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

2-Substituted 4,6-diamino-5-cyanopyrimidines of the formula

wherein R _x is hydrogen, C _r C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl and R ₂ is hydrogen, Cj-Cjoalkyl ^or C ₃ -C ₆ cycloalkyl or Rj and R ₂ together arc a radical, selected from the g up of radicals, consisting of -(CH ₂ ) ₃ -, -(CH-^- and -(CH ₂ ) ₅ -, which are useful as pesticides are known from U. S. Patent No. 4,783,468 to Kristinsson et al.. A partic arly preferred member of this group of compounds is the compound wherein Rj is hydrogen and R ₂ is cyclopropyl.

The Kristinsson et al. patent discloses that compounds of the formula I may be prepared by reacting 2-chloro-4,6-diamino-5-cyanopyrimidine of the formula

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

AUenstein et al. teach in Chem. Ber., 101, 1968, 1244-1249, that the chloro intermediate of the formula III may be synthesized by treating a slurry of 1-amino-l-cyanamino- 2,2-dicyanoethylene sodium salt of the formula Jla

with excess gaseous hydrogen chloride in absolute ether.

They further teach, in Chem. Ber., 101, 1968, 1232-1241, that this sodium salt precursor of the formula Ha may be prepared in a modest yield of 28% by reaction of sodium cyanamide with l-amino-l-ethoxy-2,2-dicyanoethylene in refluxing anhydrous ethanol. They also disclose in the same article that addition of diethyl cyanimidocarbonate to a solution of the sodium salt of malononitrile in absolute ethanol at room temperature gives l-ethoxy-l-cyanamino-2,2-dicyanoethylene sodium salt.

While the overall synthesis described above sufficed for producing laboratory amounts of compounds of the formula I, it was not completely satisfactory for larger scale production from the standpoints of safety and yield. For example, the treatment of a slurry of the sodium salt of the formula Ha with excess hydrogen chloride in absolute ether on an industrial scale would result in unacceptable fire and explosion hazards. Moreover this solvent is not suitable for subsequently reacting 2-chloro-4,6-diamino-5-cyanopyrimidine of the formula HI with an amine. Additionally, the low yield in the preparation of the compound of formula Ha severely impacts the overall economics. Thus there was a need for an improved process for the preparation of compounds of the formula I having greater safety and a better yield than that found in the art.

There has now been found a novel process for the preparation of compounds of the formula

wherein R _j is hydrogen, C _j -Cgalkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl and R ₂ is hydrogen, Cj-Cioalkyl or Cs-Cgcycloal yl or R _j and R together are a radical, selected from the group of radicals, consisting of -(CH ₂ ) ₃ -, -(CH ₂ ) ₄ - and -(CH ₂ ) ₅ -, which comprises, in one

aspect, treating a l-amino-l-cyanamino-2,2-dicyanoethylene alkali metal salt of the formula

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

with an amine of the formula R-*R ₂ NH, wherein Rj and R ₂ are as defined for formula I.

Another aspect of this invention involves the preparation of a l-amino-l-cyanamino-2,2- dicyanoethylene alkali metal salt of the formula II in good yield by reacting a l-alkoxy-l-cyanamino-2,2-dicyanoethylene alkali metal salt of the formula

wherein R ₃ is Cι-C ₄ alkyl and M ⁺ is an alkali metal cation, with an excess of ammonia at a temperature of 60 to 110°C, optionally in a polar solvent.

A further aspect of this invention involves a process for the preparation of compounds of the formula

- 4

where Rγ is hydrogen, C- _t - alkyl, C ₂ -C ₆ alkenyl or C*>-C ₆ alkynyl and R ₂ is hydrogen, Ci-C- _t oalkyl or C ₃ -C ₆ cycloalkyl or R _j and R ₂ together are a radical, selected from the group of radicals, consisting of -(CH ₂ ) ₃ -, -(CH-^- and -(CH-*^-, which comprises reacting a dialkyl cyanimidocarbonate of the formula

wherein R ₃ is C _r C ₄ alkyl, with an alkali metal salt of malononitrile or with malononitrile and an alkali metal base, at a temperature of -10 to +40°C, to give a 1-alkoxy-l- cyanamino-2,2-dicyanoethylene alkali metal salt of the formula

wherein R ₃ is C _r C alkyl and M ⁺ is an alkali metal cation, reacting this compound with an excess of ammonia at a temperature of 60 to 110°C, optionally in a polar solvent, to give a l-amino-l-cyanamino-2,2-dicyanoethylene alkali metal salt of the formula

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 of the formula

and then reacting this compound with an amine of the formula R ₁ R ₂ NH, wherein Rj and R are as defined for formula I, to give the final product.

In each of formulae IV and V, R ₃ as C _r C ₄ alkyl can be methyl, ethyl, propyl, isopropyl, any of the butyl isomers, cyclopropyl, methylcyclopropyl or cyclobutyl. Preferably R ₃ is methyl or ethyl.

The starting materials for this four step synthesis, the dialkyl cyanimidocarbonates of the 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 such compounds is disclosed in U. S. Patent No. 5,237,084.

The reaction of a dialkyl cyanimidocarbonate of the formula V with an alkali metal salt of malononitrile or with malononitrile and an alkali metal base o give a 1-alkoxy-l- cyanamino-2,2-dicyanoethylene alkali metal salt of the formula IV can be carried out by slowly adding a solution of an alkali metal salt of malononitrile to a cooled solution of the dialkyl cyanimidocarbonate of the formula V, by slowly adding a solution of an alkali metal base to a cooled solution of the dialkyl cyanimidocarbonate of the formula V and malononitrile or, preferably, by slowly adding a solution of malononitrile to a cooled solution of the dialkyl cyanimidocarbonate of the formula V and an alkali metal base. The reaction is conducted at a temperature of -10 to +40°C, advantageously at -10 to +20°C and especially at 0 to +5°C, and is nearly complete at the end of the addition. Mixing at the addition temperature for a few additional minutes allows the reaction to go to completion.

This reaction is advantageously carried out in a polar protic or aprotic solvent. Suitable protic solvents include linear and branched C ₁ -C ₄ alcohols, especially methanol and ethanol, such as 2-methoxy- or 2-ethoxyethanol, water, and mixtures of the c _* „ _^ nic compounds with each other or with water. When using water, temperatures which 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 dimethyl formamide, dimethyl acetamide and N-methylpyrrolidinone, and sulfoxides, such as dimethylsulfoxide.

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

The time of addition is not critical. The reaction works well with addition times 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 sequence leading to compounds of the formula I, based on ease of synthesis and overall economics, are the dialkyl cyanimidocarbonates of the formula V where R ₃ is methyl or ethyl, i.e. dimethyl (N-cyan- imido)-carbonate and diethyl (N-cyanimido)-carbonate.

The use of diethyl (N-cyanimido)-carbonate is especially preferred for several reasons. It is thermally more stable than dimethyl (N-cyanimido)-carbonate and it is a liquid at ambient temperatures, thus making it easier to handle. Additionally, ethanol is a preferred solvent for both the reaction of the dialkyl cyanimidocarbonate of the formula V with malononitrile and for the subsequent reaction of the compound of the formula IV with ammonia. Thus, a further advantage of using diethyl (N-cyanimido)-carbonate in combination with sodium ethoxide as a base and ethanol as a solvent is that it makes it possible to carry out both step 1 and step 2 consecutively in a one-reactor process and still not have a mixture of alcohols to recycle at the end of the second step.

The first two steps of the process can also be carried out as a one-reactor process starting from dimethyl (N-cyani ido)-carbonate, as illustrated in the experimental section. In this case, if a solvent other than an alcohol is used for the first step, for example methyl tert-butyl ether, ethanol may be added to the reaction mixture before carrying on with the second step. Although this type of approach is successful, it is less interesting from a manufacturing point of view since it gives various mixtures of solvents to recycle.

Alternatively, the first and second steps can be carried out separately, as is also illustrated in the experimental section. However, this approach is somewhat less attractive since it

adds one filtration to the overall process.

While l-ethoxy-l-cyanamino-2,2-dicyanoethylene sodium salt is known, 1-methoxy-l- cyanamino-2,2-dicyanoethylene sodium salt, whose synthesis is described in the experimental section, is believed to be novel, This compound and its synthesis are further objects of this invention.

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

M ^*" wherein M ⁺ is an alkali metal cation, preferably sodium. In Chem. Ber., 101. 1968, at page 1234 and page 1241, part 12 c), AUenstein et al. report an attempt to convert 1-ethoxy-l- cyanamino-2,2-dicyanoethylene sodium st ά (the compound of formula IV with M ⁺ as a sodium cation and R ₃ as ethyl) to l-amino-l-cyanamino-2,2-dicyanoethylene sodium salt of the formula Ha by reacting it with an ethanolic ammonia solution for four hours at 120°C. The attempt failed; only unchanged starting material was recovered in high yield.

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

Suitable polar solvents include linear and branched C-* ^alcohols, such as methanol and ethanol, C ₁ -C ₄ alkoxy-C ₁ -C alcohols, such s 2-methoxy- or 2-ethoxyethanol, acyclic or cyclic amides, such as dimethylformamide, dimethylacetamide and N-methylpyrrolidinone, acetonitrile, water, and mixtures of the organic compounds with each other or with water. Preferred polar solvents are ethanol, dimethylformamide and water. The reaction also proceeds well in excess liquid ammonia alone, which functions as both polar solvent and reactant.

The amount of ammonia used in the reaction as well as the reaction temperature and the reaction solvent can drastically affect the rate of the reaction. This is illustrated in the following table (Rx. = Reaction):

Starting Solvent NH ₃ (Mol. Temp., Rx. time, Ha:IV ratio material equiv.) °C hrs.

IV (R ₃ = Et) EtOH 20 75 50 Rx. complete

IV (R ₃ = Et) EtOH 10.1 75 48 Rx. complete

IV (R ₃ = Et) EtOH 5 75 96 2.6 : 1

IV (R ₃ = Et) EtOH 2.6 75 48 1 : 13

IV (R ₃ = Et) EtOH 10.1 75 48 Rx. complete

IV (R ₃ = Et) EtOH 9.9 100 50 Rx. complete

IV (R ₃ = Et) EtOH 10.1 150 5 Rx. complete

IV (R ₃ = Et) DMF 10 75 21 Rx. complete

IV (R ₃ = Et) H ₂ O 2.4 75 24 Rx. complete

The amount of ammonia to 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 reactions are complete after 2 days. Using 5 molar equivalents of ammonia at 75°C, the reaction is very slow and only gives a 2.6 : 1 ratio of product to starting material after 4 days. Results comparable to those obtained using 20 or 10 molar equivalents of ammonia can be obtained at higher temperatures by further extending the reaction time. At 75°C, when only 2.6 molar equivalents of ammonia are used, the reaction is extremely slow and only gives a 1 : 13 ratio of product to starting material after 2 days.

With ethanol as solvent and 10 molar equivalents of ammonia, the ammonolysis of the compound of the formula IV (R ₃ = C ₂ H ₅ ) is quite slow at 25°C and gives only partial conversion, even after 2 days. However, good results are obtained at temperatures of between 60°C and 110°C. Preferred temperatures are between 70°C and 100°C, especially temperatures of about 75 to 85°C, with or without a polar solvent. Temperatures much greater than 110°C, for example 150°C, give almost entirely by-products and should be

avoided.

As shown in the table, with dimethylformamide as solvent and 10 molar equivalents of ammonia, the reaction at 75°C is about twice as fast as with ethanol. With water as the solvent and 2.5 molar equivalents of ammonia, the ammonolysis at 75°C is also about 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 the formula II is an optimum and the ratio of product II to by-products is also an optimum. While the conversion of the compound of the formula IV to II may not be complete at this time, further extending the reaction time merely increases by-product formation and the yield of product of the formula π starts decreasing. Preferred reaction conditions are those wherein the time at which the yield of product π is an optimum occurs near the end of the conversion of the compound of the formula IV to II. The following table shows optimum reaction times with ethanol as solvent at three different reaction temperatures. The total reaction time is the time required for the starting material of the formula IV to be consumed.

Optimum

Temp., Time to optimum Reaction πa/IV ratio °C Ha cone, hrs. time , hrs.

75 40 15.6 48 100 6 5.0 20 150 1 1.0 5

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

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

The cyclization of l-amino-l-cyanamino-2,2-dicyanoethylene sodium salt by reacting a slurry of this salt with excess gaseous hydrogen chloride in absolute ether to give 2-chloro-4,6-diamino-5-cyanopyrimidine of the formula

has been previously reported in the literature. However, attempting to carry out the cyclization in tert-butyl methyl ether is unsuccessful, giving a complex mixture of products.

It has now been found that 2-chloro-4,6-diamino-5-cyanopyrimidine of the formula in can be prepared by reacting a l-amino-l-cyanamino-2,2-dicyanoethylene alkali metal salt of the formula

wherein M ⁺ is an alkali metal cation, with excess hydrogen chloride in a secondary alcohol, water or a mixture thereof. Additionally, it has been found that aqueous hydrochloric acid, preferably concentrated aqueous hydrochloric acid, can be employed in this reaction.

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

Preferred secondary alcohols are those having 3 to 6 carbon atoms, such as isopropanol, sec-butanol, methylisopropylcarbinol, diethylcarbinol, 2-pentanol, 4-methyl-2-pentanol, 4-methyl-3-pentanol, 2- and 3-hexanol and methylisobutylcarbinol, as well as cyclic secondary alcohols, such as cyclopentanol and cyclohexanol. Especially preferred secondary alcohols, because they are good solvents for both this reaction and the next step and because their low boiling points permit easy recovery by distillation, are isopropanol and sec-butanol.

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

The cyclizations are run at low temperatures such as -10 to +25°C and especially 0 to +20°C. At 0 +20°C they are usually complete within about four hours. When using water as solvent or cosolvent, the reaction mixture should not be permitted to freeze.

Hydrogen chloride gas can be sparged through a suspension of the 1-amino-l-cyanamino- 2,2-dicyanoethylene alkali metal salt in the solvent, or a previously prepared solution of HC1 in the solvent can be added to a suspension of the starting material in the same solvent. The reaction also works when the solvent is saturated with HC1 and consequently a large excess of HC1 is used.

A molar excess of gaseous hydrogen chloride or aqueous hydrochloric acid is required. It is preferred to use 3 to 6 molar equivalents c IC1, more preferably 3 to 4 molar equivalents of HC1, and most preferably about 3 molar equivalents.

While the 2-chloro-4,6-diamino-5-cyanopyrimidine intermediate of the formula III can be isolated after the first step, preferably it is converted to the final product of the formula 1 in a "one-pot" process without isolation. For these purposes it is especially preferred to use •sec-butanol or isopropanol as the solvent and about 3 equivalents of HC1. These choices make it possible to carry out both the preparation of the 2-chloro-4,6-diamino-5-cyano- pyrimidine of the formula III and its subsequent reaction with the amine of the formula RjR ₂ NH, where R ₂ and R ₂ are as defined for formula I, consecutively in the same reaction vessel. They also permit easy recovery and recycling of the solvent.

The reaction of the 2-chloro-4,6-diamino-5-cyanopyrimidine of the formula in with the amine of the formula RjR ₂ NH, where R- _j 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 at 80 to 110°C. It is convenient to conduct the reaction in a solvent which boils in the desired range and to carry out the reaction in the refluxing solvent. However, if the amine is volatile, the reaction may advantageously be run under pressure.

Reaction times vary inversely with temperature. At a temperature in the range of 80 to

110°C, the reaction generally is complete within 4 to 8 hours.

The reaction with the amine of the formula R* _t R ₂ NH is advantageously carried out in a polar protic or aprotic solvent. Suitable protic solvents include linear and branched Cx-C-ioalcohols, including cyclic alcohols, preferably Cj-Cgalcohols, C ₁ -C ₄ alkoxy-C ₁ -C alcohols, such as 2-methoxy- or 2-ethoxyethanol, water, and mixtures of the organic solvents with each other or with water. An excess of the amine of the formula R^NH is also suitable. Especially preferred protic solvents are ethanol and the secondary C ₃ -C ₆ alcohols taught to be useful for the previous reaction step. Suitable aprotic solvents include ethers, such as methyl tert-butyl ether, tetrahydrofuran and dioxane, acetonitrile and amides, such as dimethyl formamide, dimethyl acetamide and N-methylpyrrolidinone.

The reaction with the amine of the formula R**R ₂ NH is advantageously carried out in the presence of an acid scavenger. Preferably at least 2 molar equivalents of an acid scavenger are used in the reaction. Suitable acid scavengers are inorganic bases, such as sodium carbonate or sodium hydroxide, or organic bases, such as a trialkylamine or the amine of the formula RjR ₂ NH itself.

The following non-limiting examples illustrate the various reactions and reaction combinations that have been described above. Numerous modifications which do not depart from the spirit of the disclosure and examples will be apparent to those skilled in the art. They are likewise a part of this invention.

Example 1

A 500 ml, three-necked, round-bottomed flask equipped with a N ₂ inlet, mechanical agitation, thermometer and addition funnel is successively charged with dimethyl (N-cyanimido)-carbonate (78% assay; 50 g; 0.342 mol), methanol (170 ml) and malononitrile (23.7 g; 0.359 mol). The resulting mixture is cooled to 0-5°C (ice/water bath) and a solution of sodium methoxide in methanol (25% assay; 77.5 g; 0.359 mol) is added over 45 minutes while keeping the temperature in the 0-5°C range. The reaction mixture is then allowed to warm to room temperature and stirred for several hours. After filtration of the resulting slurry, the filtrate is concentrated in vacuum until more solids precipitate. This slurry is also filtered and the solids are combined. The weight of the combined solids is 61.3 g.

The combined solids are charged into a 1 1 Parr reactor and ethanol (170 ml) is added. The

Parr reactor is cooied with an ice/water bath and anhydrous ammonia (60 g; 3.529 mol) is introduced. After heating the reaction mixture to 60°C with a conesponding pressure increase to 90 pounds per square inch gage (psig) and holding for 19 hours, the reactor is or Jed to room temperature and excess ammonia is removed. Filtration of the resulting slurry affords 41 g of product.

A l l, four-necked, round-bottomed flask vented to a caustic scrubber . nd equipped with a thermometer, mechanical agitation and an addition funnel is charged with the latter product (41 g) and 1,2-dimethoxyethane (340 ml). A cold (0-5°C) solution of HC1 in 1,2-dimethoxyethane (35% assay; 180 g; 1.726 mol) is addec within 10 minutes. The reaction mixture is slowly allowed to warm to room temperature and stirred for 15 hours. After the reaction mass is cooled again to 0-5°C, 10% aqueous NaOH is added until the pH is 7-8. Filtration of the resulting mixture affords 38 g of solids. The filtrate is extracted with sec-butanol and the combined extracts are concentrated and filtered to give an additional 11 g of solids.

A 500 ml, three-necked, round-bottomed flask equipped with a condenser, N ₂ inlet, mechanical agitation and thermometer is charged with the crude product (49 g) from the previous step. Ethanol (200 ml) and cyclopropylamine (21.5 g; 0.377 mol) are successively added. The reaction mixture is heated to reflux for 5.5 hours, cooled to 0-5°C and filtered to afford 26 g of solids. Concentration of the filtrate gives an additional 4 g of solids. The combined solids are placed in water (50 ml) and 10 aqueous NaOH is added with stirring until the pH is 7-8. Filtration of the resulting slurry and drying of the recovered solids gives 21 g of 2-cyclopropylamino-4,6-diamino-5-cyanopyrimidine.

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

Example 2

A solution of dimethyl (N-cyanimido)-carbonate in tert-butyl methyl ether (14.7% assay;

146 g; 0.188 mol) is placed in a 500 ml, three-necked, round-bottomed flask equipped with an N ₂ inlet, mechanical agitation, thermometer and addition funnel. Malononitrile

(13.2 g; 0.200 mol) is added and the mixture is cooled to 0-5°C (ice/water bath). A s ^■ on of sodium methoxide in methanol (25% assay; 45.3 g; 0.210 mol) is added over

45 -tinutes while keeping the temperature in the 0-5°C range. The reaction mixture is then slowly warmed to room temperature and stured for several hours.

The above reaction mass is transferred into a 1 1 Parr reactor and ethanol (100 ml) is added. The Parr reactor is cooled with an ice/water bath and anhydrous ammonia (16 g; 0.941 mol) is introduced into the reactor. The reaction mixture is heated to 91°C (220 psig) and held for 21 hours. After the reactor is cooled to room temperature, excess ammonia is removed. The resulting slurry is filtered. The filtrate is concentrated in vacuum until more solids precipitate and then filtered again. The weight of the combined solids is 29.9 g.

A 500 ml, four-necked, round-bottomed flask vented to a caustic scrubber and equipped with a gas inlet, a thermometer, mechanical agitation, and a condenser is charged with the latter product (10 g) and sec-bu anόl (80 ml). Hydrogen chloride is sparged into the mixture until saturation for 2.5 hours, while keeping the temperature in the 0-5°C range. The reaction temperature is then slowly increased to ambient temperature and stirring is continued for several hours. Filtration of the reaction mixture affords 20.8 g of solids.

A 250 ml, three-necked, round-bottomed flask equipped with an N ₂ inlet, a thermometer and mechanical agitation is charged with the above product (20 g), sec-butanol (75 ml), cyclopropylamine (4.8 g; 0.084 mol) and sodium carbonate (16 g; 0.151 mol). After the reaction mixture is refluxed for 6 hours, it is cooled to room temperature, diluted with water (100 ml) and neutralized with cone, hydrochloric acid. Filtration of the resulting mixture affords a wet solid. The aqueous layer is separated and extracted with 5cc-butanol; the combined organic layers are concentrated until more solids precipitate, then filtered. The combined solids are dried in vacuum to give 6.2 g of product.

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

Example 3

A 500 ml, three-necked, round-bottomed flask equipped with a N ₂ inlet, mechanical agitation, thermometer and addition funnel is successively charged with dimethyl (N-cyanimido)-carbonate (78% assay; 50 g; 0.342 mol), methanol (170 ml) and malononitrile (23.7 g; 0.359 mol). The resulting mixture is cooled to 0-5°C (ice/water bath) and a solution of sodium methoxide in methanol (25% assay; 77.5 g; 0.359 mol) is added over 35 minutes while keeping the temperature in the 0-5°C range. The reaction mixture is then allowed to warm to room temperature and stirred for 5 hours. After filtration of the resulting slurry, the filtrate is concentrated in vacuum until more solids precipitate and a second filtration affords more solids. The weight of the combined solids

(still wet) is 89.3 g.

The above solids (78.0 g) are charged into a 1 1 Parr reactor and ethanol (250 ml) is added. The Parr reactor is cooled with an ice/water bath and anhydrous ammonia (60 g; 3.529 mol) is introduced. The reaction mixture is heated at 75°C (75 psig) for 22 hours. After cooling the reactor to room temperature, excess ammonia is removed. Concentration of the solvent and filtration of the resulting slurry affords 48 g of wet product.

A l l, four-necked, round-bottomed flask vented to a caustic scrubber and equipped with a gas inlet, a thermometer, mechanical agitation, and a condenser is charged with the latter product (48 g) and 1,2-dimethoxyethane (325 ml). Hydrogen chloride is sparged into the mixture for 2.5 hours, until saturation, while keeping the temperature in the 0-30°C range. The reaction temperature is then allowed to rise slowly to ambient temperature and stirring is continued for 22 hours. After filtration of the reaction mixture, the recovered solid is dissolved in water and 10% sodium hydroxide is added until the pH is 7-8. Filtration of the resulting mixture affords 42 g of wet solids.

The latter solids (42 g) are charged into a 1 1 Parr reactor. Ethanol (250 ml) is added, followed by cyclopropylamine (21 g; 0.368 mol). The reaction mixture is heated to 80°C for 5.5 hours, then cooled to ambient temperature. Filtration of the resulting slurry affords 26 g of product.

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

Example 4

A l l, three-necked, round-bottomed flask equipped with a N inlet, mechanical agitation, thermometer and addition funnel is successively charged with ethanol (200 ml), dimethyl (N-cyanimido)-carbonate (78% assay; 50.2 g; 0.343 mol) and malononitrile (22.7 g; 0.344 mol). The resulting mixture is cooled to 0-5°C (ice/water bath) and a solution of sodium methoxide in methanol (25% assay; 75.1 g; 0.347 mol) is added over 3 hours while maintaining the temperature in the 4-7°C range. The reaction mixture is then allowed to warm to room temperature and stirred for 20 hours.

The resulting reaction mass is transferred into a 21 Parr reactor and ethanol (100 ml) is added. The Parr reactor is sealed, cooled with an ice/water bath and anhydrous ammonia (33 g; 1.94 mol) is introduced into the reactor. The reaction mixture is heated at 74-78°C

(75 psig) for 20 hours. After cooling the reactor again to room temperature, excess ammonia is removed. The resulting precipitate is filtered and the filtrate is concentrated in vacuum until more solids precipitate. The combined precipitates are washed with ethanol (200 ml). The total weight of the recovered solids is 25.9 g.

A l l, four-necked, round-bottomed flask equipped with a thermometer, mechanical agitation, addition funnel and vented to a caustic scrubber is charged with the latter product (22.7 g) and 1,2-dimethoxyethane (180 ml). A cold (0-5°C) solution of HC1 in 1,2-dimethoxyethane (20.5% assay; 100 g; 0.56 mol) is added. The reaction mixture is allowed to warm to room temperature and stirred for 20 hours. After the reaction mass is cooled again to 0-5°C, it is filtered to give 35.2 g of solids.

A 500 ml, three-necked, round-bottomed flask equipped with a condenser, a nitrogen inlet, mechanical agitation and thermometer is charged with the crude product (10 g) from the previous step. Ethanol (100 ml), cyclopropylamine (5.0 g; 0.088 mol) and triethylamine (0.5 g, 0.005 mol) are successively added. Sodium carbonate (5.3 g; 0.050 mol) is then carefully added and the reaction mixture is refluxed for 9 hours, then cooled to 0-5°C and filtered. The recovered solids are washed with water (100 ml) and filtered again to afford 3.0 g of product. Concentration of the ethanol gives an additional 1.25 g of product

The overall yield of 2-cyclopropylamino-4,6-diamino-5-cyanopyrimidine from this four-step sequence is 26.2 %.

Example 5

A l l, three-necked, round-bottomed flask equipped with a N ₂ inlet, mechanical agitation, thermometer and addition funnel is successively charged with ethanol (170 ml), diethyl (N-cyanimido)-carbonate (67 % assay; 40.0 g; 0.189 mol) and malononitrile (23.5 g; 0.356 mol). The resulting mixture is cooled to 0-5°C (ice/water bath) and a solution of sodium ethoxide in ethanol (21% assay; 115 g; 0.355 mol) is added over 2 hours while maintaining the temperature in the 0-5°C range. The reaction mixture is warmed to room temperature and stirred for 20 hours.

The resulting reaction mass is transferred into a 1 1 Parr reactor. The Parr reactor is sealed, cooled with an ice/water bath and anhydrous ammonia (30 g; 1.76 mol) is introduced. The reaction mixture is heated at 82°C (70 psig) for 17 hours. After cooling the reactor again to room temperature, excess ammonia is removed. The resulting precipitate is filtered and the filtrate is concentrated in vacuum until more solids precipitate. The combined weight

of the recovered solids is 22.4 g.

A l l, four-necked, round-bottomed flask vented to a caustic scrubber and equipped with a N ₂ inlet, a thermometer, mechanical agitation, and a condenser is charged with the above product (21.6 g) and sec-butanol (200 ml). The mixture is cooled to 0-5°C and a saturated solution of hydrogen chloride in jec-butanol (100 ml) is added over 10 minutes while keeping the temperature of the reaction mixture at about 5°C. The reaction mixture is then allowed to warm to room temperature. After stirring for 1.5 hours, the resulting slurry is filtered to give 30.0 g of solids.

A l l, three-necked, round-bottomed flask equipped with a N ₂ inlet, a thermometer, a condenser and mechanical agitation is charged with the latter product (30 g), sec-butanol (180 ml), cyclopropylamine (8.3 g; 0.145 mol) and sodium carbonate (24.2 g; 0.228 mol). After the reaction mixture is refluxed for 6 hours, it is cooled to room temperature, diluted with water (200 ml) and neutralized with cone, hydrochloric acid. Filtration of the resulting mixture affords a wet solid. The aqueous layer is separated and extracted with .sec-butanol; the combined organic layers are concentrated until more solids precipitate. The combined solids are dried in vacuum to give 12.3 g of product.

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

Example 6

A l l, three-necked, round-bottomed flask equipped with a N ₂ inlet, mechanical agitation, thermometer and addition funnel is successively charged with ethanol (160 ml), dimethyl (N-cyanimido)-carbonate (83% assay; 40.0 g; 0.291 mol) and malononitrile (19.6 g; 0.297 mol). The resulting mixture is cooled to 0-5°C (ice/water bath) and a solution of sodium methoxide in methanol (25% assay; 62.8 g; 0.291 mol) is added over 3 hours while maintaining the terr erature in the 2-4°C range. The reaction mixture is then allowed to warm to room temperature and stirred for 20 hours.

The resulting reaction mass is transferred into a 21 Parr reactor and ethanol (80 ml) is added. The Pan ^* reactor is sealed, cooled with an ice/water bath and anhydrous ammonia (27.8 g; 1.63 mol) is introduced into the reactor. The reaction mixture is heated at 75°C (75 psig) for 18 hours. After cooling the reactor again to room temperature, excess ammonia is removed. The resulting precipitate is filtered and the filtrate is concentrated in vacuum until more solids precipitate. The combined precipitates are washed with

ethanol (200 ml). The total weight of the recovered solids is 37.7 g.

A l l, four-necked, round-bottomed flask equipped with a thermometer, mechanical agitation, addition funnel and vented to a caustic scrubber is charged with the latter product (23.0 g) and sec-butanol (180 ml). After the mixture is cooled to 0-5°C, a solution of HC1 in sec-butanol (14.0% assay; 96.7 g; 0.371 mol) is added over 15 minutes while maintaining a temperature of 5-10°C. The reaction mixture is 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 cyclopropylamine (21.0 g; 0.368 mol) and sodium carbonate (50.0 g; 0.472 mol), the reaction mixture is refluxed for 16 hours, cooled to 0-5°C and filtered. The recovered solids are washed with water (200 ml) and filtered again to afford 19.5 g of product. The aqueous filtrate is extracted with sec-butanol (100 ml), the extracts are combined with the organic filtrate and the solvent is concentrated to give an additional 5.3 g of product

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

Example 7

A 500 ml, three-necked, round-bottomed flask equipped with a N ₂ inlet, mechanical agitation, thermometer and addition funnel is charged with diethyl (N-cyanimido)-carbonate (90% assay; 55 g; 0.35 mol) and ethanol (87 ml). The resulting solution is cooled to 0-5°C (ice/water bath) and a solution of sodium ethoxide in ethanol (21% assay; 124 g; 2.97 mol) is added all at once. While maintaining the temperature of the reaction mixture in the 0-5°C range, a previously mixed solution of malononitrile (24.2 g; 0.37 mol) in ethanol (87 ml) is added over a period of 2 hours. At the end of the addition the solvent is evaporated and the recovered solids are dried to give l-ethoxy-l-cyanamino-2,2-dicyanoethylene sodium salt (67.6 g; 80.2% assay; 82% yield).

Example 8

A 250 ml flask equipped with magnetic stirring and a 50 ml pressure equalizing addition funnel is charged with diethyl (N-cyanimido)-carbonate (57.5% assay; 24.7 g; 0.100 mol), malononitrile (99%; 7.01 g; 0.105 mol), and water (50 ml). The resulting solution is cooled to 0-5°C (ice/water bath), and a 2.5 M aqueous NaOH solution (44 ml; 0.11 mol) is added over a period of 2.0 hours. HPLC analysis of the reaction solution shows essentially one product, identified as l-ethoxy-l-cyanamino-2,2-dicyanoethylene sodium salt.

Example 9

A l l Parr reactor is charged with l-methoxy-l-cyanamino-2,2-dicyanoethylene sodium salt (58.1 g; 0.342 mol) and ethanol (170 ml). The reactor is cooled to 0-5°C with an ice/water bath and an' 'drous ammonia (60 g; 3.529 mol) is introduced. After heating the reaction mixture at i* for 19 hours, the reactor is cooled to room temperature and excess ammonia is removed. Concentration of the resulting mixture and filtration affords 41 g (77%) of product.

Example 10

A 1 1 Parr reactor is charged with l-ethoxy-l-cyanamino-2,2-dicyanoethylene sodium salt (30.0 g; 0.163 mol) and ethanol (150 rt ^* .)• The reactor is cooled to 0-5°C with an ice/water b nth and anhydrous ammonia (28.0 g; 1.647 mol) is introduced. The reactor is heated to 75°C and the reaction mixture is maintained at this temperature for 48 hours until the end of the reaction. After completion of the reaction, the reactor is cooled to room temperature and excess ammonia is removed. Concentration of the resulting mixture and filtration affords 15 g (59%) of dry product.

Examples 11-13

These examples were run similarly to Example 10, but varying the ammonia ratio. The results are shown in the first part of the first table in the disclosure.

Example 14

A 1 1 Parr reactor is charged with l-ethoxy-l-cyanamino-2,2-dicyanoethylene, sodium salt (10 g; 54.3 mmol) and N,N-dimethylformamide (100 ml). The reactor is sealed, then cooled to 0-5°C with an ice/water bath and anhydrous ammonia (9.3 g; 547 mmol) is introduced. The reactor is heated to 75°C and the reaction r- ixture is maintained at this temperature for 21 hours to achieve nearly complete conveision of the starting material to l-amino-l-cyanamino-2,2-dicyanoethylene sodium salt. The reactor is then cooled to room temperature and excess ammonia is removed to yield l-amino-l-cyanamino-2,2- dicyanoethylene sodium salt as a solution in N,N-dimethylformamide.

Example 15

A 1 1 Parr reactor is charged with l-ethoxy-l-cyanamino-2,2-dicyanoethylene sodium salt (57.7% assay; 47.8 g; 0.150 mol), aqueous ammonia (29.6%; 23.0 ml; 0.360 mol) and water (135 ml). The reactor is sealed, heated to 75°C and the reaction mixture is maintained at this temperature for 24 hours to achieve nearly complete conversion of the starting material to l-amino-l-cyanamino-2,2-dicyanoethylene sodium salt. The reactor is

cooled to room temperature to yield the product as a filterable precipitate.

Example 16

A 1 1 Parr reactor is charged with l-ethoxy-l-cyanamino-2,2-dicyanoethylene, sodium salt (57.7% assay; 44.7 g; 0.140 mol). The reactor is sealed, cooled in an ice bath, charged with ammonia (57.5 g; 3.38 mol), and heated to 75°C for 24 hours to achieve virtually complete conversion of the starting material to l-amino-l-cyanamino-2,2-dicyanoethylene, sodium salt. The reactor is cooled to room temperature and vented to yield the product as a wet solid.

Example 17

A l l, three-necked, round-bottomed flask equipped with a N ₂ inlet, mechanical agitation, thermometer and addition funnel is successively charged with ethanol (170 ml), diethyl (N-cyanimido)-carbonate (approx. 80 % assay; 40.0 g; 0.225 mol) and malononitrile (23.5 g; 0.356 mol). The resulting mixture is cooled to 0-5°C (ice/water bath) and a solution of sodium ethoxide in ethanol (21% assay; 115 g; 0.355 mol) is added over 2 hours while maintaining the temperature in the 0-5°C range. The reaction mixture is then allowed to warm to room temperature and stirred for 20 hours.

The above reaction mass is transfened into a 1 1 Parr reactor. The Parr reactor is sealed, cooled with an ice/water bath and anhydrous ammonia (30 g; 1.76 mol) is introduced into the reactor. The reaction mixture is then heated at 82°C (70 psig) for 17 hours. After cooling the reactor to room temperature again, excess ammonia is removed. The resulting precipitate is filtered, and the filtrate is concentrated in vacuum until more solids precipitate. The combined weight of the recovered solids is 22.4 g.

Example 18

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

Example 19

A 500 ml round bottom flask equipped with magnetic stirring and a 125 ml pressure equalizing addition funnel is charged with dimethyl (N-cyanimido)-carbonate (91.4% assay; 18.7 g; 0.150 mol), malononitrile (99%; 10.5 g; 0.157 mol), and water (75 ml). The resulting solution is cooled to 0-5°C (ice/water bath), and a 2.5 M aqueous NaOH solution (66 ml; 0.165 mol) is added over a period of 2.0 hours. The resulting solution of l-methoxy-l-cyanamino-2,2-dicyanoethylene sodium salt is transferred to a 500 ml Pan- reactor, which is charged with aqueous ammonia (29.6%; 23 ml; 0.360 mol), se; ^* d, and heated to 75°C. The reaction mixture is maintained at this temperature for 24 hours to achieve complete conversion to l-amino-l-cyanamino-2,2-dicyanoethylene, sodium salt The reactor is cooled to room temperature to yield the product as an aqueous solution.

Example 20

A 3 1, four-necked, round-bottomed flask equipped with a thermometer, mechanical agitation, addition funnel and vented to a caustic scrubber is charged with l-amino-l-cyanamino-2,2-dicyanoethylene (200 g; 51.1%; 0.66 mol) and isopropanol (1030 ml). The mixture is cooled to 0-5°C and a solution of HC1 in isopropanol (18.8% assay; 626 g; 3.22 mol) is added over a period of 2 hours while maintaining the temperature of the reaction in the 0-10°C range. The reaction mixture is then warmed to room temperature and st red for 15 hours. Cyclopropylamine (151.0 g; 2.65 mol) is added all at once, followed by sodium hydroxide (100%; 51.6 g; 1.29 mol) and the reaction mixture is refluxed (82° C) for 15 hours. After cooling to 60°C, the reaction mixture is filtered. The recovered solids are washed with water (600 ml), filtered again and dried to give 108 g of product.

Example 21

A l l, four-necked, round-bottomed flask equipped with a thermometer, mechanical agitation, addition funnel and vented to a caustic scrubber is charged with l-amino-l-cyanamino-2,2-dicyanoethylene (25 g; 68.5%; 0.11 mol) and sec-butanol (197 ml). The mixture is cooled to 0-5°C and a solution of HC1 in sec-butanol (20.3 % assay; 72.5 g; 0.40 mol) is added over a period of 2 hours while maintaining the temperature of the reaction in the 0-5°C range. The reaction mixture is then warmed to room temperature and stirred overnight. Cyclopropylamine (13.8 g; 0.24 mol) is added all at once, followed by sodium hydroxide (100%; 9.7 g; 0.24 mol). The reaction mass is transfened to a Parr reactor and heated to 100°C for 8 hours. After cooling the reaction mar. to 25°C, a solution of NaOH (25%; 26.0 g; 0.16 mol) is added. The resulting mixture is stirred for 2

hours and filtered. The recovered solids are washed with water, filtered again and dried to give 18 g of product.

Example 22

A l l, four-necked, round-bottomed flask equipped with a thermometer, mechanical agitation, addition funnel and vented to a caustic scrubber is charged with 1-amino- l-cyanamino-2,2-dicyanoethylene (50 g; 50.1%; 0.27 mol) and sec-butanol (257 ml). The mixture is cooled to 0-5°C and a solution of HC1 in sec-butanol (20 % assay; 147 g; 0.81 mol) is added over a period of 30 minutes while maintaining the temperature of the reaction in the 0-5°C range. The reaction mixture is then warmed to 25°C and stirred for 1.5 hour to complete the cyclization. Cyclopropylamine (71% assay; 77.7 g; 0.967 mol) is added all at once,then the reaction mass is transferred to a Parr reactor and heated to 100°C for 4 hours. Sodium hydroxide (13 g; 0.32 mol) is added and stirring is continued for 2 hours at 80°C. After cooling the reaction mass to 25°C, water (40 g) is added. The resulting mixture is stirred for 1 hour at room temperature and filtered. The recovered solids (86 g) are refluxed for 3 hours in boiling water (860 ml); then the slurry is cooled to room temperature. The solids are filtered and dried to give 41.6 g (80%) of crude product.

Example 23

A 250 ml, three-necked, round-bottomed flask equipped with a thermometer, magnetic stirrer, and N ₂ inlet is charged with l-amino-l-cyanamino-2,2-dicyanoethylene sodium salt (10 g, 0.064 mol) and water (40 ml). The flask is cooled to 0-5°C (ice/water bath) and 36 % hydrochloric acid (25.0 g; 0.246 mol) is added within 15 minutes. The reaction mixture is allowed to warm slowly to 20-25°C and stirred for 23 hours. Filtration of the resulting slurry gives 13.4 g of wet solids.

Example 24

A 50 ml, three-necked, round-bottomed flask equipped with a thermometer, magnetic stirrer, and a N ₂ inlet is charged with l-amino-l-cyanamino-2,2-dicyanoethylene sodium salt (1.1 g, 7.1 mmol) and ethanol (20 ml). The flask is cooled to 0-5°C (ice/water bath) and a solution of HC1 in EtOH (12% assay; 4.8 g; 15.8 mmol) is added. The reaction mixture is allowed to warm slowly to 20-25°C and stirred for 20 hours. Filtration of the resulting slurry and concentration of the filtrate give 1.7 g of solids. The calculated yield, as 2-ethoxy-4,6-diamino-5-cyanopyrimidine, is 84.5%.

Example 25

A l l, four-necked, round-bottomed flask equipped with a thermometer, mechanical

agitation, addition funnel and vented to a caustic scrubber is charged with 1-amino- l-cyanamino-2,2-dicyanoethylene (60 g; 87.6%; 0.34 mol) and sec-butanol (215 g). The mixture is cooled to 0-5°C and a solution of HCl in sec-butanol (22.1 % assay; 160 g; 0.97 mol) is added over a period of 2.5 hours while maintaining the temperature of the reaction in the 0-5°C range. The reaction mixture is then warmed to room temperature and stirred overnight (15 h). Cyclopropylamine (67 g; 1.61 mol) is added all at once and the reaction mixture is refluxed for 8 hours. After cooling the reaction mass to 25°C, N,N-dimethyl- acetamide (280 g) is added and 2-butanol is removed by vacuum distillation. The distillation bottoms are cooled to room temperature, and a solution of NaOH (50%; 46.0 g; 0.58 mol) is rapidly added. The mixture is heated to 80°C under stirring and filtered through a layer of diatomaceous earth (15 g). The resulting solution of 2-cyclopro- pylamino-4,6-diamino-5-cyanopyrimidine is concentrated by vacuum distillation of N,N-dimethyl- acetamide (125 g), and 2-butanol (400 g) is added to precipitate the 2-cyclopropylamino-4,6-diamino-5-cyanopyrimidine. The resulting slurry is filtered. The recovered solids are washed with a mixture of water and methanol, filtered and dried to give 48 g (75%) of the product.