Method for preparing 4,6-dichloropyrimidine and device used in method

Abstract

A method for preparing 4,6-dichloropyrimidine, comprising the following steps: mixing malononitrile, methanol and an organic solvent to obtain a mixed solution, introducing the mixed solution and hydr

Description

TECHNICAL FIELD

[0001] The present disclosure relates to the technical field of pyrimidine preparation, and in particular to a method for preparing 4,6-dichloropyrimidine and a device used in the method. BACKGROUND

[0002] 4,6-dichloropyrimidine is a nitrogen-containing heterocyclic compound, being one of the important intermediates for synthesis of pyrimidine compounds. The 4,6-dichloropyrimidine is widely used in the synthesis of pharmaceutical products such as azoxystrobin and sulfamonomethoxine. Most of the process routes reported so far are to subject malonamide or malonate and formamide to reaction in a sodium alcohol solution (reaction formula 1), and then acidification to obtain dihydroxypyrimidine (reaction formula 2), and the dihydroxypyrimidine is then subjected chlorination to obtain the 4,6-dichloropyrimidine.

[0003] reaction formula 1: > I 2HCONH2 2CHsONa SCHjOH HCGONa

[0004]

[0005] reaction formula 2: * 3HCI 4* HCOONa ------> 4* SNaCI * HOGOH

[0006]

[0007] In the above traditional production process, many by-products are generated, with a low product yield. SUMMARY

[0008] In order to solve the problems existing in the prior art, the present disclosure provides a method for preparing 4,6-dichloropyrimidine and a device used in the method. The 4,6-dichloropyrimidine obtained by the method has a high yield.

[0009] The present disclosure provides a method for preparing 4,6-dichloropyrimidine, including the following steps:

[0010] mixing malononitrile, methanol, and an organic solvent to obtain a mixed solution, introducing the mixed solution and hydrogen chloride into a first high-gravity reactor, respectively, conducting first mixing, subjecting a resulting mixture to first reaction, and subjecting a resulting first reaction product to first refluxing into the first high-gravity reactor and then the first reaction;

[0011] repeating the first refluxing and the first reaction to obtain a first mixed solution containing 1,3-dimethoxypropylenediimine hydrochloride;

[0012] subjecting the first mixed solution containing the 1,3-dimethoxypropylenediimine hydrochloride and an organic alkali to second mixing to obtain a second mixed solution;

[0013] introducing the second mixed solution and a chlorinating agent solution into a second high-gravity reactor, conducting third mixing, subjecting a resulting mixture to second reaction, and subjecting a resulting second reaction product to second refluxing into the second high-gravity reactor and then the second reaction; and

[0014] repeating the second refluxing and the second reaction to obtain the 4,6-dichloropyrimidine.

[0015] In some embodiments, the first high-gravity reactor and the second high-gravity reactor independently have a high gravity level of 50 g to 200 g.

[0016] In some embodiments, a molar ratio of the malononitrile to the methanol is in a range of 1: 2.2-2.5.

[0017] In some embodiments, the first reaction is conducted at a temperature of -10°C to 25°C for 0.5 h to 3 h.

[0018] In some embodiments, the organic alkali is used in the form of an organic alkali solution; and the organic alkali includes one or more selected from the group consisting of triethylamine (TEA), tripropylamine (TPA), A,A-dimethylaniline (DMA), A,A-diisopropylethylamine (DIPEA), and pyridine.

[0019] In some embodiments, a molar ratio of the organic alkali to the malononitrile is in a range of 2.5-4: 1.

[0020] In some embodiments, the chlorinating agent solution includes a chlorinating agent and an organic solvent; and the chlorinating agent is one or more selected from the group consisting of phosgene, diphosgene, and triphosgene.

[0021] In some embodiments, a molar ratio of the chlorinating agent to the malononitrile is in a range of 0.5-2: 1.

[0022] In some embodiments, the second reaction is conducted at a temperature of 10°C to 80°C for 0.5 h to 3 h.

[0023] The present disclosure further provides a device used in the method described above, including a first high-gravity reactor 1, where the first high-gravity reactor 1 is provided with a product reflux pipeline 1#;

[0024] a stirring and regulating kettle 2 communicated with the first high-gravity reactor 1; and

[0025] a second high-gravity reactor 3 communicated with the stirring and regulating kettle 2, where the second high-gravity reactor 3 is provided with a product reflux pipeline 3#.

[0026] The present disclosure provides a method for preparing 4,6-dichloropyrimidine, including the following steps: mixing malononitrile, methanol, and an organic solvent to obtain a mixed solution, introducing the mixed solution and hydrogen chloride into a first high-gravity reactor, respectively, conducting first mixing, subjecting a resulting mixture to first reaction, and subjecting a resulting first reaction product to first refluxing into the first high-gravity reactor and then the first reaction; repeating the first refluxing and the first reaction to obtain a first mixed solution containing 1,3-dimethoxypropylenediimine hydrochloride; subjecting the first mixed solution containing the 1,3-dimethoxypropylenediimine hydrochloride and an organic alkali to second mixing to obtain a second mixed solution; introducing the second mixed solution and a chlorinating agent solution into a second high-gravity reactor, conducting third mixing, subjecting a resulting mixture to second reaction, and subjecting a resulting second reaction product to second refluxing into the second high-gravity reactor and then the second reaction; and repeating the second refluxing and the second reaction to obtain the 4,6-dichloropyrimidine. The 4,6-dichloropyrimidine is produced using the malononitrile as a starting raw material, and a mass transfer between reactants is enhanced by using a high-gravity process. The method greatly improves an efficiency of the reaction, shortens a reaction time, inhibits the occurrence of side reactions, and improves a yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIG. 1 shows the device used in the method for preparing the 4,6-dichloropyrimidine provided in an embodiment of the present disclosure. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0028] The present disclosure provides a method for preparing 4,6-dichloropyrimidine, including the following steps:

[0029] mixing malononitrile, methanol, and an organic solvent to obtain a mixed solution, introducing the mixed solution and hydrogen chloride into a first high-gravity reactor, respectively, conducting first mixing, subjecting a resulting mixture to first reaction, and subjecting a resulting first reaction product to first refluxing into the first high-gravity reactor and then the first reaction;

[0030] repeating the first refluxing and the first reaction to obtain a first mixed solution containing 1,3-dimethoxypropylenediimine hydrochloride;

[0031] subjecting the first mixed solution containing the 1,3-dimethoxypropylenediimine hydrochloride and an organic alkali to second mixing to obtain a second mixed solution;

[0032] introducing the second mixed solution and a chlorinating agent solution into a second high-gravity reactor, conducting third mixing, subjecting a resulting mixture to second reaction, and subjecting a resulting second reaction product to second refluxing into the second high-gravity reactor and then the second reaction; and

[0033] repeating the second refluxing and the second reaction to obtain the 4,6-dichloropyrimidine.

[0034] In the present disclosure, malononitrile, methanol, and an organic solvent are mixed to obtain a mixed solution and the mixed solution and hydrogen chloride are introduced into a first high-gravity reactor, respectively, and subjected to first mixing, a resulting mixture is subjected to first reaction, and a resulting first reaction product is subjected to first refluxing into the first high-gravity reactor and then the first reaction; and the first refluxing and the first reaction are repeated to obtain a first mixed solution containing 1,3-dimethoxypropylenediimine hydrochloride.

[0035] In some embodiments of the present disclosure, the organic solvent includes one or more selected from the group consisting of toluene, ethyl acetate, di chloroethane, dichloromethane, chloroform, tetrachloromethane, and DMF, and is preferably selected from the group consisting of the toluene, di chloroethane, and chloroform.

[0036] In some embodiments of the present disclosure, a molar ratio of the malononitrile to the methanol is in a range of 1: 2.2-2.5, and preferably 1: 2.3-2.4. In some embodiments of the present disclosure, a mass ratio of the malononitrile to the organic solvent is in a range of 1: 2-4, and preferably 1: 2.5-3.5.

[0037] In some embodiments of the present disclosure, the first high-gravity reactor has a high-gravity level of 50 g to 200 g, and preferably 100 g to 200 g. In some embodiments of the present disclosure, the first reaction is conducted at a temperature of -10°C to 25°C, and preferably 0°C to 20°C. In some embodiments of the present disclosure, the first reaction is conducted for 0.5 h to 3 h, and preferably 1 h to 2.5 h.

[0038] In the present disclosure, after the first mixed solution containing the 1,3-dimethoxypropylenediimine hydrochloride is obtained, the first mixed solution containing the 1,3-dimethoxypropylenediimine hydrochloride and an organic alkali are subjected to second mixing to obtain a second mixed solution.

[0039] In the present disclosure, the organic alkali is used in the form of an organic alkali solution. In some embodiments of the present disclosure, a solvent of the organic alkali solution is the same as the organic solvent for the first reaction, and will not be repeated here. In some embodiments of the present disclosure, the organic alkali includes one or more selected from the group consisting of TEA, TPA, DMA, DIPEA, and pyridine, and preferably the TEA. In some embodiments of the present disclosure, a molar ratio of the organic alkali to the malononitrile is in a range of 2.5-4: 1, and preferably 3-3.5: 1. In some embodiments of the present disclosure, the second mixing is conducted by stirring.

[0040] In the present disclosure, after the second mixing is completed, the organic alkali could neutralize unreacted hydrochloric acid in the first mixed solution containing the 1,3-dimethoxypropylenediimine hydrochloride, and the organic alkali could also serve as a catalyst for the second reaction.

[0041] In the present disclosure, after the second mixed solution is obtained, the second mixed solution and a chlorinating agent solution are introduced into a second high-gravity reactor, and subjected to third mixing, a resulting mixture is subjected to second reaction, and a resulting second reaction product is subjected to second refluxing into the second high-gravity reactor and then the second reaction; and the second refluxing and the second reaction are repeated to obtain the 4,6-di chloropyrimidine.

[0042] In some embodiments of the present disclosure, the second high-gravity reactor has a high-gravity level of 50 g to 200 g, and preferably 100 g to 200 g. In some embodiments of the present disclosure, the chlorinating agent includes one or more selected from the group consisting of phosgene, diphosgene, and triphosgene, and preferably the triphosgene. In the present disclosure, the chlorinating agent solution includes the chlorinating agent and an organic solvent. In some embodiments of the present disclosure, the organic solvent is the same as the organic solvent in the first reaction, and will not be repeated here.

[0043] In some embodiments of the present disclosure, a molar ratio of the chlorinating agent to the malononitrile is in a range of 0.5-2: 1, and preferably 1-1.5: 1. In some embodiments of the present disclosure, the second reaction is conducted at a temperature of 10°C to 80°C, and preferably 20°C to 60°C. In some embodiments of the present disclosure, the second reaction is conducted for 0.5 h to 3 h, and preferably 1 h to 1.5 h.

[0044] In some embodiments of the present disclosure, after the second refluxing and the second reaction are repeated, a system obtained by the second reaction is further subjected to vacuum distillation and purification in sequence.

[0045] In some embodiments of the present disclosure, the distillation is vacuum distillation. In some embodiments of the present disclosure, the solvent obtained by the vacuum distillation is recycled.

[0046] In some embodiments of the present disclosure, the purification is conducted by extracting a crude product obtained by the vacuum distillation, where an organic phase obtained by the extracting is partially transferred to a vacuum distillation device, while a remaining part is subjected to solid-liquid separation, washing, and drying in sequence. In some embodiments of the present disclosure, an extraction system is a water-organic solvent, where an organic solvent is the same as the organic solvent for the first reaction, and will not be repeated here. In some embodiments of the present disclosure, a volume ratio of water to the organic solvent in the extraction system is in a range of 5-10: 0.5-1, and preferably 7-8: 0.6-0.8. In some embodiments of the present disclosure, the extracting is conducted at a temperature of 50°C to 70°C, and preferably 60°C. In some embodiments of the present disclosure, the extracting is conducted by stirring. In some embodiments of the present disclosure, the washing is performed by subjecting a solid phase obtained by the solid-liquid separation to washing with water. In some embodiments of the present disclosure, the washing with water is conducted to reach neutrality. There is no specific limitation on the drying, and residual water on a surface of the solid phase can be removed by using common operations used by those skilled in the art.

[0047] The present disclosure further provides a device used in the method described above, including:

[0048] a first high-gravity reactor 1, where the first high-gravity reactor 1 is provided with a product reflux pipeline 1#;

[0049] a stirring and regulating kettle 2 communicated with the first high-gravity reactor 1; and

[0050] a second high-gravity reactor 3 communicated with the stirring and regulating kettle 2, where the second high-gravity reactor 3 is provided with a product reflux pipeline 3#.

[0051] As shown in FIG. 1, the device used in the method described above includes a first high-gravity reactor 1. In the present disclosure, the first high-gravity reactor 1 is provided with a product reflux pipeline 1#. In some embodiments of the present disclosure, the first high-gravity reactor 1 is further provided with a tail gas reflux pipeline 2#.

[0052] In the present disclosure, the device used in the method described above includes a stirring and regulating kettle 2 communicated with the first high-gravity reactor 1. In some embodiments of the present disclosure, the stirring and regulating kettle 2 and the first high-gravity reactor 1 are connected through a pipeline.

[0053] In the present disclosure, the device used in the method described above includes a second high-gravity reactor 3 communicated with an outlet of the stirring and regulating kettle 2.

[0054] In some embodiments of the present disclosure, the device used in the method described above further includes a vacuum distillation device 4 communicated with an outlet of the second high-gravity reactor 3. In the present disclosure, the second high-gravity reactor 3 is provided with a product reflux pipeline 3#.

[0055] In some embodiments of the present disclosure, the device used in the method described above further includes a purification kettle 5 communicated with an outlet of the vacuum distillation device 4.

[0056] In some embodiments of the present disclosure, taking the device of FIG. 1 as an example, the method includes the following steps:

[0057] mixing malononitrile, methanol, and an organic solvent to obtain a mixed solution, introducing the mixed solution and hydrogen chloride into a first high-gravity reactor, respectively, conducting first mixing, subjecting a resulting mixture to first reaction, and subjecting a resulting first reaction product to first refluxing into the first high-gravity reactor and then the first reaction;

[0058] repeating the first refluxing and the first reaction to obtain a first mixed solution containing 1,3-dimethoxypropylenediimine hydrochloride;

[0059] introducing the first mixed solution containing the 1,3-dimethoxypropylenediimine hydrochloride and an organic alkali into a stirring and regulating kettle to obtain a second mixed solution;

[0060] introducing the second mixed solution and a chlorinating agent solution into a second high-gravity reactor, conducting third mixing, subjecting a resulting mixture to second reaction, and subjecting a resulting second reaction product to second refluxing into the second high-gravity reactor and then the second reaction; and

[0061] repeating the second refluxing and the second reaction to obtain the 4,6-dichloropyrimidine.

[0062] In the present disclosure, an unreacted hydrogen chloride tail gas is refluxed to the first high-gravity reactor through the tail gas reflux pipeline 2#, and subjected to the first reaction again. In some embodiments of the present disclosure, when the hydrogen chloride is introduced into the first high-gravity reactor, a flow rate is 20 L / h to 150 L / h, and preferably 50 L / h to 120 L / h. In the present disclosure, during the first reaction, the hydrogen chloride is continuously introduced into the first high-gravity reactor at the above flow rate.

[0063] In some embodiments of the present disclosure, after the second reaction is completed, a resulting product is refluxed to the second high-gravity reactor through a product reflux pipeline 3#, and subjected to the second reaction again. The above processes are repeated to form a cycle.

[0064] In some embodiments of the present disclosure, after the second reaction is completed, a crude product obtained by the second reaction is introduced into a vacuum distillation device and subjected to vacuum distillation. A product obtained by the vacuum distillation is introduced into a purification kettle and subjected to extraction, and an organic phase obtained by the extraction is partially transferred to the vacuum distillation device, while a remaining part is sequentially subjected to solid-liquid separation, washing, and drying. In some embodiments of the present disclosure, a liquid phase obtained from the solid-liquid separation is circulated into the purification kettle for repeated use.

[0065] The technical solutions provided by the present disclosure will be described in detail below with reference to examples, but the examples should not be understood as limiting the scope of the present disclosure.

[0066] Example 1

[0067] 20 L of anhydrous methanol, 14 kg of malononitrile, and 30 L of dichloroethane were mixed evenly in a first raw material tank. A first high-gravity reactor was turned on to adjust a high-gravity level to 200 g. Raw materials were pumped into the first high-gravity reactor, and dry HC1 gas was introduced thereto at a flow rate of 50 L / h. A resulting system was adjusted to 15°C and reacted. A resulting reaction product solution and an HC1 tail gas were introduced into the first high-gravity reactor through a product reflux pipeline 1# and a tail gas reflux pipeline 2#, respectively, and subjected to cyclic reaction for 0.5 h to obtain a first mixed solution containing 1,3-dimethoxypropylenediimine hydrochloride. The first mixed solution was pumped into a stirring and regulating kettle, and a dichloroethane solution containing 70 kg of TEA was added thereto, and then stirred evenly to obtain a second mixed solution.

[0068] A second high-gravity reactor was turned on to adjust a high-gravity level to 200 g. The second mixed solution and a dichloroethane solution containing 35 kg of tri phosgene were simultaneously pumped into the second high-gravity reactor. A resulting system was reacted at 80°C. A resulting product was introduced into the second high-gravity reactor through a pipeline 3#, and subjected to cyclic reaction for 0.5 h. A resulting mixed solution was pumped into a vacuum distillation device. A solvent obtained by vacuum distillation was recycled. A resulting crude product was transferred to a purification kettle, 5 volumes of water and 0.5 volumes of the di chloroethane were added thereto. A resulting system was stirred at 70°C for 1 h. An organic phase was transferred to the vacuum distillation device, while a remaining part was centrifuged for solid-liquid separation. An obtained solid part was subjected to washing with water and then drying to obtain 4,6-dichloropyrimidine, while a liquid part obtained by the solid-liquid separation was recycled into the purification kettle for repeated use. The 4,6-dichloropyrimidine had a comprehensive yield of 96.3% and a purity of 99.81%.

[0069] Example 2

[0070] 30 L of anhydrous methanol, 22 kg of malononitrile, and 50 L of toluene were mixed evenly in a first raw material tank. A first high-gravity reactor was turned on to adjust a high-gravity level to 100 g. Raw materials were pumped into the first high-gravity reactor, and dry HC1 gas was introduced thereto at a flow rate of 80 L / h. A resulting system was adjusted to 25°C and reacted. A resulting reaction product solution and an HC1 tail gas were introduced into the first high-gravity reactor through a pipeline 1# and a pipeline 2#, respectively, and subjected to cyclic reaction for 2 h to obtain a first mixed solution. The first mixed solution was pumped into a stirring and regulating kettle, and a toluene solution containing 110 kg of DIPEA was added thereto, and then stirred evenly to obtain a second mixed solution.

[0071] A second high-gravity reactor was turned on to adjust a high-gravity level to 100 g. The second mixed solution and a toluene solution containing 60 kg of triphosgene were simultaneously pumped into the second high-gravity reactor. A resulting system was reacted at 60°C. A resulting product was introduced into the second high-gravity reactor through a pipeline 3#, and subjected to cyclic reaction for 2 h. A resulting mixed solution was pumped into a vacuum distillation device. A solvent obtained by vacuum distillation was recycled. A resulting crude product was transferred to a purification kettle, 10 volumes of water and 1 volume of the toluene were added thereto. A resulting system was stirred at 50°C for 1 h. An organic phase was transferred to the vacuum distillation device, while a remaining part was centrifuged for solid-liquid separation. An obtained solid part was subjected to washing with water and then drying to obtain 4,6-dichloropyrimidine, while a liquid part was recycled into the purification kettle for repeated use. The 4,6-dichloropyrimidine had a comprehensive yield of 95.8% and a purity of 99.37%.

[0072] Example 3

[0073] 30 L of anhydrous methanol, 22 kg of malononitrile, and 50 L of chloroform were mixed evenly in a first raw material tank. A first high-gravity reactor was turned on to adjust a high-gravity level to 50 g. Raw materials were pumped into the first high-gravity reactor, and dry HC1 gas was introduced thereto at a flow rate of 100 L / h. A resulting system was adjusted to -10°C and reacted. A resulting reaction product solution and an HC1 tail gas were introduced into the first high-gravity reactor through a pipeline 1# and a pipeline 2#, respectively, and subjected to cyclic reaction for 3 h to obtain a first mixed solution. The first mixed solution was pumped into a stirring and regulating kettle, and a chloroform solution containing 100 kg of pyridine was added thereto, and then stirred evenly to obtain a second mixed solution.

[0074] A second high-gravity reactor was turned on to adjust a high-gravity level to 50g. The second mixed solution and a chloroform solution containing 90 kg of diphosgene were simultaneously pumped into the second high-gravity reactor. A resulting system was reacted at 50°C. A resulting product was introduced into the second high-gravity reactor through a pipeline 3#, and subjected to cyclic reaction for 3 h. A resulting mixed solution was pumped into a vacuum distillation device. A solvent obtained by vacuum distillation was recycled. A resulting crude product was transferred to a purification kettle, 10 volumes of water and 1 volume of the chloroform were added, thereto. A resulting system was stirred at 60°C for 1 h. An organic phase was transferred to the vacuum distillation device, while a remaining part was centrifuged for solid-liquid separation. An obtained solid part was subjected to washing with water and then drying to obtain 4,6-di chloropyrimidine, while a liquid part was recycled into the purification kettle for repeated use. The 4,6-dichloropyrimidine had a comprehensive yield of 94.2% and a purity of 99.65%.

[0075] The above descriptions are merely preferred embodiments of the present disclosure. It should be noted that a person of ordinary skill in the art may further make several improvements and modifications without departing from the principle of the present disclosure, but such improvements and modifications should be deemed as falling within the scope of the present disclosure.

Claims

1. A method for preparing 4,6-dichloropyrimidine, comprising the following steps:mixing malononitrile, methanol, and an organic solvent to obtain a mixed solution, introducing the mixed solution and hydrogen chloride into a first high-gravity reactor, respectively, conducting first mixing, subjecting a resulting mixture to first reaction, and subjecting a resulting first reaction product to first refluxing into the first high-gravity reactor and then the first reaction;repeating the first refluxing and the first reaction to obtain a first mixed solution containing 1,3-dimethoxypropylenediimine hydrochloride;subjecting the first mixed solution containing the 1,3-dimethoxypropylenediimine hydrochloride and an organic alkali to second mixing to obtain a second mixed solution;introducing the second mixed solution and a chlorinating agent solution into a second high-gravity reactor, conducting third mixing, subjecting a resulting mixture to second reaction, and subjecting a resulting second reaction product to second refluxing into the second high-gravity reactor and then the second reaction; andrepeating the second refluxing and the second reaction to obtain the 4,6-dichloropyrimidine.

2. The method of claim 1, wherein the first high-gravity reactor and the second high-gravity reactor independently have a high gravity level of 50 g to 200 g.

3. The method of claim 1, wherein a molar ratio of the malononitrile to the methanol is in a range of 1: 2.2-2.5.

4. The method of claim 1 or 3, wherein the first reaction is conducted at a temperature of -10°C to 25°C for 0.5 h to 3 h.

5. The method of claim 1, wherein the organic alkali is used in the form of an organic alkali solution; and the organic alkali comprises one or more selected from the group consisting of triethylamine (TEA), tripropylamine (TPA), / fA-dimethylaniline (DMA), MA-diisopropylethylamine (DIPEA), and pyridine.

6. The method of claim 1 or 5, wherein a molar ratio of the organic alkali to the malononitrile is in a range of 2.5-4: 1.

7. The method of claim 1, wherein the chlorinating agent solution comprises a chlorinating agent and an organic solvent; and the chlorinating agent is one or more selected from the group consisting of phosgene, diphosgene, and triphosgene.

8. The method of claim 1 or 7, wherein a molar ratio of a chlorinating agent to the malononitrile is in a range of 0.5-2: 1.

9. The method of claim 1, wherein the second reaction is conducted at a temperature of 10°C to 80°C for 0.5 h to 3 h.

10. A device when used in the method of any one of claims 1 to 9, comprisinga first high-gravity reactor (1), wherein the first high-gravity reactor (1) is provided with a product reflux pipeline 1#;a stirring and regulating kettle (2) communicated with the first high-gravity reactor (1); anda second high-gravity reactor (3) communicated with the stirring and regulating kettle (2), wherein the second high-gravity reactor (3) is provided with a product reflux pipeline 3#.

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