CZ22496A3 - Process for preparing substituted 4,6-diamino-5-c process for preparing substituted 4,6-diamino-5-cyanpyrimidines and their intermediates yanpyrimidines and their intermediates - Google Patents

Abstract

2-substituted 4,6-diamino-5-cyanopyrimidines of formula (I) wherein R1 is hydrogen, C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl and R2 is hydrogen, C1-C10alkyl or C3-C6cycloalkyl or R1 and R2 together are a radical, selected from the group of radicals, consisting of -(CH2)3-, -(CH2)4- and -(CH2)5-, are prepared by a process which comprises reacting a dialkyl cyanimidocarbonate of formula (V), wherein R3 is C1-C4alkyl, with an alkali metal salt of malononitrile or with malononitrile and an alkali metal base, at a temperature of -10 to +40 DEG C, to give a 1-alkoxy-1-cyanomino-2,2-dicyanoethylene alkali metal salt of the formula (IV), wherein R3 is C1-C4alkyl and M<+> is an alkali metal cation, reacting this compound with an excess of ammonia at a temperature of 60 to 110 DEG C to give a 1-amino-1-cyanamino-2,2-dicyanoethylene alkali metal salt of formula (II), wherein M<+> is an alkali metal cation, reacting this salt with excess hydrogen chloride in a secondary alcohol, water or a mixture thereof as solvent to give 2-chloro-4,6-diamino-5-cyanopyrimidine, and then reacting this compound with an amine of the formula R1R2NH to give the final product.

Description

Process for the preparation of substituted and intermediates thereof

Technical field

The present invention relates to a novel process for the preparation of 2-substituted 4,6-diamine-5-cyanopyrimidines and intermediates thereof.

BACKGROUND OF THE INVENTION

2-substituted 4,6-diamino-5-cyanopyrimidines of formula I

in which

R _x is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl; and R ₂ is hydrogen, C 1 -C 10 alkyl or cycloalkyl. Or (3-6 carbon atoms), or R ₁ and R ₂ together represent a residue selected from the group consisting of - (CH ₂ ) ₃ -, - (CH ₂ ) ₄ - and - (CH ₂ ) ₅ - which are suitable as pesticides, are known to be of U.S. Pat. No. 4,783,458 to Kristinsson et al .. a particularly preferred member of this group of compounds is a compound in which R ₄ is hydrogen and R ₂ is cyclopropyl.

The patent of KRISTINSSON et al. discloses that compounds of Formula I can be prepared by the reaction of 2-chloro-4,6-diamino2

-5-cyanopyrimidine of formula III

with appropriate amines in an organic solvent or a mixture of organic solvent and water.

Allenstein et al. reported in Chem. Ber., 101, 1968, 1244-1249, that the chlorine-containing intermediate of formula III can be synthesized by reaction of a suspension of the sodium salt of 1-amino-1-cyanamino-2,2-dicyanethylene of formula IIa.

with an excess of hydrogen chloride gas in absolute ether.

Chem. Ber., 101, 1968, 1232-1241, further teaches that this precursor, the sodium salt of Formula IIa, can be prepared with a modest yield of 28% by reacting sodium cyanamide with 1-amino-1-ethoxy-2,2- with dicyanethylene in anhydrous refluxing ethanol. In the same article they also teach that adding diethyl cyanimidocarbonate to a solution of sodium malononitrile in absolute ethanol at room temperature yields 1-ethoxy-1-cyanamino-2,2-dicyanethylene sodium.

Although the above general synthesis is sufficient to prepare laboratory amounts of compounds of Formula I, it was not entirely satisfactory for larger scale production in terms of safety and yield. For example, the reaction of a suspension of the sodium salt of formula (IIa) with an excess of hydrogen chloride in absolute ether results in an unacceptable risk of fire and explosion on an industrial scale. Moreover, this solvent is not suitable for the subsequent reaction of 2-chloro-4,6-diamino-5-cyanopyrimidine of formula III with an amine. In addition, the low yield in the preparation of the compound of formula IIa significantly affects the overall economic side of the preparation. Thus, there was a need for an improved process for the preparation of compounds of Formula I, showing greater safety and better yield than the prior art.

SUMMARY OF THE INVENTION

A new process for the preparation of compounds of formula I has now been found

in which

R @ ₁ represents a hydrogen atom, a C1 -C6 alkyl group, a C2 -C6 alkenyl group or a C2 -C6 alkynyl group and

R ₂ represents a hydrogen atom, a C 1 -C 10 alkyl group or a C 3 -C 6 cycloalkyl group, or R _x and R together represent a radical selected from the group consisting of - (CH ₂ ) ₃ -, - ( CH ₂ ) ₄ - and - (CH 2) ₅ -, which comprises, in one embodiment, reacting an alkali metal salt with 1-amino-1-cyanamino-2,2-dicyanethylene of Formula II

CN CN

M ⁺ in which 1Γ represents an alkali metal cation, with an excess of hydrogen chloride in the secondary alcohol, water or a mixture thereof as solvent, and then reacting the resulting 2-chloro-4,6-diamino-5-cyanopyrimidine of formula III

(III) with an amine of formula

R _x R ₂ NH wherein R _x and R _{2 are} as defined for formula (I).

Another embodiment of the invention involves the preparation of an alkali metal salt with 1-amino-1-cyanamino-2,2-dicyanethylene of formula II in good yield, by reacting an alkali metal salt with 1-alkoxy-1-cyanamino-2,2-dicyanethylene of formula IV

CN

(IV) or ₃ wherein R ₃ represents a C 1 -C 4 alkyl group and M ⁺ represents an alkali metal cation, with an excess of ammonia at a temperature of 60 to 110 ° C, optionally in a polar solvent.

Another embodiment of the invention includes a process for the preparation of compounds of formula I

in which

R _x is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, and

R ₂ represents a hydrogen atom, a C 1 -C 10 alkyl group or a C 3 -C 6 cycloalkyl group, or R ₁ and R ₂ together represent a radical selected from the group consisting of - (CH ₂ ) ₃ -, - (CH ₂₎ ) ₄ - and - (CH _{2) 5} -, which comprises reacting a dialkyl cyanimidocarbonate .cn formula V (V)

R ₃ !

or ₃ wherein R ₃ represents a C 1 -C 4 alkyl group with an alkali metal salt of malononitrile or malononitrile and an alkali metal-containing base, at a temperature of from -10 to +40 ° C, to obtain an alkali metal salt of 1- alkoxy-1-cyanamino-2,2-dicyanethylene of formula IV

wherein R ₃ represents a C 1 -C 4 alkyl group and M ⁺ represents an alkali metal cation, reacting the compound with an excess of ammonia at a temperature of 60 to 110 ° C, optionally in a polar solvent, to obtain the alkali metal salt of l-amino 1-cyanamino-2,2-dicyanethylene of formula II

CN CN

M + in which M ⁺ represents an alkali metal cation, reacting this salt with an excess of hydrogen chloride in the secondary alcohol, water or a mixture thereof as solvent, to obtain the 2-chloro-4,6-diamino-5-cyanopyrimidine of formula III

and then reacting the compound with an amine of formula

RJR NH ₂ in which R _x and R ₂ are as defined for formula I to give the final product.

In each of formulas (IV) and (V), the C1-C4 alkyl group may be a methyl group, an ethyl group, a propyl group, an isopropyl group, any isomer of a butyl group, a cyclopropyl group, a methylcyclopropyl group or a cyclobutyl group. Preferably, R ₃ is methyl or ethyl.

The starting materials for this four-step synthesis, the dialkyl cyanimidocarbonates of formula V, are known per se or can be prepared by known methods (see, for example, The Chemistry of Amidines and Imidates, Saul Patai, Ed., John Wiley and Sons, (1975)). An improved process for the preparation of these compounds is described in U.S. Patent No. 5,237,084.

The reaction of the dialkyl cyanimidocarbonate of formula V with an alkali metal salt of malononitrile or malononitrile and an alkali metal-containing base to obtain the alkali metal salt of the 1-alkoxy-1-cyanamino-2,2-dicyanethylene of formula IV can be accomplished by slow addition of the salt solution. an alkali metal with malononitrile to a cooled solution of dialkyl cyanimidocarbonate of formula V, by slowly adding an alkali metal-containing base solution to a cooled solution of dialkyl cyanimidocarbonate of formula V and malononitrile, or preferably by slowly adding a solution of malononitrile to a cooled solution of dialkyl cyanimidocarbonate of formula and containing alkali metal. The reaction is carried out at a temperature of -10 to + 40 ° C, preferably -10 to + 20 ° C, and in particular 0 to + 5 ° C, and is almost complete at the end of the addition. Stirring at the addition temperature for several additional minutes allows the reaction to proceed completely.

This reaction is preferably carried out in a polar protic or aprotic solvent. Suitable protic solvents include linear and branched alcohols having 1 to 4 carbon atoms, in particular methanol and ethanol, alkoxy alcohols having 1 to 4 carbon atoms in the alkoxy moiety and 1 to 4 carbon atoms in the alcohol moiety, such as 2-methoxy- or 2-methoxy- -ethoxyethanol, water, and mixtures of these organic compounds with each other or with water. When using water, temperatures that would cause the reaction mixture to freeze should be avoided.

Suitable aprotic solvents include ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran and dioxane, amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidinone, and sulfoxides such as dimethylsulfoxide.

Suitable alkali metal, M ⁺ , cations are lithium, sodium or potassium, with sodium cations being preferred. Suitable alkali metal bases are hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, sodium hydroxide being preferred, and alkoxides such as sodium methoxide or ethoxide and potassium tert-butoxide, sodium methoxide and ethoxide being preferred.

The addition time is not critical. The reaction proceeds well with the addition for a period of from 0.5 to 10 hours, preferably from 1 to 4 hours and most preferably from 1.5 to 2.5 hours.

Preferred starting materials for the four-step reaction leading to compounds of formula I, for ease of synthesis and overall economic preparation, are the dialkyl cyanimidocarbonates of formula V, wherein R ₃ is methyl or ethyl, i.e. dimethyl (N-cyanimido) carbonate and diethyl (N-cyanimido) carbonate.

The use of diethyl (N-cyanimido) carbonate is particularly preferred for several reasons. It is thermally more stable than dimethyl (N-cyanimido) carbonate and is liquid at room temperatures, making it easier to handle.

In addition, ethanol is a preferred solvent for both the reaction of the dialkyl cyanimidocarbonate of formula V with malononitrile and the subsequent reaction of a compound of formula IV with ammonia. A further advantage of using diethyl (N-cyanimido) carbonate in combination with sodium ethoxide as the base and ethanol as the solvent is that it is thus possible to carry out both steps 1 and 2 in succession in a one-reactor process while not having a mixture of alcohols for recycling at the end of the second stage.

^! The first two steps of the process can also be carried out as a process using a single reaction vessel starting from dimethyl (N-cyanimido) carbonate, as illustrated in the Examples section. In this case, if a solvent other than an alcohol such as methyl tert-butyl ether is used in the first step, ethanol may be added to the reaction mixture prior to carrying out the second step. Although this type of process is successful, it is less interesting from a production point of view as it provides various solvent mixtures for recycling.

Alternatively, the first and second steps can be carried out separately, which is also illustrated in the example section. However, this process is somewhat less interesting as it adds one filtration to the overall process.

¹ While the sodium salt of l-ethoxy-l-cyanamino-2,2-dicyanoethylene is known, it is believed that the sodium salt of 1-methoxy-l-cyanamino-2,2-dicyanoethylene, whose synthesis is described in the Examples is new. This compound and its synthesis are a further object of the invention.

The second step in the reaction sequence is the reaction of the alkali metal salt with the 1-alkoxy-1-cyanamino-2,2-dicyanethylene of the general formula IV with an excess of ammonia at a temperature of from 60 to 110 ° C, optionally in a polar solvent. 1-amino-1-cyanamino-2,2-dicyanethylene of formula II

CN CN

M + wherein M ⁺ represents an alkali metal, preferably sodium, cation. Chem. Ber., 101, 1968, at page 1234 and page 1241, part 12c) are described by Allenstein et al. attempt to convert 1-ethoxy-1-cyanamino-2,2-dicyanethylene sodium (compound of formula IV with sodium cation M ⁺ and ethyl R ₃ ) to 1-amino-1-cyanamino sodium Of 2,2-dicyanoethylene of formula (IIa) by reacting this compound with ethanolic ammonia solution for four hours at 120 ° C. This experiment failed, only the unchanged starting material was isolated in high yield.

Surprisingly, it has now been found that ammonolysis of the sodium salt and other alkali metal salts with 1-ethoxy-1-cyanamino-2,2-dicyanethylene of formula IV readily proceeds at lower temperatures, in particular temperatures from 25 to 110 ° C, in the presence or in the absence of a polar solvent.

Suitable polar solvents include C 1 -C 4 linear and branched alcohols such as methanol and ethanol, C 1 -C 4 alkoxyalcohols and C 1 -C 4 alkoxy alcohols such as 2-methoxy- 2-ethoxyethanol, non-cyclic or cyclic amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidinone, acetonitrile, water, and mixtures of these organic compounds with each other or with water. Preferred polar solvents are ethanol, dimethylformamide and water. The reaction also proceeds well in excess of liquid ammonia itself, which acts as both a polar solvent and a reagent.

The amount of ammonia used in the reaction as well as the reaction temperature and the reaction solvent can substantially affect the reaction rate, as illustrated in the following table, in which the abbreviation Et stands for ethyl and DMF stands for dimethylformamide.

default material solvent- body NH ₃ (in molar equivalents) temperature (° C) reaction time (in hours) ratio IIa: IV IV _(R3 = Et) EtOH 20 May 75 50 complete reaction IV _(R3 = Et) EtOH 10.1 75 48 complete reaction IV _(R3 = Et) EtOH 5 75 96 2.6: 1 IV _(R3 = Et) EtOH 2, 6 75 48 1: 13 IV _(R3 = Et) EtOH 10.1 75 48 complete reaction IV _(R3 = Et) EtOH 9.9 100 ALIGN! 50 complete reaction IV _(R3 = Et) EtOH 10.1 150 5 complete reaction IV _(R3 = Et) IMF 10 75 21 complete reaction IV _(R3 = Et) h ₂ o 2.4 75 24 complete reaction.

The amount of ammonia for use in the ammonolysis reaction is preferably 5 to 30 molar equivalents in liquid ammonia, 5 to 20 molar equivalents in a polar organic solvent and 2 to 20 molar equivalents in water. However, the reaction rate decreases in ethanol at lower molar ratios. As shown in the table, at 75 ° C and using 20 or 10 molar equivalents of ammonia in ethanol, the reaction is complete after 2 days. Using 5 molar equivalents of ammonia at 75 ° C, the reaction is very slow and after 4 days only a product to starting material ratio of 2.6: 1 is obtained. Results comparable to those achieved with 20 or 10 molar equivalents of ammonia can be obtained. at higher temperatures by further prolonging the reaction time. At 75 ° C using only 2.6 molar equivalents of ammonia, the reaction is extremely slow and after 2 days only a 1: 13 ratio of product to starting material is obtained.

Using ethanol as the solvent and 10 molar equivalents of ammonia, ammonolysis of the compound of formula IV (wherein R ₃ is ethyl) at 25 ° C is rather slow and only a partial conversion is achieved, even after 2 days. However, good results are obtained at temperatures between 60 ° C and 110 ° C. Preferred temperatures are between 70 ° C and 100 ° C, in particular about 75-85 ° C, in the presence or absence of a polar solvent. At temperatures higher than 110 ° C, for example 150 ° C, by-products are obtained almost exclusively and should therefore be avoided.

As shown in the table, the reaction at about 75 ° C with dimethylformamide as solvent and with 10 molar equivalents of ammonia is approximately twice as fast as with ethanol. With water as the solvent and 2.5 molar equivalents of ammonia, ammonolysis at 75 ° C is also approximately twice as fast as with ethanol and 10 molar equivalents of ammonia.

Since some by-products are formed even at low temperatures, there is a time at which the concentration of the product of formula (II) is optimal and the ratio of product (II) to by-products is also optimal. While the conversion of the compound of formula (IV) to the compound of formula (II) may not be complete at this time, further elongation of the reaction time only increases by-product formation and the yield of the product of formula (II) begins to decrease. Preferred reaction conditions are those in which the time at which the yield of product II is optimal is near the end of the conversion of the compound of formula IV to the compound of formula II. The following table shows optimal reaction times with ethanol as solvent at three different reaction temperatures. The total reaction time is the time required for the consumption of the starting material of formula IV.

temperature time to optimal optimal ratio reaction time (in ° C) concentration of compound IIIa compound (hours) (hours) IIIa: IV

75 40. 15.6 48 100 ALIGN! 6 5.0 20 May 150 1 1.0 5

For other temperatures and solvents, the optimal reaction time can be readily determined by routine experimentation.

In addition to the novel process described above, the compounds of formula (II) may conveniently be prepared in high yield according to the copending application Serial No. 08 / 097,098.

Cyclization of 1-amino-1-cyanamino-2,2-dicyanethylene sodium by reacting a suspension of this salt with excess hydrogen chloride gas in absolute ether to give 2-chloro-4,6-diamino-5-cyanopyrimidine of formula III

has been previously reported in the literature. However, the attempt to carry out cyclization in tert-butyl methyl ether is unsuccessful since it is obtained

and:

complex product mix.

It has now been found that 2-chloro-4,6-diamino-5-cyanopyrimidine of formula III can be prepared by reacting an alkali metal salt with 1-amino-1-cyanamino-2,2-dicyanethylene of formula II

CN CN

in cream M ⁺ represents an alkali metal cation, with an excess of hydrogen chloride in the secondary alcohol, water or a mixture thereof. In addition, it has been found that aqueous hydrochloric acid, preferably concentrated aqueous hydrochloric acid, may be used in this reaction.

Surprisingly, this reaction can be carried out in a protic solvent, even in water as the solvent, since in the prior art absolute ether and hydrogen chloride gas were used. It is also surprising that this reaction is successful in the secondary alcohol, since in the primary alcohol the solvent reacts to form 2-alkoxy-4,6-diamino-5-cyanopyrimidine. However, the desired 2-chloro-4,6-diamino-5-cyanopyrimidine of formula III is obtained in good yield in the secondary alcohol, water or mixture thereof.

Preferred secondary alcohols are those having 3 to 6 carbon atoms such as isopropanol, sec-butanol, methyl isopropylmethanol, diethylmethanol, 2-pentanol,

4-methyl-2-pentanol, 4-methyl-3-pentanol, 2- and 3-hexanol and methyl isobutylmethanol, as well as cyclic secondary alcohols such as cyclopentanol and cyclohexanol. Isopropanol and sec-butanol are particularly preferred secondary alcohols because they are good solvents for both this reaction and the next step and because their low boiling points allow easy isolation by distillation.

When 2-chloro-4,6-diamino-5-cyanopyrimidine is prepared in a secondary alcohol or a mixture thereof with water as a solvent, it is preferred to use the same secondary alcohol for the subsequent reaction with an amine of the formula R _X R, NH, R ₁ and R ₂ are as defined for formula (I).

The cyclization is carried out at low temperatures such as -10 to +25 ° C, and in particular Ό to +20 ° C. At 0 to +20 ° C, they are usually complete within about four hours. When using water as a solvent or solvent component, the reaction mixture should not be frozen.

Hydrogen chloride gas may be blown through a suspension of the alkali metal salt with 1-amino-1-cyanamino-2,2-dicyanethylene in a solvent, or a previously prepared solution of hydrogen chloride in a solvent may be added to a suspension of the starting material in the same solvent. The reaction also proceeds when the solvent is saturated with hydrogen chloride and consequently a large excess of hydrogen chloride is used.

A molar excess of hydrogen chloride gas or aqueous hydrochloric acid is required. It is preferred to use 3 to 6 molar equivalents of HCl, more preferably 3 to 4 molar equivalents of HCl, and most preferably about 3 molar equivalents.

Although the intermediate 2-chloro-4,6-diamino-5-cyanopyrimidine of formula III can be isolated after the first step, it is preferably converted to the final product of formula I in a one-pot process without isolation. For this purpose, it is particularly preferred to use sec-butanol or isopropanol as solvent and about 3 equivalents of HCl. lato option enables to carry out the preparation of 2-chloro-4,6-diamino-5-cyanopyrimidine of the formula III and its subsequent reaction with the amine of the formula R ^ NH, in which R _x and R ₂ are as defined in formula I, gradually in the same reaction vessel. It also allows easy isolation and recycling of the solvent.

The reaction of 2-chloro-4,6-diamino-5-cyanopyrimidine of formula III with an amine of formula R _X R ₂ NH, wherein R 1 and R ₂ are as defined for formula I, is carried out at temperatures of about 50 to 150 ° C, preferably about 70 to 120 ° C, and especially 80 to 110 ° C. It is expedient to carry out the reaction in a solvent which boils within the desired range and to carry out the reaction in a refluxing solvent. However, if the amine is volatile, the reaction can be advantageously carried out under pressure.

The reaction time varies in indirect proportion to temperature. At a temperature in the range of 80 to 110 ° C, the reaction is generally complete within 4 to 8 hours.

The reaction with an amine of the formula R _X R ₂ NH is preferably carried out in a polar protic or aprotic solvent. Suitable protic solvents include linear and branched alcohols having 1 to 10 carbon atoms, including cyclic alcohols, preferably alcohols having 3 to 6 carbon atoms, alkoxy alcohols having 1 to 4 carbon atoms in the alkoxy moiety and 1 to 4 carbon atoms in the alcohol moiety, such as 2-methoxy- or 2-ethoxyethanol, water, and mixtures of these organic compounds with each other or with water. An excess of an amine of the formula R _X R ₂ NH is also suitable. Particularly preferred protic solvents are ethanol and C 3 -C 6 secondary alcohols which have been reported to be suitable for the preceding reaction step. Suitable aprotic solvents include ethers such as methyl tert-butyl ether, tetrahydrofuran and dioxane, acetonitrile and amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidinone.

The reaction with an amine of the formula R _X R ₂ NH is preferably carried out in the presence of an acid binding agent. Preferably, at least 2 molar equivalents of the acid binding agent are used in the reaction. Suitable acid binding agents are inorganic bases, such as sodium carbonate or sodium hydroxide, or organic bases, such as trialkylamine or the amine itself of the formula R 1 R. NH.

The following non-limiting examples illustrate the various reactions and combinations of reactions described above. Numerous modifications will be apparent to those skilled in the art which do not depart from the nature of the description and examples. These modifications are also part of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

In a 500 ml three-necked round-bottomed flask equipped with nitrogen inlet, mechanical stirrer, thermometer and addition funnel was sequentially charged 50 g (0.342 mol) of 78% dimethyl (N-cyanimido) carbonate, 170 ml of methanol and 23.7 g. (0.359 mol) malononitrile. The resulting mixture was cooled to 0-5 ° C in an ice / water bath and 77.5 g (0.359 mol) of a 25% solution of sodium methoxide in methanol was added over 45 minutes, maintaining the temperature between 0-5 Deň: 32 ° C. The reaction mixture was then allowed to warm to room temperature and stirred for several hours. After filtration of the resulting suspension, the filtrate is concentrated in vacuo until more solid precipitates. This suspension was also filtered and the solids mixed. The weight of the mixed solids was 61.3 g.

The combined solids were charged to a 11r Parr reactor and 170 ml of ethanol were added. The Parr reactor was cooled in an ice-water bath and 60 g (3.529 mol) of anhydrous ammonia was introduced. After the reaction mixture was heated to 60 ° C with a corresponding pressure increase to 0.74 MPa and held for 19 hours, the reactor was cooled to room temperature and excess ammonia was removed. Filtration of the resulting suspension gave 41 g of product.

In a 1 L 4-necked round-bottomed flask vented to an alkaline washing machine equipped with a thermometer, mechanical stirrer and addition funnel was charged the above product (41 g) and 340 mL of 1,2-dimethoxyethane. 180 g (1.726 mol) of a 35% cold (0-5 ° C) solution of hydrogen chloride in 1,2-dimethoxyethane are added over 10 minutes. The reaction mixture was allowed to warm slowly to room temperature and stirred for 15 hours. The reaction mixture was recooled to 0-5 ° C and then 10% aqueous sodium hydroxide was added until the pH reached 7-8. Filtration of the resulting mixture gave 38 g of a solid. The filtrate was extracted with sec-butanol and the combined extracts were concentrated and filtered to give an additional 11 g of solid.

In a 500 ml three-necked round bottom flask equipped with a condenser, nitrogen inlet, mechanical stirrer and thermometer, was charged the crude product from the previous step (49 g). 200 ml of ethanol and 21.5 g (0.377 mol) of cyclopropylamine are added successively. The reaction mixture was heated to reflux for 5.5 hours, cooled to 0-5 ° C and filtered to give 26 g of a solid. Concentration of the filtrate gave an additional 4 g of solid. The combined solids are taken up in 50 ml of water and 10% aqueous sodium hydroxide is added with stirring until the pH reaches 7-8. Filtration of the resulting suspension and drying of the isolated solid gave 21 g of 2-cyclopropylamino-4,6-diamino-5-quanopyrimidine.

The overall yield of this 4-step synthesis of 2-cyclopropylamino-4,6-diamino-5-cyanopyrimidine starting from dimethyl (N-cyanimido) carbonate is 32%.

Example 2

In a 500 ml three-necked round bottom flask equipped with nitrogen inlet, mechanical stirrer, thermometer and addition funnel was charged 146 g (0.188 mol) of a 14.7% solution of dimethyl (N-cyanimido) carbonate in tert-butyl methyl ether. 13.2 g (0.200 mol) of malononitrile are added and the mixture is cooled to 0-5 ° C in an ice / water bath. 45.3 g (0.210 mol) of a 25% solution of sodium methoxide in methanol are added over 45 minutes, maintaining the temperature in the range of 0-5 ° C. The reaction mixture was then slowly warmed to room temperature and stirred for several hours.

The above reaction mixture was transferred to a IIIa Parr reactor and 100 ml of ethanol were added. The Parr reactor was cooled in an ice / water bath and 16 g (0.941 mol) of anhydrous ammonia was introduced into the reactor. The reaction mixture was heated to 91 [deg.] C (1 atm) and held for 21 hours. Then the reactor was cooled to room temperature and excess ammonia was removed. The resulting suspension was filtered. The filtrate was concentrated in vacuo until more solids precipitated and then filtered again. The weight of the mixed solids was 29.9 g.

A 500 ml four-necked round-bottomed flask vented to an alkaline scrubber equipped with a gas inlet, a thermometer, a mechanical stirrer and a condenser was charged with the above product (10 g) and 80 ml of sec-butanol. Hydrogen chloride was bubbled through the mixture until saturation for 2.5 hours while maintaining the temperature at 0-5 ° C. The reaction temperature is then slowly raised to room temperature and stirring is continued for several hours. Filtration of the reaction mixture yielded 20.8 g of a solid.

In a 250 ml three-necked round-bottomed flask equipped with nitrogen inlet, thermometer and mechanical stirrer, place the above product (20 g), 75 ml sec-butanol,

4.8 g (0.084 mol) of cyclopropylamine and 16 g (0.151 mol) of sodium carbonate. The reaction mixture was heated at reflux for 6 hours, cooled to room temperature, diluted with 100 mL of water and neutralized with concentrated hydrochloric acid. Filtration of the resulting mixture gave a wet solid. The aqueous layer was separated and extracted with sec-butanol, the combined organic layers were concentrated until more solids precipitated and then filtered. The combined solids were dried under vacuum to give 6.2 g of product.

The overall yield of this four-step synthesis of 2-cyclopropylamino-4,6-diamino-5-cyanopyrimidine starting from dimethyl (N-cyanimido) carbonate is 52%.

Example 3

In a 500 ml three-necked round-bottomed flask equipped with nitrogen inlet, mechanical stirrer, thermometer and addition funnel was sequentially charged 50 g (0.342 mol) of 78% dimethyl (N-cyanimido) carbonate, 170 ml of methanol and 23.7 g. (0.359 mol) malononitrile. The resulting mixture was cooled to 0-5 ° C in an ice / water bath and 77.5 g (0.359 mol) of a 25% solution of sodium methoxide in methanol was added over 35 minutes while maintaining the temperature in the range of 0-5 Deň: 32 ° C. The reaction mixture was then allowed to warm to room temperature and stirred for 5 hours. After filtration of the resulting suspension, the filtrate is concentrated in vacuo until more solid precipitates and additional solids are obtained by a second filtration. The weight of the mixed solids (still wet) was 89.3 g.

The above solids (78.0 g) were charged to a 11r Parr reactor and 250 ml of ethanol were added. The Parr reactor was cooled in an ice-water bath and 60 g (3.529 mol) of anhydrous ammonia was introduced. The reaction mixture was heated to 75 ° C (60 psi) for 22 hours. After cooling the reactor to room temperature, excess ammonia was removed. Concentration of the solvent and filtration of the resulting suspension gave 48 g of wet product.

Dc of a 1 L 4-neck round bottom flask vented to an alkaline scrubber and equipped with a gas inlet, thermometer, mechanical stirrer and condenser was charged with the above product (48 g) and 325 mL of 1,2-dimethoxyethane. Hydrogen chloride was bubbled through the mixture until saturation for 2.5 hours, maintaining the temperature in the range of 0-30 ° C. The reaction temperature was then allowed to slowly rise to room temperature and stirring was continued for 22 hours. After filtration of the reaction mixture, the isolated solid is dissolved in water and 10% sodium hydroxide is added until the pH reaches 7-8. Filtration of the resulting mixture: 42 g of wet solid is obtained.

The above solids (42 g) were charged to a 1 L Parr reactor. 250 mL of ethanol was added followed by 21 g (0.368 mol) of cyclopropylamine. The reaction mixture was heated at 80 ° C for 5.5 hours and then cooled to room temperature. Filtration of the resulting suspension yielded 26 g of product.

The overall yield of 2-cyclopropylamino-4,6-diamino-5-cyanopyrimidine from this reaction sequence is 40%.

Example 4

200 ml of ethanol, 50.2 g (0.343 mol) of 78% dimethyl (N-cyanimido) carbonate and 22 ml are successively introduced into a 1-L three-necked round-bottomed flask equipped with nitrogen inlet, mechanical stirrer, thermometer and addition funnel. 7 g (0.344 mol) of malononitrile. The resulting mixture is cooled to 0-5 ° C in an ice / water bath and 75.1 g (0.347 mol) of a 25% solution of sodium methoxide in methanol is added over 3 hours, maintaining the temperature in the range of 4 - Low: 14 ° C. The reaction mixture was then allowed to warm to room temperature and stirred for 20 hours.

The resulting reaction mixture was transferred to a 21r Parr reactor and 100 mL of ethanol was added. The Parr reactor is sealed, cooled in an ice / water bath, and 33 g (1.94 mol) of anhydrous ammonia are introduced into the reactor. Heat the reaction mixture at 74-78 ° C (20 psi) for 20 hours. After the reactor was again cooled to room temperature, excess ammonia was removed. The resulting precipitate was filtered off and the filtrate was concentrated in vacuo until more solid precipitated. The combined precipitates are washed with 200 ml of ethanol. The total weight of the isolated solids was 25.9 g.

In a 1 L 4-necked round-bottom flask equipped with a thermometer, mechanical stirrer and addition funnel and vented to an alkaline washing machine was charged the above product (22.7 g) and 180 mL of 1,2-dimethoxyethane. 100 g (0.56 mol) of a 20.5% cold (0-5 ° C) solution of hydrogen chloride in 1,2-dimethoxyethane are added. The reaction mixture was allowed to warm to room temperature and stirred for 20 hours. The reaction mixture was recooled to 0-5 ° C and filtered to give 35.2 g of a solid.

In a 500 ml three-necked round-bottom flask equipped with a condenser, nitrogen inlet, mechanical stirrer and thermometer, was charged the crude product from the previous step (10 g). 100 ml of ethanol, 5.0 g (0.088 mol) of cyclopropylamine and 0.5 g (0.005 mol) of triethylamine are added successively. Sodium carbonate (5.3 g, 0.050 mol) was then added carefully and the reaction mixture was heated at reflux for 9 hours, then cooled to 0-5 ° C and filtered. The isolated solid was washed with 100 mL of water and filtered again to give 3.0 g of product. Concentration of ethanol gave an additional 1.25 g of product.

The overall yield of 2-cyclopropylamino-4,6-diamino-5-cyano-23-pyrimidine from this four-step reaction sequence was 26.2%.

Example 5

170 ml of ethanol, 40.0 g (0.189 mol) of 67% diethyl (N-cyanimido) carbonate and 23 ml are successively introduced into a 1-L three-necked round-bottomed flask equipped with nitrogen inlet, mechanical stirrer, thermometer and addition funnel. 5 g (0.356 mol) of malononitrile. The resulting mixture was cooled to 0-5 ° C in an ice / water bath and 115 g (0.355 mol) of a 21% solution of sodium ethoxide in ethanol was added over 2 hours, maintaining the temperature at 0-5 ° C. . The reaction mixture was warmed to room temperature and stirred for 20 hours.

The resulting reaction mixture was transferred to a 1 L Parr reactor. The Parr reactor was sealed, cooled in an ice / water bath, and 30 g (1.76 mol) of anhydrous ammonia was introduced. Heat the reaction mixture at 82 ° C (60 psi) for 17 hours. After the reactor was again cooled to room temperature, excess ammonia was removed. The resulting precipitate was filtered off and the filtrate was concentrated in vacuo until more solid precipitated. The total weight of the isolated solids was 22.4 g.

In a 1 L 4-neck round bottom flask vented to an alkaline scrubber equipped with nitrogen inlet, thermometer, mechanical stirrer and condenser was charged the above product (21.6 g) and 200 mL sec-butanol. The mixture was cooled to 0-5 ° C and 100 mL of a saturated solution of hydrogen chloride in sec-butanol was added over 10 minutes while maintaining the temperature of the reaction mixture at about 5.0 ° C. The reaction mixture was then allowed to warm to room temperature. After stirring for 1.5 hours, the resulting suspension was filtered to give 30.0 g of a solid.

A 1 L 3-neck round bottom flask equipped with nitrogen inlet, thermometer, condenser and mechanical stirrer was charged with the above product (30 g), 180 mL sec-butanol, 8.3 g (0.145 mol) cyclopropylamine and 24.2 g ( 0.228 mol) of sodium carbonate. The reaction mixture was heated at reflux for 6 hours, then cooled to room temperature, diluted with 200 mL of water and neutralized with concentrated hydrochloric acid. Filtration of the resulting mixture gave a wet solid. The aqueous layer was separated and extracted with sec-butanol. The combined organic layers were concentrated until more solid precipitated. The combined solids were dried! under vacuum to give 12.3 g of product.

The overall yield of 2-cyclopropylamino-4,6-diamino-5-cyanopyrimidine from this four-step synthesis starting from diethyl (N-cyanimido) carbonate is 35.7%.

Example 6

In a 1 L three-necked round-bottomed flask equipped with nitrogen inlet, mechanical stirrer, thermometer and addition funnel was gradually added 160 mL of ethanol, 40.0 g (0.291 mol) of 83% dimethyl (N-cyanimido) carbonate and 19, 6 g (0.297 mol) of malononitrile. The resulting mixture was cooled to 0-5 ° C in an ice / water bath and 62.8 g (0.291 mol) of a 25% solution of sodium methoxide in methanol was added over 3 hours, maintaining the temperature between 2-4 Deň: 32 ° C. The reaction mixture was then allowed to warm to room temperature and stirred for 20 hours.

The resulting reaction mixture was transferred to a 21r Parr reactor, and 80 mL of ethanol was added. The Parr reactor is sealed, cooled in an ice / water bath, and 27.8 g (1.63 mol) of anhydrous ammonia is introduced into the reactor. The reaction mixture was heated to 75 ° C (18 psi) for 18 hours. After the reactor was again cooled to room temperature, excess ammonia was removed. The resulting precipitate was filtered off and the filtrate was concentrated in vacuo until more solid precipitated. The combined precipitates are washed with 200 ml of ethanol. The total weight of the isolated solids was 37.7 g.

The above product (23.0 g) and 180 ml of sec-butanol are placed in a 1-L 4-necked round-bottomed flask equipped with a thermometer, mechanical stirrer and addition funnel and vented to an alkaline scrubber. The mixture was cooled to 0-5 ° C, then 96.7 g (0.371 mol) of a 14.0% solution of hydrogen chloride in sec-butanol was added over 15 minutes while maintaining the temperature at 5-10 ° C. The reaction mixture was stirred for 3 hours at 0-5 ° C, then allowed to warm to room temperature and stirred for an additional 15 hours. After addition of 21.0 g (0.368 mol) of cyclopropylamine and 50.0 g (0.472 mol) of sodium carbonate, the reaction mixture was heated to reflux for 16 hours, cooled to 0-5 ° C and filtered. The isolated solids were washed with 200 mL of water and filtered again to give 19.5 g of product. The aqueous filtrate was extracted with 100 mL of sec-butanol, the extracts were combined with the organic filtrate, and the solvent was concentrated to give an additional 5.3 g of product.

The overall yield of this four-step synthesis using two-reactor synthesis of 2-cyclopropylamino-4,6-diamino-5-cyanopyrimidine, starting from dimethyl (N-cynaimido) carbonate, is 44.8%.

Example 7

In a 500 mL three neck round bottom flask equipped with nitrogen inlet, mechanical stirrer, thermometer and addition funnel was charged 55 g (0.35 mol) of 90% diethyl (N-cyanimido) carbonate and 87 mL of ethanol. The resulting solution was cooled to 0-5 ° C in an ice / water bath, and 124 g (2.97 mol) of a 21% solution of sodium ethoxide in ethanol was added in one portion. While maintaining the temperature of the reaction mixture at 0-5 ° C, a premixed solution of 24.2 g (0.37 mol) of malononitrile in 87 ml of ethanol was added over 2 hours. After the addition was complete, the solvent was evaporated and the isolated solid was dried to give 67.6 g of 1-ethoxy-1-cyanamino-2,2-dicyanethylene sodium salt of 80.2% purity. Yield 82%.

Example 8

A 250 ml flask equipped with a magnetic stirrer and a 50 ml pressure equalizing addition funnel was charged with 24.7 g (0.100 mol) of 57.5% diethyl (N-cyanimido) carbonate, 7.01 g (0.105 mol). 99% malononitrile and 50 ml water. The resulting solution was cooled to 0-5 ° C in an ice / water bath and 44 mL (0.11 mol) of a 2.5 M aqueous sodium hydroxide solution was added over a period of 2.0 hours. Analysis of the reaction solution by means of high performance liquid chromatography revealed a substantially single product, identified as the sodium salt of 1-ethoxy-1-cyanamino-2,2-dicyanethylene.

Example 9

To a 1 L Parr reactor was charged 58.1 g (0.342 mol) of 1-methoxy-1-cyanamino-2,2-dicyanethylene sodium salt and 170 ml of ethanol. The reactor was cooled to 0-5 ° C in an ice-water bath and 60 g (3.529 mol) of anhydrous ammonia was introduced. After heating the reaction mixture at 60 ° C for 19 hours, the reactor was cooled to room temperature and excess ammonia was removed. Concentration of the resulting mixture and filtration afforded 41 g (77%) of the product.

Example 10

To a 1 L Parr reactor was charged 30.0 g (0.163 mol) of 1-ethoxy-1-cyanamino-2,2-dicyanethylene sodium salt and 150 mL of ethanol. The reactor was cooled to 0-5 ° C in an ice / water bath and anhydrous ammonia (28.0 g, 1.647 mol) was introduced. The reactor was heated to 75 ° C and kept at this temperature for 48 hours until the reaction was complete. Upon completion, the reaction was cooled to room temperature and excess ammonia was removed. Concentration of the resulting mixture and filtration gave 15 g (59%) of dry product.

Examples 11 - 13

These examples were carried out similarly to Example 10 but with different ammonia ratios. The results are shown in the first part of the first table in this description.

Example 14

To a 1 L Parr reactor was charged 10 g (54.3 mmol) of 1-ethoxy-1-cyanamino-2,2-dicyanethylene sodium salt and 100 ml of N, N-dimethylformamide. The reactor was sealed, then cooled to 0-5 ° C in an ice / water bath and anhydrous ammonia (9.3 g, 547 mmol) was introduced. The reactor is heated to 75 ° C and held at this temperature for 21 hours to achieve almost complete conversion of the starting material to the sodium salt of 1-amino-1-cyanamino-2,2-dicyanethylene. The reactor was then cooled to room temperature and excess ammonia was removed to give 1-amino-1-cyanamino-2,2-dicyanethylene sodium as a solution in N, N-dimethylformamide.

Example 15

To a 1 L Parr reactor was charged 47.8 g (0.150 mol) of 57.7% 1-ethoxy-1-cyanamino-2,2-dicyanethylene sodium salt, 23.0 ml (0.360 mol) 29.6% aqueous ammonia and 135 ml of water. The reactor is sealed, heated to 75 ° C and kept at this temperature for 24 hours to achieve almost complete conversion of the starting material to the sodium salt of 1-amino-1-cyanamino-2,2-dicyanethylene. The reactor was then cooled to room temperature to give the product as a filterable precipitate.

Example 16

A 4.7 liter (0.140 mol) 57.7% sodium salt of 1-ethoxy-1-cyanamino-2,2-dicyanethylene was charged to a 1 L Parr reactor. The reactor is sealed, cooled in an ice bath, 57.5 g (3.38 mol) of ammonia are added and heated to 75 ° C for 24 hours to achieve substantially complete conversion of the starting material to 1-amino sodium salt. -1-cyanamino-2,2-dicyanethylene. The reactor was cooled to room temperature and vented to give the product as a wet solid.

Example 17

170 ml of ethanol, 40.0 g (0.225 mol) of approximately 80% diethyl- (N-cyanimido) carbonate and 23 ml of ethanol are added successively to a 1-liter three-necked round-bottomed flask equipped with nitrogen inlet, mechanical stirrer, thermometer and addition funnel. 1.5 g (0.356 mol) of malononitrile. The resulting mixture was cooled to 0-5 ° C in an ice / water bath and 115 g (0.355 mol) of a 21% solution of sodium ethoxide in ethanol was added over 2 hours, maintaining the temperature in the range of 0-5 Deň: 32 ° C. The reaction mixture was then allowed to warm to room temperature and stirred for 20 hours.

The above reaction mixture was transferred to a 1 L Parr reactor. The Parr reactor was sealed, cooled in an ice / water bath, and 30 g (1.76 mol) of anhydrous ammonia was introduced into the reactor. The reaction mixture was then heated at 82 ° C (60 psi) for 17 hours. After the reactor was again cooled to room temperature, excess ammonia was removed. The resulting precipitate was filtered off and the filtrate was concentrated in vacuo until more solid precipitated. The total weight of the isolated solids was 22.4 g.

Example 18

In a 500 ml round bottom flask equipped with a magnetic stirrer and a 125 ml pressure equalizing addition funnel was charged 39.7 g (0.251 mol) 90% diethyl (N-cyanimido) carbonate, 17.5 g (0.262 mol) 99% malononitrile and 125 ml water. The resulting solution was cooled to 0-5 ° C in an ice / water bath and 110 mL (0.275 mol) of a 2.5 M aqueous sodium hydroxide solution was added over a period of 2.0 hours. The resulting solution of 1-ethoxy-1-cyanamino-2,2-dicyanethylene sodium salt was transferred to a 500 ml Parr reactor to which 38.4 ml (0.601 mol) of 29.6% aqueous ammonia was added, sealed, and heated to 75 ° C. The reaction mixture is maintained at this temperature for 24 hours to achieve complete conversion to the sodium salt of 1-amino-1-cyanamino-2,2-dicyanethylene. The reactor was cooled to room temperature to give the product as a filterable precipitate.

Example 19

In a 500 ml round bottom flask equipped with a magnetic stirrer and a 125 ml pressure equalizing addition funnel was charged 18.7 g (0.150 mol) 91.4% dimethyl (N-cyanimido) carbonate, 10.5 g (0.157) mol) 99% malononitrile and 75 ml water. The resulting solution was cooled to 0-5 ° C in an ice / water bath and 6.6 ml (0.165 mol) of a 2.5 M aqueous sodium hydroxide solution was added over a period of 2.0 hours. The resulting 1-methoxy-1-cyanamino-2,2-dicyanethylene sodium solution was transferred to a 500 ml Parr reactor to which was added 23 ml (0.360 mol) of 29.6% aqueous ammonia, sealed, and heated to temperature 75 ° C. The reaction mixture is maintained at this temperature for 24 hours to achieve complete conversion to the sodium salt of 1-amino-1-cyanamino-2,2-dicyanethylene. The reactor was cooled to room temperature to give the product as an aqueous solution.

Example 20

In a 3-L 4-necked round-bottom flask equipped with a thermometer, mechanical stirrer and addition funnel and vented to an alkaline scrubber was charged 200 g (0.66 mol) of 51.1% 1-amino-1-cyanamino-2,2 -dicyanethylene and 1030 ml of isopropanol. The mixture was cooled to 0-5 ° C and 626 g (3.22 mol) of an 18.8% solution of hydrogen chloride in isopropanol was added over 2 hours, maintaining the temperature of the reaction mixture at 0-10 ° C. The reaction mixture was then warmed to room temperature and stirred for 15 hours. 151.0 g (2.65 mol) of cyclopropylamine are added in one portion followed by 51.6 g (1.29 mol) of 100% sodium hydroxide and the reaction mixture is heated to reflux (82 ° C) for 15 hours. hours. After cooling to 60 ° C, the reaction mixture was filtered. The isolated solid was washed with 600 ml of water, filtered again and dried to give 108 g of product.

Example 21

25 g (0.11 mol) of 68.5% 1-amino-1-cyanamino-2,2 is charged into a 1 liter 4-neck round bottom flask equipped with a thermometer, mechanical stirrer and addition funnel and vented to an alkaline scrubber. -dicyanethylene. and 197 ml sec-butanol. The mixture is cooled to 0-5 ° C and 72.5 g (0.40 mol) of a 20.3% solution of hydrogen chloride in sec-butanol are added over a period of 2 hours, maintaining the reaction temperature between 0-5 ° C. C. The reaction mixture was then warmed to room temperature and stirred overnight. 13.8 g (0.24 mol) of cyclopropylamine are added in one portion followed by 9.7 g (0.24 mol) of 100% sodium hydroxide. The reaction mixture was transferred to a Parr reactor and heated at 100 ° C for 8 hours. After cooling the reaction mixture to 25 ° C, 26.0 g (0.16 mol) of 25% sodium hydroxide solution are added. The resulting mixture was stirred for 2 hours and filtered. The isolated solid was washed with water, filtered again and dried to give 18 g of product.

Example 22

50 g (0.27 mol) of 50.1% 1-amino-1-cyanamino-2,2 are charged into a 1-liter, 4-neck round-bottom flask equipped with a thermometer, mechanical stirrer and addition funnel and vented to an alkaline scrubber. -dicyanethylene and 257 ml sec-butanol. The mixture was cooled to 0-5 ° C and 147 g (0.81 mol) of a 20% solution of hydrogen chloride in sec-butanol was added over 30 minutes while maintaining the temperature of the reaction mixture at 0-5 ° C. The reaction mixture was then warmed to 25 ° C and stirred for 1.5 hours to complete the cyclization. 77.7 g (0.967 mol) of 71% cyclopropylamine are added in one portion and then the reaction mixture is transferred to a Parr reactor and heated at 100 ° C for 4 hours. 13 g (0.32 mol) of sodium hydroxide are added and stirring is continued for 2 hours at 80 ° C. After cooling the reaction mixture to 25 ° C, 40 g of water are added. The resulting mixture was stirred for 1 hour at room temperature and filtered. The isolated solid (86 g) was heated to reflux for 3 hours in 860 ml of boiling water, and then the suspension was cooled to room temperature. The solid was filtered and dried to give 41.6 g (80%) of the crude product.

Example 23

In a 250 ml three-necked round-bottom flask equipped with a thermometer, magnetic stirrer and nitrogen inlet was added 10 g (0.064 mol) of 1-amino-1-cyanamino-2,2-dicyanethylene sodium salt and 40 ml of water. The flask was cooled to 0-5 ° C in an ice / water bath and 25.0 g (0.246 mol) of 36% hydrochloric acid was added over 15 minutes. The reaction mixture was allowed to warm slowly to 20-25 ° C and stirred for 23 hours. Filtration of the resulting suspension yielded 13.4 g of a wet solid.

Example 24

In a 50 ml three-necked round-bottom flask equipped with a thermometer, magnetic stirrer and nitrogen inlet was charged 1.1 g (7.1 mmol) of 1-amino-1-cyanamino-2,2-dicyanoethylene sodium salt and 20 ml of ethanol. The flask was cooled to 0-5 ° C in an ice / water bath and 4.8 g (15.8 mmol) of 12% hydrogen chloride in ethanol was added. The reaction mixture was allowed to warm slowly to 20-25 ° C and stirred for 20 hours. Filtration of the resulting suspension and concentration of the filtrate gave 1.7 g of a solid. The yield, calculated as 2-ethoxy-4,6-diamino-5-cyanopyrimidine, was 84.5%.

Example 25

60 g (0.34 mol) of 87.6% 1-amino-1-cyanamino-2,2 is charged into a 1 liter 4-neck round-bottom flask equipped with a thermometer, mechanical stirrer and addition funnel and vented to an alkaline washing machine. -dicyanethylene and 215 ml sec-butanol. The mixture was cooled to 0-5 ° C during 2.5 hours and 160 g (0.97 mol) of 22.1% solution of HCl in sec-butanol, wherein the reaction temperature ranges from 0 to 5 ^e C The reaction mixture was then warmed to room temperature and stirred overnight (15 hours). 67 g (1.61 mol) of cyclopropylamine are added in one portion and the reaction mixture is heated to reflux for 8 hours. After cooling the reaction mixture to 25 ° C, 280 g of N, N-dimethylacetamide was added and the 2-butanol was removed by distillation in vacuo. The distillation residue was cooled to room temperature and 46.0 g (0.58 mol) of 50% sodium hydroxide solution was added rapidly. The mixture was heated with stirring to 80 ° C and filtered through a pad of 15 g of diatomaceous earth. The resulting solution of 2-cyclopropylamino-4,6-diamino-5-cyanopyrimidine is concentrated by distilling off 125 g of N, N-dimethylacetamide in vacuo and 400 g of 2- (cyclopropylamino-4,6-diamino-5-cyanopyrimidine) are added to precipitate 2-cyclopropylamino-4,6-diamino-5-cyanopyrimidine. butanol. The resulting suspension was filtered. The isolated solid was washed with a mixture of water and methanol, filtered and dried to give 48 g (75%) of product.

Claims (21)

PATENT CLAIMS A process for the preparation of a substituted 4,6-diamino-5-cyanopyrimidine of the general formula I wherein R _x is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, and R ₂ represents a hydrogen atom, a C 1 -C 10 alkyl group or a C 3 -C 6 cycloalkyl group, or R ₂ and R ₂ together represent a radical selected from the group consisting of - (CH ₂ ) ₃ -, - (CH ₂₎ ) ₄ - and - (CH _{2) 5} -, characterized by reacting an alkali metal salt of l-amino-l-cyanamino-2,2-dicyanoethylene formula II CN CN (II) in which M ⁺ represents an alkali metal cation, with an excess of hydrogen chloride in the secondary alcohol, water or a mixture thereof as solvent, and then the resulting 2-chloro-4,6-diamino-5-cyanopyrimidine of formula III is reacted with an amine of the general formula R ^ NH wherein R _x and R _{mají are} as defined for Formula I. 2. Method according to claim 1, characterized in that R represents a hydrogen atom and R ₂ is cyclopropyl. 3. The process of claim 1 wherein M * is an alkali metal cation selected from the group consisting of lithium, sodium, and potassium. The process of claim 1 wherein the secondary alcohol is selected from the group consisting of C 3 -C 6 secondary alcohols. The process according to claim 4, wherein the C 3 -C 6 secondary alcohol is isopropanol or sec-butanol. A process according to claim 1 wherein the reaction of 2-chloro-4,6-diamino-5-cyanopyrimidine with an amine of the formula R _X R ₂ NH is carried out in an organic solvent. 7. The process of claim 6 wherein the organic solvent is a secondary alcohol having from 3 to 6 carbon atoms. The process of claim 7, wherein the C 3 -C 6 secondary alcohol is isopropanol or sec-butanol. 9. The process of claim 1 wherein the reaction of an alkali metal salt with 1-amino-1-cyanamino-2,2-dicyanethylene of formula II wherein M ^& lt ^{; +} & gt ^; is an alkali metal cation with an excess of hydrogen chloride in the secondary alcohol. water or mixtures thereof both as a solvent and the reaction of the resulting 2-chloro-4,6-diamino-5-cyanopyrimidine of formula III (III) with an amine of formula R _X R ₂ NH in which R, _L and R ₂ are as defined for formula I, is carried out in the same secondary alcohol, without isolation of compound III. Process according to claim 1, characterized in that 3 to 6 molar equivalents of hydrogen chloride are used. Process according to Claim 10, characterized in that 3 to 4 molar equivalents of hydrogen chloride are used. 12. The process of claim 10 wherein aqueous hydrogen chloride is used 13. A process according to claim 1, wherein the alkali metal salt of amino-2,2-dicyanethylene of formula II is 1-amino-1-cyanoCN. NHn (II) 'N in which M ⁺ represents an alkali metal cation, reacts with an excess of hydrogen chloride in the secondary alcohol, water or a mixture thereof as a solvent at a temperature of -10. to + 25 ° C. Process according to Claim 13, characterized in that the alkali metal salt of 1-amino-1-cyanamino-2,2-dicyanethylene of the general formula II CN. -Ν ^{/ kterémχ} ΝΗ ₂ (II) in which M ⁺ represents a sodium cation, reacts with 3-4 molar equivalents of hydrogen chloride in isopropanol, sec-butanol, water or a mixture thereof as a solvent at a temperature of from 0 to +20 ° C. 15. A process for the preparation of an alkali metal salt of 1-amino-1-cyanamino-2,2-dicyanethylene of formula II CN CN Μ * ^- (II) wherein M ⁺ represents an alkali metal cation, characterized by reacting an alkali metal salt with 1-alkoxy-1-cyanamino-2,2-dicyanethylene of formula IV (IV) wherein R ₃ represents an alkyl group having 1 to 4 carbon atoms and M * represents an alkali metal cation, with an excess of ammonia at 60 to 110 ° C, in the presence or absence of a polar solvent. 16. The method according to claim 15, characterized in that R ₃ represents a methyl or ethyl group, and M ⁺ represents a sodium cation. The method of claim 15, wherein the polar solvent is an alcohol-containing alcohol 1-4 carbon atoms, a non-cyclic or cyclic amide, water, or a mixture of the above organic compounds with each other or with water. 18. The process of claim 17 wherein the polar solvent is ethanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, water, or a mixture of the above organic compounds with or with each other. 19. The process of claim 15, wherein from about 2 to about 20 molar equivalents of ammonia are used per mole of the compound of formula (IV). 20. A process for the preparation of a substituted 4,6-diamino-5-cyanr ₂ &apos; : d in which R _x is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl; and R ₂ represents a hydrogen atom, a C 1 -C 10 alkyl group or a C 3 -C 6 cycloalkyl group, or R ₁ and R ₂ together represent a radical selected from the group consisting of - (CH ₂ ) ₃ -, - (CH _{2) 14} -a - (CK ₂ ) ₅ -, characterized in that it is subjected to a reaction of a dialkyl cyanimidocarbonate of the general formula V (V) CN ₃ or ₃ in which R ₃ represents an alkyl group having 1 to 4 carbon atoms, with an alkali metal salt of malononitrile, or malononitrile and an alkali metal-containing base, at a temperature of from -10 to +40 ° C, to obtain the alkali metal salt of 1-alkoxy-1-cyanamino-2,2-dicyanethylene of formula IV CN CN In R ₃ wherein R ₃ represents a C 1 -C 4 alkyl group and M ⁺ represents an alkali metal cation, this compound is reacted with an excess of ammonia at 60 to 110 ° C to obtain the alkali metal salt of 1-amino-1- cyanamine-2,2-dicyanethylene of formula II CN CN in which M ⁺ represents an alkali metal cation, this salt is reacted with an excess of hydrogen chloride in the secondary alcohol, water or a mixture thereof as solvent, to obtain the 2-chloro-4,6-diamino-5-cyanopyrimidine of formula III and then reacting this compound with an amine of formula R ₁ R ₂ NH in which R _x and R ₂ are as defined for formula I to give the final product, 4-substituted, 6-diamino-5-cyanopyrimidines of the formula I. 21. tuového A process according to claim 20 for the preparation of a compound of formula (I) wherein: R _x represents a hydrogen atom and R ₂ represents a cyclopropyl group, characterized by reacting the dialkyl cyanimidocarbonates formula V .cn _OR3 (V) wherein R ₃ represents a methyl or ethyl group, with the sodium salt of malononitrile or with malononitrile and a base comprising sodium, at a temperature of from -10 to +40 ° C, to obtain the sodium salt of 1-alkoxy-1-cyanamino-2,2-dicyanethylene of formula IV CN CN (IV) wherein R ₃ represents a methyl or ethyl group and M ⁺ represents a sodium cation, this compound is reacted in the presence of from 2 to 20 molar equivalents of ammonia at 60 to 110 ° C and in the presence or absence of a polar solvent to obtain the sodium salt of 1-amino-1-cyanamino-2,2-dicyanethylene of formula II (II) wherein M ⁺ is sodium cation, the salt is reacted with 3 to 6 moles of hydrogen chloride in isopropanol, sec-butanol, water or a mixture thereof as a solvent to give 2-chloro-4,6-diamino-5-cyanopyrimidine of formula III (III) and then reacting the compound with an amine of formula I in an organic solvent. R _x R ₂ NH in which R _x represents a hydrogen atom and R 1 represents a cyclopropyl group, to give the final product, substituted 4,6-diamino-5-cyanopyrimidine of the general formula