Dr. jur. F. Redies, Dr. rer. nat. Β. Redies and Dr. rer. nat. D. Türk, patent attorneys, Düsseldorf-Benrath, Erich-Ollenhauer-Str. 7th

in free form or in the form of its salts.

The new compound has good antibacterial properties. For example, it points to experimental Infection in animals, e.g. B. in mice, a very good healing effect against gram-positive and gram-negative bacteria such as streptococci, staphylococci, pneumococci and coli bacilli. It has advantages over comparable known compounds. So is done according to the Experiments, the amount of sulfonamide excreted in human urine is much less acetylated. It can therefore be used as a chemotherapeutic agent, e.g. B. in bacterial infections, especially of the urinary tract, Find use. But it is also suitable as an additive to animal feed.

6 - (p-Aminobenzenesulfonamido) -2 - (methoxymethyl) -4-methoxypyrimidine (A) was compared with the known commercial product 6- (p-aminobenzenesulfonamido) -2,4-dimethoxypyrimidine (B) with regard to its chemotherapeutic properties and its toxicity. As the following table shows, A was found to be effective in the mouse (ED50 = dose with 50% curative effect in mg / kg

Named as inventor:

Dr. Paul Schmidt, Therwil;

Dr. Ernst Swiss,

Dr. Kurt Eichenberger,

Dr. Max Wilhelm, Basel (Switzerland)

Claimed priority:

Switzerland of December 14, 1962 (14 734), of February 26, 1963 (2447), of October 25, 1963 (13 134)

• po simultaneously with the ip infection) superior to substance B for various indications and toxicity (LD50 of A = 1400 mg / kg iv, LD ₅₀ of B = 1000 mg / kg iv).

Test organism ED ₅₀ Substance A
therapeutic index
(LD ₅₀ : ED ₅₀ ) ED ₅₀ Substance B
therapeutic index
(LD00: ED00) 760 1.8 880 1.1 Sc. pyogenes 38 340 4.1 400 2.5 Ε. coli 205 54 26th 107 9.3 Staph, aureus 10 61 23 104 9.6

709 638/545

The new compound is obtained by methods known per se by either

a) a compound of the general formula II
CH ₂ -O-CH ₃

OCH ₃

with a compound of the general formula III

SO ₂ -Yi

converts, with one of the radicals Y and Yi being the free amino group and the other one against represents an amino group exchangeable radical, Z represents the amino group or a by Represents reduction or hydrolysis into the amino group convertible substituents Zi, or b) a compound of the general formula IV

SO ₂ -NH

CH ₂ -O- CH ₃

where Z has the meaning given and X is a halogen atom or an ammonium group means, reacts with a methylate

and in compounds obtained according to procedures a) and b) which contain the radical Zi, in the p-position of the benzene nucleus forms and / or maintains the amino group by reduction or hydrolysis Cleaves and / or obtained bis-p-Z-benzenesulfonyl compounds to give the monop-Z-benzenesulfonyl compounds free compounds by adding bases to their salts or salts obtained by treatment converted into the free compounds with acidic agents.

These reactions take place in a manner known per se with those known from sulfonamide chemistry Groups. So you can z. B. a p-Z-benzenesulfonic acid, preferably in the form of its reactive functional acid derivatives, such as a p-Z-benzenesulfonic acid halide or anhydride, especially that Chloride, in which Z has the meaning given above, with a compound of the general formula II convert, wherein Y stands for the free amino group. The usual condensing agents can be used here be e.g. B. alkali carbonates, but especially tertiary organic bases such as pyridine, picoline, Lutidine, collidine, lower trialkylamines, such as trimethylamine or triethylamine, or N, N'-tetraalkyldiaminoalkanes, z. B. N, N'-tetramethyl-w, cu'-diaminohexane, or the aminopyrimidine itself and optionally the usual diluents such as water, benzene, toluene, methylene chloride, chloroform, Methyl ethyl ketone, acetone, dioxane and nitrobenzene or mixtures thereof. Here you can depending on the reaction conditions, such as the presence of condensing agents or diluents, the reaction temperature or the use of an excess of sulfonic acid halide, bis-p-Z-benzenesulfonyl compounds as by-products or for The main thing is to gain in a manner known per se, possibly simultaneously with the conversion from Z into the amino group, into the monop-Z-benzenesulfonyl compounds.

So the bis-compounds z. B. by hydrolysis or aminolysis, optionally simultaneously with any hydrolysis of the radical Zi. converted into the mono compounds.
However, compounds of the general formulas II and III can also be reacted with one another in the customary manner, in which Yi is the free amino group and Y is a free or appropriately substituted, such as alkylated or benzylated mercapto group, a methoxy group, an alkylsulfonyl group, such as methylsulfonyl group, an ammonium group or a Means halogen atom. It is advantageous to start from 6-halo-2- (methoxymethyl) -4-methoxypyrimidines, such as from 6 - chloro - 2 - (methoxymethyl) - 4 - methoxypyrimidine, or from 6-ammonium-2- (methoxymethyl) -4-methoxypyrimidine salts, such as From 6 - trialkylammonium - 2 - (methoxymethyl) - 4 - methoxypyrimidine salts, e.g. B. from the halides. If 6 - halogen -, - alkylsulfonyl or ammonium compounds are used, mandasp-Z-benzenesulfonic acid amide is expediently used in the form of a metal salt, e.g. B. an alkali or alkaline earth metal salt, or works in the presence of such salts forming condensation agents. When using the 6-alkylsulfonyl or 6-ammonium-2- (methoxymethyl) -4-methoxypyrimidines, the use of an acid amide, such as a lower alkanoyl amide, e.g. B. acetamide or dimethylformamide, proven to be particularly advantageous as diluents. The last-mentioned processes, starting from the 6-halogen-, -alkylsulfonyl- or -ammoniumpyrimidines, have the advantage that they can be carried out very well with pZ-benzene-sulfonic acid amides, in which Z represents the free amino group, while Z is expedient in the other processes represents a radical Zi which allows the formation of the amino group.

Any subsequent conversion of the radical Zi into the amino group takes place in and of itself known way.

The radical X in a compound of the general formula IV is z. B. a chlorine or bromine atom or a trialkylammonium group, which in a known manner with a methylate, for. B. a Alkali metal methylate which can be converted into the methoxy group.

Zi radicals which can be converted into the amino group by hydrolysis are, for. B. acylamino groups especially aliphatic acylamino groups such as carbalkoxyamino groups, e.g. B. the carbethoxyamino group, Alkanoylamino groups, such as the propionyl, butyryl or caproylamino group, but above all the acetylamino group, dihalophosphorylamino groups, e.g. B. the dichlorophosphorylamino group, or methylidene amino groups, such as. B. alkylidene or benzylidene amino groups, especially the isopropylidene or benzylidene amino group. The acyl radicals in the acylamino groups can also be acyl radicals be of dibasic acids. So you can

also starting materials of the general formulas III a and IVa

Yi

SO ₂ -Yi

SO ₂ -NH

IIIa

CH ₂ OCH ₃

IVa

CH ₂ OCH ₃

- "ΜΉ— V

SO ₂ -NH

N-

15th

20th

use where R is the acyl radical of a dibasic acid, especially carbonic acid, or z. Belly represents an alkanedicarboxylic acid and Yi and X have the meanings given.

A radical that can be converted into the amino group by reduction is, for example, one by hydrogenolysis cleavable acylamino group, such as the carbobenzoxyamino group, or the nitro group or an azo group, such as aryl group, especially the phenylazo group, in the latter case especially Compounds of the general formulas IIIb and IVb

35

IIIb

40

ι —NH

CH ₂ OCH ₃

IVb

-SO ₂ -NH

✓CH ₂ OCH ₃ N X '

45

50

can be used as starting material, in which Yi and X have the meanings given.

The hydrolysis, aminolysis or reduction of the groups mentioned are known per se Way done.

A particularly advantageous way of working is that one p-acetylamino-benzenesulfochloride reacted with 6-amino-2- (methoxymethyl) -4-methoxypyrimidine and hydrolyzed the condensation product.

Depending on the process conditions and starting materials, the end product is obtained in free form or in the form of its salts. Specifically, metal salts are to be mentioned as salts, in particular those with Alkali, alkaline earth or earth metals such as sodium, potassium, calcium, magnesium or aluminum. the Salts of the new compound can be converted into the free compound in a manner known per se are with acidic agents, e.g. B. with acids. On the other hand, the free sulfonamide obtained can through Reaction with bases, in particular with therapeutically suitable bases, such as hydroxides of alkali, Alkaline earth or earth metals, e.g. B. sodium, potassium or calcium hydroxides, converted into its salts will.

These or other salts of the new compound can also be used to purify the sulfonamide compound obtained serve by converting the free sulfonamide into a salt, separating this and off the salt in turn releases the free sulfonamide.

Some of the starting materials are known or, if they are new, can be based on known ones Methods are obtained.

The invention is illustrated in the following examples.

example 1

To a solution of 8.5 g of 2- (methoxymethyl) -4-methoxy-6-aminopyrimidine in 75 cm ^{3 of} pyridine, 13 g of p-acetylamino-benzenesulfonyl chloride are added with stirring over the course of 30 minutes. After the reaction has subsided, the mixture is heated to 90 ° C. for 1 hour. 750 cm ^{3 of} water are then added and the pH is adjusted to about 2 by adding concentrated hydrochloric acid while cooling with ice. The deposited precipitate is boiled for 2 hours with 500 cm ^{3 of} 2 η sodium hydroxide solution, the alkaline solution is filtered off and the filtrate is neutralized with concentrated hydrochloric acid while it is still warm. The 6- (p-aminobenzenesulfonamido) -2- (methoxymethyl) -4-methoxypyrimidine formed separates out in crystalline form. After recrystallization from alcohol, it melts at 139 to 140 ° C.

The 2-methoxymethyl-4-methoxy-6-aminopyrimidine used as the starting material can be manufactured as follows in a manner not claimed:

38.6 g of 2 - (methoxymethyl) - 4,6 - dichloropyrimidine are reacted with 250 cm ^{3 of} 12% ammoniacal ethanol in an autoclave for 10 hours at 80 ^° C. After cooling, the mixture is evaporated to dryness. From the residue 2 - (methoxymethyl) - 4 - chloro - 6 - aminopyrimidine is obtained in white needles by recrystallization from water, mp 102 ° C.

17.3 g of 2- (methoxymethyl) -4-chloro-6-aminopyrimidine are ^{dissolved in 150 cm 3 of} methanol in an autoclave and 10.8 g of sodium methylate are added. The reaction mixture is kept shaking at 120 ^° C. for 10 hours and then evaporated to dryness after cooling. The 2- (methoxymethyl) -4-methoxy-6-aminopyrimidine melts at 93 to 94 ° C.

Example2

8.5 g of 2- (methoxymethyl) -4-methoxy-6-aminopyrimidine are dissolved in 75 cm ^{3 of} pyridine, and 12 g of p-nitrobenzenesulfonyl chloride are added in portions. After the exothermic reaction has subsided, the solution is stirred for a further 24 hours, poured onto ice and acidified to a pH of 2 to 3 with concentrated hydrochloric acid. The precipitate is dissolved in 250 cm ^{3 of} 70% ethanol with the addition of sodium hydroxide solution and hydrogenated with Raney nickel as a catalyst. The catalyst is filtered off, the solution evaporated to dryness, with a little

Claims (1)

Water digested and filtered off again. After recrystallization from ethanol, 6- (p-aminobenzene sulfonamido) - 2 - (methoxymethyl) - 4 - methoxypyrimidine obtained, mp 139 to 140 ° C. Example3 34.4 g of sulfanilamide, 27.6 g of potassium carbonate and 12 g of acetamide are heated ^{together to about 120 ° C. while stirring.} 18.8 g of 2- (methoxymethyl) -4-methoxy-6-chloropyrimidine are added dropwise to this over a period of 10 minutes, and the mixture is stirred at 140 ° C. for a further 2 hours. The cooled mass is ^{treated with 75 cm 3 of} water and clarified at 90 ° C. using activated charcoal. The pH of the filtrate is adjusted to 8 to 8.2 and the mixture is cooled to 15 ° C. The unreacted sulfanilamide is filtered off and the filtrate is stirred into ice water in acetic acid so that the pH always remains about 5. The 6- (p-aminobenzenesulfonamido) -2- (methoxymethyl) -4-methoxypyrimidine which is identical to the product prepared in Example 1 thus precipitates. Example 4 16.4 g of 6- (p-aminobenzenesulfonamido) - 2 - (methoxymethyl) - 4 - chloropyrimidine are reacted with 13.5 g of sodium methylate in 250 cm ^{3 of} methanol at 160 ° C. for 24 hours in a sealed tube. The solution is concentrated to 100 cm ³ . Stirring into water and neutralizing with acetic acid gives 6 - (p-aminobenzenesulfonamido) -2 - (methoxymethyl) -4-methoxypyrimidine, which is identical to the product prepared in Example 1. The 6- (p-aminobenzenesulfonamido) -2 - (methoxymethyl) -4-chloropyrimidine used as the starting material can be obtained in unclaimed fashion as follows: 355 g of methoxyacetonitrile are added to 300 cm ^{3 of} ethanol and hydrogen chloride, dried over concentrated sulfuric acid, is passed in at O ^{a C until saturation.} The reaction mixture is left to stand in the refrigerator at + 5 ° C. overnight. It is then quickly filtered off with suction and the still ether-moist methoxyacetimino-ethyl ether hydrochloride is introduced into 500 cm ^{3 of} 12% strength ammoniacal ethanol with cooling. After shaking for 12 hours, the precipitated ammonium chloride is filtered off and the filtrate is concentrated in vacuo at 50.degree. The methoxyacetamidine hydrochloride crystallizes out and, after recrystallization from ethanol-ether, melts at 70.degree. 148 g of this amidine hydrochloride are dissolved together with 160 g of malonic acid diethyl ester in 300 cm ^{3 of} methanol; at 50 ° C., a sodium methylate solution composed of 69 g of sodium and 700 cm ^{3 of} methanol is added dropwise with stirring over the course of one hour, and the mixture is stirred at this temperature for 12 hours. The reaction mixture is evaporated to dryness in vacuo, the residue is dissolved in hot water and the solution is neutralized with glacial acetic acid. On cooling, the 4,6-dihydroxy-2- (methoxymethyl) pyrimidine separates out in crystalline form. The substance decomposes at 210 ° C 78 g of this compound are ^{heated together with 300 cm 3 of} phosphorus oxychloride and 101 g of triethylamine at 140 ° C. in an oil bath I ¹ I for ₂ hours. The 2- (methoxymethyl) -4,6-dichloropyrimidine is obtained directly in pure form, mp 41 ^° C., by fractional distillation. A mixture of 19.3 g of 2- (methoxymethyl) -4,6-dichloropyrimidine, 17.2 g of p-aminobenzenesulfonamide and 13.8 g of anhydrous potash is heated to 150 ° C. for 2 hours, carbon dioxide being released with foaming. On cooling, the reaction mixture solidifies, 150 cm ^{3 of} water are added, the undissolved p-aminobenzenesulfonamide is separated off and the filtrate is neutralized with concentrated hydrochloric acid, the 6- (p-aminobenzenesulfonamido) -2- (methoxymethyl) -4-chlo ^ yrimidine fails. It is purified by boiling with water and recrystallization from alcohol, mp 150 to 151 ^cC Example 5 3.9 g of 6- (p-aminobenzenesulfonamido) -2- (methoxymethyl) - 4 - (trimethylammonium) - are reacted for 8 hours in a bomb tube with 0.6 g of sodium methylate in 50 cm ³ of absolute methanol at ⁰ C IOO chloride - pyrimidine. The solution is concentrated and stirred into water. Neutralization with acetic acid gives the 6- (p-aminobenzenesulfonamido) -2- (methoxymethyl) -4-methoxypyrimidine identical to the product prepared in Example 1. The 6- (p-aminobenzenesulfonamido) -2- (methoxymethyl) -4- (trimethylammonium) pyrimidine chloride used as starting material is obtained in a manner not claimed if 8.2 g of 6 - (p -aminobenzenesulfonamido) - Leave 2 - (methoxymethyl) -4-chloropyrimidine with 40 cm ^{3 of} 8.5% benzene trimethylamine solution for 3 days, distill off the benzene in vacuo, shake the residue with 100 ml of absolute ether, the yellow impurity dissolving, and the salt slips off. Claim: Process for the preparation of 6- (p-aminobenzenesulfonamido) -2 - (methoxymethyl) -4-methoxypyrimidine of formula I. H ₂ N SO ₂ -NH CH ₂ -O-CH ₃ OCH ₃ and its salts, characterized in that either a) a compound of the general formula II CH ₂ - O - CH ₃ OCH ₃ with a compound of the general formula III converts, one of the radicals Y and Yi being the free amino group and the other being one represents a radical exchangeable for an amino group, Z represents the amino group or