CN111440212B

CN111440212B - Phosphorus-containing compound and preparation method thereof

Info

Publication number: CN111440212B
Application number: CN202010418443.8A
Authority: CN
Inventors: 郝智慧; 郝江南; 崔亮亮; 解龙霄; 赵乐凯
Original assignee: China Agricultural University
Current assignee: China Agricultural University
Priority date: 2020-05-18
Filing date: 2020-05-18
Publication date: 2021-04-27
Anticipated expiration: 2040-05-18
Also published as: CN111440212A

Abstract

The invention relates to a synthetic method of sodium tolodin, which comprises the steps of adding N, N-dimethyl meta-methylaniline, phosphorus trichloride and a catalyst into a solvent, heating for reaction, then dropwise adding a reaction solution into a sodium hydroxide aqueous solution in an ice bath, stirring until a product is separated out, filtering to obtain a crude product of the sodium tolodin, and carrying out hot filtration, cooling and crystallization on the crude product to obtain a refined product of the sodium tolodin.

Description

Phosphorus-containing compound and preparation method thereof

Technical Field

The invention relates to a chemical synthesis preparation of a phosphorus supplement, a metabolism promoter and an immunity enhancer, namely a preparation method of tolidine sodium phosphate, belonging to the field of medical chemical synthesis.

Background

Todinphos sodium full-name [4- (dimethylamino) -2-methylphenyl]Sodium phosphite of the formula C₉H₁₃NNaO₂P, molecular weight 221.17, is a phosphorus supplement, a metabolism promoter and an immunity enhancer. Tolidine sodium has been used in human medicine since 1920 for the treatment of conditions such as physical weakness caused by surgery and infectious diseases, and chronic stress and mental and physical exertion. The tolidine sodium phosphate also has long-term application in veterinary medicine, and is mainly used for treating and preventing parturition and perinatal diseases, young animal development and nutrition disorder, and paresis caused by skeleton growth and limb extension disorder. Support and fixThe sodium phosphate was first developed and marketed by Hoechst in germany in 1999, and many veterinary drugs using tolidine as a raw material drug are available abroad nowadays, including Vetphos Plus in india, Foston 20% in uk, Metaphosol in germany, phosphononic in ireland, phosphononic 20% in france, and the like. No similar products are on the market at home, most of the raw material medicaments of the tolidine phosphate are produced on a domestic reagent platform, but the raw material medicaments are produced and sold as standard products, and manufacturers for actual mass production hardly exist. The application range of the tolidine sodium phosphate is wide, and the research on the preparation of the tolidine sodium phosphate has important significance for animal husbandry, breeding industry and pet industry.

The disclosed synthetic method of the tolidine sodium phosphate comprises the following steps:

german patent DE 3939779 describes a process for the synthesis of tolidine sodium phosphate: heating N, N-dimethyl meta-methylaniline and phosphorus trichloride in a mixed water bath to 110 ℃, stirring for 4h, stirring the reaction solution, adding the reaction solution into a sodium hydroxide ice water solution, distilling to remove the N, N-dimethyl meta-methylaniline until the solution starts to crystallize, washing the crystals with ice-cold saturated saline solution, and recrystallizing with alcohol to obtain the refined product of the tolidine sodium phosphate. The patent does not note the yield, and according to the actual operation (comparative example 1 and comparative example 2), the synthesis process has very low yield and only a few products can be obtained; the post-treatment is time-consuming and labor-consuming, and requires distillation to remove raw materials and a large amount of water; and the product obtained by crystallization is accompanied by salt and subsequently needs alcohol to remove. The method provided by the invention is simple and convenient to operate and improves the yield.

The inventor researches the existing synthesis method and finds that the existing method has the following defects:

1 the synthesis process has a very low yield,

2 the post-treatment operation of the synthesis process is time-consuming and labor-consuming, and requires distillation to remove unreacted starting materials and large amounts of water

To obtain the product.

Disclosure of Invention

The invention aims to overcome the problems in the prior synthesis technology, and provides a synthetic method of the sodium tolodin according to the existing reaction conditions.

The technical scheme of the invention is as follows: a synthetic method of tolidine sodium phosphate comprises the following steps:

step 1, adding N, N-dimethyl meta-methylaniline, phosphorus trichloride and a catalyst into a solvent, and heating for reaction;

step 2, cooling, dripping the reaction liquid into a quantitative sodium hydroxide aqueous solution, stirring for reaction, and filtering;

and 3, filtering out the solid, adding a solvent, heating, refluxing, carrying out hot filtration, carrying out spin drying on the filtrate to obtain a crude product, and recrystallizing the crude product to obtain a refined product.

The mol ratio of the N, N dimethyl meta-methylaniline and the catalyst in the step 1 is 1: 0.01-0.3.

The molar ratio of the N, N dimethyl meta-methylaniline to the phosphorus trichloride in the step 1 is 1: 1-2.

The catalyst in the step 1 is one or more of pyridine, ferric trichloride, boron trifluoride and triethylamine.

The temperature rise reaction temperature in the step 1 is room temperature-150 ℃.

The molar ratio of the addition amount of the sodium hydroxide to the phosphorus trichloride in the step 2 is 3: 1.

and 3, the solvent used in the refining process is one or more of methanol, ethanol, ethyl acetate, acetone and DMF.

Compared with the original synthesis process, the method overcomes the defects of time and labor waste of the original process; the reaction time, the molar ratio and the catalyst are screened again, the instrument conditions required by the reaction are reduced, the operation is simplified, and the yield is improved.

On the basis of the existing synthesis process, the invention improves the raw materials and the post-treatment mode, and the main improvement points are as follows:

1, the reaction time and the feed ratio are adjusted, the catalyst and the solvent are added, and the problem of the later reaction stage is solved

The increase in the viscosity of the system leads to an increase in the yield due to the difficulty in handling.

2, the addition of the sodium hydroxide aqueous solution is changed, and the filtration replaces the distillation, so that the energy loss is reduced, the operation is simplified, and the efficiency is improved.

Through the improvement, the beneficial effects of the invention are as follows:

1 the system is mixed after the reaction of the original synthesis process is finished, the viscosity is large, the yield is actually less than 15%, and the reaction yield can reach about 50% by improving the feeding and subsequent treatment modes.

2, a large amount of solvent with high boiling point needs to be distilled originally, a large amount of time and energy needs to be consumed, and the problem can be solved only by filtration.

The beneficial effects of the present invention are further illustrated by comparative experimental data as follows:

TABLE 1 (note: molar ratio of N, N-dimethyl-m-methylaniline to phosphorus trichloride to catalyst)

The method of the present invention, wherein the relevant reaction conditions are obtained by screening, the screening process and method are as follows:

1, controlling other conditions to be unchanged, screening the reaction charge ratio, and balancing the actual benefit with the yield to obtain the optimal charge ratio.

	Molar ratio of	Catalyst and process for preparing same	Reaction time	Yield of
					1	3：1	Boron trifluoride	24h	5.9％
2	1：1.2	Boron trifluoride	24h	8.9％
					3	1：1.5	Boron trifluoride	24h	32.8％
4	1：2	Boron trifluoride	24h	41.9％
					5	1：2.5	Boron trifluoride	24h	42.3％

TABLE 2 (Note: molar ratio of N, N-dimethyl-m-methylaniline to phosphorus trichloride)

And 2, controlling other conditions to be unchanged, and obtaining the optimal reaction time according to the balance between actual benefit and yield on the basis of determining the reaction charge ratio.

TABLE 3 (Note: molar ratio of N, N-dimethyl-m-methylaniline to phosphorus trichloride)

3, controlling other conditions to be unchanged, screening the reaction catalyst, and determining the used catalyst according to the balance between actual benefit and yield.

	Molar ratio of	Catalyst (0.1eq)	Reaction time	Yield of
					1	1：2	Boron trifluoride	24h	41.9％
2	1：2	Ferric chloride	24h	35.7％
					3	1：2	Triethylamine	24h	47.3％
4	1：2	Pyridine compound	24h	43.8％

TABLE 4 (Note: molar ratio of N, N-dimethyl-m-methylaniline to phosphorus trichloride)

And 4, controlling other conditions to be unchanged, screening the amount of the reaction catalyst, and determining the used catalyst according to the balance between actual benefit and yield.

	Molar ratio of	Amount of Triethylamine	Reaction time	Yield of
					1	1：2	0.1	24h	20.9％
2	1：2	0.2	24h	47.3％
					3	1：2	0.3	24h	47.5％

TABLE 5 (Note: molar ratio of N, N-dimethyl-m-methylaniline to phosphorus trichloride)

Drawings

FIG. 1 is a reaction scheme.

Detailed Description

Example 1

244g of 244g N, N-dimethyl-m-methylaniline and 69g of phosphorus trichloride were weighed out and added to 50ml of chloroform, 7g of boron trifluoride was added thereto, and the mixture was reacted at 100 ℃ for 24 hours.

After cooling, the reaction solution is dripped into 200ml of 23 percent sodium hydroxide aqueous solution by ice bath, after dripping, the filtration is finished, a filter cake is washed by ethanol with the temperature of minus 10 ℃, and the obtained solid is dried to obtain a crude product. Adding ethanol, refluxing, pulping, filtering, cooling, crystallizing, and filtering to obtain refined product with yield of 11.1%.

Example 2

68g N, N-dimethyl-m-methylaniline and 164g of phosphorus trichloride were weighed out and added to 50ml of chloroform, and 7g of boron trifluoride was added thereto and heated under reflux for 24 hours.

After cooling, the reaction solution is dripped into 500ml of 23 percent sodium hydroxide aqueous solution by ice bath, after dripping, the filtration is finished, a filter cake is washed by ethanol with the temperature of minus 10 ℃, and the obtained solid is dried to obtain a crude product. Adding methanol, refluxing, pulping, filtering, cooling, crystallizing, and filtering to obtain refined product with yield of 8.9%.

Example 3

68g N, N-dimethyl-m-methylaniline and 205g of phosphorus trichloride were weighed into 50ml of chloroform, and 16g of ferric trichloride was added thereto, followed by heating and refluxing for 24 hours.

After cooling, the reaction solution is dripped into 700ml of 23 percent sodium hydroxide aqueous solution by ice bath, after the dripping is finished, the filtration is carried out, the filter cake is washed by ethanol with the temperature of minus 10 ℃, and the obtained solid is dried to obtain the crude product. Adding methanol, refluxing, pulping, filtering, cooling, crystallizing, and filtering to obtain refined product with yield of 20.8%.

Example 4

68g N, N-dimethyl-m-methylaniline and 205g of phosphorus trichloride were weighed into 50ml of chloroform, and 200g of pyridine was added thereto, followed by heating and refluxing for 24 hours.

After cooling, the reaction solution is dripped into 700ml of 23 percent sodium hydroxide aqueous solution by ice bath, after the dripping is finished, the filtration is carried out, a filter cake is washed by ethanol with the temperature of minus 10 ℃, and the obtained solid is dried to obtain a crude product. Adding methanol, refluxing, pulping, filtering, cooling, crystallizing, and filtering to obtain refined product with yield of 28.7%.

Example 5

68g N N-dimethyl-m-methylaniline and 274g phosphorus trichloride were weighed into 50ml chloroform, 10g triethylamine was added, and the mixture was heated under reflux for 24 hours.

After cooling, the reaction solution is dripped into 1000ml of 23 percent sodium hydroxide aqueous solution by ice bath, after dripping, the filtration is finished, a filter cake is washed by ethanol with the temperature of minus 10 ℃, and the obtained solid is dried to obtain a crude product. Adding DMF, refluxing, pulping, filtering, precipitating solid, cooling, crystallizing, and filtering to obtain refined product with yield of 47.3%.

Comparative example 1

122g N, N-dimethyl m-methylaniline and 69g of phosphorus trichloride are weighed into a flask, heated to 100 ℃ and stirred for reaction for 4 hours.

Stirring the reaction solution and dropwise adding the reaction solution into 200ml of 35% sodium hydroxide ice water solution, distilling after dropwise adding, removing at most more N, N-dimethyl m-methylaniline, supplementing water until the system is completely dissolved, continuing distilling until crystals are separated out, cooling for crystallization, filtering, washing the crystals with ice-cold saturated sodium chloride solution, and repeating for multiple times to obtain a crude product. The obtained solid is filtered and recrystallized by methanol heat to obtain a refined product, and the yield is 2.4 percent.

Comparative example 2

Weighing 169g N, adding N-dimethyl m-methylaniline into a flask, heating to 75 ℃, stirring and dropwise adding 69g of phosphorus trichloride, keeping the temperature at 50 ℃, and naturally heating the system to 75 ℃.

Stirring the reaction solution and dropwise adding the reaction solution into 200ml of 35% sodium hydroxide ice water solution, distilling after dropwise adding, removing at most more N, N-dimethyl m-methylaniline, supplementing water until the system is completely dissolved, continuing distilling until crystals are separated out, cooling for crystallization, filtering, washing the crystals with ice-cold saturated sodium chloride solution, and repeating for multiple times to obtain a crude product. The obtained solid is filtered and recrystallized by ethanol heat to obtain a refined product, and the yield is 4.5 percent.

2 reaction test record

270g N, N-dimethyl m-methylaniline is weighed into a 2L four-mouth bottle, 250ml of chloroform is weighed into the four-mouth bottle, and the system is stirred mechanically and is orange red. 275g of phosphorus trichloride is measured and added dropwise, and the dropwise addition is finished about 0.5 h. 40g of triethylamine is measured and dripped, and the system is yellow after about ten minutes of dripping is finished. The temperature is increased to 80 ℃, and the reaction is started for 24 hours. The system is slightly turbid at the beginning of the process, the reflux liquid is oily, and the system gradually becomes orange yellow and clear along with the reaction. 1500ml of 23% aqueous sodium hydroxide solution was prepared in an ice bath and mechanically stirred. The reaction system is naturally cooled and slowly dripped into the prepared sodium hydroxide aqueous solution, and the process ensures that the reaction solution is less in contact with water vapor and air. After the dropwise addition, the mixture was stirred for 3 hours. Filtering, filtering to remove solid, drying under pressure, and filtering for 20 min. Adding 4 times of methanol, heating, refluxing, thermally pulping for 2h, cooling, thermally filtering at 50 deg.C, and spin-drying the filtrate to obtain crude product, dissolving the crude product in 4 times of methanol under heating, cooling to-10 deg.C, crystallizing, and filtering to obtain 47.3% yield.

Claims

1. A synthetic method of tolidine sodium phosphate is characterized by comprising the following steps:

weighing 68g of N, N-dimethyl m-methylaniline and 274g of phosphorus trichloride, adding into 50ml of chloroform, adding 10g of triethylamine, and carrying out heating reflux reaction for 24 hours; after cooling, dropwise adding the reaction solution into 1000ml of 23% sodium hydroxide aqueous solution in an ice bath, filtering after dropwise adding, washing a filter cake with ethanol at the temperature of-10 ℃, and drying the obtained solid to obtain a crude product; adding DMF, refluxing, pulping, filtering, precipitating solid, cooling, crystallizing, and filtering to obtain refined product with yield of 47.3%.