CN112028821A - Synthetic method of 2-methyl-3-methoxy-4-chloropyridine - Google Patents
Synthetic method of 2-methyl-3-methoxy-4-chloropyridine Download PDFInfo
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- CN112028821A CN112028821A CN202011027284.5A CN202011027284A CN112028821A CN 112028821 A CN112028821 A CN 112028821A CN 202011027284 A CN202011027284 A CN 202011027284A CN 112028821 A CN112028821 A CN 112028821A
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a method for synthesizing 2-methyl-3-methoxyl-4-chloropyridine, which comprises the steps of carrying out chlorination reaction by using solid phosgene instead of phosphorus oxychloride, carrying out catalytic reaction by using organic base, and recovering a byproduct phosgene at low temperature by using a solvent in the process, thereby achieving the purposes of high-efficiency reaction, pollution reduction, raw material utilization rate improvement and the like. The invention has obvious advantages of cost reduction, safety improvement and environmental protection, so the process can improve the yield, reduce consumption and three wastes and reduce the cost, and is very suitable for industrial production.
Description
Technical Field
The invention belongs to the field of fine chemical engineering manufacturing, in particular relates to synthesis of a medical intermediate, and relates to a synthesis method of 2-methyl-3-methoxyl-4-chloropyridine.
Background
Pantoprazole can be used for treating gastrointestinal tract diseases caused by helicobacter pylori, is a proton pump inhibitor medicine with good effect, and is widely applied internationally. In the prior art, the 2-chloromethyl-3, 4-dimethoxypyridine hydrochloride is one of two intermediates for synthesizing pantoprazole, and in the synthesis method of the 2-chloromethyl-3, 4-dimethoxypyridine hydrochloride, maltol is taken as an initial raw material, methylation reaction is carried out under an alkaline condition, then ammoniation and chlorination are carried out to obtain 2-methyl-3-methoxy-4-chloropyridine (B3), and then hydrogen peroxide oxidation, sodium methoxide methoxylation, acetyl isomerization and secondary chlorination salt formation are carried out to obtain the pantoprazole hydrochloride. 2-methyl-3-methoxy-4-chloropyridine (B3) is a key intermediate for synthesizing 2-chloromethyl-3, 4-dimethoxypyridine hydrochloride, and because the synthesis yield is not too high in all current literature reports and three wastes are serious, the improvement and optimization of the synthesis process of 2-methyl-3-methoxy-4-chloropyridine is necessary.
In the presently disclosed methods for synthesizing 2-methyl-3-methoxy-4-chloropyridine, 2-methyl-3-methoxy-4H-pyridine (B2) is used as a raw material, and a large excess of phosphorus oxychloride is used as a reactant reaction solvent. However, the phosphorus oxychloride is greatly excessive in the synthesis process, the risk of acid mist and the like exists in the reaction process, the phosphorus oxychloride is difficult to remove after the reaction is finished, the existing methods for removing the excessive phosphorus oxychloride in the literature include reduced pressure distillation, alkali addition neutralization and ice water hydrolysis, the treatment methods have the advantages of high temperature, difficulty in control and low yield, and the waste acid water generated after treatment is seriously polluted and has large treatment difficulty, so that the treatment method becomes the bottleneck of industrial production, and the industrial production of pantoprazole is influenced.
Disclosure of Invention
The invention aims to overcome the defects of high production difficulty, low yield and serious pollution in the prior art, and provides a synthetic method of 2-methyl-3-methoxy-4-chloropyridine (B3), which has the advantages of mild reaction conditions, convenient, safe and reliable process operation, high product yield and low cost and solves the problems in the prior art.
The technical scheme adopted by the invention is as follows:
synthetic method of 2-methyl-3-methoxy-4-chloropyridine
Step 1: solid phosgene is weighed and dissolved completely at room temperature using a solvent or a solvent which absorbs phosgene.
Step 2: the dried 2-methyl-3-methoxy-4H-pyridine (B2) is added into the solvent, and the temperature is raised to promote the dissolution.
And step 3: the catalyst was added to the B2 solution and dissolved with thorough stirring.
And 4, step 4: the temperature was controlled, and the phosgene solution was slowly dropped into the B2 solution.
And 5: repeating steps 3 and 4.
Step 6: and after the solid phosgene solution is dripped, continuously preserving the temperature and stirring for reaction.
And 7: after the heat preservation is finished, heating to the set temperature, and stirring for heat preservation reaction.
And 8: in the process of steps 3 to 7, a large amount of hydrogen chloride and phosgene are generated by the system, and the generated gas is subjected to multi-stage low-temperature absorption of a solvent and then is used in the solid phosgene solution preparation process of step 1.
And step 9: after the reaction is finished, cooling, slowly dropping ammonia water into the reaction liquid for neutralization, and adjusting the pH value to about 8.
Step 10: and after the neutralization is finished, removing solid impurities by a filter pressing mode. Standing, separating lower oily substance, extracting upper water layer with solvent once, and mixing organic phases.
Step 11: concentrating the organic phase solution under reduced pressure, and collecting the remaining clear solution as 2-methyl-3-methoxy-4-chloropyridine (B3).
Further, in the step 1, the phosgene content in the phosgene solution is 5-50%, preferably 20-40%. The amount (Kg) of phosgene is 0.1 to 5 times, preferably 1 to 3 times the amount (Kg) of raw material B2. The solid phosgene includes diphosphine (trichloromethyl chloroformate) and triphosgene (bis (trichloromethyl) carbonate).
Further, the moisture content of the dried B2 in step 2 is less than 0.5%, preferably less than 0.3%. The purity is 94% or more, preferably 97% or more.
Further, the solvent used in step 2 includes dichloromethane, dichloroethane, chloroform, acetonitrile, DMF and DMAC, preferably dichloromethane and acetonitrile. The amount (L) of the solvent is 1 to 10 times, preferably 2 to 6 times of the amount (Kg) of the raw material.
Further, the catalyst used in step 3 includes triethylamine, trimethylamine, DMF, DMAC, triphenylamine, N ' -dimethylaniline and N ', N ' -diethylaniline, preferably triethylamine. The amount (L) of the catalyst is 0.01 to 0.5 times, preferably 0.1 to 0.4 times of the amount (Kg) of the raw material.
Further, the addition of the catalyst and the phosgene solution in steps 3,4 and 5 was carried out in batches, with a minimum of 2 batches. The temperature of the solution is controlled to be 0-20 ℃ during the addition. The phosgene solution is added dropwise for not less than 1 hour.
Further, a large amount of hydrogen chloride and gaseous phosgene generated in the system in the process of steps 3-7 are subjected to multi-stage low-temperature absorption by a third solvent, and then are used for preparing a solid phosgene solution instead of the first solvent in the step 1. The third solvent may be selected from the same solvents as the first solvent and combinations thereof.
And further, stirring and carrying out heat preservation reaction for 1-24 hours, preferably 2-8 hours after the dropwise adding in the step 6 is finished.
Further, in the step 7, the temperature of the system L is 30-70 ℃, and preferably 40-55 ℃; stirring and heat preservation are carried out for 2-48 hours, preferably 8-16 hours.
Further, phosgene in the step 8 is absorbed at a low temperature of-40 to 0 ℃, preferably-20 to-10 ℃.
Further, after the reaction in the step 9 is completed, cooling to 0-20 ℃, slowly dropping ammonia water, and adjusting the pH value to about 8. The concentration of the ammonia water is 1-40%, preferably 10-30%. The amount of ammonia (L) is 0.2-8 times, preferably 1-3 times of the amount of raw materials (Kg).
Further, the extraction solvent in step 10 includes water-insoluble organic solvents such as dichloromethane, dichloroethane, chloroform, cyclohexane, benzene, toluene, etc., and it is preferable to use the same solvent as in step 1, preferably dichloromethane, from the viewpoint of the process. The amount (L) of the solvent is 1 to 10 times, preferably 2 to 6 times of the amount (Kg) of the raw material.
Further, in the step 11, the extractant is quickly distilled out by adopting quick distillation equipment such as molecular distillation, flash evaporation and falling film evaporator, and the distillation time is 0.1 min to 8 h, preferably 1 min to 0.5 h; the temperature is 40-60 ℃; the vacuum degree is 95KPa to 101 KPa.
The invention uses solid phosgene to replace phosphorus oxychloride to carry out chlorination reaction, uses organic base to carry out catalytic reaction, and recovers the byproduct phosgene at low temperature by using a solvent in the process, thereby achieving the purposes of high-efficiency reaction, pollution reduction, raw material utilization rate improvement and the like.
The invention has the advantages of obvious cost reduction, 1.5 tons of triphosgene per ton and more than 2 tons of phosphorus oxychloride per ton, but the yield of the solid phosgene method can be improved by 10 percent, and the cost of the raw material is obviously reduced.
The invention also improves the safety aspect, the phosphorus oxychloride belongs to highly toxic liquid, the liquid reacts violently when meeting water and explodes, the distillation and recovery process of the phosphorus oxychloride exists in the reaction stage, and the potential safety hazard of production is higher. The solid phosgene can be conveniently transported and stored, and the production process does not have a distillation process, so that the safety and controllability are strong.
The invention has more obvious advantages in the aspect of environmental protection, and because the phosphorus oxychloride process has low conversion rate and more high-salinity wastewater, the phosphorus oxychloride process also has solid waste, and each ton of products generates about 12 tons of wastewater (containing vacuum pump wastewater) and 100KG of solid waste (asphalt is salted and cannot be treated). The triphosgene process has high conversion rate, wherein each ton of process wastewater is about 3 tons, mainly ammonium chloride-containing wastewater, 9 tons of waste hydrochloric acid produced by the tail gas absorption tower, and about 20KG of solid waste per ton of product. And the sewage produced by the process has single component and is easy to treat.
Therefore, the process of the invention can improve the yield, reduce the consumption and three wastes, reduce the cost and is very suitable for industrial production.
FIG. 1 is a flow chart of the process for the synthesis of 2-methyl-3-methoxy-4-chloropyridine (B3) of the present invention.
Detailed Description
The invention is further explained in detail below with reference to the figures and the specific examples. It should be understood that the examples are only for illustrating the present invention and are not intended to limit the scope of the present invention. Furthermore, it should be understood that various changes or modifications can be made by those skilled in the art after reading the description of the present invention, and such equivalents also fall within the scope of the protection defined by the present application.
Example 1
150g of the dried starting material 2-methyl-3-methoxy-4H-pyridine (i.e. B2, 95.0% purity, 4.5% major impurity, 0.3% water content) was placed in a flask, stirred, and 500mL of dichloromethane was added, heated to reflux for dissolution, for about 3 hours. Then poured into a 5L reaction kettle. Then 25mL of triethylamine was added to the reaction vessel, and the mixture was fully stirred and dissolved.
225g of triphosgene was weighed into a round-bottom flask, 400mL of methylene chloride was added, and the solution was completely dissolved at room temperature. The triphosgene solution was poured into a constant pressure dropping funnel on the reaction kettle. And (3) starting refrigerant circulation, cooling to a set temperature (5-15 ℃ in the kettle), and slowly dripping the triphosgene solution to ensure that the bubbles in the tail gas absorption device are not too violent, wherein the dripping time is not less than 2 hours. After the addition, 25mL of triethylamine was added to the reactor, and a new solution of 225g of triphosgene in 400mL of dichloromethane was added dropwise.
After the dropwise addition, stirring and heat preservation are carried out for 8 hours. And after the heat preservation is finished, pressing the reaction liquid in the reaction kettle into the other reaction kettle. Starting the heat conducting oil circulation of the reaction kettle, heating to a set temperature (40-55 ℃ in the kettle), stirring and preserving heat for 12 hours.
After the reaction is finished, naturally cooling and discharging the reaction liquid. Ammonia water is slowly dropped into the reaction liquid under the ice water bath condition, and the PH value is adjusted to about 8. And after the neutralization is finished, removing solid impurities by a filter pressing mode. After standing for 1-2 hours, the lower oily substance was separated, the upper aqueous layer was extracted once with 200mL of methylene chloride, and the aqueous layer was separated. The organic phases are combined and stirred uniformly.
The organic phase solution was concentrated under reduced pressure (vacuum degree 0.09, material temperature 60 ℃) to obtain 151 g of product with a purity of 97% after the concentration under reduced pressure.
As shown in figure 1, phosgene overflowing from a chlorination kettle in the production process is absorbed by a third solvent (one of dichloromethane, dichloroethane, trichloromethane and acetonitrile) of a three-stage absorption kettle, and the third solvent for absorbing the phosgene is returned to a mixing kettle to be used as a first solvent.
Example 2
The tail gas from example 1 was subjected to three absorption stages, each with 400ML of dichloromethane, at-10 ℃. 150g of triphosgene is newly weighed and dissolved in the primary absorption liquid and the secondary absorption liquid respectively, and the solution is fed in two batches.
Otherwise, the supernatant obtained after the concentration under reduced pressure was 150g, having a purity of 97%, as in the example.
Example 3
30g of the dried starting material 2-methyl-3-methoxy-4H-pyridine (B2, purity 95.0%, main impurity 4.5%, water content 0.3%) and 78g of methylene chloride were put into a 500ml three-necked flask and stirred to dissolve. The temperature is kept below 40 ℃, and 146g of phosphorus oxychloride is slowly dropped into the clear solution.
After the dropwise addition, slowly heating to 60-65 ℃ to evaporate dichloromethane, basically removing fractions (mixture of dichloromethane and phosphorus oxychloride) at 82-85 ℃, and then carrying out heat preservation and reflux for 7h at 82-85 ℃.
After the reaction is completed, the excess POCl is distilled off under reduced pressure (0.095 MPa) at 75-80 DEG C3。
Slowly adding the above material liquid into 180g of crushed ice water, stirring and quenching, heating to 50-55 ℃, stirring for 2 hours, and hydrolyzing. The aqueous phase was cooled to below 25 ℃ and neutralized with about 60g of ammonia to pH =8, stirring was stopped and allowed to stand for 2 h.
Extracted three times with 150mL dichloromethane and the organic phases are combined. And (3) carrying out reduced pressure spin drying at 60 ℃ to obtain 26.5g of brown aromatic B3 product with the purity of 96.7%.
Claims (6)
1. A synthetic method of 2-methyl-3-methoxyl-4-chloropyridine is characterized by comprising the following steps:
step 1: weighing solid phosgene, and completely dissolving the solid phosgene into a phosgene solution with the solid phosgene content of 5-50% by using a first solvent at room temperature; the solid phosgene is one of trichloromethyl chloroformate and trichloromethyl triphosgene carbonate; the first solvent is one of dichloromethane, dichloroethane, trichloromethane and acetonitrile;
step 2: adding dried raw material 2-methyl-3-methoxy-4H-pyridine B2 into a second solvent to form a B2 solution, heating to promote dissolution, wherein the water content of the dried B2 is lower than 0.5%, the purity is more than 94%, and the dosage ratio is that 1-10 liters of the second solvent is used for each kg of raw material B2; the second solvent is one of dichloromethane, dichloroethane, trichloromethane, acetonitrile, DMF and DMAC;
and step 3: adding a catalyst into the B2 solution, and fully stirring and dissolving the mixture, wherein the using amount of the catalyst is 0.01-0.5L per Kg of raw material B2, and the catalyst is one of triethylamine, trimethylamine, DMF, DMAC, triphenylamine, N ' -dimethylaniline and N ', N ' -diethylaniline;
and 4, step 4: controlling the temperature, slowly dropping phosgene solution into the B2 solution, and controlling the weight ratio of the solid phosgene to the raw material B2 to be 0.1-5: 1;
and 5: repeating steps 3 and 4;
step 6: after the phosgene solution is dripped, keeping the temperature at 0-20 ℃, and stirring for reaction for 1-24 hours;
and 7: after the heat preservation is finished, heating to the set temperature of 30-70 ℃, and stirring for heat preservation reaction for 2-48 hours;
and 8: after the reaction is finished, cooling to-40-0 ℃, slowly dropwise adding ammonia water into the reaction liquid for neutralization, and adjusting the pH value to 7-8;
and step 9: removing solid impurities by filter pressing after neutralization, standing, separating out lower oily substance, extracting upper water layer with extractant once, and mixing to obtain oily substance; the extracting agent is one of non-water-soluble organic solvents such as dichloromethane, dichloroethane, chloroform, cyclohexane, benzene and toluene, and the dosage of the extracting agent is 1-10 liters per Kg of water layer raw material;
step 10: the oily substance is concentrated under reduced pressure, and the residual clear liquid is the product 2-methyl-3-methoxy-4-chloropyridine B3.
2. The method for synthesizing 2-methyl-3-methoxy-4-chloropyridine according to claim 1, characterized in that a large amount of hydrogen chloride and gaseous phosgene generated in the system during the steps 3-7 are subjected to multi-stage low-temperature absorption by a third solvent and then are used for preparing a solid phosgene solution instead of the first solvent in the step 1.
3. The method for synthesizing 2-methyl-3-methoxy-4-chloropyridine according to claim 1, wherein the catalyst and the phosgene solution are added in steps 3,4 and 5 in batches, the addition is divided into at least 2 batches, and the solution temperature is controlled to be 0-20 ℃ during the addition.
4. The method for synthesizing 2-methyl-3-methoxy-4-chloropyridine according to claim 1, wherein the stirring and heat preservation reaction is preferably carried out for 2-8 hours after the dropwise addition in the step 6.
5. The method for synthesizing 2-methyl-3-methoxy-4-chloropyridine according to claim 1, wherein the temperature of the system in the step 7 is preferably raised to 40-55 ℃, and the stirring and heat preservation are preferably carried out for 8-16 hours.
6. The method for synthesizing 2-methyl-3-methoxy-4-chloropyridine according to claim 1, wherein in step 11, the solvent is distilled off for 0.1 min to 8 hours at a temperature of 40 ℃ to 60 ℃; the vacuum degree is 95KPa to 101 KPa.
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Cited By (2)
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| CN112996798A (en) * | 2020-12-28 | 2021-06-18 | 安徽金禾实业股份有限公司 | Chlorination method of sucrose-6-carboxylate |
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Application publication date: 20201204 |