Study on techniques of synthesizing lactide of polylactic monomer(I)

The poly-lactic(PLA)has been used widely in the medicine vontrollingreleasing , the surgery seam vanishing line and the bone fracture fixed materialfor its good biological compatibility , biological degradability, and degraded aswater and carbon dioxide, especially decomposed in the body safely.

At present，there are two kinds of synthetic methods to get the poly-lactic acid mainly--Lactic acid directly synthetic method and laetide ring-open polymerization synthetic method(also called the indirect mothed)，but in order that the poly-lactic acid has well mechanical intensity and universal applied value in biomedical fields，mostly the ladtide ring-open polynerization synthetic method was adopted．So the lactide as important raw materials of the PLA has viml function.

In recent years, many rearches on the technology of the lactide ring-openpolymerization have been carryied on, however there are some questi? ns such ashigh costs , low in yield and the purity etc. On the base of these problems ,theartical studied in the poly-lactic acid intermedia----the technology of lactide. Inthe course of studying, we make use of the industrial product lactide acid as theraw material and prepare the lactide by two steps (or three steps ), throughstuding the temperature influence oncondensationpolymetization anddepolymetization, catalyst , reaction concrete process and dehydrating amount tothe influence reacting to solve, explored the lactide preparation craft, weobtained the synthesis lactide the best synthesis condition : First the free waterremoved in the rection system at 80℃~90℃ and reduced presssure, then 1%(w/w)catalyst acetic acid zinc added,and dimethylbenzene as dehydrating agentunder the atmospheric pressure dehydrates the condensation.During the processwe must rigidly control removed the water volume of 30ml, and c( ntrol low-molecular polymer polymerization degree, then rised to 260℃~ 270℃ anddistilled out the lactide of the production under the vacuum . The remaining water content and the lactic acid content in the product was determined. Thelactide best yield was 78% excelled described in literature.The crude lactide canbe crystallize from ethyl acetate, the yield after purified was 75%, the meltingpoint is 96℃~97℃, The infrared and the nuclear magnetic resonancespectrums finally indicate that the obtained structure conforms to the report lactide structure.

This research obtained the technology condition and excellent productivity. It was worth noting that duting its condensation process,we avoided fell pressesduring the reaction process reported as ever literature and the addeddimethyibenzene as dehydrating agent can be recycled by distilled out in thefinally process , so reduced the energy consumption and the cost and had thecertain significance and the applied value.

I. Introduction

1.1 Introduction

In recent years, with the increasing severity of environmental pollution, research on biodegradable materials has become more active, and its application fields have involved food packaging, agricultural films and medical materials. Among them, medical biodegradable materials are the most concerned. With the increasing demand for biodegradable materials, people continue to develop qualified materials. Polylactic acid (PLA) and its polymers are one of the most widely used biodegradable materials. It belongs to the straight-chain lipid polyester family. The ester bonds in it can be hydrolyzed and biodegraded, and the final metabolites are CO? and H?O. Because its degradation products are non-toxic and have good biocompatibility, it has received worldwide attention.

Since polylactic acid is the most widely used and promising polymer material in the field of medical engineering, polylactic acid and its copolymer materials are harmless to organisms, so it has attracted great attention from both medical materials and health protection. Therefore, its synthesis method, physical properties, degradability and other properties have been studied in depth in many aspects. Its preparation mainly includes lactic acid direct polycondensation method, lactide ring-opening polymerization method, etc. Although the method for preparing polylactic acid by direct condensation of lactic acid is simple and convenient, it can generally only obtain low molecular weight polylactic acid, and the polymerization temperature is high, the carbonization phenomenon is obvious, and the product is oxidized and discolored. In order to improve the relative molecular weight of polylactic acid, make it have certain mechanical strength and mechanical properties, and achieve practical value in the fields of biomedicine, the preparation of high molecular weight polylactic acid is more to use lactide, that is, 3,6-dimethyl-1,4--oxa-hexane-2,5-diketone as raw material to melt ring-opening polymerization (Ring-Opening Polymerization) to form polylactic acid under the action of catalyst, and the molecular weight of the obtained PLA can be as high as 1 million or more. It can be seen from this that lactide plays a vital role in the production of polylactic acid as an important raw material for preparing high molecular weight PLA. The process of generating lactide from lactic acid is mainly divided into two steps: 1. Lactic acid generates lactic acid oligomers through polycondensation reaction: 2. The oligomers are depolymerized into lactide. The quality of its preparation and production process, the preparation cost and the purity determine the cost and purity of high molecular weight PLA.

With the progress of society and the development of economy, people's awareness of environmental protection has gradually increased, and the demand for green materials has become more urgent. As a monomer for synthesizing polylactic acid and its copolymers, the importance of its yield and purity in production is self-evident. Although many researchers have devoted themselves to research in this area and have made considerable progress, if it is put into mass production, there is still a lot of work to be done in terms of production continuity, yield, recovery and cost. If we can further study its production process on this basis, in order to obtain a lactide synthesis route with high yield, high purity and suitable for industrial production, it will be of great significance in the production of polylactic acid, a biodegradable material that has attracted much attention, as well as in protecting the environment and promoting human health.

1.2 Problems faced by traditional polymer materials

Polymer materials with a long history have many advantages and many problems. For various natural polymer materials, the annual output of synthetic polymer materials of about 10^8 tons can be said to be insignificant. However, most polymer products are for short-term use, which brings a series of problems to the use of polymer materials. First of all, this unreasonable use method has caused a huge waste of precious non-renewable petroleum resources, the raw materials of polymer materials. In addition, a large number of synthetic polymers are constantly accumulating, such as the problem of waste caused by plastics, which is very serious, such as occupying land, polluting soil resources, threatening the safety of wild animals, etc. Therefore, countries around the world, all walks of life, legislative bodies, environmental protection organizations, etc. have expressed great concern. In Europe, the United States, Japan and other countries, government regulations have strictly controlled industries that use a large number of polymer materials, such as packaging, water treatment, papermaking, and textiles. In recent years, my country has also continuously increased its efforts in environmental protection. The treatment of polymer waste has received special attention.

In developed Western countries, the physical recycling of polymer materials has entered the practical stage. However, this treatment method requires the classification and cleaning of waste, so it is not practical for household garbage with complex components, and is mainly used to recycle industrial scraps.

The chemical method of recycling has application prospects for some specific polymers. For example, nylon 66 can be obtained by aminolysis to obtain monomers, which are then condensed into polymers. But now only the chemical ring of PET has entered the practical stage. The cracking of polymer waste into small molecular products under certain conditions is also very promising.

Incineration is also one of the methods, which is a relatively common waste treatment method. Incineration requires that the organic part must be 100% converted and no toxic substances can be produced. Since combustion releases a large amount of CO?, it aggravates the greenhouse effect, and the heavy metals, NOx, SO?, polycyclic hydrocarbons and other substances that may be released are directly polluting the environment.

The method that needs to be emphasized is also the development direction of agricultural polymer materials, which is degradation. Various forms of degradation can solve the problem of polymer waste treatment, among which biodegradation is the most promising. Comprehensively and thoroughly solving the problem of polymer leather treatment requires comprehensive utilization of the above methods. Recycling and incineration can solve the problem in the short term, and it is realistic. But in the long run, biodegradation is the most promising.

1.3 Overview of degradable polymer materials

In 1987, the book "Definition of Biomaterials" defined "biodegradation" as: "the gradual destruction of materials caused by specific biological activities".

1.3.1 Classification of degradable materials

Degradable materials are divided into synthetic materials and natural materials according to water sources. Synthetic materials can be divided into polyesters, polyanhydrides, polyamides, polycarboxylates, etc. according to the structural characteristics of the main chain of macromolecules: natural materials are mainly divided into two categories: polysaccharides and proteins. Degradable materials can be divided into three types according to the degradation method: chemical degradation materials, biological degradation materials and physical degradation materials.

1.3.2 Development of degradable biomaterials

As early as the early 1970s, researchers pointed out in a series of patents and reports that PCL is a biodegradable polymer suitable for a variety of uses. It was also pointed out that PCL is compatible or partially compatible with many other polymer materials, thus pioneering the research on polymer blends as biodegradable materials. In the 1980s, due to the rising cost of treating municipal solid waste and the general attention paid to environmental issues worldwide, a new upsurge in the research of biodegradable materials began in developed countries such as Europe and Japan. Since 1989, more research work has focused on using starch or starch blends as new biodegradable materials to replace traditional synthetic polymers. Recently, the application of hydroxy acid polymers, such as PLA, PGA, PHA and fiber series, in biodegradation has also received attention.

In the early days of the development of biodegradable materials, people modified traditional synthetic polymers to make them have certain degradability, which are mainly divided into two categories: photodegradation and biodegradation. Photodegradable plastics are a type of material that can be rapidly photoaged under sunlight conditions. However, photodegradation is only possible under the action of sunlight. When the waste is buried underground, the material will not degrade due to lack of light, water or oxygen. Biodegradable plastics are based on polyolefins, supplemented with appropriate photosensitizers, biodegradants, pro-oxidants and degradation controllers.

In summary, although these so-called degradable materials based on traditional synthetic polymers have the characteristics of easy processing and low cost, their inherent incomplete degradability limits their use. In addition, there are also disadvantages such as high cost, implicit environmental pollution caused by pulp production, and waste of forest resources with a long regeneration cycle. In this form, the development of completely biodegradable and environmentally friendly materials based on natural renewable resources will have great economic and social benefits.

1.3.3 Biodegradable polymer materials

Biodegradable polymers are a type of degradable materials. Since the development of degradable materials, biodegradable polymer materials have received widespread attention. Biodegradable polymers refer to a type of polymer materials that can be degraded or enzymatically hydrolyzed in organisms, and the small molecules generated are absorbed by the body and excreted from the body. The main awards of biodegradable polymers that have been studied and developed so far are natural polymers, microbial synthetic polymers, and artificial synthetic polymers. Natural degradable polymers include starch, cellulose, polysaccharides, chitin, chitosan and its derivatives; biodegradable polymers synthesized by microorganisms include polyhydroxyalkyl alcohol esters, poly (B-malate), etc.; artificially synthesized biodegradable polymers include poly α-hydroxy acid esters, polycaprolactone, polycyanopropionate, etc. According to the structure and properties, they can be divided into block copolymers, cationic polymers, smart polymers, etc.

1.3.3.1 Degradation mechanism of biodegradable polymers

The biodegradation of polymers refers to the process of degradation and assimilation of polymers under biological action. The microorganisms that play a biodegrading role mainly include fungi, bacteria or algae. The mechanism of action can be mainly divided into three categories: (1) Biophysical action: Due to the growth of biological cells, the polymer components are hydrolyzed, ionized or protonated, resulting in mechanical destruction and splitting into oligomer fragments; (2) Biochemical action: Microorganisms act on polymers to produce new substances (CH4, CO? and H?O); (3) Direct action of enzymes: The part eroded by microorganisms causes the plastic to split or oxidatively collapse. Biodegradation is not a single mechanism, but a complex biophysical and biochemical synergistic effect, accompanied by mutually reinforcing physical and chemical processes.

1.3.3.2 Research on biodegradable polymers

1. Natural degradable polymers

Valuable biodegradable plastics can be made by using cellulose, lignin and starch in plants, chitosan, polyglucosamine, animal glue in animals, and algae in marine organisms. Starch and its derivatives are modified as the focus of filling plastics because of their good biodegradability and low price, and their grafts have broad application prospects in many aspects. On the other hand, high-content starch-based polymers can be used as completely biodegradable polymers. Blending modified starch with synthetic biodegradable polymers such as PVA, PHB, PHV, PHBV, and PCL to improve the degradability and mechanical properties of the product is an aspect that is currently being studied more.

2. Artificially synthesized degradable polymers

The research and development of biodegradable polyesters and aliphatic polycarbonates is also of great significance. Especially the latter can artificially bring C0? into the material cycle. For example, copolymerization of CO2 and ethylene oxide can produce polyethylene carbonate with good biodegradability and biocompatibility. Other materials of this type include polycaprolactone, copolymers of aliphatic polyesters and aromatic polyesters, polyacrylic esters synthesized from aliphatic polyesters and nylon, and polyhydroxyalkanoates.

3. Microbial synthesis of biodegradable polymers

W.R.Gyace has put biodegradable plastics synthesized by microorganisms into production. Japan's Kaneka Chemical Industry Co., Ltd. and the U.S. P&G Company have signed an agreement on the joint production of biodegradable polymer PHBH (copolyester of 3-hydroxybutyric acid and 3-hydroxyhexanoic acid). PHBH is prepared by the aggregation of polymers inside microorganisms and then refined using culture technology. Kaneka intends to achieve industrial production of this copolymer by the end of 2005 or the beginning of 2006.

1.4 Degradable polymer material polylactic acid

Polylactic acid is an important biodegradable product of lactic acid. It does not exist in nature. It is a new type of biodegradable polymer material chemically synthesized with lactic acid as a monomer. It is non-toxic, non-irritating, has excellent biocompatibility, is biodegradable and absorbable, has high strength, good plasticity, and is easy to process and shape. Polylactic acid is enzymatically decomposed in the body and eventually forms carbon dioxide and water, which does not pollute the environment. Therefore, it is considered to be the most promising biodegradable polymer material and has attracted much attention at home and abroad. Polylactic acid is widely used in the medical field.

1.4.1 Development history of polylactic acid

Polylactic acid as a polymer material has attracted people's attention very early. In 1913, the French synthesized polylactic acid by polycondensation, but the yield was low, the molecule was small, and the mechanical properties were poor. Therefore, it was not used as a structural material. In 1954, DuPont began to prepare polylactic acid using an indirect method, that is, first preparing lactide, and then ring-opening polymerization of the purified lactide to obtain high molecular weight polylactic acid. At that time, DuPont's purpose of preparing polylactic acid was only to obtain durable polyester fiber materials, but polylactic acid would slowly degrade in a humid environment, and its use value was far less than that of polyethylene terephthalate (PET) with superior performance, so the results of indirect synthesis of polylactic acid did not attract enough attention. In the late 1960s, researchers at Cyanamid discovered that polylactic acid and its copolymers could be used to prepare absorbable sutures. Later in the 1970s, researchers further discovered that polylactic acid has good biocompatibility with human tissues, does not cause tissue inflammation, and has no obvious excretion reaction. People began to realize that polylactic acid has a wide range of medical uses, and research on polylactic acid as a biomedical polymer material began to develop rapidly.

Later, researchers began to conduct in-depth research on the synthesis of high molecular weight and optically active polylactic acid. Now, Kulkarmmi's two-step method is generally used to prepare lactide and polylactic acid.

1.4.2 Application of polylactic acid materials

Polylactic acid (PLA) is a polymer with excellent biocompatibility and biodegradability. It is approved by the FDA and is mainly used in the medical field. Its main uses include drug controlled release, bone materials, surgical sutures and ophthalmic materials.

1.4.2.1 Sustained release of drugs:

The controlled release of drugs is to combine drugs or other bioactive tissues with substrates so that the drugs are released into the environment at a certain rate within a certain period of time through diffusion and other methods. Polylactic acid and its copolymers can be made into specific drug dosage forms based on the properties, release requirements and administration routes of drugs. At present, some sustained-release drugs are mainly prepared by solution molding and hot pressing into tablets, such as polyacid double-layer sustained-release tablets of insulin, polylactic acid spheres of gentamicin, block implants of growth hormone-releasing hormone, hollow polylactic acid fibers of hormone levonorgestrel, etc. Polylactic acid can also be made into some films, emulsions and other dosage forms to achieve the effect of controlled-release drugs. The current research hotspot is to prepare more complex synthetic drug preparations that can effectively control release and target treatment, such as layered particles, microspheres, microcapsules and nanoparticles.

In 1970, researchers first used polylactic acid as a long-acting sustained-release preparation for drugs, and in 1979, researchers launched progesterone/PLGA sustained-release capsules. In the past three decades, polylactic acid and its copolymers have been used as soluble substrates for controlled-release preparations of drugs with short half-life, poor stability, easy degradation and large toxic side effects, effectively broadening the route of administration, reducing the number and amount of administration, improving the bioavailability of drugs, and minimizing the toxic side effects of drugs on the whole body, especially the liver and kidneys.

In recent years, people have vigorously studied and developed biodegradable nano controlled-release drug delivery systems. They are mainly prepared by emulsion evaporation, self-emulsifying solvent diffusion, salting-out/emulsification-diffusion technology and supercritical fluid technology. Natural polymers such as hemoglobin have disadvantages such as difficulty in purification, high production cost, low drug loading and rapid leakage of water-soluble drugs when used as nano controlled-release drug delivery materials. In contrast, polylactic acid nanoparticles have many advantages as carriers for drug delivery and controlled release: (1) ultra-small size, able to pass through tissue gaps; (2) controlled release drug delivery, prolonging biological half-life; (3) easy to achieve targeted and biological drug delivery; (4) reducing the number of drug administrations, reducing or avoiding toxic side effects; (5) enhancing drug stability. Therefore, drug-loaded polylactic acid nano controlled release system is mainly used for drug administration with large toxic side effects, short biological half-life, and easy degradation by dust enzymes, and has been widely concerned by people.

1.4.2.2 Bone materials:

The demand for polymer materials used in the human body is increasing, and the requirements are becoming more and more stringent. Polymer materials used in the human body must be non-toxic, suitable for biodegradability, good biocompatibility, and have certain ability to interact with certain specific cells. Polylactic acid basically meets the above requirements in terms of properties. Traditional medical polymer materials include polytetrafluoroethylene, silicone oil, silicone rubber, etc., but each has many unsatisfactory aspects. The emergence of polylactic acid effectively makes up for the shortcomings of these products and has gradually become the dominant variety of polymer materials used in the human body. There are two main requirements for polylactic acid in the field of bone internal fixation materials: one is that the implanted polymer gradually degrades during the wound healing process, and it is mainly used for fracture internal fixation materials. Such as bone splints, bone screws, etc. Another is that the polymer should degrade slowly over a considerable period of time, and tissue cells should be cultured on the material in the early stage or within a certain period of time to allow them to grow into tissues, organs, such as cartilage, liver, blood vessels, nerves and skin.

In the 1980s, polylactic acid was successfully used in bone materials. A large number of clinical trials have shown that polylactic acid, as a fixation material in the human body, has a low incidence of inflammation after implantation, high strength, and basically no infection after surgery. At present, the pace of research and application is being accelerated at home and abroad, and it is expected to be used in the repair and cultivation of tissues such as blood vessels, ligaments, skin, and liver.

1.4.2.3 Surgical sutures:

Lactic acid and its copolymers are used as surgical sutures. They can be automatically degraded and absorbed after the wound heals, and there is no need to remove the sutures after surgery. Once the polylactic acid quasi-combining suture came out, it was immediately favored by doctors and has been widely used in various surgeries. Polylactic acid surgical sutures have strong tensile strength and can effectively control the degradation rate of polymers. As the wound heals, the sutures automatically and slowly degrade. At present, major domestic hospitals are also using excellent polylactic acid sutures imported from abroad. In recent years, research on PLA as surgical sutures has mainly focused on the following aspects: (1) In order to improve the mechanical strength of sutures, it is necessary to synthesize high molecular weight polylactic acid and improve the suture processing technology. Researchers have investigated the effect of polymerization conditions on relative molecular mass. At the same time, some people believe that melt-spun PLLA fibers can maintain their strength and stability for a longer time; (2) Synthesis of optically active polymers. Semi-crystalline PDLA and PLLA have higher mechanical strength, larger stretch ratio and lower shrinkage than amorphous PDLLA, and are more suitable for surgical sutures; (3) Multifunctionalization of sutures. Non-steroidal anti-inflammatory drugs are added to sutures to inhibit local inflammation and foreign body rejection reactions. Plasticizers such as collagen, low molecular weight polylactic acid and other inorganic salts are added to sutures to increase the toughness of sutures and regulate the degradation rate of polymers. In addition, the copolymer of lactide and caprolactone can also be used as absorbable surgical gauze.

1.4.2.4 Ophthalmic materials:

With the gradual increase in work and study pressure, the incidence of eye diseases is gradually increasing, especially retinal detachment, which has become one of the common eye diseases. Usually surgical treatment is solved by implanting filler water on the surface of the sclera. Traditionally, silicone rubber and Silicone sponges, these two substances cannot be degraded and can easily cause foreign body reactions. The use of polylactic acid as a filling material can effectively solve the above problems. For example, some reports use polylactide polymerized under the trigger of stannous octoate. Lactic acid is used to make a diaphragm. It has been shown through the bed that this diaphragm has a certain degree of degradation in tissues and meets the requirements for scleral support time in retinal detachment repair surgery. It is a very ideal ophthalmic material.

1.4.2.5 Tissue repair materials:

The requirements of tissue repair materials are that the polymer degrades slowly over a considerable period of time, and tissue cells are cultured on the material in the early stage or for a certain period of time to allow them to grow into tissues, such as anti-adhesion membranes. During the healing process of the dura mater after trauma, the brain will adhere to the surrounding tissues, and the surrounding new blood vessels will grow into the brain tissue to form scabs, which is the pathological basis for clinical diseases such as epilepsy, headaches, and brain dysfunction. The artificial dura mater made of polylactic acid can ensure that new membrane-like tissue is formed before the polymer is degraded, avoiding cerebrospinal fluid overflow after surgery, and effectively preventing the occurrence of inflammation of surrounding tissues.

1.5 Domestic and foreign research status of polylactic acid monomer-lactide

The direct method of preparing lactide with lactic acid as raw material is generally completed in three steps. First, lactic acid is used as raw material and ZnO, SnClz or SnOctz as catalyst. Lactic acid is dehydrated at less than 160℃ and reduced pressure to form PLA oligomers (PLA Oligomers) (molecular weight is generally less than 2000). The water generated by polycondensation is removed under reduced pressure to break the balance and make the reaction favorable for polycondensation; then PLA oligomers are depolymerized at a higher temperature (200℃~280℃) and a certain pressure to generate lactide crude product; finally, the crude product is purified by the recombination method to obtain the finished lactide product. The researchers evaporated the internal parent ester generated by the reaction by reducing pressure. In this way, on the one hand, the depolymerization equilibrium of PLA oligomers can be moved in the direction that is favorable for depolymerization, and more importantly, the oxygen content in the reactor can be reduced, thereby reducing oxidative discoloration and coking. Despite this, the degree of oxidation discoloration and coking is still serious, and the energy consumption is high, and the refined yield is generally 20%~30%. In order to overcome these shortcomings as much as possible, the researchers have made further improvements to the above-mentioned method. They introduced gasified solvents such as gasified toluene and steam into the reactor while reducing the pressure. The researchers introduced N? into the reactor, attempting to use these fast-flowing "inert gases" (gases that do not react with the reaction mixture) to quickly take the generated lactide out of the reactor to reduce the residence time of lactide in the high-temperature reactor, thereby reducing the occurrence of side reactions. At the same time, since the oxygen in the reactor is almost completely replaced by these gases, discoloration and coking caused by oxidation are avoided, which greatly improves the yield and purity of lactide. However, since the entire reaction system is closed, the "inert gas" is not easy to remove and recycle from the product, and when the gasified solvent or steam is used as the "inert gas", more solvent or water will remain in the lactide, which makes the refining of lactide more complicated.

The above methods are all aimed at the depolymerization stage, and the total crude yield can reach up to 80%. In these studies, no measures are taken for dehydration of the previous polycondensation process, and the decompression operation in the polycondensation stage is also a reason for the high energy consumption.

1.6 Proposal and content of this research topic

1.6.1 Proposal of the topic

As mentioned above, polylactic acid, as an important green polymer, has a very broad application prospect. However, the application of polylactic acid in biomedicine requires it to have a certain mechanical strength and good molding and processing performance. Therefore, the ultimate goal of its synthesis research is to prepare high-quality polylactic acid materials, which puts forward high requirements on the relative molecular weight and its distribution that are closely related to the basic properties of polylactic acid.

At present, the preparation of polylactic acid with high relative molecular weight mainly adopts the indirect polymerization method, that is, first prepare the intermediate lactide, and then open the lactide for ring polymerization. Then lactide plays a key role in the production of polylactic acid. However, based on the research on the synthesis of lactide over the years, there are still many problems. They are mainly concentrated in the aspects of high energy consumption, high cost, insufficient yield and purity, which cause the market price of lactide to remain high. The analysis of the synthesis methods reported in the literature found that the main reason for the low yield and poor purity was that there was no better measure for the key step in the reaction process - "polycondensation dehydration". We will conduct a major study on this issue. At the same time, we will also study the effect of a new "green catalyst" - a macroporous resin - on the synthesis. In addition, studies have shown that in the polymerization process of polylactic acid, the purity of lactide has a significant effect on the relative molecular mass of the product. Generally, the purity of the intermediate lactide is required to reach more than 99%, the water content is less than 0.15%, and the combined amount of carboxylic acid and water is less than 1.00%. Therefore, lactide needs to be recrystallized and purified multiple times. We will analyze different product solvents. In short, improving the existing process and obtaining high-yield lactide is our ultimate goal.

1.6.2 Main research contents of this paper

(1) The synthetic process route of lactide, the monomer of biodegradable material polylactic acid, is studied. The main research contents include: selecting suitable water-carrying agent according to the reaction conditions in the polycondensation process, solving the dehydration problem in the polycondensation process, and comparing the effects of adding water-carrying agent on the synthesis yield before and after.

(2) After determining the suitable water-carrying agent, other process conditions for synthesizing lactide are studied. The main contents include: polycondensation temperature and depolymerization temperature, catalyst type and feed ratio, and reaction time. The optimal process conditions for synthesizing lactide after adding water-carrying agent are determined. The method for determining the lactic acid content in the crude lactide can be the sodium methoxide non-aqueous titration method. The water content is determined by the Karl-Fischer trace water method.

(3) The crude lactide product is purified by recrystallization. The effects of different recrystallization solvents and the number of recrystallizations on the purity of the product are studied.

II. Related theories of research work

2.1 Synthesis of polylactic acid

As mentioned above, there are two main methods for synthesizing polylactic acid: direct method and indirect method. The following will describe them separately:

2.1.1 Direct method

That is, polylactic acid is synthesized by direct dehydration condensation reaction of lactic acid. The reaction formula is as follows:

In the direct polycondensation method, there is a balance of free acid, water, polyester and lactide in the system, and it is not easy to obtain high molecular weight polymers. The relative molecular weight of PLA synthesized by the early direct method is not greater than 4000, the strength is extremely low, it is easy to decompose, and it is not practical. In 1995, researchers used lactic acid as a raw material to prepare PLA with an average relative molecular weight of 300,000 by solution polycondensation. Subsequently, researchers reported a method for preparing high relative molecular weight PLA by bulk polymerization (melt polycondensation). However, the catalysts used in these two methods are highly toxic and difficult to remove. Therefore, using non-toxic catalysts or direct polycondensation without borrowing agents to generate high relative molecular weight PLA will be the focus of future research.

2.1.2 Indirect method

People have always paid more attention to the ring-opening polymerization of lactide (i.e., the indirect method). This polymerization method is relatively easy to implement and can produce PLA with a relative molecular mass of 700,000 to 1 million. People have made detailed studies on the reaction conditions of lactide ring-opening polymerization. These factors mainly include catalyst concentration, monomer purity, polymerization vacuum, polymerization temperature, and polymerization time. The most important of these are the purification of lactide and the selection of catalysts.

Different catalysts are used for ring-opening polymerization, and the polymerization mechanism is also different. So far, people have proposed three reaction mechanisms for the ring-opening polymerization of lactide: anionic ring-opening polymerization, cationic ring-opening polymerization, and coordinated ring-opening polymerization. The initiator of anionic ring-opening polymerization is mainly alkali metal compounds, such as sodium alcoholate, potassium alcoholate, butyl lithium, etc. The initiation mechanism is that the negative ion nucleophilic attack on the carbonyl group of lactide breaks the acyloxy bond. It is characterized by fast reaction speed, high activity, and can be polymerized in solution and bulk, but side reactions are not easy to eliminate, and it is not easy to obtain polymers with high relative molecular mass. There are not many initiators that can initiate LA cationic polymerization. Researchers believe that only methyl trifluoromethanesulfonate and trifluoromethanesulfonic acid are real cationic initiators for flash cross-linking ring-opening polymerization, while other so-called cationic initiators are initiated under the co-catalysis of catalysts and a small amount of impurities in the system, such as water. This argument has actually been confirmed in the research results of researchers as early as a long time ago.

In ring-opening polymerization, coordination ring-opening polymerization has always been the focus of people's attention. The catalysts used are organic aluminum compounds, tin compounds, rare earth compounds, etc. Metallic aluminum can form coordination compounds with different ligands to catalyze LA ring-opening polymerization to obtain macromolecular monomers, and then copolymers with grafted and star structures can be prepared. The reaction shows the characteristics of active polymerization to a certain extent. Almost all tin salts have catalytic activity for the ring-opening polymerization of propyl esters, among which stannous octoate is one of the most widely used and most effective catalysts. Its advantages are high monomer conversion rate, low catalyst dosage, and the production of polymers with high relative molecular mass. Researchers believe that stannous octoate is only a catalyst, and the real initiator is the very few hydroxyl-bearing impurities in the system. Rare metal elements have strong complexing ability. Researchers believe that the use of rare earth initiators to initiate the ring-opening polymerization of lactide is mainly completed through coordination, deprotonation, and insertion. The reaction speed is fast, the product has a high relative molecular mass, and has the characteristics of active polymerization.

2.2 Lactide

2.2.1 Properties and synthesis of lactide

At present, the preparation of PLA and its copolymers generally adopts the ring-opening polymerization method, that is, lactide (LA) is first synthesized from lactic acid, and LA is then ring-opened to prepare PLA and its copolymers. Lactic acid molecules contain one chiral carbon atom, and its dimer epiphyseal contains two chiral carbon atoms. Therefore, the former has two optical isomers and the latter has four. Among them, L-lactic acid is prepared by bioengineering, racemic lactic acid can be prepared by racemization of L-lactic acid or by petrochemical synthesis, and LLA (L-lactide) and DLLA (D, L-lactide) are prepared by the corresponding lactic acid split reaction.

Different optically active lactides have different melting points. Lactide has a white solid state, is easy to absorb water and hydrolyze, is slightly soluble in ethanol, and is easily soluble in ketones.

There are many methods for synthesizing lactide, and the decompression method is generally used, that is: the preparation of lactide is to react lactic acid at a certain temperature for about 10 hours, evaporate the product lactide, and then recrystallize it in ethyl acetate for purification. The reaction equation is as follows:

In addition, lactide can also be prepared by atmospheric pressure N?, CO? gas flow method to prepare D, L-lactide. The reaction principle of atmospheric pressure gas flow method is the same as that of decompression method, and heating and catalyst are also required, but no decompression operation is required. Usually, an inert gas flow (nitrogen, carbon dioxide) is used to reduce the partial pressure of lactide vapor and take the generated lactide out of the reaction zone to reduce the residence time of lactide in the high-temperature reactor, thereby avoiding the reaction failure caused by insufficient system vacuum. At the same time, since the oxygen in the reactor is almost completely replaced by these gases, discoloration and coking caused by oxidation are avoided, which greatly improves the yield and purity of lactide. The biggest advantage of the atmospheric pressure gas flow method is the high success rate of operation, but because the gas flow often takes away some materials, the yield of the product lactide is lower than that of the subtraction method. In the atmospheric pressure method, a high boiling point solvent can also be used to reduce the partial pressure of lactide and distill it azeotropically. For example, researchers used biphenyl and diphenyl ether to dehydrate at 180°C, added stannous octoate and distilled at 240°C~255°C to obtain lactide with a yield of 82%.

There are not many studies on the preparation of lactide by one-step reaction. The researchers converted the aqueous lactic acid into steam and passed it into a high-temperature reactor, and then obtained the lactide product under the catalysis of alumina. This reaction is a vapor-liquid phase reaction, and its reaction mechanism may be that the lactic acid condenses to first obtain a linear dimer of lactic acid, and then the dimer cyclizes and condenses into a cyclic dimer. They further dissolved lactic acid in an organic solvent (such as toluene) to make a low-concentration lactic acid solution, added an acidic ion exchange resin, and heated and dehydrated it to directly obtain lactide.

There are also some experiments to prepare lactide with other raw materials. For example, researchers used 2-halogenated propionic acid alkali metal salts as raw materials and non-aqueous solvents as media to prepare lactide at 200℃~250℃ and 2.53MPa. The reaction principle is shown in the following formula, where X represents Cl, Br, I, and the most commonly used is CI; A represents Li, Na, K, etc., and the most commonly used is Na; B represents Mg, Ca, Sr, Ba, and the most commonly used is Ca.

The reaction rate of this process is fast, and the reaction time generally does not exceed 2h. Since the boiling points of the non-aqueous solvents used, such as lactone, butanone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate and ether, are lower than the reaction temperature (200℃~250℃), the reaction needs to be completed under pressure. The pressure is generally close to the vapor pressure of the solvent at the reaction temperature (about 2.53MPa). The biggest disadvantage of this method is that it is not easy to completely remove the unreacted halogenated propionate from the finished product. The yield is generally about 35%, and the product purity can reach 98%. B Some people heat lactic acid containing 9.89% ethyl lactate and 1% p-MeC6H3SO3H at 145℃ to react, and selectively generate linear dimers in the first few minutes; lactic acid-ethyl lactate (long-term reaction will generate oligomers with higher polymerization degree), and the reaction product is collected by thin-layer evaporation dish distillation to obtain linear dimers with higher purity. At room temperature, the dimer is catalyzed by 1% p-MeC6H4SO3 for ester exchange reaction, and distilled with n-propyltoluene at a ratio of 19:1, during which lactide is generated.

2.2.2 Purification method of lactide

The crude lactide prepared often contains a small amount of water, lactic acid and its oligomers and other impurities, which must be refined before being used in the preparation of polylactic acid. To obtain polylactic acid with a high relative molecular weight, the monomer must have a high purity. In addition, if polylactic acid products are used as implant materials in the human body, the control of impurities is more stringent, generally requiring the monomer purity to reach more than 99.00% and the water content to be less than 0.15%.

There are generally three types of purification methods for lactide:

(1) Recrystallization method: Recrystallization is the most commonly used method, and it takes more than three recrystallizations to reach the required purity. The solvents used are ether, ethyl acetate, 2-butanone, propylene glycol, benzene, isopropanol, etc. The researchers investigated the dissolution of lactide in 20 commonly used organic solvents during the process of continuous heating from -10℃ to 96℃ and the recrystallization products after cooling. The amount of lactide dissolved in various solvents and the recrystallization recovery rate under the same test conditions were compared, and the applicability of various solvents to the lactide recrystallization process was discussed. The researchers improved the method of lactide recrystallization and used a benzene-ethyl acetate mixed solvent system for lactide recrystallization. The advantages of using this system are high yield, low solvent consumption, and melting point that meets the requirements. The researchers used sodium methoxide non-aqueous titration and Karl-Fischer method to quantitatively analyze the residual lactic acid and water in lactide, which helps to more precisely control the process in the purification of lactide.

(2) Gas-assisted degassing: This method can purify cyclic esters such as lactide, glycolide and their mixtures. It is a solvent that allows cyclic esters to be quickly separated from impurities as vapor components in the airflow and can recover cyclic esters from the airflow.

(3) Hydrolysis method: In fact, this is a method for removing the meso isomer from crude lactide to obtain high optical purity lactide. The operation is to contact the mixture containing meso lactide with water and hydrolyze the meso lactide.

2.2.3 Determination of trace water and lactic acid content in lactide

Quantitatively knowing the amount of lactic acid and water remaining in lactide helps to more precisely control the process in the purification and polymerization of lactide. The lactide sample can be quantitatively analyzed by sodium methoxide non-aqueous titration and Karl Fischer method.

2.2.3.1 Determination of lactic acid content

In a non-aqueous system, the free acid in the sample is titrated with potassium methoxide or sodium methoxide. In addition to lactic acid, the acidic impurities may also include lactic acid dimers, trimers, etc., but the titration result is converted into lactic acid content.

1. Calibration of sodium methoxide standard solution:

Accurately weigh about 50 mg of benzoic acid in a 100 mL conical flask, add 25 mL of anhydrous methanol and two drops of 0.2% phenolphthalein alcohol solution, slowly pass dry N?, start the stirrer to dissolve the sample (about 5 minutes), then use anhydrous methanol solution of about 0.02 mol of sodium methoxide to be calibrated to drip to the light red end point. The concentration of this sodium methoxide solution is calculated according to the following formula

c=mB/V x 122.1

Where: c-concentration of sodium methoxide standard solution, mol/L, V-volume of sodium methoxide standard solution consumed by titrating sample, mL, mB-mass of benzoic acid, mg, 122.1-molecular weight of benzoic acid

2. Determination method:

Accurately weigh 1.8~2.0 g of lactide sample in a 100 mL conical flask, and titrate with the calibrated sodium methoxide solution according to step 1. The lactic acid content is calculated as follows:

Lactic acid mass fraction (%) = c*V × 90.08/m × 100

Where: m - sample mass. mg 90.08-lactic acid molecular weight

2.2.3.2 Determination of water content in lactide

1. Calibration of Karl-Fischer reagent:

First, add 25ml of anhydrous methanol to a 50ml titration bottle, turn on the electromagnetic stirrer, and use Karl-Fischer reagent to titrate the water contained in the solvent and the air in the plate until the light spot of the galvanometer stops swinging, and the scale of the Karl-Fischer reagent at this time is the "starting point" (0mL) of the next titration. Then use a 10μL micro-injector to add slightly more than 10mg of distilled water, and record its mass accurately to 0.1mg (the weight difference between the micro-injector and the analytical balance before and after the water is injected), and then use Karl-Fischer reagent to titrate under stirring until the light spot of the galvanometer stops swinging as the end point. The amount of water T equivalent to each mL of reagent is calculated as follows:

T=mass of distilled water (mg) Volume of reagent consumed after the "starting point" (mL)

2. Determination method:

Accurately weigh about 6g of lactide sample in a 50mL titration bottle, but do not add water, stir for 3~5min, and start titration even if the sample is not completely dissolved. Titrate with Karl-Fischer reagent to the end point V1 under stirring, but the sample should be completely dissolved before the end point (Karl-Fischer reagent can help the sample dissolve), and calculate the water content as follows:?

Water mass fraction (%) = V1*T/m × 100

(V1 is the volume of Karl-Fischer reagent consumed from the "starting point", mL

2.3 Sections of this chapter

(1) The synthesis method of biodegradable island molecule material polylactic acid was discussed. There are two commonly used methods for the synthesis of polylactic acid: direct method and indirect method. In order to obtain high molecular weight, high quality, and satisfactory polylactic acid, the indirect method of ring-opening polymerization of lactide is usually adopted. Therefore, the quality, yield, and purity of the obtained lactide are particularly important.

(2) The physical and chemical properties and synthesis methods of lactide were studied. There are two methods for the synthesis of lactide: atmospheric pressure and vacuum method. The atmospheric pressure method and vacuum method have the same principle, but the yield of the atmospheric pressure method is lower than that of the vacuum method, so the vacuum method should be used to synthesize lactide. That is, oligomers are first generated, and then depolymerized to generate lactide.

(3) The purification methods of lactide include recrystallization, gas-assisted evaporation, and hydrolysis. The most suitable method for the current study of illicit drugs is recrystallization, and ether, ethyl acetate, 2-butanone, acetone, benzene, and isolactone can be selected as recrystallization solvents.

(4) The lactic acid content in the crude lactide can be determined by the sodium methoxide non-aqueous titration method, and the water content can be determined by the Karl-Fischer trace water method.

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