NO751158L - - Google Patents

Description

Procedure for manufacturing new ones

organic compounds.

The present invention relates to a process for the production of new diaminopyridines of formula I

in which R and R' are the same or different and in each case means a secondary or tertiary alkyl group with up to 7 carbon atoms, R^ stands for hydrogen or an alkyl group with 1-4 carbon atoms, and either R£ means hydrogen if R^ stands for hydrogen, or R2 means hydrogen, chlorine or bromine if R^ stands for an alkyl group with 1-4 carbon atoms, R^ means hydrogen, a cyano group or a residue of formula -COR^, in which R^ means amino, an alkyl group with 1- 4 carbon atoms or a residue of formula II

in which either R^, R^ and R^ are the same or different and in the individual case means hydrogen, fluorine, chlorine, bromine or an alkyl or an alkoxy group with in the individual case 1>-3 carbon atoms, with the condition that R^, R^ and R^ do not stand for halogen

i or to sti 11 ing of the phenyl residue or 2 of the substituents R,-, R^ and R^, if these are located on neighboring carbon atoms, together mean a methylenedioxy group, and the second of these substituents has the above meaning, with the condition that if R^ stands for a cyano group, R and R<1> are the same or different and mean in the individual case a tert.alkyl residue with 4-7 carbon atoms.

The compounds of formula I can be transferred in their salts and vice versa.

The peculiarity of the method according to the invention is that either

a) compounds of formula Ia,

wherein R, R<1> and R^ have the above meaning and R^1 has that

the same meaning as R^, with the exception that this cannot stand for an alkanoyl group, is prepared by compounds of the formula

III

in which R^ and R^<1> have the above meaning and either X and X' are the same or different and in each case stand for chlorine

or bromine, or one of the substituents X and X<1>means chlorine or bromine and the other stands for R-NH- or R'-NH-, in which R and R<*>have the above meaning, are reacted with an amine or an amine mixture of formula IV

in which R/R' has the above-mentioned meaning, b) or compounds of formula Ib^ in which R and R' have the above-mentioned meaning, R^<»> means an alkyl group with 1-4 carbon atoms and R^• stands for an alkyl group with 1-4 carbon atoms or represents a residue of formula II, is prepared by reacting compounds of formula Va in which R and R^' have the above meaning in the presence of a strong base with compounds of formula VI

wherein R' and R^<1> have the above meaning, or

c) compounds of formula IS

in which R, R', R^ and have the above meaning, are produced

in that compounds of formula Id

\ in which R, R R^ and R^ have the above meaning and R^" stands for an alkyl group with 1-4 carbon atoms, is hydrolyzed or

d) compounds of formula le

in which R, R<1>, R^1 and R^ have the above meaning, and R^ 1 stands for chlorine or bromine, are prepared by compounds of formula If

in which R, R', R^1 and R^ have the above meaning, are chlorinated or brominated in an inert organic solvent, or

e) compounds of formula lg

in which R, R', and R^ have the above meaning and R^<1>" means an alkyl group with 1-4 carbon atoms, are prepared by compounds of formula VIII,

in which R, R', R^ and R^•<1> have the above meaning, are hydrolyzed.

The procedure specified under a) can be carried out as described

in the following:

The reaction of the compounds of formula III with the compounds

with formula IV conveniently takes place at temperatures from 20 to 200°C, preferably at 160 to 180°C, as it is preferred to carry out the reaction at higher temperatures if amines with formula IV are used, with a large volume and steric hindrance, e.g. .tert.alkylamines. The reaction conveniently takes place in an inert organic solvent, e.g. an alkanol with 1-4 carbon atoms, e.g. ethanol. Instead of an inert organic solvent, an excess of the amine can form the reaction medium.

With the help of the reaction, two amino groups can be introduced, if in the compounds of formula III X and X' in the individual case stand for chlorine or bromine, or mean a single amino group if one of these substituents already means an amino group.

If two amino groups are introduced, two equivalents of the compounds of formula IV are used and if one amino group is introduced, at least one equivalent of the compounds of formula IV is used. A small surplus e.g. 10% of the amino component is suitably used as an acid-binding agent.

In the compound of formula III, X and X' are, if they mean halogen, preferred to chlorine. If in the desired end products R and R' are different, and X and X<*> in the starting compounds with formula III in the individual case means chlorine or bromine, a mixture of amines with formula IV is used, whereby a mixture of end products. These can be separated in a manner known per se. For the production of such mixed-substituted compounds, it is however appropriate to use compounds of formula Illa as starting compounds

in which R.^ and 1 have the above meaning and either X^ stands for chlorine or bromine and X1' stands for R'-NH- or X1 stands for R-NH- and X' stands for chlorine or bromine. However, these starting compounds can also be used for the preparation of compounds of formula Ia, in which R and R' are the same. Compounds of formula Illa can be prepared by reacting compounds of formula IIIb in which R 1 and R 1 have the above-mentioned meaning and X 2 and X 2 1 are the same or different and in the individual cases stand for chlorine or bromine, with an amine of formula IV . The reaction of the compounds of formula IIIb with the compounds of formula IV is suitably carried out at temperatures of 20 to 25°C, suitably in an inert organic solvent such as e.g. an alkano1 with 1-4 carbon atoms, especially ethanol. The reaction, in which the compounds of formulas IIIb and IV are suitably used in a ratio of 1:1, leads to a mixture of compounds of formula IIIa, in which either X represents an amino group, which corresponds to the compound IV used, or leads to a compound with formula Illa, in which X1<1> stands for an amino group, which corresponds to the compound of formula IV used. The composition of this mixture depends on the nature of the amine used. E.g. relatively sterically unhindered amines will preferably replace the hydrogen atom in the 2-position. In any case, the individual isomers for use in method a) can be separated and purified in a manner known per se. The procedures specified under section b) can be carried out as described in the following

The strong bases used in the reaction of the compounds of formula Va with the compound of formula VI are e.g. a lower alkyl-. lithium, e.g. methyl or n-butyl lithium, sodium or potassium lower alkoxides, e.g. sodium methoxide or potassium t-butoxide, alkali metal hydroxides, e.g. lithium, sodium or potassium hydroxide, metal hydrides such as sodium or calcium hydride, and lithium di-isopropylamides, preferably the latter or n-butyllithium. An equivalent of the base calculated on the compounds of formula VI is preferably used. The reaction is suitably carried out at temperatures from 15 to 60°C, preferably from 20 to 30°C under an inert gas atmosphere, preferably a nitrogen atmosphere. The reaction conveniently takes place in an inert organic solvent, e.g. an acyclic ether of 5-10 carbon atoms,

a cyclic ether, e.g. p-dioxane or tetrahydrofuran, a 2-lower alkoxyethyl ether, e.g. bis-2-methoxyethyl ether or bis-2-ethoxyethyl ether, and a lower alkyl ether of ethylene glycol, e.g. 1,2-dimethoxyethane, 1,2-diethoxyethane or 1-ethoxy-2-methoxyethane. Tetrahydrofuran and p-dioxane are preferred. Mixtures of these solvents with alkanes, e.g. with 6-10 carbon atoms,

can also be used. The reaction time can e.g. 30

to 180 minutes, especially 30 to 120 minutes. The molar ratio between the amidine of formula VI and the ketoketonimide of formula V conveniently amounts to -l^l even if a small excess, e.g. up to 10% of the latter can also be used. When carrying out method b), non-identifiable by-products are often obtained. The desired connections with

formula Ib can, however, be isolated from the mixture in a manner known per se. The by-products can, however, suitably, after isolation, also be transferred into the compounds of formula Ib. For this purpose, the by-products are heated at temperature

of 35 to 70°C, preferably 40 to 60°C in an inert organic solvent, e.g. a solvent as described above for method b), or a lower alcohol, such as ethanol, methanol or isopropanol, or an aqueous mixture. The heating should preferably be carried out for 1 to 60, preferably 5 to 30 minutes.

The starting compounds of formula VI can conveniently be obtained

in that compounds of formula V

wherein ' and R' have the above meaning, or a compound of formula VII

in which R' and R^<1> have the above meaning and A~ is an anion which does not participate in the reaction, e.g. a perchlorate, tetrafluoroborate, methyl sulfate, ethyl sulfate, bisulfate, chloride, bromide, iodide or p-toluenesulfonate, is reacted with ammonia.

The reaction of the compounds of formula V or the compounds of formula VII with ammonia is conveniently carried out in an inert organic solvent, e.g. methylene chloride, using anhydrous liquid ammonia for this. The reaction conveniently takes place at temperatures of -40 to -60°C with stirring, e.g.

for 5 to 60 minutes. The turnover conveniently takes place in an inert gas atmosphere, e.g. nitrogen atmosphere.

The compounds of formula V, including those compounds of formula

Va, which in the method under section b) are used as starting compounds, are either known or can be prepared in a manner known per se from known starting compounds. A suitable method consists in that corresponding compounds of formula VII are reacted with a base using that of Woodward et

al., in J. Am. Chem. Soc. 88, 3169-3170, described method. The method is preferably carried out so that a triethylamine is used as a base and methylene dichloride as an inert organic solvent. For this reaction, temperatures of -10 to 0°C are appropriate, and the reaction time can e.g. make between 15 minutes and 4 hours. Ammonia can also be used for this purpose, although this is not preferred if it is desirable to isolate the compounds of formula V, since ammonia reacts with these as described above and thereby gives compounds of formula VI.

The obtained compounds with formulas V and VI can be isolated and

cleaned in a manner known per se.

Both starting compounds in method b) can be obtained by treating compounds of formula VII with ammonia. An alternative to method b) therefore constitutes the production of these starting materials in situ and possibly only as a temporary intermediate product. In this process variant, a compound of formula VII is treated. with ammonia conveniently at temperatures of 15 to 30°C, preferably 15 to 25°C. The turnover is carried out appropriately using

anhydrous ammonia in an inert organic solvent. Suitable solvents are halogenated lower alkanes such as methyl dichloride, 1,2-dichloroethane, 1,2-dibromoethane, chloroform, 1,1,1-trichloroethane -

and 1-bromo-2-chloroethane, dialkyl ethers with 5-10 carbon atoms, cyclic ethers such as p-dioxane or tetrahydrofuran, N,N-dimethylacetamide and formic acid amides, e.g. formamide and its mono- or di-lowers

alkyl derivatives, such as N-ethylformamide',.. N./.N-dimethylformamide or diethyl-formamide or N-methyl-N-ethylformamide. Halogenated lower alkanes, especially methylene dichloride are preferred. The reaction is suitably carried out in an inert gas atmosphere, e.g.

in a nitrogen atmosphere, and the reaction time is e.g. 2 to 10

days, especially 3 to 5 days. The ratio between ammonia and compounds of formula VII can be up to 3:2, but it is preferred to add ammonia in a large 5- to 200-fold excess.

The procedure specified under c) can be carried out as described

in the following:

The hydrolysis of the compounds of formula Id can be carried out on i

and known manner, e.g. using aqueous mineral acids, e.g. hydrochloric acid, or organic acids, e.g. methanesulfonic acid. The procedure conveniently takes place in an inert organic solvent, e.g. a lower alcohol, such as methanol,

and suitably at temperatures of 50 to 70°C, preferably at the boiling temperature of the reaction mixture. The reaction time can e.g. make 90 minutes to 5 hours, especially 150 minutes to 4 hours. Preferably, from 1.02 to 1.1 equivalents of acid and from 1.2 to 2 equivalents of water are used. The hydrolysis can also suitably be carried out with a base, e.g. hydroxylamine hydrochloride, the reaction temperature being suitably 20 to 50°C, preferably 20 to 30°C and the reaction time e.g. 5 to 120 minutes.

The method indicated under section d) can be carried out as described in the following: The chlorination or bromination of the compounds of formula If is suitably carried out using N-chloro- or N-bromosuccinimide as chlorinating or brominating agent. Instead of these chlorinating or brominating agents, a solution of gaseous chlorine or liquid bromine in an inert organic solvent can also be used for this purpose. The reaction temperature should suitably be 0 to 30°C, preferably

20 to 25°C if N-chloro- or N-bromosuccinimide is used and from

0 to 10°C if chlorine or bromine is used. Suitable solvents are lower alkanols such as ethanol and carbon tetrachloride, or if chlorine or bromine are used, glacial acetic acid. The reaction duration can be from 5 to 12 hours, preferably from 1 to 3 hours.

The procedure specified under paragraph one can be carried out as described in the following:

The hydrolysis of the compounds of formula VIII can be carried out

in a usual way for the hydrolysis of animiras to ketones, e.g. using an acid, preferably acetic acid. Preferably, a dilute acid is used, especially a 0.01 to 0.1 N acetic acid. The reaction temperature is preferably 60 to 100°C and the reaction times from 5 to 120 minutes.

The obtained compounds of formula I can be isolated and purified in a manner known per se.

The method described under section b) is preferably used for the preparation of compounds of formula Ib, in which one or both substituents R and R' stand for tert-alkyl.

The compounds with formulas III, IV and VII which are used as starting compounds are either known or can be prepared in a manner known per se from known starting compounds, e.g. as described in the following example 2a) for the compounds of formula VII.

The compounds of formula VIII, which are used as starting compounds in method e), can e.g. is prepared by reacting a compound of formula Ihn, in which it has the above meaning and RQ and R • are the same or different and in the individual case a secondary or tertiary alkyl with up to 7 carbon atoms, in an inert organic solvent with compounds of formula IX

in which R^<11>' has the above-mentioned meaning and Q stands for lithium-magnesium bromide or -magnesium chloride and the resulting adduct is then hydrolysed.

The turnover of the compounds of formula Ihn with the compounds

with formula IX can be carried out in a usual manner for the conversion of a nitrile into an imine by means of a Grignard reaction. Preferably, at least 3, preferably 3.01 to 20 equivalents of the compounds of formula IX are used for the reaction, and the reaction is conveniently carried out at temperatures from 0 to 100°C, preferably at the boiling temperature of the reaction mixture. Suitable solvents are ethers, such as tetrahydrofuran, or diethyl ether, especially their mixtures, and the reaction duration can e.g. make 2 to 24 hours. The subsequent hydrolysis can e.g. carried out in a way usual for the hydrolysis of lithium or Grignard adducts, e.g. using aqueous ammonium chloride, at temperatures of e.g. -10 to 0°C.

If desired, the obtained compounds of formula VIII can be isolated and purified in a manner known per se. However, the compounds are obtained in situ and can thus also be used without further purification in the next method step.

The compounds of formula Ihn, which are used for the preparation of the starting compounds under section e), are outside the scope of protection according to formula I and are either known or can be prepared in a manner known per se from known starting material, e.g. using a method analogous to method a).

The compounds of formula I are distinguished by an extremely favorable therapeutic effect. In particular, the compounds of formula I are distinguished by an anti-obesity effect and an anti-diabetic effect. The compounds can then be used to combat obesity and as antidiabetics. The daily dose of the compounds of formula I should be from 75 to 1500 mg, which can also be administered in smaller amounts of 20 to 750 mg 2-4 times a day or in slow-release form. A preferred daily dose is from 150 to 450 mg, possibly supplemented in 3

doses of 50 to 150 mg or in slow-release form.

The compounds of formula I can be supplied in the form of the free bases or in the form of their pharmaceutically acceptable acid addition salts which have the same degree of action as the free bases. Acids suitable for salt formation are hydrochloric acid, hydrobromic acid and methanesulfonic acid.

The compounds of formula I can be mixed with usual pharmaceutically acceptable diluents or carriers and can be mixed together with other additives and supplied in the form of capsules.

The preferred meanings of R, R<1>, R^, R^ and R^ are the following: R: tert.alkyl with 4-7 carbon atoms, preferably 4-6 carbons atoms, especially tert.butyl,;

R': tert.alkyl with 4-7, preferably 4-6 carbon atoms, in particular

tert.butyl,;

R^: alkyl with 1-4, preferably 1-3 carbon atoms, especially ethyl

or methyl,

R2: hydrogen or bromine, preferably hydrogen,

R3: hydrogen, cyano or -C0R41'1 in which R^'' means alkyl with 1-4 carbon atoms, especially 1-3 carbon atoms, amino or a group of formula IIa, in which R5<1> and • are the same or different and in the individual case means hydrogen, ethyl, methyl, methoxy or ethoxy.

R has preferably the same meaning as R' and R' has in particular a different meaning than cyano or carboxymethyl bg preferably stands for hydrogen, acetyl, propionyl or 4-methoxy-»-benzoyl.

The particularly preferred linking groups are those which combine the above meanings, especially those which constitute a combination of all preferred meanings. The particularly preferred compound is 3-acetyl-2,6-di-t-butyl-amino-4-methylpyridine.

Example 1; 2, 6- di- t-butylamino- 3- cyano- 4- methyl- pyridine

1 g of 2,6-dichloro-3-cyano-4-methylpyridine and approximately 40 ml of t-butylamine (distilled over sodium hydride) heated in an autoclave at 200°C for 5 hours. A further heating for 4 hours at the same temperature does not lead to any change in the reaction mixture. The reaction mixture is set aside overnight and then evaporated under reduced pressure. This results in a rubbery residue. This gummy solid residue is partitioned between water, containing small amounts of sodium carbonate, and chloroform and the aqueous phase is then extracted twice with chloroform. The three chloroform phases are combined, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is dissolved in 10 ml of chloroform and the solution is diluted with hexane to 70 ml. The small amount of crystals thus formed is filtered off and the filtrate is introduced into a column in which there is a slurry of 50 ml of silica gel in hexane containing 20% chloroform, the elution taking place with the same solvent mixture. The first 130 ml of the eluate is discarded and the subsequent 100 ml of eluate is evaporated, whereby 6-t-butylamino-2-chloro-3-cyano-4-methylpyridine with a melting point of 109°C is obtained.

The next fractions containing the desired compound are combined, evaporated under reduced pressure and hexane is added. After removal of hexane at reduced pressure, the residue is crystallized in a refrigerator whereby 2,6-di-t-butylamino-3-cyano-4-methylpyridine with a melting point of 134-138°C is obtained.

Example 2:

Using the method described in example 1 and suitable starting compounds in approximately equivalent quantities, the following compounds are obtained: a) 2,6-di-t-butylamino-3(4'-methoxybenzoyl)-4-methylpyridine with melting point 12 7 -129°C, b) 2,6-di-t-butylamino-4-methylpyridine whose methanesulfonate melts at 179-182°C,

c) ,2,6-di-t-butylaminopyridine,

d) 3-benzoyl-2,6-di-t-butylamino-4-methylpyridine,

e) 2,6-di-t-butylamino-3-(4'-methylbenzoyl)-4-methylpyridine,

f) 2,6-di-sec.-butylamino-4-methylpyridine,

g) 2-α-amylamino-6-t-butylamino-4-methylpyridine and

h) 2,6-di-t-butylamino-3-carbamoyl-4-methylpyridine.

Example 3: 3-acetyl-2,6-di-t-butylamino-4-methylpyridine

a) 2-t-butyl-5-methylisoxazolium

A mixture of 1 kg of 5-methylisoxazole and 892 g of t-butanol is stirred under nitrogen at 0°C and then slowly added over 2*2 hours with vigorous stirring at 0 to 5°C 6.37 kg of 60%^ '/ perchloric acid . The resulting suspension is allowed to reach room temperature and stirred overnight. The reaction mixture is then added slowly to a mixture of 20 1 tetrahydrofuran and 10 liters at 0 to 10°C over the course of 2 hours with stirring. The resulting mixture is then cooled to -5°C and then stirred for a further 2 hours. The thereby precipitated 2-t-butyl-5-methylisoxazolium perchlorate is filtered off and washed with ether. The compound melts at 120 to 122°C. A further amount of the compounds is obtained from the mother liquor. This amount melts at 118 to 121°C.

b) N-t-butyl-3-hydroxybu^

I) A solution of 100 g of 2-t-butyl-5-methylisoxazolium perchlorate

in 200 ml of methylene chloride is added with stirring to a mixture of 60 ml of anhydrous ammonia and 240 ml of methylene chloride at -50°C in a nitrogen atmosphere. The reaction mixture is then set aside to assume room temperature and then washed with a saturated sodium chloride solution. The methylene chloride phase is dried over anhydrous magnesium sulfate. After removal of the methylene chloride at reduced pressure, a residue is obtained. It is recrystallized from ethyl acetate to obtain N•-t-butyl-3-hydroxybutenamidine with a melting point of 118-120°C. Upon further recrystallization from ethyl acetate, a melting point of 126-129°C is obtained.

II) A solution of 900 g of 2-t-butyl-5-methylisoxazolium perchlorate

in 1.8 l of methylene chloride, which was dried over alumina, is added a mixture of 900 ml of freshly distilled ammonia and 900 ml of methylene chloride which was dried over alumina, with -50 to

-60°C with stirring. The reaction mixture is then set aside until it has reached room temperature and stirred overnight. Excess ammonia is removed using a suction device at 20

to 25°C over the course of 1 hour. The precipitate formed is filtered off and washed with methylene chloride. The combined filtrates and washing liquids are washed twice, each time with 2 1 of saturated aqueous potassium carbonate-

solution, dried over anhydrous sodium sulfate and filtered off. After removal of methylene chloride under reduced pressure and a temperature of approximately 45°C, a residue is obtained which, after recrystallization from ethyl acetate and washing with ethyl acetate/ether, gives N<1->t-butyl-3-hydroxybutenamidine with a melting point of 126-129°C. A further quantity which can likewise be obtained melts at 119-125°C.

c) 4-t-butylamino-3-buten-2-one

A mixture of 700 ml of triethylamine and 1.5 l of methylene chloride is dried

over aluminum oxide and cooled to a temperature of -10 to

-5°C. Next, <1> kg of 2-t-butyl-5-methylisoxazolium perchlorate is added in small portions over the course of 2 hours, while the temperature of the reaction mixture is kept at -5 to 0°C with vigorous stirring. After completion of the addition*, the reaction mixture is stirred for a further 1 hour at -5 to 0°C. The reaction mixture is then introduced into 38 1 of carbon tetrachloride at room temperature with vigorous stirring, an oily solid being precipitated. 7.5 kg of anhydrous sodium sulphate are then added and the reaction mixture is stirred for 30 minutes. The suspension is filtered off and the residue obtained is washed with carbon tetrachloride. The combined filtrates and washing liquids are evaporated at 50°C and reduced pressure whereby a dark orange-yellow oil is obtained. Distillation in high vacuum (0.8 mm Hg) at 54-55°C yields 4-t-butylamino-3-buten-2-one.

d) β-acetyl-2^6-di-t-butylamino-4^

I) 3.17 g of the N'-t-butyl-3-hydroxybutenamidine obtained in method step b) is suspended in 20 ml of tetrahydrofuran and the suspension is added to a mixture of 12.7 ml of a 1.6 molar solution of a butyllithium in hexane under nitrogen atmosphere. The subsequent exothermic reaction gives a solution with a temperature of 40°C. The solution is stirred at 30 tik 40°C for 45 minutes and then 2.8 g of the 4-t-butyl-imino-3-buten-2-one obtained in method step c) is added in 8 ml of tetrahydrofuran at 30 to 38°C , followed by a further addition of 2 ml of tetrahydrofuran. After 10 minutes a precipitate occurs. The agitation is continued further

35 minutes and the reaction mixture is set aside overnight, (thin layer chromatography of the reaction mixture after 45 minutes and the following morning is the same). The reaction mixture is cooled to -5°C and 2 ml of a saturated ammonium chloride solution is added to the mixture. Sufficient chloroform and a trace of methanol are then added, whereby a solution is formed. This is evaporated at reduced pressure, whereby a mixture of oil and solids is obtained. The mixture is distributed between chloroform and water and a small portion (approx. ^ g) of a white insoluble substance is filtered off. The aqueous phase is extracted again with chloroform and the chloroform phase is combined with the chloroform phase" from the initial distribution. The combined chloroform phases are dried over anhydrous magnesium sulfate, filtered and evaporated to a brown oil. The brown oil is dissolved in a small amount of methanol at 40 °C and up

water is added to the solution obtained until a permanent cloudiness occurs. Thereby 3-acetyl-2,6-di-t-butylamino-4-methylpyridine crystallizes out in the form of yellow needles. After washing with small amounts of a 1:1 mixture of methanol and water, the compound melts at 127-128°C.

N.M.R. (CDC13): 1.43 6 (9 Broton Singlet)

Section 1.47 (9 Proton-Singiett)

2.32 S (3 Proton Singlet)

2.43 (3 Proton Singlet)

4.60 S (1 wide Proifcon band replaceable)

5.47 (1 ^br ed >rqton Single)

9, 94 8 { 1 wide Proton band exchangeable)

I.R. (CHC13): 3440, 2985, 1720.(relatively weak), 1605-1580, 1525, 1450, 1420, 1390,

1360, 1290, 1210, 960 cm"<1>.

UV (CH,0H)Smaks222 ^ (£= 13.650)

* max 267 T (6= 15'°00)

max 286 m/(6= 10'670)

Amaks368 T (6= 20'500)

II) A mixture of 468 g of the N'-t-butyl-3-hydroxybutenamidine obtained in method step b) and 6 1 of anhydrous tetrahydrofuran is stirred under nitrogen at room temperature and then 1.92 1 of a 1.6 molar solution of n -butyllithium in hexane at such a rate that the reaction mixture remains at a temperature of 20 to 40°C. After the addition is complete, the reaction mixture is stirred at room temperature for a further 1 hour. A solution of 417 g of it is then added in process step

c) obtained 4-t-butylimino-3-buten-2-one in 2 1 anhydrous tetrahydrofuran dropwise while cooling so that the reaction temperature

remains at 20 to 25°C. After the addition is complete, the reaction mixture is stirred overnight at room temperature and then approximately 1.2 1 of a saturated aqueous ammonium chloride solution is added, whereby a voluminous off-white precipitate is formed. 12 1 of methanol and 12 kg of anhydrous sodium sulphate are then added and the reaction mixture is filtered through diatomaceous earth. The filtrate is evaporated under reduced pressure to dryness and the residue is dissolved in 25 1 chloroform. The chloroform solution is washed twice with 25 L of water and once with 25 L of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and filtered through silica gel. The clear yellow filtrate is evaporated to dryness at about 50°C under reduced pressure and 5 1 of petroleum ether are added while cooling.This gives 3-acetyl-2,6-di-t-butylamino-4-methylpyridine with a melting point of 127-129°C.

The free base of the compound can be converted into its hydrobromide by dropwise addition of a 1.6 N solution of gaseous hydrogen bromide in ether to a solution of the free base in ether at 0 to 10°C with subsequent stirring for 1 hour. The precipitate formed is washed with ether and extracted with chloroform. The extract is added to activated animal charcoal, ■ the mixture is filtered through diatomaceous earth, the filtrate is evaporated at reduced pressure and thereby the hydrobromide of 3-acetyl-2,6-di-t-butylamino-4-methylpyridine is obtained with a melting point of 172-175°C.

As described above, but with replacement of ethereal hydrogen bromide solution with a 5.5 N solution of gaseous hydrogen chloride in ether or a solution of methanesulfonic acid in ether, the hydrochloride of the above-mentioned compound with melting point 164-166°C and the methanesulfonate of the above-mentioned compound are obtained with melting point 118-121°C..

Example 4: 3-acetyl-2,6-di-t-butylamino-4-methylpyridine

a) Unidentified by-product

73.6 mL of a 1.622 M solution of n-butyllithium in hexane (119 mmol)

is added to a solution of 18.6 g of the N<1->t-butyl-3-hydroxybutenamidine obtained in method step b) in example 3 in tetrahydrofuran at 25 to 40°C under nitrogen. After completion of the first exothermic reaction, the reaction mixture is cooled to room temperature by stirring over the course of 1 hour. A solution of 16.6 g of the 4-t-butylimino-3-buten-2-one obtained in method step c) in example 3 in tetrahydrofuran is then added dropwise at room temperature (23-25°C). The reaction mixture is stirred overnight. Next, 4 ml of a saturated aqueous ammonium chloride solution is added, followed by sufficient methanol to obtain a cloudy solution. This is evaporated at reduced pressure. The residue obtained is distributed between chloroform and water and the insoluble white solid is isolated by filtration. This substance melts at 130°C (during decomposition).

Elemental analysis: C 55.8-56%

H 8.3-8.4%

N 11.7%

N.M.R. (CD3OD): $1.43 (Single)

1.47 S (Singlet)

2.23 S (Singlet)

4.80 S (Singlet)

I.R. (Nujol): 3370, 3280, 3120, 2880-2890, 1605, 1580,

1500, 1460, 1420, 1400, 1385, 1370,.1255,

1240, 1230, 1180, 1125, 1095, 1050, 1010,

990, 970 cm"<1>;

UV (methanol): 218 mja (6=4431% release)

264 mu (6=638 1% discharge)

365 mu (£,=6501% discharge)

The chloroform phase from the distribution between chloroform and water is dried and evaporated under reduced pressure, obtaining a brown solid. On treatment of the brown solid with methylene chloride is obtained

an insoluble solid with a melting point of 130°C (under decomposition).

b) 3-acetyl-2^6-di-t-butylamine-4-methyl

I) A small amount of the compound from reaction step a)

is recrystallized from methanol/water whereby 3-acetyl-2,6-di-t-butylamino-4-methylpyridine is obtained in the form of a yellow chloroform-insoluble precipitate with a melting point of 127-128°C (the melting point of a mixture of this compound with the same connection obtained in other ways is not discounted.

II) The compound obtained in method step a) is heated to boiling for 5 minutes in aqueous methanol. This precipitates yellow crystals which are filtered off and washed with a 1:1 mixture of methanol. The 3-acetyl-2,6-di-t-butylamino-4-methylpyridine thus obtained melts at 127-128°'©.

Example 5: 2,6-di-t-butylamino-3-(4'-methoxybenzoyl)-4-methylpyridine

a) N 3 -t-butyl-3-hydroxy-3-

N'-t-butyl-3-hydroxy-3-(4'-methoxyphenylj-propenamidine with

melting point 166-168°C can be obtained using the methods described in examples 3 a) and 3 b) using suitable starting compounds in approximately equivalent amounts.

b) 2^6-di-t-butylamino-3(4'-methoxybenzoyl)-4-methylpyridine

1.24 ml of a 1.6 molar solution of n-butyllithium in hexane is added

slowly a solution of 500 mg of N<1->t-butyl-3-hydroxy-3-(4'-methoxy-phenyl)-propenamidine in 10 ml of dry tetrahydrofuran which is stirred under nitrogen. The temperature in the reaction mixture rises during the addition to 35°C. The reaction mixture is stirred for 15 minutes and then 2.2 ml of a 1 M solution of the 4-t-butylamino-3-buten-2-one obtained using method step c) in example 3 in dioxane is slowly added. The reaction mixture is then stirred for a further 1 hour and .1 ml of a saturated aqueous ammonium chloride solution is added. The reaction mixture is extracted with chloroform and water and the chloroform extract is dried over sodium sulphate. After evaporation at reduced pressure, an oil is obtained. This is dissolved in ether and the ethereal solution is washed with 2 N hydrochloric acid and then twice with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is recrystallized from ether/heptane whereby 2,6-di-t-butylamino-3-(4'-methoxybenzoyl)-4-methylpyridine with melting point 127-129 oC is obtained.

Example 6: 3-acetyl-2,6-di-t-butylamino4-methylpyridine

About 60 ml of anhydrous ammonia is condensed in a container containing 60 ml of methylene chloride. The reaction mixture is kept at a temperature that does not exceed -30°C. A solution of 50 g of 2-t-butyl-5-methyl-isoxazolium perchlorate in 100 ml of methylene chloride is then quickly added. The reaction mixture is set aside until it has reached room temperature and is then stirred for 4 days at room temperature. The methylene chloride is then removed under reduced pressure, as a rubbery solid is formed which, after treatment with water, turns into a yellow solid. After recrystallization from methanol/water, 3-acetyl-2,6-di-t-butylamino-4-methylpyridine is obtained with a melting point of 128-129°C.

Example 7:

Using the method in one of examples 3-6 and suitable starting compounds in approximately equivalent amounts, one arrives at the compounds in example 3 (only analogous to example 5), 2a) (analogous to examples 3, 4 and 5), 2 b) and 2 e) and the following compounds:

a) 2,6-di-isopropylamino-4-ethyl-3-propionylpyridine/

b) 3-acetyl-2,6-di-t-amylamino-4-methylpyridine,

c) 2,6-di-t-butylamino-3-(4'-methylbenzoyl)-4-methylpyridine,

d) 2,6-di-t-butylamino-4-ethyl-3,-propionylpyridine and

e) 3-acetyl-2,6-di-(1,1-diethylpropylamino)-4-methylpyridine.

Example 8: 2,6-di-t-butylamino-4-methylpyridine

A mixture of 4.22 g of 3-acetyl-2,6-di-t-butylamino-4-methylpyridine, 1 ml of methanesulfonic acid and 0.5 ml of water in 50 ml of methanol and heated for 3 hours to boiling. That on cooling formed precipitates are filtered off and the filtrate is evaporated. By treating the residue with ethers, 2,6-di-fc-butylamino-4-methylpyridine-methanesulfonate is obtained with a melting point of 168°C (with cleavage). After recrystallization from ethyl acetate, the compound melts at 181-182° C. A further amount with a melting point of 179-181°C is obtained from the mother liquor.

Example 9:

Using the method described in example 8 and corresponding starting compounds in approximately equivalent amounts leads to the compounds in examples 2c), 2f) and 2g).

Example 10: 31-acetyl-5-bromo-2,6-di-t-butylamino-4-methylpyridine

534 mg of N-bromosuccinimide (recrystallized from water) is added in small portions to a solution of 831 mg of 3-acetyl-2, 6-di-t-butylamino-4-methylpyridine in 20 ml of carbon tetrachloride and 5 ml of ethanol and the reaction mixture is set aside over overnight at room temperature. The reaction mixture is evaporated under reduced pressure and the residue

is distributed between ether and water. The organic phase is dried over anhydrous sodium sulfate and evaporated under reduced pressure. This results in yellow crystals. After recrystallization from methanol/water, 3-acetyl-5-bromo-2,6-di-t-butylamino-4-methylpyridine with melting point 99-100°C is obtained.

Example 11:

Using the method described in example 10

and corresponding starting compounds in roughly equivalent amounts, 3-acetyl-5-chloro-2,6-di-t-butylamino-4-methylpyridine is obtained.

Example 12: 3-acetyl-2,6-di-t-butylaminopyridine

250 ml of a 0.4 molar solution of methyllithium in diethyl ether is added dropwise to a solution of 6 g of 3-cyano-2,6-di-t-butylaminopyridine in 350 ml of dry tetrahydrofuran at -15°C under stirring and nitrogen atmosphere. Then the mixture is set aside until it assumes room temperature and then it is heated for 4 hours to boiling. After boiling is finished, cool to 0°C and a solution of 17 g of ammonium chloride in 100 ml of water at -4 to -10°C is added to the mixture. Tetrahydrofuran and ether are removed under reduced pressure and the residue is distributed between methylene chloride and water. The methylene chloride layer is dried over anhydrous sodium sulfate and the methylene chloride is then removed under reduced pressure. The crude imine obtained (the compound of formula VIII) is then added to 100 ml of a 0.01 N acetic acid and the mixture is heated for 2 hours at 80°C. The mixture is then cooled and extracted with methylene chloride. The methylene chloride extract is evaporated under reduced pressure and the crude 3-acetyl-2,6-di-t-butylaminopyridine obtained is purified by chromatography on silica gel.

Claims (1)

Process for the preparation of new diaminopyridines of formula I in which R and R' are the same or different and in each case means a secondary or tertiary alkyl group with up to 7 carbon atoms, R^ stands for hydrogen or an alkyl group with 1-4 carbon atoms, and either R^ means hydrogen if R^ stands for hydrogen, or R^ means hydrogen, chlorine or bromine if R^ stands for an alkyl group with 1-4 carbon atoms, R^ means hydrogen, a cyano group or a residue of the formula -COR^, in which R^ means amino, an alkyl group with 1-4 carbon atoms or a residue of formula II in which either R^, R^ or R^ are the same or different and in the individual case means hydrogen, fluorine, chlorine, bromine or an alkyl or an alkoxy group with in the individual case 1-3 carbon atoms, with the proviso that R^ , R^ or R^ does not stand for halogen in the ortho position of the phenyl residue, or 2 of the substituents R^ , R^ and R^ , if they are on riabocarbon atoms, together mean a methylenedioxy group and a another of these subs ten tuents has the above-mentioned meaning, with the condition that if R^ stands for a cyano group, R and R' are the same or different and mean in the individual case a tert.alkyl residue with 4-7 carbon atoms, characterized by ata) compounds of formula Ia in which R, R' and R^ have the above meaning and R^ has the same meaning as R^ , with the exception that it does not stand for an alkanoyl group, is produced by compounds of formula III in which R^ and R^' have the above meaning and either X and X' are the same or different and in the individual case stand for chlorine or bromine, or one of the substituents X and X' means chlorine or bromine and the other stands for R -NH- or' R <*-> NH, in which R and R <1> have the above meaning, is reacted with an amine or an amine mixture of formula IV; in which R/R' has the above meaning, b) compounds of formula Ib ; in which R and R <1> have the above meaning, R^<1> means an alkyl group with 1-4 carbon atoms and R^ ' stands for an alkyl group with 1-4 carbon atoms or a residue of formula II, is produced by compounds of formula Va; in which R and R^<1> have the above meaning, in the presence of a strong base is reacted with compounds of formula VI; in which R' and R^' have the above meaning, c) . compounds of formula 16; "in which R, R', R^ and R_ have the above meaning, are prepared in that compounds of formula Id; in which R, R», R^ and R2 have the above meaning and R^" stands for an alkyl group with 1-4 carbon atoms, are hydrolyzed, d) compounds of formula le; in which R, R', R^<*> and R^ have the above-mentioned meaning and R2 ' stands for chlorine or bromine, are produced by compounds with the formula If in which R, R', R^<1> and R^ have the above meaning, are chlorinated or brominated in an inert organic solvent, or e) compounds of formula lg in which R,R' and R 1 have the above meaning, and R^1 1 1 means an alkyl group with 1-4 carbon atoms or phenyl, is prepared by that compounds of formula VIII in which R, R', R^ and R^ ''' have the above meaning, are hydrolyzed.