WO2011060624A1

WO2011060624A1 - Process for preparing 2-methyl-4-amino-5-cyanopyrimidine

Info

Publication number: WO2011060624A1
Application number: PCT/CN2010/001883
Authority: WO
Inventors: Fen-er CHEN; Xiaodong Ma; Lei Zhao; Fangjun Xiong
Original assignee: Fudan University; Dsm Ip Assets B.V.
Priority date: 2009-11-23
Filing date: 2010-11-23
Publication date: 2011-05-26
Also published as: CN102712602B; CN102712602A

Abstract

A process for synthesizing 2-methyl-4-amino-5-cyanopyrimidine is provided. It is characterized by reacting malononitrile with an ionic salt compound (III) in a certain solvent under the effect of an alkali, and condensing the product thereof without separation directly with ethanamidine hydrochloride to form a ring in the presence of an alkali, so as to prepare 2-methyl-4-amino-5-cyanopyrimidine (I).

Description

A process for preparing 2-memyl-4-amino-5-cyanopyrimidine Technical Field

The present invention belongs to the field of medicine and chemistry, and particularly it is a process for preparing 2-methyl-4-amino-5-cyanopyrimidine (I) using malononitrile as a starting material.

(I)

Background Art

2-methyl-4-amino-5-cyanopyrimidine (I) is an important intermediate for synthesizing Vitamin Bl. The preparation processes already reported regarding this compound are mainly synthesis methods using malonic acid derivatives as starting materials, synthesis methods using 3-(dimethylamine) ethyl cyanide as a starting material, and synthesis methods using N,N-dimethylformamide diethyl acetal as a starting material. In German patent 671787, French patent 819596, Norwegian patent 59015 and

Swiss patents 193951 and 193952, each reported the process for preparing 2-methyl-4-amino-5-cyanopyrimidine (I) using malonate as a starting material. In this process, an ethoxymethylene malonic ester (EMME) (IV) was first prepared, then it was condensed with ethanamidine hydrochloride, so as to obtain 2-methyl-4-hydroxy-5-alkoxyl carbonyl pyrimidine (V), and then this compound was successively subjected to chlorination, ammoniation and amidation for dehydrating, so as to obtain the target product (I); however, the route of this process was long, the yield was low and the environmental pollution was serious, so it had no value for practical application.

(IV) (V) (I) Todd A et al {Journal of Chemical Society, 1937, 1364) improved the above process by first using cyanoacetate as a starting material to prepare ethoxyl methylene cyanoacetate (VI), then condensing it with ethanamidine to form a ring, and then subjecting the ring to ammoniation for dehydrating so as to obtain 2-methyl-4-amino-5-cyanopyrimidine (I), which shortened the synthesis route but this approach still had the above disadvantages and had no value for industrial production.

POCIs

(VI) (I) Greww R et al were the first to report {Physiologische Chemie, 1936, 89, 242;

Naturwiss, 1936, 24, 657) a process for preparing 2-methyl-4-amino-5-cyanopyrimidine (I) by using malononitrile for preparing 2-ethoxy methylene malononitrile (VII) and then condensing it with ethanamidine to form a ring. In patents US 2235638, DE 667990, DE 670635, DE 25432440, CH 215659, US 2271503, DE 731562, DE 25443 and US 2184720, Merck Company and Hoffmann-La Roche Company made continuous optimizations around this process, and finally, Hoffmann-La Roche Company achieved an industrial production process for preparing 2-memyl-4-amino-5-cyanopyrimidine (I) by using malononitrile as the starting material, condensing the same with ethyl orthoformate in the presence of acetic anhydride to prepare 2-ethoxy methylene malononitrile (VII), and then under the effects of ammonia condensing the same with ethyl ethylimidoate to form a ring. However, since the reaction conditions are critical, the process route and equipment are complicated, production costs are high and there is environmental pollution, it is of great interest to develop a process route of a higher efficiency.

(VH)

In US patents US 3655716, US 3655716, US 3689498, US 3742015, US 3792076, US 3853946, US 3900511, US 3901888, US 3965141 and US 3966791, processes were reported for preparing the compound respectively by using 3-(dimethylamine) propyl cyanide and ^N-dimethylformamide diethyl acetal as starting materials to prepare the common intermediates (VIII) and (IX), and then the compound (IX) was finally made into the compound (I) by different routes and a series of conversions. Although 3-(dimethylamine) propyl cyanide and N,N-dimethylformamide diethyl acetal are cheap and easily available, these two processes have long routes, are complicated in processing, have high production costs and serious environmental pollution, so it is difficult for them to realized industrialized production.

Contents of the invention

An object of the present invention is to solve the problems existing in the prior art, to provide a process for preparing 2-methyl-4-arrdno-5-cyanopyrimidine (I) which is simple in processing procedure, effective, environment-friendly, and suitable for industrialized production.

The present invention uses malononitrile as the starting material, and particularly it is carried out by: condensing malononitrile, under the effects of an alkali, with an ionic salt compound (III) in a certain solvent; and having the product (II), without separation, condensed directly with ethanamidine hydrochloride in the presence of an alkali, then preparing 2-methyl-4-amino-5-cyanopyrimidine (I); wherein the total yield of these three steps is around 70% and the content is > 98%. This synthesis route features by being simple in the processing procedure, highly efficient and environment-friendly.

The synthesis route of the present invention is as follows:

(ΙΠ) (Π) (I)

wherein, R¹ and R², being the same or different, are each hydrogen, a linear or branched Q - C₈ alkyl, a C₂ - C₈ alkoxy, a C₃ - C_g cycloalkane group, a C₂ - Qalkenyl, a C₃ - C₈ alkyloxyalkenyl, an aralkyl or aralkenyl group, a 5 - 8 member heterocycle having S, O, N; R³ is -OR⁵ or -N (R⁵ , R⁶), wherein, R⁵ and R⁶ are the same as R¹ and R²; and in which X is an ionic salt of Q - C₈ alkyl sulphonate, an ionic salt of C₆ - Cj₂ aryl sulphonate, or an ionic salt of tetrafluoroborate.

In the present invention, malononitrile reacts with the compound (ΠΙ) under the effects of an alkali according to a molar ratio of 1 : 0.5 - 10 : 0.5 - 10, at a reaction temperature of -50°C to 50°C and for a reaction time of 5 min to 5 h, so as to prepare conveniently and effectively the compound (II); and the compound (II), without separation and purification, reacts directly under the effects of an alkali with ethanamidine hydrochloride by a molar ratio of 1 : 1 - 5 : 1 - 5, at a reaction temperature of 0°C to 30°C and for a reaction time of 1 to 20 h; and after having completed the reaction, the same is filtered and washed and dried to obtain the compound (I) in high efficiency, high yield and high purity. The organic solvent used in the reaction is halogenated hydrocarbon (such as dichloromethane, chloroform, 1,2-dichlorethane, carbon tetrachloride, etc.); aliphatic hydrocarbon (such as hexane, heptane, octane, nonane, methyl cyanides, ethyl acetate, etc.); aromatic hydrocarbon (such as benzene, toluene, xylene, nitrobenzene, etc.); various halogenated aromatic hydrocarbon (such as chlorobenzene, etc.); solvents of ethers (such as ethylether, methyl tert-butyl ether, tetrahydrofuran or 1,4- phendioxin, etc.). These solvents have wide supply sources and low costs and are easily available and convenient to recycle. The alkali used can be selected from a wide range, such as the low-cost and easily available sodium methylate, sodium hydroxide and sodium carbonate can satisfy the requirements of the reactions. The compound (ΓΠ) used in the present invention preferably uses an ionic salt formed from N,N-dimethylformamide and dimethyl sulphate by a molar ratio of 1 : 0.5 - 2, at a temperature of 0°C to 100°C, and for a reaction time of 1 h to 5 h.

The compound (I) in the present invention is obtained by filtration. The product treated by this way contains a small amount of sodium methyl sulfate, which can be easily removed by cooled solvents of alcohols (methanol, ethanol, etc.) or water.

The compound (I) in the present invention is obtained by filtration. The filtrate after the filtration contains a small amount of the product. By evaporating the methanol, dissolving the obtained brown solid into water, filtering the same, drying the filter residues, and then dissolving the filter residues in methanol, filtering the same, and drying the filter residues, then the product can be recovered.

The preferred reaction conditions of the present invention are as follows:

the compound (III) is preferably an ionic salt formed by the reaction of

N,N-dimethylformamide and dimethyl sulphate, with a reaction molar ratio of 1 : 1 - 1.2, at a temperature of 60°C to 90°C and for a reaction time of 3 h to 5 h.

The molar ratio of malononitrile, the compound (ΙΠ) and the alkali is 1 : 1 - 3 : 1 - 3, the reaction temperature is -20°C to 0°C and the reaction time is 5 min to 2 h.

The molar ratio of the compound (II), the alkali and ethanamidine hydrochloride is 1 : 1 - 2 : 1 - 2, the reaction temperature is 0°C to 50°C and the reaction time is 8 to 30 h. The organic solvent is preferably methanol, which has wide supply sources and low costs and is easily available and convenient for recycling.

The alkali is preferably sodium methylate, which is of low cost and has wide supply sources.

The present invention is simple in processing, of high efficiency, mild in the conditions, environment-friendly, high in yield, good in quality and suitable for industrialized productions. Embodiments

The following embodiments are used to better describe the contents of the present invention. However, those skilled in the art can understand that the scope of the present invention is defined by the claims of the present application. Embodiment 1

DMF (28.71 g, 392.80 mmol) was introduced into a 1000 mL three-necked bottle, it was heated to 70°C, and dimethyl sulphate (49.49 g, 392.80 mmol) was slowly added dropwise therein, then it was reacted for 3.5 h at this temperature and cooled to ≤ -5°C (internal temperature) thereafter; then 200 mL of methanol solution of sodium methylate (21.21 g, 392.80 mmol) was slowly added dropwise therein (with such an addition speed that it maintained the internal temperature < -5°C); after that, it was reacted at the temperature for 5 min and then malononitrile (25.44 g, 385.10 mmol) was slowly added dropwise therein (with such an addition speed that it maintained the internal temperature < -5°C); then it was stirred at the temperature for 30 min and then added therein 220 mL of methanol solution of ethanamidine ( 24.59 g, 423.61 mmol), it was stirred for 5 min, and reacted at the normal temperature 20°C (20°C to 25°C) for 15 h; and after having completed the reaction, it was stirred for 1 h in an ice bath, then it was filtered, washed with cold methanol, and vacuum dried (50°C, 2 h, - 0.1 MPa) to obtain 36.70 g of white solid, with a yield of 71.11%. 1H-NMR(DMSO, 400 MHz): 8.588(5, 1H), 1.770(br s, 2H), 2.368(5, 1H),

¹³C- MR(CDC1₃, 400 MHz): 170.534, 162.797, 151.545, 116.125, 87.138.

Embodiment 2

DMF (28.71 g, 392.80 mmol) and dimethyl sulphate (49.49 g, 392.80 mmol) were introduced into a 1000 mL three-necked bottle, it was heated to 72°C, reacted for 3.5 h and then cooled to < -5°C (internal temperature); then 200 mL ethanol solution of sodium ethylate (21.21 g, 392.80 mmol) was slowly added dropwise therein (with such an addition speed that it maintained the internal temperature < -5°C); after that, it was reacted at the temperature for 5 min and then malononitrile (25.44 g, 385.10 mmol) was slowly added dropwise therein (with such an addition speed that it maintained the internal temperature < -5°C); then it was stirred at the temperature for 30 min and then 220 mL of ethanol solution of ethanamidine(24.59 g, 423.61 mmol) was added therein, it was stirred for 5 min, and reacted at the normal temperature 20°C (20°C to 25°C) for 15 h; and after having completed the reaction, it was stirred in an ice bath for 1 h, then it was filtered, washed with cold methanol, and vacuum dried (50°C, 2 h, - 0.1 MPa) to obtain 34.41 g of white solid, with a yield of 68.61%.

Embodiment 3

DMF (28.71 g, 392.80 mmol) and dimethyl sulphate (49.49 g, 392.80 mmol) were introduced into a 1000 mL three-necked bottle, it was heated to 75 °C, reacted for 3.5 h and cooled to <0°C (internal temperature); then 200 mL methanol solution of sodium methylate (21.21 g, 392.80 mmol) was slowly added dropwise therein (with such an addition speed that it maintained the internal temperature <0°C); after that, it was reacted at the temperature for 5 min and then malononitrile (25.44 g, 385.10 mmol) was slowly added dropwise therein (with such an addition speed that it maintained the internal temperature <0°C); then it was stirred at the temperature for 30 min and then added therein 220 mL of methanol solution of ethanamidine ( 24.59 g, 423.61 mmol), it was stirred for 15 min, and reacted at 30°C for 20 h; and after having completed the reaction, it was stirred in an ice bath for 1 h, then it was filtered, washed with cold methanol, and vacuum dried (50°C, 2 h, - 0.1 MPa) to obtain 34.2 g of white solid, with a yield of 66.32%.

Embodiment 4

DMF (28.71 g, 392.80 mmol) and dimethyl sulphate (49.49 g, 392.80 mmol) were introduced into a 1000 mL three-necked bottle, it was heated to 72°C, reacted for 3.5 h and cooled to < -5°C (internal temperature); then 200 mL methanol solution of sodium methylate (21.21 g, 392.80 mmol) was added dropwise slowly therein (with such an addition speed that it maintained the internal temperature < -5°C); after that, it was reacted at the temperature for 5 min and then malononitrile (21.60 g, 327.33 mmol) was slowly added dropwise therein (with such an addition speed that it maintained the internal temperature < -5°C); then 220 mL of methanol solution of ethanamidine (24.59 g, 423.61 mmol) was stirred at the temperature for 30 min and added therein, it was stirred for 5 min, and reacted at the normal temperature 20°C (20 °C to 25 °C) for 15 h; and after having completed the reaction, it was stirred in an ice bath for 1 h, then it was filtered, washed with cold methanol, and vacuum dried (50°C, 2 h, - 0.1 MPa) to obtain 28.80 g of white solid, with a yield of 65.67%.

Embodiment 5

DMF (28.71 g, 392.80 mmol) was introduced into a 1000 mL three-necked bottle, it was heated to 70°C, added dropwise slowly therein dimethyl sulphate (49.49 g, 392.80 mmol), it was reacted for 3.5 h at this temperature and cooled to < 0°C - (internal temperature) after that; then 200 mL methanol, malononitrile (25.44 g, 385.10 mmol) and Na₂C0₃(46.96 g , 471.36 mmol) were introduced therein successively and it was reacted at 0°C for 20 min; and after having completed the reaction, it was filtered, the filtrate was concentrated under pressure and dissolved with DCM (100 mL), it was filtered and the filtrate was concentrated to obtain the compound (II).

The abovementioned compound (II) prepared was dissolved with 50 mL methanol, 170 mL methanol solution of ethanamidine (24.59 g, 423.61 mmol) was added therein in an ice bath, it was stirred for 5 min and reacted at the normal temperature 20°C (20 °C to 25 °C) for 15 h; and after having completed the reaction, it was stirred in an ice bath for 1 h, then it was filtered, washed with cold methanol, and vacuum dried (50°C, 2 h, -0.1 MPa) to obtain 30.40 g of white solid, with a yield of 58.91%.

Embodiment 6

DMF (28.71 g, 392.80 mmol) was introduced into a 1000 mL three-necked bottle, it was heated to 70°C, dimethyl sulphate (49.49 g, 392.80 mmol) was slowly added dropwise therein, after that it was reacted for 3.5 h at this temperature and cooled to < -5°C (internal temperature); then 200 mL methanol solution of sodium methylate (21.21 g, 392.80 mmol) was slowly added dropwise therein (with such an addition speed that it maintained the internal temperature < -5°C); after that, it was reacted at the temperature for 5 min and then malononitrile (25.44 g, 385.10 mmol) was slowly added dropwise therein (with such an addition speed that it maintained the internal temperature < -5°C); then it was stirred at the temperature for 30 min and then added therein 220 mL of methanol solution of ethanamidine ( 24.59 g, 423.61 mmol), it was stirred for 5 min and reacted at the normal temperature 20°C (20 °C to 25 °C) for 15 h; and after having completed the reaction, it was stirred in an ice bath for 1 h, then it was filtered, washed with cold methanol, and vacuum dried (50°C, 2 h, -0.1 MPa) to obtain 31.88 g of white solid, with a yield of 61.78%..

Claims

1 / 4 Claims

1. A process for preparing 2-memyl-4-arnino-5-cyanopyrimidine (I) using malononitrile as a starting material, characterized in that it undergoes the following procedure

(I) (II) (ΠΙ)

(1) reacting malononitrile with an ionic salt compound (III) in an organic solvent under the effects of an alkali so as to prepare a compound (II), in which formula R¹ and R², being the same or different, are each hydrogen, a linear or branched Q - C₈ alkyl, a C₂ - C₈ alkoxy, a C₃ - C₈ cycloalkyl, a C₂ - C₈ alkenyl, a C₃ - C_s alkyloxy alkenyl, an aralkyl or aralkenyl, and a 5-8 member heterocycle containing S, O and N; R³ is -OR⁵ or -N (R⁵,R⁶), wherein R⁵ and R⁶ are the same as R¹ and R²; and X is an ionic salt of Cj - Cg of alkyl sulphonate, an ionic salt of Ce - C_!2 aryl sulphonate, or an ionic salt of tetrafluoroborate; wherein, the molar ratio of malononitrile, the compound (III) and the alkali is 1 : 0.5 - 10 : 0.5 - 10, the reaction temperature is -50°C to 50°C, and the reaction time is 5 min to 5 h;

(2) after the completion of the above reaction, condensing the product (II), with it being separated and purified or without any treatment, with ethanamidine hydrochloride to form a ring under the effects of an alkali; and then having the product filtered, washed and dried to obtain the compound (I); wherein, the molar ratio of the compound (II), the alkali and ethanamidine hydrochloride is 1 : 1 - 10 : 1 - 10, the reaction temperature is 0°C to 50°C and the reaction time is Ih to 30 h.

2. The process as claimed in claim 1, characterized in that said alkalis in steps (1) and (2) are the same or different inorganic alkalis, such as metallic hydroxides or metallic carbonates, metallic hydrocarbonates, or organic alkalis such as alkoxy or aralkyl metallic alkalis (A) or alkyl or aralkyl metallic alkalis (B) or dialkylamine 2 / 4 metallic alkalis (C) or bis(trimethylsilyl)amine metallic alkalis (D),

A: ROM

in formula A, R is a Q - C₆ alkoxy or aralkoxy; and M is Li, Na or K;

B: RM

in formula B, R is a Q - C₆ alkoxyl or aralkoxyl; and M is Li, Na or K;

C: R¹(R²)NM

in formula C, R¹ and R² are the same or different Q - C₆ alkoxyls or the same or different aralkoxyls; and M is Li, Na or K; and

D: [(C¾)₃Si]₂M

in formula D, R^! and R² are the same or different C_t - C₆ alkoxyls or the same or different aralkoxyls; and M is Li, Na or K.

3. The process as claimed in claim 2, characterized in that said inorganic alkalis in steps (1) and (2), being the same or different, are sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, and sodium bicarbonate.

4. The process as claimed in claim 2, characterized in that said organic alkalis in steps (1) and (2), being the same or different, are sodium methylate, potassium methylate, sodium ethoxide, potassium ethoxide, sodium t-butoxide and potassium t-butoxide.

5. The process as claimed in claim 1, characterized in that said solvents in steps (1) and (2), being the same or different, are one or more of solvents of halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, esters, ethers or alcohols.

6. The process as claimed in claim 5, characterized in that said solvents in steps (1) and (2) are methanol, ethanol, isopropanol, toluene or dichloromethane, and preferably methanol. 3 / 4

7. The process as claimed in claim 1, characterized in that the molar ratio of malononitrile, the compound (ΠΙ) and the alkali is 1 : 0.5 - 10 : 0.5 - 10, the reaction temperature is -50°C to 50°C, and the reaction time is 5 min to 5 h.

8. The process as claimed in claim 1, characterized in that the molar ratio of the compound (Π), the alkali and ethanamidine hydrochloride is 1 : 1 - 10 : 1 - 10, the reaction temperature is 0°C to 5°C, and the reaction time is lh to 30 h.

9. The process as claimed in claim 1, characterized in that malononitrile is condensed with the ionic salt compound (III) and the product (II) can be condensed with ethanamidine hydrochloride after having been separated and purified under the effects of the alkali; or after having been completed the reaction of malononitrile, the product (Π) may condense directly with ethanamidine without any treatment to form a ring, so as to prepare the compound (I).

10. The process as claimed in claim 1, characterized in that the compound (III) used in step (1) is preferably an ionic salt formed from N,N-dimethylfoimamide and dimethyl sulphate, with the molar ratio of these two being 1 : 0.5 - 2, the reaction temperature being 0°C to 100°C, and the reaction time being 1 h to 5 h.

11. The process as claimed in claim 1, characterized in that the product obtained after the filtration in step (2) has a small amount of sodium salt of monomethyl sulfate and the method for removing this salt is to wash the product using a cold organic solvent or water.

12. The process as claimed in claim 11, the organic solvent used for washing the product to remove the sodium salt of monomethyl sulfate is one or more of the solvents of halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, esters, ethers or alcohols, and preferably the alcohols, wherein methanol, ethanol and isopropanol are more preferable. 4 / 4

13. The process as claimed in claim 1, characterized in that , the process for recovering the small amount of product in the filtrate after the filtration in step (2) comprises: evaporating methanol to obtain a brown solid, then dissolving the solid in water and filtering the same, drying the filter residues and then dissolving the filter residues in methanol and filtering the same, and then drying the filter residues so as to obtain the product