阅读说明：本技术 一种盐酸二甲双胍蒸馏残渣的绿色回收工艺 (Green recovery process of metformin hydrochloride distillation residue ) 是由 张福建 杨大伟 王连进 赵英霞 王宁宁 赵宝文 于钊国 李建 于 2020-07-17 设计创作，主要内容包括：本发明提供一种盐酸二甲双胍蒸馏残渣的绿色处理回收工艺,该方法包括以下步骤：加成生成盐酸二甲双胍、环合生成N,N-二甲基-1,3,5-三嗪-2,4-二胺、碱解回收盐酸二甲胺和氯化钾,具体涉及对一种盐酸二甲双胍生产蒸馏残渣进行处理得到盐酸二甲双胍、N,N-二甲基-1,3,5-三嗪-2,4-二胺(用于阻燃剂)、盐酸二甲胺、氯化钾的绿色工艺,整个过程流畅,易于操作,实现了工业废物高效资源化利用的目的,具有明显的经济效益与社会效益；本发明所述盐酸二甲双胍蒸馏残渣的回收工艺,碱解回收盐酸二甲胺和氯化钾,冷凝的水可回用,本发明不产生任何废液。(The invention provides a green treatment and recovery process of metformin hydrochloride distillation residues, which comprises the following steps: the method comprises the steps of performing addition to generate metformin hydrochloride, performing cyclization to generate N, N-dimethyl-1, 3, 5-triazine-2, 4-diamine, and recovering dimethylamine hydrochloride and potassium chloride through alkaline hydrolysis, and particularly relates to a green process for treating distillation residues in metformin hydrochloride production to obtain metformin hydrochloride, N-dimethyl-1, 3, 5-triazine-2, 4-diamine (used as a flame retardant), dimethylamine hydrochloride and potassium chloride, wherein the whole process is smooth and easy to operate, the aim of efficient resource utilization of industrial wastes is fulfilled, and obvious economic and social benefits are achieved; according to the recovery process of the metformin hydrochloride distillation residue, dimethylamine hydrochloride and potassium chloride are recovered by alkaline hydrolysis, condensed water can be recycled, and no waste liquid is generated.)

1. A green recovery process of metformin hydrochloride distillation residues is characterized by comprising the following steps: addition to produce metformin hydrochloride, cyclization to produce N, N-dimethyl-1, 3, 5-triazine-2, 4-diamine, and alkaline hydrolysis to recover dimethylamine hydrochloride and potassium chloride.

2. The green recycling process of metformin hydrochloride distillation residue as claimed in claim 1, wherein the addition reaction is performed to form metformin hydrochloride, part of DMF is added for the first time, the metformin hydrochloride distillation residue is added, the temperature is raised to 120-160 ℃ within 28-32min, and the temperature is maintained for 3-4h after the material is completely dissolved by adding the water separating agent, the distillation is carried out with water to 144-146 ℃.

3. The green recovery process of metformin hydrochloride distillation residue according to claim 2, wherein after the heat preservation is finished, DMF solvent is added for the second time, the temperature is reduced to 70-80 ℃, and metformin hydrochloride is obtained by suction filtration and drying.

4. The process for the green recovery of the metformin hydrochloride distillation residue according to claim 2, wherein the step of recovering the metformin hydrochloride distillation residue from the distillation residue is further carried out,

adding dicyandiamide, wherein the molar ratio of the total amount of dicyandiamide to dimethylamine hydrochloride in feed liquid is 1.01-1.05: 1; the water diversion agent is a benzene compound.

5. The process for green recovery of metformin hydrochloride distillation residue according to claim 2, wherein the water-separating agent is one of m-xylene and o-xylene; the volume ratio of the water separating agent to the solvent is 1: 4.5-5.5.

6. The process for green recovery of metformin hydrochloride distillation residue according to claim 3, wherein the volume ratio of DMF in the first addition to DMF in the second addition is 2: 1; the volume-mass ratio of the total amount of DMF to the metformin hydrochloride distillation residue is as follows: 1.5 ml/g.

7. The process for the green recovery of the metformin hydrochloride distillation residue according to any one of claims 1 to 6, wherein the metformin hydrochloride distillation residue comprises the following components in percentage by mass:

24.5 to 25.5 percent of metformin hydrochloride; 4.5 to 5.5 percent of dicyandiamide; 29.5 to 30.5 percent of dimethylamine hydrochloride; 29.5 to 30.5 percent of N, N-dimethyl-1, 3, 5-triazine-2, 4-diamine; the balance of amine compound impurities.

8. The process for green recovery of metformin hydrochloride distillation residue as claimed in claim 1, wherein the cyclization reaction to N, N-dimethyl-1, 3, 5-triazine-2, 4-diamine is carried out at 150 ℃ and 160 ℃ and the acid used for DMF decomposition is inorganic acid.

9. The process for green recovery of metformin hydrochloride distillation residue as claimed in claim 8, wherein the first portion of purified water and inorganic acid are added to the DMF filtrate obtained after addition to form metformin hydrochloride, the temperature is maintained at 160 ℃ at 150 ℃ for 4-5h, after the solvent is completely recovered, the temperature is controlled at 80-90 ℃, the second portion of purified water is added dropwise within 30-60min, and after pH =7-8 is adjusted, the temperature is reduced to 10-15 ℃ for suction filtration.

10. The process for green recovery of metformin hydrochloride distillation residue according to claim 9, wherein the volume ratio of the first part of purified water to the second part of purified water is 1: 3.5-4.5; the volume-mass ratio of the addition amount of the first part of purified water to the metformin hydrochloride in the DMF filtrate is 0.4-0.45 ml/g; the molar ratio of the inorganic acid to the metformin hydrochloride in the DMF filtrate is 0.65-0.7: 1; the inorganic acid is hydrochloric acid or sulfuric acid.

Technical Field

The invention relates to the technical field of synthesis in the pharmaceutical industry, in particular to a green recovery process of various materials in metformin hydrochloride distillation residues.

Background

Metformin is a white crystal or crystalline powder, and is mainly used for treating type II diabetes, especially obese type II diabetes, which is ineffective in simple diet control and physical exercise treatment. It can be used together with insulin to reduce insulin consumption and prevent hypoglycemia. The 2005 international diabetes union (IDF) guidelines promulgated further clear that metformin hydrochloride is the cornerstone of type II diabetes drug therapy. In 2006, the American Diabetes Association (ADA) and the european diabetes research institute (EASD) have together released a new consensus on type II diabetes treatment, i.e., newly diagnosed type II diabetes patients should use metformin hydrochloride while taking lifestyle intervention and use it as a first-line drug throughout the entire course of diabetes treatment. After the metformin hydrochloride falls off and rises for nearly 60 years, metformin hydrochloride becomes the most widely used oral hypoglycemic medicament worldwide, and the safety and the effectiveness of the hypoglycemic medicament are widely accepted.

Diabetes is one of the most serious public health problems worldwide in the 21 st century, and the number of diabetic patients worldwide has increased to 4.15 million according to data published by the international diabetes union. In high-income countries, up to 91% of adult diabetics are type II diabetics, and furthermore, according to the International diabetes Association (IDF), about 1.93 million diabetics are undiagnosed worldwide. With the continuous increase of the knowledge of the clinical application of metformin hydrochloride, the metformin hydrochloride has a greater and greater contribution to human beings.

In addition, with the development of the research on metformin, metformin not only has the function of reducing blood sugar, but also has multiple beneficial biological functions, and is known as a "psychotropic drug" by researchers at home and abroad in recent years. The new application mainly shows anti-aging, weight-losing, blood pressure-reducing effect on obese hypertension patients, treatment of perennial ovarian syndrome (PCOS) and the like.

The industrialized production method of the metformin hydrochloride comprises the following two methods:

(1) solvent method

In the presence of an organic solvent, dicyandiamide and dimethylamine hydrochloride are subjected to addition reaction under the conditions of different temperatures and reaction times, and the types of the solvents used in the reaction mainly comprise:

(a) alcohols: such as n-butanol, isoamyl alcohol, n-pentanol, cyclohexanol, ethylene glycol;

(b) malonamides: such as N, N-dimethylformamide, N-dimethylacetamide;

(c) dimethyl sulfoxide;

(d) benzene compounds: such as toluene, o-xylene, m-xylene, p-xylene;

(e) ethers, such as ethylene glycol monomethyl ether, propylene glycol monomethyl ether.

The reaction temperature of the solvent method is generally 120-160 ℃, and the reaction time is generally 6-12 h.

(2) Melting process

Under higher temperature, the raw material dicyandiamide and dimethylamine hydrochloric acid are directly melted into liquid and then further reacted to generate the metformin hydrochloride. The synthesis method has simple process principle and short production period, but still has the following defects:

(a) the raw materials are in solid state in the incomplete reaction and the early-stage raw materials and the finished products are in solid state in the later stage, and the subsequent refining is difficult because the proportion of the raw materials in the finished products which are in short-term homogeneous reaction and poor homogeneity is large:

(b) the conversion rate of raw materials is low, the product yield is low, and the product benefit is poor;

(c) the production has potential safety hazard, the melting temperature of dicyandiamide and dimethylamine is over 160 ℃, the two materials have high reaction speed when the melting points are higher than the melting points, the two materials basically react instantaneously, and the materials are flushed when the temperature rises quickly in a short time;

(d) the requirements on equipment materials are strict, the equipment investment is large, and the operation is difficult to control.

In conclusion, the organic solvent used in the reaction process of the solvent method is used as an intermediate medium and does not participate in the reaction, dicyandiamide and dimethylamine hydrochloride can be well dissolved, the reaction is promoted to be homogeneous, the heat is stable, the reaction is fully carried out, impurities are thoroughly removed after mother liquor separation, and the obtained product has lower impurity content and higher purity, and is a method preferentially adopted by manufacturers.

In terms of energy utilization, after the addition reaction using a solvent, the solvent needs to be distilled and recovered, and a distillation residue containing a large amount of impurities is generated. The distillation residue is only treated as solid waste because of its relatively complicated components. Therefore, from the aspects of clean production, resource recycling, environmental protection and the like, a process for green recovery of distillation residues, and recovery of products and byproducts thereof are urgently needed.

Disclosure of Invention

In order to solve the technical problems, the invention provides a green recovery process of distillation residues, which comprises the steps of adding dicyandiamide into the distillation residues, carrying out addition reaction on dicyandiamide and dimethylamine hydrochloride to obtain metformin hydrochloride, carrying out hydrolysis and cyclization reactions, filtering to obtain N, N-dimethyl-1, 3, 5-triazine-2, 4-diamine (used as a flame retardant), and finally collecting to obtain dimethylamine hydrochloride and solid potassium chloride, so that the effective recovery and utilization of the distillation residues are realized.

The invention aims to:

(1) the recovery process of the invention has no generation of three wastes, and all the recovered products can be continuously used for industrial production, thereby realizing the complete effective recovery and utilization of products and materials in the distillation residues;

(2) the yield of the recovered metformin hydrochloride and the N, N-dimethyl-1, 3, 5-triazine-2, 4-diamine is high.

In order to solve the technical problems, the invention adopts the following technical scheme:

a green recovery process of metformin hydrochloride distillation residues is characterized by comprising the following steps: addition to produce metformin hydrochloride, cyclization to produce N, N-dimethyl-1, 3, 5-triazine-2, 4-diamine, and alkaline hydrolysis to recover dimethylamine hydrochloride and potassium chloride.

The following is a further improvement of the above technical solution:

adding a part of solvent DMF for the first time to generate metformin hydrochloride, adding metformin hydrochloride distillation residues, heating to 120-130 ℃ to fully dissolve the materials, adding a water separating agent, carrying out distillation to bring water to 144-146 ℃, then adding dicyandiamide, heating to 120-160 ℃ within 28-32min, and keeping the temperature for 3-4 h; the temperature is preferably 145-155 ℃.

And after the heat preservation is finished, adding a solvent DMF for the second time, cooling to 70-80 ℃, carrying out suction filtration, and drying to obtain the metformin hydrochloride.

Adding dicyandiamide, wherein the molar ratio of the total amount of dicyandiamide to dimethylamine hydrochloride in feed liquid is 1.01-1.05: 1; the water diversion agent is a benzene compound.

The water separating agent is one of m-xylene and o-xylene; the volume ratio of the water separating agent to the solvent is 1: 4.5-5.5.

The volume ratio of the first-time added part of the solvent DMF to the second-time added solvent DMF is 2: 1; the volume-mass ratio of the total amount of DMF to the metformin hydrochloride distillation residue is as follows: 1.5 ml/g.

The metformin hydrochloride distillation residue comprises the following components in percentage by mass:

24.5 to 25.5 percent of metformin hydrochloride; 4.5 to 5.5 percent of dicyandiamide; 29.5 to 30.5 percent of dimethylamine hydrochloride; 29.5 to 30.5 percent of N, N-dimethyl-1, 3, 5-triazine-2, 4-diamine; the balance of amine compound impurities.

According to the liquid phase quantitative analysis, the main components of the metformin hydrochloride distillation residue are as follows:

a: metformin hydrochloride, cas: 1115-70-4, the mass ratio is 25%;

b: dicyandiamide, cas: 461-58-5, the mass ratio is 5%;

c: dimethylamine hydrochloride, cas: 506-59-2, the mass ratio is 30%;

d: n, N-dimethyl-1, 3, 5-triazine-2, 4-diamine (flame retardant), cas: 4039-98-9, 30% by mass;

e: other impurities, mainly amine compounds, are 10% by mass.

The cyclization reaction is carried out to generate N, N-dimethyl-1, 3, 5-triazine-2, 4-diamine, the cyclization temperature is 150-160 ℃, and the acid used for decomposing DMF is inorganic acid.

Adding a first part of purified water and inorganic acid into DMF filtrate obtained after addition to generate metformin hydrochloride, keeping the temperature at 160 ℃ for 4-5h, controlling the temperature at 80-90 ℃ after the solvent is completely recovered, dropwise adding a second part of purified water within 30-60min, adjusting the pH =7-8, and cooling to 10-15 ℃ for suction filtration.

The volume ratio of the first part of purified water to the second part of purified water is 1: 3.5-4.5; the volume-mass ratio of the addition amount of the first part of purified water to the metformin hydrochloride in the DMF filtrate is 0.4-0.45 ml/g; the molar ratio of the inorganic acid to the metformin hydrochloride in the DMF filtrate is 0.65-0.7: 1; the inorganic acid is hydrochloric acid or sulfuric acid.

According to the invention, through analyzing the components of the metformin hydrochloride distillation residue, firstly, a certain amount of dicyandiamide is added according to the proportion, the dimethylamine hydrochloride is added to generate metformin hydrochloride, and the metformin hydrochloride and the filtrate are obtained through solid-liquid separation. Adding a small amount of water and hydrochloric acid into the filtrate, distilling to recover DMF, promoting formic acid generated by DMF decomposition to cyclize with residual metformin hydrochloride to generate a flame retardant, adding alkaline water to adjust the pH value, and filtering to obtain the flame retardant; and then heating the filtrate for alkaline hydrolysis, absorbing dimethylamine gas generated by the decomposition of amine compounds by hydrochloric acid solution to obtain dimethylamine hydrochloride, finally adjusting the pH of the residual liquid by hydrochloric acid, and evaporating to dryness to obtain a solid containing potassium chloride.

The invention relates to the following reaction equation:

adding dicyandiamide and dimethylamine hydrochloride in distillation residues to synthesize the metformin hydrochloride.

Formic acid produced by hydrolysis of DMF reacts with residual metformin hydrochloride to produce N, N-dimethyl-1, 3, 5-triazine-2, 4-diamine (flame retardant)

Compared with the prior art, the invention has the following beneficial effects:

(1) the recovery process of the metformin hydrochloride distillation residue generates metformin hydrochloride by adding a proper amount of dicyandiamide, and recovers the metformin hydrochloride contained in the distillation residue, wherein the molar yield of the metformin hydrochloride reaches 102.7 percent, and the purity is more than or equal to 99.0 percent.

(2) The recovery process of the metformin hydrochloride distillation residue generates N, N-dimethyl-1, 3, 5-triazine-2, 4-diamine through cyclization, the molar yield is 98%, and the purity is more than or equal to 99.0%.

(3) According to the recovery process of the metformin hydrochloride distillation residue, dimethylamine hydrochloride and potassium chloride are recovered by alkaline hydrolysis, condensed water can be recycled, and no waste liquid is generated.

Detailed Description