Synthesis method and application of long-chain alkane diacid mono-tert-butyl ester

Abstract

The invention discloses a synthesis method and application of long-chain alkane diacid mono-tert-butyl ester, and relates to the technical field of medicine synthesis. The synthesis method comprises the following steps: taking long-chain alkane diacid as an initial raw material, reacting with an alcohol solvent and SOCl2, and carrying out monohydrolysis by using barium hydroxide to obtain long-chain alkane acid monoester barium salt subjected to unilateral hydrolysis; undissolved salt of the long-chain alkanoic acid monoester barium salt directly reacts with tert-butyl alcohol under the condition of trifluoroacetic anhydride to generate mixed ester; and selectively hydrolyzing the monoester on the other side by using the mixed ester in an alkaline solution to obtain a target product. The synthesis method of the long-chain alkane diacid mono-tert-butyl ester provided by the invention is controllable in quality, simple and convenient to operate, capable of obtaining a high-yield and high-quality target product of the long-chain alkane diacid mono-tert-butyl ester, easy to control related impurities, simple and convenient to operate, high in safety and suitable for batch production.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to a synthesis method of long-chain alkanedioic acid mono-tert-butyl ester and application thereof. Background Art

[0002] Long-chain alkanedioic acid mono-tert-butyl ester is a key intermediate for the synthesis of long-acting side fragments of antidiabetic drugs (GLP-1).

[0003] With the improvement of living standards, the incidence of diabetes at home and abroad has shown a clear upward trend, and the domestic incidence of diabetes has exceeded 3.2%. So far, insulin is a special polypeptide hormone compound for the treatment of diabetes, but because insulin itself is a protein, it is easily hydrolyzed and inactivated by proteases in the stomach and intestines, so it can only be used by injection. In order to relieve the pain of injection for patients, the long-acting drug is a more ideal means. For example, semaglutide developed by Novo Nordisk and telpotide developed by Eli Lilly and Company, the Lys in the peptide chain is modified with short-chain PEG and octadecanoic acid fatty chain, which greatly improves hydrophilicity, enhances the binding force with albumin, and tightly binds to cover the DPP-4 enzyme hydrolysis site, and also helps to reduce renal excretion, prolong biological half-life, and achieve a long circulation effect.

[0004] Long-chain alkanedioic acid mono-tert-butyl ester is also used as ① plastic auxiliary agent: as a plasticizer, it can increase the softness and ductility of plastics and is often used in polyvinyl chloride (PVC) and other plastic products. ② Lubricant: Long-chain alkanedioic acid mono-tert-butyl ester can be used as a lubricant for mechanical equipment to reduce wear and friction. ③ Industrial raw materials: The compound can also be used as a raw material for chemical synthesis, such as the synthesis of certain fluorescent agents and pigments.

[0005] Long-chain alkanedioic acid mono-tert-butyl ester is a key fragment intermediate of the side chain of long-acting polypeptide drugs and has extremely high commercial value. However, its current problems such as immature preparation process and low yield greatly limit its large-scale production.

[0006] In view of this, the present invention is proposed. Summary of the invention

[0007] The purpose of the present invention is to provide a synthesis method of long-chain alkanedioic acid mono-tert-butyl ester and application thereof.

[0008] The present invention is achieved in that:

[0009] In a first aspect, the present invention provides a method for synthesizing long-chain alkanedioic acid mono-tert-butyl ester, comprising:

[0010] S1, using a long-chain alkanedioic acid as a starting material, reacting with an alcohol solvent and SOCl2 to obtain a long-chain diester;

[0011] S2, the long-chain diester is subjected to monohydrolysis with barium hydroxide to obtain a unilaterally hydrolyzed long-chain alkanoic acid monoester barium salt;

[0012] S3, the unsalted barium salt of the long-chain alkanoic acid monoester directly reacts with tert-butyl alcohol under trifluoroacetic anhydride conditions to generate a mixed ester;

[0013] S4, selectively hydrolyzing the monoester on the other side of the mixed ester in an alkaline solution to obtain the target product.

[0014] In an optional embodiment, the barium hydroxide is added dropwise to the long-chain diester in the form of a methanol solution of barium hydroxide;

[0015] Preferably, the mass ratio of barium hydroxide to methanol in the barium hydroxide methanol solution is 1:3-4;

[0016] Preferably, the dropping speed of the methanol solution of barium hydroxide is 30 to 50 kg / h;

[0017] Preferably, the molar ratio of the long-chain diester to the barium hydroxide is 1:0.7-0.9.

[0018] In an optional embodiment, the long-chain diester is first mixed with a base liquid as a reaction substrate solution, and then the methanol solution of barium hydroxide is added dropwise, and the reaction is carried out at 20 to 30° C. for 6 to 8 hours;

[0019] Preferably, the base liquid comprises water and methanol in a mass ratio of 1:5 to 15;

[0020] Preferably, the mass ratio of the long-chain diester to the base liquid is 1:9-12.

[0021] In an optional embodiment, after the long-chain diester and the barium hydroxide undergo a monohydrolysis reaction, the process further includes filtering, collecting the filter cake, slurrying the filter cake with a mixed solvent of 4-6 times n-heptane and MTBE, then suction filtering and collecting the filter cake again, and drying;

[0022] Preferably, the mass ratio of the n-heptane to the MTBE is 3-5:1.

[0023] In an optional embodiment, the step of directly reacting the undissolved barium salt of the long-chain alkanoic acid monoester with tert-butyl alcohol under trifluoroacetic anhydride conditions comprises:

[0024] Stirring the long-chain alkanoic acid monoester barium salt and tetrahydrofuran for 4-6 minutes, adding part of the trifluoroacetic anhydride dropwise, stirring for 20-40 minutes after the addition is complete, adding the tert-butyl alcohol, reacting at room temperature for 3-4 hours, adding the remaining trifluoroacetic anhydride, and continuing the reaction at room temperature for 2-3 hours;

[0025] Preferably, the equivalent ratio of the long-chain alkanoic acid monoester barium salt, part of the trifluoroacetic anhydride and the remaining trifluoroacetic anhydride is 1:2.4-3.6:1.2-1.8;

[0026] Preferably, the mass ratio of the long-chain alkanoic acid monoester barium salt to the tert-butyl alcohol is 1:0.6-0.9;

[0027] In an optional embodiment, after the reaction of the long-chain alkanoic acid monoester barium salt and the tert-butanol is completed, the process further comprises stirring and washing with a 4-6% sodium bicarbonate aqueous solution, extracting twice with 4-6 times methyl tert-ether, combining the organic phases, and washing with a saturated sodium bicarbonate aqueous solution; collecting the organic phases, drying the alkaline solution organic phase with anhydrous magnesium sulfate, filtering, and concentrating at 50° C. until there is no fraction to obtain a white solid, which is the mixed ester.

[0028] In an optional embodiment, the step of selectively hydrolyzing the monoester on the other side of the mixed ester under alkaline solution comprises: mixing the mixed ester with methanol, adding the alkaline solution dropwise, reacting for 4-5 hours, then adding 2-4 times of water to the system, adjusting the pH to 3-4 with hydrochloric acid, stirring for 8-12 minutes, then extracting, combining the organic phases, washing, drying, filtering and concentrating the organic phases;

[0029] Preferably, the alkaline solution includes sodium hydroxide or barium hydroxide, and the equivalent ratio of the mixed ester to the sodium hydroxide is 1:0.8-1.5, and the equivalent ratio of the mixed ester to the barium hydroxide is 1:0.5-1.2.

[0030] In an optional embodiment, the reaction of the long-chain alkanedioic acid, the alcohol solvent and the SOCl2 comprises:

[0031] The long-chain alkanedioic acid and the alcohol solvent were stirred at room temperature for 10-30 min, and then the SOCl2 was added dropwise, and the reaction was monitored by TLC until the end point;

[0032] Preferably, the mass ratio of the long-chain alkanedioic acid, the alcohol solvent and the SOCl2 is 1:4-5:0.3-0.5;

[0033] Preferably, the long-chain alkanedioic acid is a C16-C22 long-chain alkanedioic acid;

[0034] Preferably, the alcohol solvent comprises methanol or ethanol.

[0035] In an optional embodiment, after the reaction of the long-chain alkanedioic acid, the alcohol solvent and the SOCl2, the reaction system is further included being cooled to 8-12°C, filtered, and the filter cake is washed with water; the filter cake is collected, a 4-6% aqueous sodium bicarbonate solution is slowly added to the filter cake, and stirred for 20-40 minutes; filtered, the filter cake is rinsed with water, the filter cake is collected, and dried at 50-60°C for 12 hours.

[0036] In a second aspect, the present invention provides the use of long-chain alkanedioic acid mono-tert-butyl ester prepared by the synthesis method of long-chain alkanedioic acid mono-tert-butyl ester as described in any of the aforementioned embodiments in the preparation of plastic adjuvants, lubricants, fluorescent agents, pigments or long-acting polypeptide drugs.

[0037] The present invention has the following beneficial effects:

[0038] The synthesis method of long-chain alkane dioic acid mono-tert-butyl ester provided by the present invention uses long-chain alkane dioic acid as a starting material, reacts with an alcohol solvent and SOCl2 to obtain a long-chain diester; then, barium hydroxide is used to selectively hydrolyze one side of the long-chain diester to obtain a long-chain alkane acid monoester barium salt. In the process of obtaining the long-chain alkane acid monoester barium salt, the long-chain alkane acid monoester barium salt is precipitated from the reaction system as a precipitate, and the reaction is terminated, so that no further hydrolysis is performed to generate a diacid. In the present invention, the long-chain alkane acid monoester barium salt is directly reacted with tert-butyl alcohol under trifluoroacetic anhydride conditions without being desalted to generate a mixed ester; generally, carboxyl salts cannot be used to directly form esters, and need to be dissociated into free acids before being salified; but when the long-chain alkane acid monoester barium salt is free, the ester on the other side will be hydrolyzed to generate a diacid. Regardless of whether hydrochloric acid, acetic acid, or formic acid is used for dissociation, hydrolysis occurs, and the hydrolyzed diacid generates impurities such as di-tert-butyl ester and diacid in subsequent steps. Therefore, the present invention directly uses the long-chain alkanoic acid monoester barium salt for esterification under specific conditions (trifluoroacetic anhydride), which not only shortens the production cycle, but also avoids the monoester hydrolysis problem caused by the dissociation of the salt. Finally, the mixed ester is selectively hydrolyzed on the other side of the monoester in an alkaline solution to obtain the target product. The synthesis method of the long-chain alkane dioic acid mono-tert-butyl ester provided by the present invention has controllable quality and is easy to operate. The target product long-chain alkane dioic acid mono-tert-butyl ester with high yield and high quality can be obtained, and the related impurities are easy to control, and the operation is simple and convenient, with high safety, and can be suitable for mass production. DETAILED DESCRIPTION

[0039] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0040] The present invention provides a method for synthesizing long-chain alkanedioic acid mono-tert-butyl ester, which comprises:

[0041] The long-chain alkane dioic acid is used as a starting material, reacted with an alcohol solvent and SOCl2 to obtain a long-chain diester; the long-chain diester is monohydrolyzed with barium hydroxide to obtain a long-chain alkanoic acid monoester barium salt after unilateral hydrolysis; the unhydrolyzed long-chain alkanoic acid monoester barium salt is directly reacted with tert-butyl alcohol under trifluoroacetic anhydride conditions to generate a mixed ester; the mixed ester is selectively hydrolyzed in an alkaline solution to obtain the target product.

[0042] Its synthetic formula is as follows:

[0043]

[0044] In the present invention, barium hydroxide is used to selectively hydrolyze one side of the long-chain diester. The mechanism of the selective hydrolysis is to precipitate the precipitate (barium salt of long-chain alkanoic acid monoester) generated by the reaction from the reaction system to terminate the reaction, so that the hydrolysis to generate the diacid is not continued. Further, the long-chain alkanoic acid monoester barium salt is directly used for esterification in the present invention. However, under normal circumstances, the carboxyl salt cannot be directly used for esterification, and needs to be dissociated into free acid before salting; but when the long-chain alkanoic acid monoester barium salt provided by the present invention is free, the methyl (or ethyl) ester on the other side will be hydrolyzed to generate the diacid. Regardless of whether hydrochloric acid, acetic acid, or formic acid is used for dissociation, there is a hydrolysis phenomenon. The hydrolyzed diacid produces impurities such as di-tert-butyl ester and diacid in the subsequent steps. Therefore, in the present invention, the long-chain alkanoic acid monoester barium salt is directly used for esterification, which not only shortens the production cycle, but also avoids the monoester hydrolysis problem caused by the dissociation of the salt. Subsequently, the mixed ester is selectively hydrolyzed. The entire synthesis process has few side reactions, related impurities are easy to control, and the operation is simple and safe, which is suitable for mass production.

[0045] Specifically, the present invention provides a method for synthesizing long-chain alkanedioic acid mono-tert-butyl ester comprising the following steps:

[0046] S1. Using long-chain alkanedioic acid as the starting material, reacting with an alcohol solvent and SOCl2 to obtain a long-chain diester.

[0047] Specifically, a long-chain alkanedioic acid and an alcohol solvent are stirred at room temperature for 10-30 minutes, and then SOCl2 is added dropwise, and the reaction is monitored by TLC until the end point; the reaction system is cooled to 8-12°C, filtered, and the filter cake is washed with water; the filter cake is collected, and a 4-6% aqueous sodium bicarbonate solution is slowly added to the filter cake, and stirred for 20-40 minutes; the filter is filtered, the filter cake is rinsed with water, the filter cake is collected, and dried at 50-60°C for 12 hours.

[0048] The mass ratio of the long-chain alkanedioic acid, the alcohol solvent and SOCl2 is 1:4-5:0.3-0.5; preferably, the long-chain alkanedioic acid is a C16-C22 long-chain alkanedioic acid, for example, C16, C18, C20, C22. Preferably, the alcohol solvent includes methanol or ethanol.

[0049] S2. The long-chain diester is subjected to monohydrolysis with barium hydroxide to obtain a unilaterally hydrolyzed long-chain alkanoic acid monoester barium salt.

[0050] In the present invention, the precipitate (barium salt of long-chain alkanoic acid monoester) generated by the reaction of long-chain diester and barium hydroxide is precipitated from the reaction system to terminate the reaction, thereby not continuing to hydrolyze to generate diacid. The above reaction is achieved through the dynamic equilibrium of the reaction, rather than through the strength of the alkalinity.

[0051] The reaction mechanism of step S2 is:

[0052]

[0053] Therefore, the amount of barium hydroxide used, the method of adding materials, etc. will also have a great impact on the reaction process. Further, the selection of the type and amount of solvent for the reaction is very difficult and needs to be determined through a series of experiments.

[0054] Specifically, when barium hydroxide is hydrolyzed, if solid alkali is directly added, the local alkali concentration will be too high during the hydrolysis, and it will be difficult to control the degree of hydrolysis, and it is easy to over-hydrolyze. Therefore, in the present invention, methanol is used to first dissolve the barium hydroxide to prepare a methanol solution of barium hydroxide, and then the solution is added to the reaction system by dropwise addition to avoid excessive local alkali concentration and excessive hydrolysis, making it easier to control the reaction process.

[0055] The mass ratio of barium hydroxide to methanol in the barium hydroxide methanol solution is 1:3-4; preferably, the dropping speed of the barium hydroxide methanol solution is 30-50 kg / h; and the molar ratio of the long-chain diester to the barium hydroxide is 1:0.7-0.9.

[0056] This step not only requires that the barium hydroxide be dissolved before adding the material, but also that a certain amount of water be added in advance to the reaction system to ensure that the barium hydroxide added dropwise into the reaction system will not precipitate out of the system due to the salting-out effect, which ultimately leads to a slow reaction process or even incomplete reaction. Therefore, in the present invention, the long-chain diester is first mixed with the base liquid as a reaction substrate solution, and then a methanol solution of barium hydroxide is added dropwise, and the reaction is carried out at 20 to 30°C for 6 to 8 hours; wherein the base liquid includes water and methanol in a mass ratio of 1:5 to 15; preferably, the ratio of water to methanol is 1:6 to 10, and the mass ratio of the long-chain diester to the base liquid is 1:10 to 12.

[0057] Among them, when the proportion of methanol in the base liquid is too small (for example, water: methanol = 1:5), the reaction is faster and a small amount of diacid will be produced. When the proportion of methanol is too large (for example, water: methanol = 1:15), the reaction is slow and the reaction time is too long, which will also lead to the production of a small amount of diacid.

[0058] After the long-chain diester and barium hydroxide undergo a monohydrolysis reaction, the process further includes filtering, collecting the filter cake, slurrying the filter cake with a mixed solvent of 4-6 times normal heptane and MTBE, then filtering and collecting the filter cake again, and drying; preferably, the mass ratio of normal heptane to MTBE is 3-5:1.

[0059] S3. The undissolved barium salt of the long-chain alkanoic acid monoester directly reacts with tert-butyl alcohol under trifluoroacetic anhydride conditions to generate a mixed ester.

[0060] Since desalting not only increases the production process and production cycle, but also produces 4% to 15% of diacid, thereby increasing the possibility of impurities in subsequent steps, the present invention ultimately chooses to directly react barium salt with tert-butyl alcohol to produce tert-butyl ester.

[0061] Specifically, stir the long-chain alkanoic acid monoester barium salt with tetrahydrofuran for 4-6 minutes, add part of trifluoroacetic anhydride dropwise, stir for 20-40 minutes after the addition is completed, add tert-butyl alcohol, react at room temperature for 3-4 hours, add the remaining trifluoroacetic anhydride, and continue to react at room temperature for 2-3 hours. In the present invention, by adding trifluoroacetic anhydride twice, it can be ensured that the reaction is complete and there is no residual raw material. The trifluoroacetic anhydride provided by the present invention can make the long-chain alkanoic acid monoester barium salt react with tert-butyl alcohol without desalting, while under normal circumstances, the long-chain alkanoic acid monoester barium salt cannot directly form an ester, and needs to be dissociated into free acid before salting; but when the monomethyl (or ethyl) ester barium salt is free, the other side of the methyl (or ethyl) ester will be hydrolyzed to generate a diacid. Regardless of whether hydrochloric acid, acetic acid, or formic acid is used for desalination, there is a hydrolysis phenomenon, and the hydrolyzed diacid produces impurities such as di-tert-butyl ester and diacid in the subsequent steps. Its mechanism is as follows:

[0062]

[0063] The reaction conditions for the monoacid after being freed and then reacted with the tert-butyl ester are usually EDCI, (Boc)2O / DMAP, methanesulfonic acid, SOCl2, etc. It is found in experiments that under these conditions, the long-chain alkanoic acid monoester barium salt tert-butyl alcohol cannot react normally, or even if the reaction occurs, a large amount of raw materials are not completely reacted. The reason is that the trifluoroacetic anhydride of the present invention can directly desalt the barium salt and free it after adding it to the system, and then the mono-tert-butyl ester is added to the tert-butyl alcohol, and then the trifluoroacetic anhydride is added twice to make the reaction more thorough.

[0064]

[0065] Therefore, in this step, the barium salt is directly used for esterification, which not only shortens the production cycle, but also avoids the problem of monomethyl (or ethyl) ester hydrolysis caused by the dissociation salt.

[0066]

[0067] The equivalent ratio of the long-chain alkanoic acid monoester barium salt, part of trifluoroacetic anhydride and the remaining trifluoroacetic anhydride is 1:2.4-3.6:1.2-1.8; the mass ratio of the long-chain alkanoic acid monoester barium salt and tert-butyl alcohol is 1:0.6-0.9.

[0068] After the reaction of the long-chain alkanoic acid monoester barium salt and tert-butyl alcohol is completed, the method further comprises the steps of stirring and washing with a 4-6% sodium bicarbonate aqueous solution, extracting twice with 4-6 times methyl tert-ether, combining the organic phases, and washing with a saturated sodium bicarbonate aqueous solution; collecting the organic phases, drying the organic phases with anhydrous magnesium sulfate, filtering the organic phases, and concentrating at 50° C. until there is no fraction, to obtain a white solid, which is the mixed ester.

[0069] S4. The mixed ester is selectively hydrolyzed in an alkaline solution to obtain the monoester on the other side to obtain the target product.

[0070] Specifically, the mixed ester is mixed with methanol, an alkaline solution is added dropwise, the reaction is carried out for 4-5 hours, then 2-4 times of water is added to the system, the pH is adjusted to 3-4 with hydrochloric acid, stirred for 8-12 minutes, then extracted, the organic phases are combined, and the organic phases are washed, dried, filtered and concentrated; preferably, the alkaline solution includes sodium hydroxide or barium hydroxide, the equivalent ratio of the mixed ester to sodium hydroxide is 1:0.8-1.5, and the equivalent ratio of the mixed ester to barium hydroxide is 1:0.5-1.2.

[0071] Among them: the selectivity of Ba(OH)2 hydrolysis is mainly to first use its alkalinity to hydrolyze the methyl (or ethyl) ester, and the obtained mono-tert-butyl ester will form a salt with the barium ion and precipitate from the reaction system, thereby terminating further hydrolysis and obtaining the target product.

[0072] The selectivity of NaOH hydrolysis mainly depends on controlling its dosage, taking advantage of the easy hydrolysis of methyl (or ethyl) ester to make it consume sodium hydroxide first, and further controlling the reaction temperature to prevent the tert-butyl end from being hydrolyzed.

[0073] In addition, the present invention provides the use of long-chain alkanedioic acid mono-tert-butyl ester prepared by the above-mentioned synthesis method of long-chain alkanedioic acid mono-tert-butyl ester in the preparation of plastic adjuvants, lubricants, fluorescent agents, pigments or long-acting polypeptide drugs.

[0074] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.

[0075] Example 1

[0076] This embodiment provides a method for synthesizing hexadecanedioic acid mono-tert-butyl ester, which comprises the following steps:

[0077] S1. Add 100g of hexadecanedioic acid and 500g of methanol to a 2L three-necked flask; stir at room temperature for 0.5h; drop 49.84g of SOCl2 into the reaction system; monitor the reaction to the end point by TLC. Cool the system to 10°C, filter, and wash the filter cake with a small amount of water; collect the filter cake, slowly add 500g of 5% sodium bicarbonate aqueous solution to the filter cake, and stir for 0.5h; filter, rinse the filter cake with water, collect the filter cake, and dry it at 50-60°C for 12h; obtain dimethyl hexadecanedioate, weighing 106g, with HPLC purity of 99.1%;

[0078] S2. Add 105g of dimethyl hexadecanedioate, 682.5g of methanol and 105g of water to a 3L three-necked flask and stir for 30min; then dropwise add a methanol solution of barium hydroxide octahydrate (79g of barium hydroxide octahydrate dissolved in 3.4 times MeOH 268.6g); react at 20-30°C for 8h; monitor the reaction by TLC until it is complete; filter and collect the filter cake, and beat the filter cake with 5 times of mixed solvent (n-heptane: MTBE = 4:1) for 1h; filter and collect the filter cake, and dry it at 40-50°C for 12h to obtain barium salt of monomethyl hexadecanedioate, weighing 120g;

[0079] S3, add 610g tetrahydrofuran, 120g barium salt of hexadecanedioic acid monomethyl ester to a 5L reaction bottle, stir for 5min; add 172.7g trifluoroacetic anhydride (3.0eq), stir for 30min after the addition, add 99.5g tert-butyl alcohol; react for 4h at RT, add 86.4g trifluoroacetic anhydride, react for 3h at RT; stir and wash with 5% sodium bicarbonate aqueous solution; extract twice with 5 times methyl tert-ether, combine the organic phases, wash once with saturated sodium bicarbonate aqueous solution; collect the organic phase, dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate at 50°C until there is no fraction to obtain a white solid, which is hexadecanedioic acid monomethyl ester monotert-butyl ester, weighing: 91.5g;

[0080] S4. Add 450g methanol and 90g monomethyl hexadecanedioate monotert-butyl ester to the reaction bottle; stir, heat to 55°C, add dropwise an aqueous solution of barium hydroxide (71.6g barium hydroxide dissolved in 2 times water); react for 4h; add 3 times water to the system, adjust pH to 3-4 with 4N hydrochloric acid, and stir for 10min; add 5 times EA to extract twice, combine the organic phases, and then wash with 5 times saturated brine, dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate the filtrate at 40-50°C to obtain a white solid, which is the crude product of mono-tert-butyl octadecane dioate; the crude product is purified by crystallization with n-heptane and ethanol to obtain the finished product of mono-tert-butyl hexadecanedioate, with a purity of 99.3% detected by HPLC, and weighing: 71g.

[0081] Example 2

[0082] This embodiment provides a method for synthesizing octadecane dioic acid mono-tert-butyl ester, which comprises the following steps:

[0083] S1. Add 100g of octadecane dioic acid and 500g of methanol to a 2L three-necked flask; stir at room temperature for 10-30min; drop 45.39g of SOCl2 into the reaction system; monitor the reaction to the end point by TLC. Cool the system to 10°C, filter, and wash the filter cake with a small amount of water; collect the filter cake, slowly add 500g of 5% sodium bicarbonate aqueous solution to the filter cake, and stir for 30min; filter, rinse the filter cake with water, collect the filter cake, and dry it at 50-60°C for 12h; obtain dimethyl octadecane dioate, weighing 105g, with HPLC purity of 99.2%;

[0084] S2. Add 105g of dimethyl octadecane dioate, 682.5g of methanol and 105g of water to a 3L three-necked flask and stir for 30min; then drop a methanol solution of barium hydroxide octahydrate (72.53g of barium hydroxide octahydrate dissolved in 246.6g of 3.4 times MeOH); react at 20-30°C for 8h; perform TLC until the reaction is complete; filter and collect the filter cake, and beat the filter cake with 5 times of mixed solvent (n-heptane: MTBE = 4:1) for 1h; filter and collect the filter cake, dry it at 40-50°C for 12h, and dry it to obtain barium salt of monomethyl octadecane dioate, weighing 122g;

[0085] S3, add 610g tetrahydrofuran, 120g octadecane dioic acid monomethyl ester barium salt to a 5L reaction bottle, stir for 5min; add 162.3g trifluoroacetic anhydride (3.0eq) dropwise, and the mixture is complete; stir for 30min, add 93.2g tert-butyl alcohol; react for 4h at RT, add 81.1g trifluoroacetic anhydride, and react for 3h at RT; stir and wash with 5% sodium bicarbonate aqueous solution; extract twice with 5 times methyl tert-ether, combine the organic phases, and wash once with saturated sodium bicarbonate aqueous solution; collect the organic phases, dry the organic phases with anhydrous magnesium sulfate, filter, and concentrate at 50°C until there is no fraction to obtain a white solid, which is octadecane dioic acid monomethyl ester monotert-butyl ester, weighing: 90.5g;

[0086] S4. Add 450g methanol and 90g octadecane dioic acid monomethyl ester monotert-butyl ester to the reaction bottle, stir, heat to 55°C, add dropwise an aqueous solution of barium hydroxide (66.4g barium hydroxide dissolved in 2 times water); react for 4h, add 3 times water to the system, adjust pH to 3-4 with 4N hydrochloric acid, and stir for 10min; add 5 times EA to extract twice, combine the organic phases, and then wash with 5 times saturated brine, dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate the filtrate at 40-50°C to obtain a white solid, which is the crude product of octadecane dioic acid monotert-butyl ester; the crude product is purified by crystallization with n-heptane and ethanol to obtain the finished product of octadecane dioic acid monotert-butyl ester, the purity of which is 99.7% by HPLC, and the weight is 74g.

[0087] Example 3

[0088] This embodiment provides a method for synthesizing mono-tert-butyl eicosanedioate, which comprises the following steps:

[0089] S1. Add 100g of eicosanedioic acid and 500g of methanol to a 2L three-necked flask; stir at room temperature for 10-30min; drop 38.52g of SOCl2 into the reaction system (about 20min to complete the drop); monitor the reaction to the end point by TLC. Cool the system to 10°C, filter, and wash the filter cake with a small amount of water; collect the filter cake, slowly add 500g of 5% sodium bicarbonate aqueous solution to the filter cake, and stir for 30min; filter, rinse the filter cake with water, collect the filter cake, and dry it at 50-60°C for 12h; obtain dimethyl eicosanedioate, weighing 105g, with a HPLC purity of 99.3%;

[0090] S2. Add 105g of dimethyl eicosandioate, 682.5g of methanol and 105g of water to a 3L three-necked flask and stir for 30min; then drop a methanol solution of barium hydroxide octahydrate (67.1g of barium hydroxide octahydrate dissolved in 228.1g of 3.4 times MeOH); react at 20-30°C for 8h; perform TLC until the reaction is complete; filter and collect the filter cake, and beat the filter cake with 5 times of mixed solvent (n-heptane: MTBE = 4:1) for 1h; filter and collect the filter cake, and dry it at 40-50°C for 12h to obtain barium salt of monomethyl eicosandioate, weighing 119g;

[0091] S3, add 610g tetrahydrofuran, 119g barium salt of monomethyl eicosandioate to a 5L reaction bottle, stir for 5min; add 153.1g trifluoroacetic anhydride (3.0eq), stir for 30min after the addition, add 87.9g tert-butyl alcohol; react for 4h at RT, add 76.5g trifluoroacetic anhydride, react for 3h at RT; stir and wash with 5% sodium bicarbonate aqueous solution; extract twice with 5 times methyl tert-ether, combine the organic phases, wash once with saturated sodium bicarbonate aqueous solution; collect the organic phase, dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate at 50°C until there is no fraction to obtain a white solid, which is monomethyl hexadecanedioate monotert-butyl ester, weighing: 92g;

[0092] S4. Add 450g methanol and 90g monomethyl eicosanedioate monotert-butyl ester to the reaction bottle, stir, heat to 55°C, add dropwise an aqueous solution of barium hydroxide (61.8g barium hydroxide dissolved in 2 times water); react for 4h; add 3 times water to the system, adjust pH to 3-4 with 4N hydrochloric acid, and stir for 10min; add 5 times EA to extract twice, combine the organic phases, and then wash with 5 times saturated brine, dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate the filtrate at 40-50°C to obtain a white solid, that is, the crude product of mono-tert-butyl eicosanedioate; the crude product is purified by crystallization with n-heptane and ethanol to obtain the finished product of mono-tert-butyl eicosanedioate, the purity of which is 99.6% as detected by HPLC, and weighed: 75g.

[0093] Example 4

[0094] This embodiment provides a method for synthesizing mono-tert-butyl docosane diacid ester, which comprises the following steps:

[0095] S1. Add 100g of docosane dioic acid and 500g of methanol to a 2L three-necked flask; stir at room temperature for 30min; drop 38.52g of SOCl2 into the reaction system (about 20min to complete the drop); monitor the reaction to the end point by TLC. Cool the system to 10°C, filter, and wash the filter cake with a small amount of water; collect the filter cake, slowly add 500g of 5% sodium bicarbonate aqueous solution to the filter cake, and stir for 30min; filter, rinse the filter cake with water, collect the filter cake, and dry it at 50-60°C for 12h; obtain dimethyl docosane dioate, weighing 105g, with HPLC purity of 99.3%;

[0096] S2. Add 105g of dimethyl docosane dioate, 682.5g of methanol and 105g of water to a 3L three-necked flask and stir for 30min; then drop a methanol solution of barium hydroxide octahydrate (62.3g of barium hydroxide octahydrate dissolved in 3.4 times MeOH 211.8g); react at 20-30°C for 8h; perform TLC until the reaction is complete; filter and collect the filter cake, and beat the filter cake with 5 times of mixed solvent (n-heptane: MTBE = 4:1) for 1h; filter and collect the filter cake, and dry it at 40-50°C for 12h to obtain barium salt of monomethyl docosane dioate, weighing 121g;

[0097] S3, add 610g tetrahydrofuran, 120g barium salt of monomethyl docosane dioate to a 5L reaction bottle, stir for 5min; add 144.9g trifluoroacetic anhydride (3.0eq), stir for 30min after the addition, add 83.1g tert-butyl alcohol; react for 4h at RT, add 72.4g trifluoroacetic anhydride, react for 3h at RT; stir and wash with 5% aqueous sodium bicarbonate solution; extract twice with 5 times methyl tert-ether, combine the organic phases, wash once with saturated aqueous sodium bicarbonate solution; collect the organic phase, dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate at 50°C until there is no fraction to obtain a white solid, which is monomethyl hexadecanedioate monotert-butyl ester, weighing: 90g;

[0098] S4. Add 450g methanol and 90g monomethyl tert-butyl docosane dioate to the reaction bottle, stir, heat to 55°C, add dropwise an aqueous solution of barium hydroxide (57.9g barium hydroxide dissolved in 135g 2 times water), and react for 4h; add 3 times water to the system, adjust the pH to 3-4 with 4N hydrochloric acid, and stir for 10min; add 5 times EA to extract twice, combine the organic phases, and then wash with 5 times saturated brine, dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate the filtrate at 40-50°C to obtain a white solid, i.e., crude mono-tert-butyl docosane dioate; the crude product is purified by crystallization with n-heptane and ethanol to obtain the finished mono-tert-butyl docosane dioate, the purity of which is 99.4% by HPLC, and weighs 73g.

[0099] Example 5

[0100] This embodiment is basically the same as Embodiment 2, except that step S4 is different:

[0101] Add 270g tetrahydrofuran and 90g octadecane dioic acid monomethyl ester monotert-butyl ester to the reaction bottle, stir, add sodium hydroxide aqueous solution (11.7g sodium hydroxide dissolved in 2 times water 23.4g), heat to 55°C, and react for 4h; add 3 times water to the system, adjust pH to 3-4 with 4N hydrochloric acid, and stir for 10min; add 5 times EA to extract twice, combine the organic phases, wash twice with 5% sodium bicarbonate, and then wash with 5 times saturated brine, dry the organic phase with anhydrous magnesium sulfate, filter: collect the filtrate, concentrate the filtrate at 40-50°C to obtain a white solid, which is the crude product of octadecane dioic acid monotert-butyl ester; the crude product is purified by crystallization with n-heptane and ethanol to obtain the finished product of octadecane dioic acid monotert-butyl ester, the purity of which is 99.6% by HPLC, and weighing: 74g.

[0102] Example 6

[0103] This embodiment provides a method for synthesizing hexadecanedioic acid mono-tert-butyl ester, which comprises the following steps:

[0104] S1. Add 100g of hexadecanedioic acid and 500g of methanol to a 2L three-necked flask; stir at room temperature for 10-30min; drop 49.84g of SOCl2 into the reaction system; monitor the reaction to the end point by TLC. Cool the system to 10°C, filter, and wash the filter cake with a small amount of water; collect the filter cake, slowly add 500g of 5% sodium bicarbonate aqueous solution to the filter cake, and stir for 30min; filter, rinse the filter cake with water, collect the filter cake, and dry it at 50-60°C for 12h; obtain dimethyl hexadecanedioate, weighing 106g, with HPLC purity of 99.1%;

[0105] S2. Add 105g of dimethyl hexadecanedioate, 1000g of methanol and 100g of water to a 3L three-necked flask and stir for 30min; then dropwise add a methanol solution of barium hydroxide octahydrate (79g of barium hydroxide octahydrate dissolved in 237g of 3 times MeOH); react at 20-30°C for 13h; monitor the reaction by TLC until it is complete; filter and collect the filter cake, and beat the filter cake with 5 times of mixed solvent (n-heptane: MTBE = 4:1) for 1h; filter and collect the filter cake, and dry it at 40-50°C for 12h to obtain barium salt of monomethyl hexadecanedioate, weighing 120g;

[0106] S3, add 610g tetrahydrofuran, 120g barium salt of hexadecanedioic acid monomethyl ester to a 5L reaction bottle, stir for 5min; add 135.0g trifluoroacetic anhydride (2.4eq), stir for 30min after the addition, add 95.3g tert-butyl alcohol; react for 3-4h at RT, add 101.26g trifluoroacetic anhydride (1.8eq), react for 3h at RT; stir and wash with 5% sodium bicarbonate aqueous solution; extract twice with 5 times methyl tert-ether, combine the organic phases, wash once with saturated sodium bicarbonate aqueous solution; collect the organic phase, dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate at 50°C until there is no fraction to obtain a white solid, which is hexadecanedioic acid monomethyl ester monotert-butyl ester, weighing: 91.5g;

[0107] S4. Add 450g methanol and 90g monomethyl hexadecanedioate monotert-butyl ester to the reaction bottle; stir, heat to 55°C, add dropwise an aqueous solution of barium hydroxide (71.6g barium hydroxide dissolved in 3 times water); react for 4h; add 3 times water to the system, adjust pH to 3-4 with 4N hydrochloric acid, and stir for 10min; add 5 times EA to extract twice, combine the organic phases, and then wash with 5 times saturated brine, dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate the filtrate at 40-50°C to obtain a white solid, which is the crude product of mono-tert-butyl octadecane dioate; the crude product is purified by crystallization with n-heptane and ethanol to obtain the finished product of mono-tert-butyl hexadecanedioate, with a purity of 99.4% detected by HPLC, and weighing: 70g.

[0108] Example 7

[0109] This embodiment provides a method for synthesizing hexadecanedioic acid mono-tert-butyl ester, which comprises the following steps:

[0110] S1. Add 100g of hexadecanedioic acid and 500g of methanol to a 2L three-necked flask; stir at room temperature for 10-30min; drop 49.84g of SOCl2 into the reaction system; monitor the reaction to the end point by TLC. Cool the system to 10°C, filter, and wash the filter cake with a small amount of water; collect the filter cake, slowly add 500g of 5% sodium bicarbonate aqueous solution to the filter cake, and stir for 30min; filter, rinse the filter cake with water, collect the filter cake, and dry it at 50-60°C for 12h; obtain dimethyl hexadecanedioate, weighing 106g, with HPLC purity of 99.1%;

[0111] S2. Add 105g of dimethyl hexadecanedioate, 1500g of methanol and 100g of water to a 3L three-necked flask and stir for 30min; then dropwise add a methanol solution of barium hydroxide octahydrate (79g of barium hydroxide octahydrate dissolved in 316g of 4 times MeOH); react at 20-30°C for 22h; monitor the reaction by TLC until it is complete; filter and collect the filter cake, and beat the filter cake with 5 times of mixed solvent (n-heptane: MTBE = 4:1) for 1h; filter and collect the filter cake, and dry it at 40-50°C for 12h to obtain barium salt of monomethyl hexadecanedioate, weighing 120g;

[0112] S3, add 610g tetrahydrofuran, 110g barium salt of hexadecanedioic acid monomethyl ester to a 5L reaction bottle, stir for 5min; add 202.53g trifluoroacetic anhydride (3.6eq), stir for 30min after the addition, add 95.3g tert-butyl alcohol; react for 3.5h at RT, add 67.51g trifluoroacetic anhydride (1.2eq), react for 3 hours at RT; stir and wash with 5% sodium bicarbonate aqueous solution; extract twice with 5 times methyl tert-ether, combine the organic phases, wash once with saturated sodium bicarbonate aqueous solution; collect the organic phase, dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate at 50°C until there is no fraction to obtain a white solid, which is hexadecanedioic acid monomethyl ester monotert-butyl ester, weighing: 84.3g;

[0113] S4. Add 450g methanol and 84g monomethyl hexadecanedioate monotert-butyl ester to the reaction bottle; stir, heat to 55°C, add dropwise an aqueous solution of barium hydroxide (66.6g barium hydroxide dissolved in 4 times water); react for 4 hours; add 3 times water to the system, adjust pH to 3-4 with 4N hydrochloric acid, and stir for 10 minutes; add 5 times EA to extract twice, combine the organic phases, and then wash with 5 times saturated brine, dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate the filtrate at 40-50°C to obtain a white solid, which is the crude product of mono-tert-butyl octadecane dioate; the crude product is purified by crystallization with n-heptane and ethanol to obtain the finished product of mono-tert-butyl hexadecanedioate, the purity of which is 99.3% by HPLC, and weighing: 63.3g.

[0114] Comparative Example 1

[0115] This comparative example is substantially the same as Example 1, except that in step S2 of this comparative example, barium hydroxide is directly added in a solid form all at once.

[0116] Comparative Example 2

[0117] This comparative example is substantially the same as Example 1, except that in step S2 of this comparative example, barium hydroxide is directly added in batches as a solid.

[0118] Comparative Example 3

[0119] This comparative example is substantially the same as Example 1, except that the barium hydroxide in step S2 is replaced by other medium-strong inorganic base (calcium hydroxide) in this comparative example.

[0120] Comparative Example 4

[0121] This comparative example is basically the same as Example 2, except that step S3 is different. In this comparative example, DMAP and (Boc)2O are used as solvents, specifically comprising:

[0122] Add 976.0 g of tert-butanol, 120.0 g of octadecane dioic acid monomethyl ester, 2.55 g of (Boc)2O2, and finally 86.4 g of DMAP to the reactor; stir the reaction at room temperature for 2 h, and adjust the pH to 3 with 4N hydrochloric acid; add 366.0 g of dichloromethane to extract the finished product, wash it twice with 20% brine, dry it with anhydrous sodium sulfate, filter it, and concentrate the filtrate at 45-50° C. to obtain a solid, which is octadecane dioic acid monomethyl ester mono-tert-butyl ester, weighing 89 g.

[0123] Comparative Example 5

[0124] This comparative example is basically the same as Example 2, except that step S3 is different. In this comparative example, DMAP and (Boc)2O are used as solvents, specifically comprising:

[0125] To the reaction kettle, 976.0 g of tert-butanol, 142.0 g of octadecane dioic acid monomethyl ester barium salt, 22.55 g of (Boc)2O, and finally 86.4 g of DMAP were added; the reaction was stirred at room temperature for 6 h, and no target product was generated according to TLC monitoring.

[0126] Experimental Example 1

[0127] The above examples and comparative examples were tested by TLC+HPLC. When the proportion of mono-tert-butyl ester was ≥95%, the selectivity was considered good, and when the proportion of mono-tert-butyl ester was <95%, the selectivity was considered poor. When the diacid after hydrolysis was ≤5%, the impurities were considered to be small, and when the diacid after hydrolysis was >5%, the impurities were considered to be large. The test results are as follows:

[0128]

[0129] From the data comparison of Example 1 and Comparative Examples 1-2 in the above table, it can be seen that the alkali used in step S2 has a poor effect regardless of whether it is added all at once or in batches, and a large amount of diacid is produced; only the methanol solution of the alkali can be added dropwise, the reaction time is short, and the amount of diacid produced is small. At the same time, the use of other medium-strong inorganic bases in Comparative Example 3 will also result in a large amount of diacid produced by hydrolysis and poor selectivity; from the data comparison of Example 1 and Comparative Examples 4 and 5, it can be seen that in the (Boc)2O and DMAP system in step S3, the free acid can react normally. Although the raw material reaction is relatively thorough, the color of the system is dark and there are many impurities. The removal of impurities and color greatly reduces the yield; the use of barium salts almost does not react.

[0130] Experimental Example 2: Examining the ratio of the base liquid (water and methanol) in step S2

[0131] This experimental example is carried out according to the operation of step S2 in Example 1, except that the ratio of the base solution (water and methanol) in step S2 is adjusted in this example, and then the hydrolysis conditions under different base solution ratios are detected, wherein the detection method of the diacid includes: TLC judgment. Please refer to the following table for specific adjustment and detection results:

[0132]

[0133] As can be seen from the above table, the ratio of water to methanol in the base liquid of the present invention is between 1:5-15, which can achieve good hydrolysis effect and produce less diacid, and the preferred range is 1:6-10. When the ratio of water to methanol is less than 1:5, excessive hydrolysis will occur and the yield of the product will be reduced. When the ratio of water to methanol is greater than 1:15, the reaction time will be prolonged, and diacid will also be produced due to the prolonged time.

[0134] Experimental Example 3 - Investigation of the situation before and after the desalination of the long-chain alkanoic acid monoester barium salt in step S3

[0135] (1) Investigate whether the monomethyl (or ethyl) ester will be hydrolyzed to produce diacid when the salt is first dissolved

[0136] The operation method includes: using the acids in the following table to desalt the long-chain alkanoic acid monoester barium salt to detect whether it produces diacids. The TLC ratio detection method includes: preparing a standard solution for comparison.

[0137] Acid used Whether diacid is produced TLC percentage Acetic acid (acetic acid) yes 4～6％ Formic acid yes 5～7％ 2mol / L HCl yes 10～15％ <![CDATA[1mol / L H2SO4]]> yes 10～15％

[0138] Since desalting not only increases the production process and production cycle, but also produces 4% to 15% of diacid, thereby increasing the possibility of impurities in subsequent steps, the present invention ultimately chooses to directly react barium salt with tert-butyl alcohol to produce tert-butyl ester.

[0139] (2) Investigation of the esterification reaction conditions of long-chain alkanoic acid monoester barium salt without desalination

[0140]

[0141] It can be seen from the above table that the long-chain alkanoic acid monoester barium salt can only react with tert-butanol to form an ester under the condition of TFAA when it is not desalted, while other conditions (EDCI, (Boc)2O+DMAP, methanesulfonic acid, SOCl2, etc.) cannot react or cannot react fully, which fully proves the importance of TFAA selection in the present invention.

[0142] (3) Investigation of the esterification reaction conditions of long-chain alkanoic acid monoester barium salt after desalting

[0143] The barium salt of a long-chain alkanoic acid monoester is desalted (the specific steps include: adding 600g of water to 120g of barium salt, stirring, controlling the temperature at 10-30°C, slowly adding acetic acid, adjusting the pH to 2-3, filtering, washing, crystallizing to remove the diacid, and drying to obtain the product); the free monomethyl ester obtained after desalting is crystallized and purified and then reacted with the tert-butyl ester.

[0144] Reaction conditions Whether to react Is the reaction complete? EDCI / tert-Butanol yes No, about 20% of raw materials remaining <![CDATA[(Boc)2O / DMAP / tert-butanol]]> yes yes Methanesulfonic acid / isobutylene yes yes <![CDATA[SOCl2 / tert-butanol]]> yes No, about 30% of raw materials remaining

[0145] It can be seen from the above table that when the long-chain alkanoic acid monoester barium salt is desalted, the above reaction conditions can achieve the reaction of the long-chain alkanoic acid monoester barium salt with tert-butanol. However, combined with the result table when the long-chain alkanoic acid monoester barium salt is not desalted, it can be seen that the TFAA selected in the present invention can achieve the esterification reaction between the long-chain alkanoic acid monoester barium salt and tert-butanol directly.

[0146] Experimental Example 4 - Selection of Alkaline Solution in Step S4

[0147] This experimental example is carried out according to the operation of step S4 in Example 1, except that the selection of the alkaline solution in step S4 is adjusted in this experimental example, and then the reaction conditions under different alkaline solutions are detected. For specific adjustment and detection results, please refer to the following table:

[0148]

[0149]

[0150] As can be seen from the above table, in the present invention, NaOH or Ba(OH)2·8H2O is preferably used as the alkaline solution, which can better promote the complete reaction of the raw materials, and at the same time can also reduce the generation of diacids, and the selectivity is better.

[0151] In summary, the synthesis method of long-chain alkane dioic acid mono-tert-butyl ester provided by the present invention uses long-chain alkane dioic acid as a starting material, reacts with an alcohol solvent and SOCl2 to obtain a long-chain diester; then, barium hydroxide is used to selectively hydrolyze one side of the long-chain diester to obtain a long-chain alkane acid monoester barium salt. In the process of obtaining the long-chain alkane acid monoester barium salt, the long-chain alkane acid monoester barium salt is precipitated from the reaction system as a precipitate, and the reaction is terminated, so that no further hydrolysis is performed to generate a diacid. In the present invention, the long-chain alkane acid monoester barium salt is directly reacted with tert-butyl alcohol under trifluoroacetic anhydride conditions without being desalted to generate a mixed ester; in general, carboxyl salts cannot be used to directly form esters, and need to be dissociated into free acids before being salified; but when the long-chain alkane acid monoester barium salt is free, the ester on the other side will be hydrolyzed to generate a diacid. Regardless of whether hydrochloric acid, acetic acid, or formic acid is used for dissociation, hydrolysis occurs, and the hydrolyzed diacid generates impurities such as di-tert-butyl ester and diacid in subsequent steps. Therefore, the present invention directly uses the long-chain alkanoic acid monoester barium salt for esterification under specific conditions (trifluoroacetic anhydride), which not only shortens the production cycle, but also avoids the monoester hydrolysis problem caused by the dissociation of the salt. Finally, the mixed ester is selectively hydrolyzed on the other side of the monoester in an alkaline solution to obtain the target product. The synthesis method of the long-chain alkane dioic acid mono-tert-butyl ester provided by the present invention has controllable quality and is easy to operate. The target product long-chain alkane dioic acid mono-tert-butyl ester with high yield and high quality can be obtained, and the related impurities are easy to control, and the operation is simple and convenient, with high safety, and can be suitable for mass production.

[0152] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing long-chain alkanedioic acid mono-tert-butyl ester, characterized in that: It includes: S1, using a long-chain alkanedioic acid as a starting material, reacting with an alcohol solvent and SOCl2 to obtain a long-chain diester; S2, the long-chain diester is subjected to monohydrolysis with barium hydroxide to obtain a unilaterally hydrolyzed long-chain alkanoic acid monoester barium salt; S3, the unsalted barium salt of the long-chain alkanoic acid monoester directly reacts with tert-butyl alcohol under trifluoroacetic anhydride conditions to generate a mixed ester; S4, selectively hydrolyzing the monoester on the other side of the mixed ester in an alkaline solution to obtain the target product.

2. The method for synthesizing long-chain alkanedioic acid mono-tert-butyl ester according to claim 1, characterized in that: The barium hydroxide is added dropwise to the long-chain diester in the form of a methanol solution of barium hydroxide; Preferably, the mass ratio of barium hydroxide to methanol in the barium hydroxide methanol solution is 1:3-4; Preferably, the dropping speed of the methanol solution of barium hydroxide is 30 to 50 kg / h; Preferably, the molar ratio of the long-chain diester to the barium hydroxide is 1:0.7-0.

9.

3. The method for synthesizing long-chain alkanedioic acid mono-tert-butyl ester according to claim 2, characterized in that: The long-chain diester is first mixed with the base liquid as a reaction substrate solution, and then the methanol solution of barium hydroxide is added dropwise, and the reaction is carried out at 20-30° C. for 6-8 hours; Preferably, the base liquid comprises water and methanol in a mass ratio of 1:5 to 15; Preferably, the mass ratio of the long-chain diester to the base liquid is 1:9-12.

4. The method for synthesizing long-chain alkanedioic acid mono-tert-butyl ester according to any one of claims 1 to 3, characterized in that: After the long-chain diester and the barium hydroxide undergo a monohydrolysis reaction, the process further includes filtering, collecting a filter cake, slurrying the filter cake with a mixed solvent of 4-6 times normal heptane and MTBE, then suction filtering and collecting the filter cake again, and drying; Preferably, the mass ratio of the n-heptane to the MTBE is 3-5:

1.

5. The method for synthesizing long-chain alkanedioic acid mono-tert-butyl ester according to claim 1, characterized in that: The step of directly reacting the undissolved barium salt of the long-chain alkanoic acid monoester with tert-butyl alcohol under the condition of trifluoroacetic anhydride comprises: Stirring the long-chain alkanoic acid monoester barium salt and tetrahydrofuran for 4-6 minutes, adding part of the trifluoroacetic anhydride dropwise, stirring for 20-40 minutes after the addition is complete, adding the tert-butyl alcohol, reacting at room temperature for 3-4 hours, adding the remaining trifluoroacetic anhydride, and continuing the reaction at room temperature for 2-3 hours; Preferably, the equivalent ratio of the long-chain alkanoic acid monoester barium salt, part of the trifluoroacetic anhydride and the remaining trifluoroacetic anhydride is 1:2.4-3.6:1.2-1.8; Preferably, the mass ratio of the long-chain alkanoic acid monoester barium salt to the tert-butyl alcohol is 1:0.6-0.

9.

6. The method for synthesizing long-chain alkanedioic acid mono-tert-butyl ester according to claim 5, characterized in that: After the reaction of the long-chain alkanoic acid monoester barium salt and the tert-butyl alcohol is completed, the method further comprises the steps of stirring and washing with a 4-6% sodium bicarbonate aqueous solution, extracting twice with 4-6 times methyl tert-ether, combining the organic phases, and washing with a saturated sodium bicarbonate aqueous solution; collecting the organic phases, drying the organic phases with anhydrous magnesium sulfate, filtering the organic phases, and concentrating at 50° C. until there is no fraction, to obtain a white solid, which is the mixed ester.

7. The method for synthesizing long-chain alkanedioic acid mono-tert-butyl ester according to claim 1, characterized in that: The step of selectively hydrolyzing the monoester on the other side of the mixed ester under alkaline solution comprises: mixing the mixed ester with methanol, adding the alkaline solution dropwise, reacting for 4-5 hours, then adding 2-4 times of water to the system, adjusting the pH to 3-4 with hydrochloric acid, stirring for 8-12 minutes, then extracting, combining the organic phases, washing, drying, filtering and concentrating the organic phases; Preferably, the alkaline solution includes sodium hydroxide or barium hydroxide, the equivalent ratio of the mixed ester to the sodium hydroxide is 1:0.8-1.5, and the equivalent ratio of the mixed ester to the barium hydroxide is 1:0.5-1.

2.

8. The method for synthesizing long-chain alkanedioic acid mono-tert-butyl ester according to claim 1, characterized in that: The reaction of the long-chain alkanedioic acid, the alcohol solvent and the SOCl2 comprises: The long-chain alkanedioic acid and the alcohol solvent were stirred at room temperature for 10-30 min, and then the SOCl2 was added dropwise, and the reaction was monitored by TLC until the end point; Preferably, the mass ratio of the long-chain alkanedioic acid, the alcohol solvent and the SOCl2 is 1:4-5:0.3-0.5; Preferably, the long-chain alkanedioic acid is a C16-C22 long-chain alkanedioic acid; Preferably, the alcohol solvent comprises methanol or ethanol.

9. The method for synthesizing long-chain alkanedioic acid mono-tert-butyl ester according to claim 8, characterized in that: After the reaction of the long-chain alkanedioic acid, the alcohol solvent and the SOCl2, the reaction system is cooled to 8-12°C, filtered, and the filter cake is washed with water; Collect the filter cake, slowly add 4-6% sodium bicarbonate aqueous solution to the filter cake, and stir for 20-40 minutes; filter, rinse the filter cake with water, collect the filter cake, and dry it at 50-60°C for 12 hours.

10. Use of long-chain alkanedioic acid mono-tert-butyl ester prepared by the synthesis method of long-chain alkanedioic acid mono-tert-butyl ester according to any one of claims 1 to 9 in the preparation of plastic adjuvants, lubricants, fluorescent agents, pigments or long-acting polypeptide drugs.

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