EP0711285A1 - Procede de preparation de 4,6-diamino-5-cyanopyrimidines substituees - Google Patents

Procede de preparation de 4,6-diamino-5-cyanopyrimidines substituees

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Publication number
EP0711285A1
EP0711285A1 EP94923734A EP94923734A EP0711285A1 EP 0711285 A1 EP0711285 A1 EP 0711285A1 EP 94923734 A EP94923734 A EP 94923734A EP 94923734 A EP94923734 A EP 94923734A EP 0711285 A1 EP0711285 A1 EP 0711285A1
Authority
EP
European Patent Office
Prior art keywords
formula
alkali metal
process according
dicyanoethylene
cyanamino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP94923734A
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German (de)
English (en)
Inventor
Jean-Marie Assercq
Heinz Peter Schwemlein
Jeffrey William Perine
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
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Ciba Geigy AG
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Publication date
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Publication of EP0711285A1 publication Critical patent/EP0711285A1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/50—Three nitrogen atoms

Definitions

  • the present invention relates to a novel process for the preparation of certain 2-substituted 4,6-diamino-5-cyanopyrimidines and their intermediates.
  • 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.
  • 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.
  • 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
  • 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
  • R 3 is C ⁇ -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
  • R ⁇ 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
  • 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
  • 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
  • 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.
  • R 3 as C r C 4 alkyl can be methyl, ethyl, propyl, isopropyl, any of the butyl isomers, cyclopropyl, methylcyclopropyl or cyclobutyl.
  • R 3 is methyl or ethyl.
  • 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.
  • 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 * Stamm ⁇ nic compounds with each other or with water.
  • methanol and ethanol such as 2-methoxy- or 2-ethoxyethanol
  • water and mixtures of the c * Stamm ⁇ nic compounds with each other or with water.
  • 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.
  • 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.
  • 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.
  • a solvent other than an alcohol for example methyl tert-butyl ether
  • ethanol may be added to the reaction mixture before carrying on with the second step.
  • the first and second steps can be carried out separately, as is also illustrated in the experimental section.
  • this approach is somewhat less attractive since it adds one filtration to the overall process.
  • 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 + is an alkali metal cation, preferably sodium.
  • AUenstein et al. report an attempt to convert 1-ethoxy-l- cyanamino-2,2-dicyanoethylene sodium st ⁇ (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.
  • 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 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.
  • the reaction rate decreases in ethanol at lower molar ratios.
  • the reaction 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.
  • the reaction is extremely slow and only gives a 1 : 13 ratio of product to starting material after 2 days.
  • the reaction at 75°C is about twice as fast as with ethanol.
  • the ammonolysis at 75°C is also about twice as fast as with ethanol and 10 molar equivalents of ammonia.
  • reaction conditions are those wherein the time at which the yield of product ⁇ 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.
  • 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
  • M + is an alkali metal cation, with excess hydrogen chloride in a secondary alcohol, water or a mixture thereof.
  • aqueous hydrochloric acid preferably concentrated aqueous hydrochloric acid, can be employed in this reaction.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • anhydrous ammonia 60 g; 3.529 mol
  • the reactor is or Jed to room temperature and excess ammonia is removed. Filtration of the resulting slurry affords 41 g of product.
  • 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.
  • 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 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 overall yield of 2-cyclopropylamino-4,6-diamino-5-cyanopyrimidine from this sequence is 40%.
  • 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.
  • the overall yield of 2-cyclopropylamino-4,6-diamino-5-cyanopyrimidine from this four-step sequence is 26.2 %.
  • 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, 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • diethyl (N-cyanimido)-carbonate 90% assay; 39.7 g; 0.251 mol
  • malononitrile 99%; 17.5 g; 0.262 mol
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

4,6-diamino-5-cyanopyrimidines substituées en position 2 de formule (I) dans laquelle R1 est hydrogène, alkyle C1-C-6, alcényle C2-C6 ou alcynyle C2-C6 et R2 est hydrogène, alkyle C1-C10, ou cycloalkyle C3-C6 ou R1 et R2 ensemble sont un radical choisi dans le groupe de radicaux constitué de -(CH2)3-, -(CH2)4- et -(CH2)5- qui sont préparées selon un procédé consistant à faire réagir un cyanimidocarbonate de dialkyle de formule (V) dans laquelle R3 est alkyle C1-C4 avec un sel de métal alcalin de malononitrile ou avec de l'amononitrile et une base se métal alcalin, à une température de -10 à +40°C pour obtenir un sel de métal alcalin de 1-alcoxy-1-cyanamino-2,2-dicyanoéthylène de formule (IV) dans laquelle R3 est alkyle C1-C4 et M+ est un cation de métal alcalin, à faire réagir ledit composé avec un excès de gaz ammoniac à une température de 60 à110°C pour obtenir un sel de métal alcalin de 1-amino-1-cyanamino-2,2-dicyanoéthylène de formule (II) dans laquelle M1 est un cation de métal alcalin, à faire réagir ce sel avec un excès de chlorure d'hydrogène dans un alcool secondaire, de l'eau ou un mélange des deux en tant que solvant pour obtenir de la 2-chloro-4,6-diamino-5-cyanopyrimidine et à faire réagir ensuite ce composé avec une amine de formule R¿1?R2NH pour obtenir le produit final.
EP94923734A 1993-07-26 1994-07-14 Procede de preparation de 4,6-diamino-5-cyanopyrimidines substituees Withdrawn EP0711285A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US9714193A 1993-07-26 1993-07-26
US97141 1993-07-26
US21098094A 1994-03-21 1994-03-21
US210980 1994-03-21
PCT/EP1994/002312 WO1995003282A2 (fr) 1993-07-26 1994-07-14 Procede de preparation de 4,6-diamino-5-cyanopyrimidines substituees

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EP0711285A1 true EP0711285A1 (fr) 1996-05-15

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EP (1) EP0711285A1 (fr)
JP (1) JPH09500632A (fr)
CN (1) CN1128024A (fr)
AU (1) AU7385994A (fr)
BG (1) BG100366A (fr)
BR (1) BR9407024A (fr)
CA (1) CA2166989A1 (fr)
CZ (1) CZ22496A3 (fr)
FI (1) FI960332A0 (fr)
HU (1) HUT73357A (fr)
IL (1) IL110425A0 (fr)
LV (1) LV11463B (fr)
NO (1) NO960307L (fr)
SK (1) SK10396A3 (fr)
WO (1) WO1995003282A2 (fr)

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US6255316B1 (en) * 1997-08-27 2001-07-03 Novartis Animal Health Us, Inc. Dicyclanil polymorphs and hydrates and their preparation
US8273899B2 (en) 2007-04-19 2012-09-25 Nippon Soda Co., Ltd. Method for production of N-(2-amino-1,2-dicyanovinyl)imidates, method for production of N-(2-amino-1,2-dicyanovinyl)formamidine, and method for production of aminoimidazole derivatives
CN102250017A (zh) * 2011-06-15 2011-11-23 扬州天和药业有限公司 地昔尼尔的一种合成方法
CN102399193A (zh) * 2011-12-15 2012-04-04 连云港市亚晖医药化工有限公司 4,6-二氨基-2-环丙胺基-5-腈基嘧啶的制备方法
CN104130197A (zh) * 2014-07-29 2014-11-05 华中农业大学 2,4,6-三氨基-5-氰基嘧啶的化学合成方法
CN104649982B (zh) * 2015-02-26 2016-12-07 齐鲁晟华制药有限公司 一种地昔尼尔的制备方法
CN107056655B (zh) * 2017-01-22 2018-12-04 营口三征新科技化工有限公司 一种1-氨基-1-氰氨基-2,2-二氰乙烯钠盐的制备方法
CN106966922B (zh) * 2017-03-28 2020-10-27 中国科学院大学 一种功能化取代的二氰基乙烯类化合物的合成方法

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DE1135913B (de) * 1960-11-08 1962-09-06 Bayer Ag Verfahren zur Herstellung von 2-Methyl-4-amino-5-cyanpyrimidin
US3226424A (en) * 1962-10-03 1965-12-28 Hoffmann La Roche Process for preparing 2-lower alkoxy-1,1-dicyanoethylene and 2-amino-1,1-dicyanoethylene
US4783468A (en) * 1986-04-30 1988-11-08 Ciba-Geigy Corporation Insecticidal 5-pyrimidine carbonitriles

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WO1995003282A3 (fr) 1995-04-13
CN1128024A (zh) 1996-07-31
JPH09500632A (ja) 1997-01-21
CZ22496A3 (en) 1996-04-17
NO960307D0 (no) 1996-01-25
FI960332A7 (fi) 1996-01-24
HUT73357A (en) 1996-07-29
WO1995003282A2 (fr) 1995-02-02
CA2166989A1 (fr) 1995-02-02
SK10396A3 (en) 1996-09-04
BR9407024A (pt) 1996-09-10
BG100366A (en) 1996-07-31
AU7385994A (en) 1995-02-20
IL110425A0 (en) 1994-10-21
LV11463B (en) 1996-12-20
HU9503959D0 (en) 1996-03-28
LV11463A (lv) 1996-08-20
NO960307L (no) 1996-01-25
FI960332A0 (fi) 1996-01-24

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