Preparation method of alkyl diacid mono-tert-butyl ester compound
By using immobilized lipase to catalyze the formation of monomethyl alkyl diacid from alkyl diacid, followed by hydrolysis under alkaline conditions to generate monotert-butyl alkyl diacid, the problems of long reaction routes, high costs, and difficult purification in existing technologies are solved, and an efficient and low-cost preparation method is achieved.
Patent Information
- Application Number
- CN202410965839.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-07-18
- Publication Date
- 2026-01-20
AI Technical Summary
Existing methods for preparing alkyl diacid monotert-butyl esters suffer from problems such as long reaction routes, high costs, low selectivity, and difficult post-processing.
The alkyl diacid reacted with methanol using the immobilized lipase Novozym 435 to produce a monomethyl ester, which then reacted with tert-butanol in the presence of a condensing agent and an activator to form an intermediate. The intermediate was then hydrolyzed under alkaline conditions to obtain alkyl diacid monotert-butyl ester.
It achieves a simple preparation process, short reaction route, low material cost, improved atom utilization and product purity, and simple post-processing, making it suitable for large-scale production.
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Abstract
Description
TECHNICAL FIELD
[0001] The application belongs to the technical field of drug synthesis, and particularly relates to a preparation method of an alkyl diacid mono-tert-butyl ester compound. BACKGROUND
[0002] The alkyl diacid mono-tert-butyl ester compound is an important organic compound, and its molecular structure comprises an alkyl diacid and a tert-butyl alcohol group. The compound has wide application and research value in the fields of industrial production and scientific research.
[0003] Among them, octadecanedioic acid mono-tert-butyl ester is one of the starting materials for synthesizing the side chain of the polypeptide drug semaglutide, and the quality thereof is crucial for synthesizing semaglutide. At present, the preparation method of octadecanedioic acid mono-tert-butyl ester mainly adopts chemical synthesis: (1) taking tetradecanedioic acid as a raw material, octadecanedioic acid mono-tert-butyl ester is synthesized through condensation, reduction, ring opening and single protection; (2) taking hexadecanedioic acid monobenzyl ester as a starting material, octadecanedioic acid mono-tert-butyl ester is synthesized through carbon chain extension and reduction deprotection.
[0004] However, if a material with less than 18 carbon chains is used as a starting material to synthesize octadecanedioic acid mono-tert-butyl ester, the reaction route is long, the cost is high, and the atom economy is low. If octadecanedioic acid is directly condensed, the reaction selectivity is low, and octadecanedioic acid bis-tert-butyl ester is inevitably generated, which is an unfavorable factor for scale-up production and increases the difficulty of post-treatment purification. SUMMARY
[0005] Therefore, the technical problem to be solved by the application is to provide a preparation method of an alkyl diacid mono-tert-butyl ester compound, which has a shorter route and higher product purity.
[0006] The application provides a preparation method of an alkyl diacid mono-tert-butyl ester compound, which comprises the following steps:
[0007] S1) reacting alkyl diacid and methanol under the catalysis of immobilized lipase Novozym 435 to obtain alkyl diacid monomethyl ester;
[0008] S2) reacting the alkyl diacid monomethyl ester with tert-butyl alcohol in the presence of a condensing agent and an activating agent to obtain an intermediate;
[0009] S3) hydrolyzing the intermediate under alkaline conditions to obtain an alkyl diacid mono-tert-butyl ester compound.
[0010] Preferably, the number of carbon atoms of the alkyl group in the alkyl diacid is 14-20.
[0011] The molar ratio of the alkyl diacid to methanol is 1:(1-1.2).
[0012] Preferably, the step S1) is carried out in an organic solvent; the polarity of the organic solvent is less than 4.3.
[0013] Preferably, the alkyl diacid is octadecanedioic acid;
[0014] The organic solvent is tetrahydrofuran.
[0015] Preferably, the mass of the immobilized lipase Novozym 435 is 5% to 20% of the mass of the alkyl diacid.
[0016] Preferably, the condensing agent is selected from one or more of dicyclohexyl carbodiimide, diisopropyl carbodiimide and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide;
[0017] The activating agent is selected from 4-N,N-dimethylpyridine and / or 1-hydroxybenzotriazole.
[0018] Preferably, the ratio of the alkyl diacid monomethyl ester to tert-butyl alcohol is 100 g:(5 to 15) L;
[0019] The molar ratio of the alkyl diacid monomethyl ester to the condensing agent is 1:(1 to 1.5);
[0020] The molar ratio of the alkyl diacid monomethyl ester to the activating agent is 1:(0.01 to 0.1).
[0021] Preferably, the temperature of the reaction in the step S1) is 36°C to 40°C; the reaction time is 5 to 6 hours;
[0022] The temperature of the reaction in the step S2) is 40°C to 60°C; the reaction time is 6 to 12 hours.
[0023] Preferably, the basic condition in the step S3) is provided by an aqueous solution of a basic compound; the basic compound is selected from one or more of lithium hydroxide, sodium carbonate and sodium hydroxide;
[0024] The molar ratio of the intermediate to the basic compound is 1:(1.5 to 2.5); the concentration of the aqueous solution of the basic compound is 0.5 to 1.5 mol / L.
[0025] Preferably, after the hydrolysis in the step S3) is completed, the reaction system is concentrated to 2 / 3 to 1 / 3 of the volume, dichloromethane is added for extraction, the organic phase is concentrated to 1 / 4 to 1 / 6 of the volume of dichloromethane, methyl tert-butyl ether is added for precipitation, and the alkyl diacid mono-tert-butyl ester compound is obtained
[0026] The application provides a preparation method of an alkyl diacid mono-tert-butyl ester compound, and comprises the following steps: S1) reacting alkyl diacid with methanol under the catalysis of immobilized lipase Novozym 435 to obtain alkyl diacid monomethyl ester; S2) reacting the alkyl diacid monomethyl ester with tert-butyl alcohol in the presence of a condensing agent and an activating agent to obtain an intermediate; and S3) hydrolyzing the intermediate under alkaline conditions to obtain the alkyl diacid mono-tert-butyl ester compound. Compared with the prior art, the alkyl diacid is used as a starting material, the carboxyl group at one end is protected by forming a methyl ester by using an enzyme catalyst, the selectivity problem of generating a tert-butyl ester at one end is avoided, the carboxyl group at the other end is converted into a tert-butyl ester by a condensation reaction, the methyl ester is selectively removed by using an alkaline environment due to the large steric hindrance of the tert-butyl ester, and the alkyl diacid mono-tert-butyl ester with high quality can be obtained by simple recrystallization, the preparation method has the advantages of simple preparation process, short reaction route, low material cost, few side reactions, improved atom utilization rate, improved raw material conversion rate and product purity, the intermediate products are all solid, the post-treatment and purification are simple, and the production can be easily scaled up. BRIEF DESCRIPTION OF DRAWINGS
[0027] Figure 1 A mass spectrum of the octadecanedioic acid mono-tert-butyl ester obtained in Example 1 of the application;
[0028] Figure 2 A liquid phase purity graph of the octadecanedioic acid mono-tert-butyl ester obtained in Example 2 of the application. DETAILED DESCRIPTION
[0029] The technical solutions in the embodiments of the application will be apparently and completely described in combination with the embodiments of the application, obviously, the described embodiments are only part of the embodiments of the application, rather than all the embodiments. Based on the embodiments in the application, all other embodiments obtained by those skilled in the art without creative labor fall within the protection scope of the application.
[0030] The application provides a preparation method of an alkyl diacid mono-tert-butyl ester compound, and comprises the following steps: S1) reacting alkyl diacid with methanol under the catalysis of immobilized lipase Novozym 435 to obtain alkyl diacid monomethyl ester; S2) reacting the alkyl diacid monomethyl ester with tert-butyl alcohol in the presence of a condensing agent and an activating agent to obtain an intermediate; and S3) hydrolyzing the intermediate under alkaline conditions to obtain the alkyl diacid mono-tert-butyl ester compound.
[0031] In the application, the sources of all raw materials are not specially limited and can be commercially available.
[0032] alkyl diacid is preferably 14-20, more preferably 16-18, and even more preferably 18; the molar ratio of the alkyl diacid to methanol is preferably 1:(1-1.2), more preferably 1:(1.1-1.2), and even more preferably 1:1.2; the immobilized lipase Novozym 435 is a lipase immobilized on acrylic resin, derived from a non-specific lipase of Candida antarctica, and in the present application, its mass is preferably 5%-20% of the mass of the alkyl diacid, more preferably 8%-15%, even more preferably 10%-12%, and most preferably 10%; the reaction is preferably carried out in an organic solvent; the polarity of the organic solvent is preferably less than 4.3; the organic solvent is preferably an ether organic solvent, and more preferably tetrahydrofuran; the ratio of the organic solvent to the alkyl diacid is preferably (0.5-1.5) L:100 g, more preferably (0.8-1.2) L:100 g, and even more preferably 1 L:100 g; the temperature of the reaction is preferably 36°C-40°C, and more preferably 38°C; the reaction time is preferably 5-6 h; in a specific embodiment provided in the present application, step S1) is specifically as follows: the alkyl diacid is mixed with an organic solvent, then methanol is added and stirred at room temperature, the immobilized lipase Novozym 435 is added, and the reaction is carried out by heating; after the reaction is completed, the alkyl diacid monomethyl ester is obtained by preferably filtering, concentrating, and recrystallizing; the recrystallization is preferably carried out using acetonitrile; and the ratio of the solvent used in the recrystallization to the alkyl diacid is preferably (1-1.5) L:100 g, and more preferably 1.2 L:100 g.
[0033] The alkyl diacid monomethyl ester is reacted with tert-butyl alcohol in the presence of a condensing agent and an activating agent to obtain an intermediate; the ratio of the alkyl diacid monomethyl ester to tert-butyl alcohol is preferably 100 g:(0.5-1.5) L, more preferably 100 g:(0.8-1.2) L, and even more preferably 100 g:1 L; the condensing agent is preferably one or more of dicyclohexyl carbodiimide (DCC), diisopropyl carbodiimide (DIC), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI); the molar ratio of the alkyl diacid monomethyl ester to the condensing agent is preferably 1:(1-1.5), more preferably 1:(1.1-1.2); the activating agent is preferably 4-N,N-dimethylpyridine (DMAP) and / or 1-hydroxybenzotriazole (HOBT); the molar ratio of the alkyl diacid monomethyl ester to the activating agent is preferably 1:(0.01-0.1), more preferably 1:(0.03-0.08), even more preferably 1:(0.04-0.06), and most preferably 1:0.05; the reaction temperature is preferably 40-60°C; the reaction time is preferably 6-12 h; after the reaction is completed, the reaction mixture is preferably cooled to room temperature, filtered, concentrated, recrystallized, and the intermediate is obtained; the recrystallization is preferably performed using isopropyl alcohol; the ratio of the solvent used in the recrystallization to the alkyl diacid monomethyl ester is preferably (0.5-1.5) L:100 g, more preferably (0.8-1.2) L:100 g, and even more preferably 1 L:100 g.
[0034] The intermediate is hydrolyzed under basic conditions; the basic conditions are preferably provided by an aqueous solution of a basic compound; the basic compound is preferably one or more of lithium hydroxide, sodium carbonate, and sodium hydroxide; the molar ratio of the intermediate to the basic compound is preferably 1:(1.5-2.5), more preferably 1:(1.8-2.2), and even more preferably 1:2; the concentration of the aqueous solution of the basic compound is preferably 0.5-1.5 mol / L, more preferably 0.8-1.2 mol / L, and even more preferably 1 mol / L; in one specific embodiment provided by the present application, the intermediate is preferably mixed with an organic solvent before the aqueous solution of the basic compound is added; the organic solvent can be any organic solvent known to those skilled in the art without any particular limitation, and is preferably acetonitrile in the present application; the ratio of the intermediate to the organic solvent is preferably 100 g:(0.1-1) L, more preferably 100 g:(0.3-0.8) L, even more preferably 100 g:(0.4-0.6) L, and most preferably 100 g:0.5 L; the hydrolysis is preferably performed at room temperature; the hydrolysis time is preferably 3-4 h.
[0035] After the hydrolysis, the reaction system is preferably concentrated to 2 / 3-1 / 3 of the volume, dichloromethane is added for extraction, the organic phase is concentrated to 1 / 4-1 / 6 of the volume of dichloromethane, and then methyl tert-butyl ether is added for precipitation to obtain the alkyl diacid mono-tert-butyl ester compound; more preferably, the reaction system is concentrated to 1 / 2 of the volume, dichloromethane is added for extraction, the organic phase is concentrated to 1 / 5 of the volume of dichloromethane, and then methyl tert-butyl ether is added for precipitation to obtain the alkyl diacid mono-tert-butyl ester compound; the ratio of dichloromethane to the intermediate is preferably (0.5-1.5) L: 100 g, more preferably (0.8-1.2) L: 100 g, and more preferably 1 L: 100 g; the ratio of methyl tert-butyl ether to the intermediate is preferably (0.5-1) L: 100 g, more preferably (0.6-0.9) L: 100 g, and more preferably 0.8 L: 100 g; after the precipitation, filtration, washing, and drying are preferably performed to obtain the alkyl diacid mono-tert-butyl ester compound; the drying is preferably vacuum drying; and the temperature of the drying is preferably 40-60°C, more preferably 40-50°C, and more preferably 40°C.
[0036] In one specific embodiment provided in the present application, the alkyl diacid is octadecanedioic acid; and the alkyl diacid mono-tert-butyl ester compound is octadecanedioic acid mono-tert-butyl ester.
[0037] In one specific embodiment provided in the present application, the octadecanedioic acid mono-tert-butyl ester is prepared according to the following method: (1) first, compound A and tetrahydrofuran are mixed in a three-necked reaction flask, then methanol is added, the stirring speed is reduced, and then immobilized lipase Novozym 435, which is a nonspecific lipase derived from Candida antarctica and immobilized on acrylic resin, is added, then the temperature is increased to 38°C for reaction, the reaction system changes from turbidity to clarity, after the reaction of octadecanedioic acid is completed as determined by high-performance liquid chromatography, filtration, concentration, and recrystallization are performed to obtain solid compound B; (2) compound B and tert-butyl alcohol are mixed in a three-necked reaction flask, stirring is started at room temperature, DMAP and DCC are added in sequence, then the temperature is increased to 60°C, the reaction solution is detected by high-performance liquid chromatography, after the reaction of compound B is completed, the reaction system is cooled to room temperature, and then filtration, concentration, and recrystallization are performed to obtain solid compound C; and (3) compound C and acetonitrile are mixed in a reaction flask, aqueous lithium hydroxide solution is added, reaction is performed at room temperature, high-performance liquid chromatography is used to determine that the raw material compound has reacted completely, the reaction system is concentrated, extracted with dichloromethane, dried with anhydrous sodium sulfate, filtered, concentrated, and recrystallized to obtain compound D, octadecanedioic acid mono-tert-butyl ester.
[0038]
[0039] The alkyl diacid is used as a starting material, the carboxyl at one end is protected by forming a methyl ester by using an enzyme catalyst, the selectivity problem of forming a tert-butyl ester at one end is avoided, the carboxyl at the other end is formed into a tert-butyl ester by a condensation reaction, finally, the tert-butyl ester is not easy to be removed under alkaline conditions due to the large steric hindrance, the methyl ester can be selectively removed by using an alkaline environment, and high-quality alkyl diacid mono-tert-butyl ester can be obtained by simple recrystallization, the preparation method has the advantages of simple preparation process, short reaction route, low material cost, few side reactions, improved atom utilization, improved raw material conversion rate and product purity, and the intermediate products are all solid, the post-treatment and purification are simple, and the production can be easily scaled up.
[0040] In order to further illustrate the present application, the preparation method of the alkyl diacid mono-tert-butyl ester compound provided by the present application is described in detail below in combination with examples.
[0041] The reagents used in the following examples are commercially available.
[0042] Example 1
[0043] A synthesis method of octadecane diacid mono-tert-butyl ester comprises the following steps:
[0044] (1) Compound A 100 g (0.318 mol) and tetrahydrofuran 1 L (10V) are mixed in a three-necked reaction bottle, mechanical stirring is started, then methanol 12.2 g (0.382 mol) is added, stirring is carried out at room temperature, the stirring speed is reduced, immobilized lipase Novozym 435 is added, the mass of the immobilized lipase Novozym 435 is 10 g (10%), then the temperature is increased to 38 degrees Celsius for reaction, the reaction is carried out for 5-6 hours, the reaction system changes from turbidity to clarity, after the reaction of octadecane diacid is completed by high-performance liquid chromatography, filtration is carried out, concentration is carried out, recrystallization is carried out by using acetonitrile 1.2 L (12V), and solid compound B 99.2 g is obtained by filtration, the purity is 98.5%, and the yield is 95%.
[0045] (2) Compound B 99.2 g (0.302 mol) and tert-butyl alcohol 0.992 L (10V) are mixed in a three-necked reaction bottle, stirring is started at room temperature, DMAP 1.85 g (0.0151 mol) and DCC 74.3 g (0.36 mol) are added thereto in sequence, then the temperature is increased to 60 degrees Celsius, the reaction is carried out for 6-7 hours, the reaction liquid is detected by high-performance liquid chromatography, the peak of compound B disappears, after the reaction system is cooled to room temperature, filtration is carried out, the filtrate is concentrated, recrystallization is carried out by using isopropyl ether 0.992 L (10V), and solid compound C 111.5 g is obtained by filtration, the purity is 98.7%, and the yield is 96%.
[0046] (3) Compound C 111.5 g (0.290 mol) and acetonitrile 0.5575 L (5 V) were mixed in a reaction flask, and lithium hydroxide aqueous solution was added thereto, wherein lithium hydroxide 13.9 g (0.58 mol) and water 0.5575 L (5 V), and the reaction was carried out at room temperature for 3 to 4 hours. The disappearance of the peak of the starting material compound C was confirmed by high performance liquid chromatography, and the reaction system was concentrated to 5 V, dichloromethane 1.115 L (10 V) was added thereto, and extraction was carried out. After the organic phase was dried with anhydrous sodium sulfate, it was filtered, concentrated to 2 V, methyl tert-butyl ether 0.892 L (8 V) was added thereto, and a solid was precipitated. The solid was filtered, washed, and the filter cake was placed in a vacuum oven at 40°C until the weight was constant, to obtain compound D monotert-butyl octadecandioate 103.1 g, purity 99.15%, yield 96%.
[0047] The compound D monotert-butyl octadecandioate obtained in Example 1 was analyzed by mass spectrometry, and the mass spectrum thereof is shown in Figure 1
[0048] The compound D monotert-butyl octadecandioate obtained in Example 1 was analyzed by high performance liquid chromatography, and the liquid chromatography purity thereof is shown in Figure 2
[0049] Example 2
[0050] A method for synthesizing a monotert-butyl octadecandioate, comprising the following steps:
[0051] (1) Compound A 100 g (0.318 mol) and tetrahydrofuran 1 L (10 V) were mixed in a three-necked reaction flask, and mechanical stirring was started. Then, methanol 12.2 g (0.382 mol) was added, and stirring was carried out at room temperature. The stirring speed was reduced, and immobilized lipase Novozym 435 was added in an amount of 10 g (10%), and then the temperature was increased to 38°C to carry out the reaction. The reaction was carried out for 5 to 6 hours, and the reaction system changed from turbid to clear. After the reaction of octadecandioic acid was completed by high performance liquid chromatography, it was filtered, concentrated, recrystallized with acetonitrile 1.2 L (12 V), and filtered to obtain solid compound B 99.2 g, purity 98.5%, yield 95%.
[0052] (2) Compound B 99.2 g (0.302 mol) and tert-butyl alcohol 0.992 L (10V) were mixed in a three-necked reaction flask, stirring was started at room temperature, DMAP 1.85 g (0.0151 mol) and DCC 74.3 g (0.36 mol) were added successively, then the temperature was raised to 40 degrees Celsius, and the reaction was carried out for 10-12 hours. The reaction liquid was detected by high performance liquid chromatography. When the peak of compound B disappeared, the reaction system was cooled to room temperature, filtered, concentrated, recrystallized with isopropyl ether 0.992 L (10V), and filtered to obtain solid compound C 109.2 g with a purity of 98.2% and a yield of 94%.
[0053] (3) Compound C 109.2 g (0.284 mol) and acetonitrile 0.546 L (5V) were mixed in a reaction flask, and lithium hydroxide aqueous solution was added, wherein lithium hydroxide 13.6 g (0.568 mol) and water 0.546 L (5V). The reaction was carried out at room temperature for 3-4 hours. When the peak of the raw material compound C disappeared, the reaction system was concentrated to 5V, dichloromethane 1.092 L (10V) was added for extraction, and the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated to 2V, methyl tert-butyl ether 0.873 L (8V) was added, and solid was precipitated. After filtration and washing, the filter cake was placed in a vacuum oven at 40 degrees Celsius until the weight was constant, to obtain compound D octadecanedioic acid mono-tert-butyl ester 94.7 g with a purity of 98.2% and a yield of 90%.
[0054] Example 3
[0055] A method for synthesizing octadecanedioic acid mono-tert-butyl ester, comprising the following steps:
[0056] (1) Compound A 100 g (0.318 mol) and tetrahydrofuran 1 L (10V) were mixed in a three-necked reaction flask, mechanical stirring was started, then methanol 12.2 g (0.382 mol) was added, stirring was carried out at room temperature, the stirring speed was reduced, and immobilized lipase Novozym 435 was added with a mass of 10 g (10%). Then the temperature was raised to 38 degrees Celsius, and the reaction was carried out for 5-6 hours. The reaction system changed from turbidity to clarity. After the reaction of octadecanedioic acid was completed by high performance liquid chromatography, the reaction system was filtered, concentrated, recrystallized with acetonitrile 1.2 L (12V), and filtered to obtain solid compound B 99.2 g with a purity of 98.5% and a yield of 95%.
[0057] (2) Compound B 99.2g (0.302mol) and tert-butyl alcohol 0.992L (10V) were mixed in a three-necked flask, stirring was started at room temperature, DMAP 1.85g (0.0151mol) and DCC 74.3g (0.36mol) were added successively, then the temperature was raised to 60 degrees Celsius, and the reaction was carried out for 6-7 hours. The reaction liquid was detected by high performance liquid chromatography. When the peak of compound B disappeared, the reaction system was cooled to room temperature, filtered, concentrated, recrystallized with isopropyl ether 0.992L (10V), and filtered to obtain solid compound C 111.5g with a purity of 98.7% and a yield of 96%.
[0058] (3) Compound C 111.5g (0.290mol) and acetonitrile 0.5575L (5V) were mixed in a flask, and an aqueous solution of sodium carbonate was added, wherein sodium carbonate 61.5g (0.580mol) and water 0.5575L (5V). The reaction was carried out at room temperature for 3-4 hours. The peak of the raw material compound C accounted for 1.2% by high performance liquid chromatography. The reaction time was prolonged, but the proportion of the raw material did not change. The reaction system was concentrated to 5V, dichloromethane 1.115L (10V) was added for extraction, and the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated to 2V, and then methyl tert-butyl ether 0.892L (8V) was added. Solid was precipitated, filtered, washed, and the filter cake was placed in a vacuum oven at 40 degrees Celsius until the weight was constant to obtain compound D octadecanedioic acid mono-tert-butyl ester 98.8g with a purity of 98.8% and a yield of 92%.
[0059] Example 4
[0060] A method for synthesizing octadecanedioic acid mono-tert-butyl ester, comprising the following steps:
[0061] (1) Compound A 100g (0.318mol) and tetrahydrofuran 1L (10V) were mixed in a three-necked flask, and mechanical stirring was started. Then, methanol 12.2g (0.382mol) was added, and stirring was carried out at room temperature. The stirring speed was reduced, and immobilized lipase Novozym 435 was added with a mass of 10g (10%). Then, the temperature was raised to 38 degrees Celsius, and the reaction was carried out for 5-6 hours. The reaction system changed from turbid to clear. After the reaction of octadecanedioic acid was completed by high performance liquid chromatography, it was filtered, concentrated, recrystallized with acetonitrile 1.2L (12V), and filtered to obtain solid compound B 99.2g with a purity of 98.5% and a yield of 95%.
[0062] (2) Compound B 99.2 g (0.302 mol) and tert-butyl alcohol 0.992 L (10 V) were mixed in a three-necked flask, stirring was started at room temperature, DMAP 1.85 g (0.0151 mol) and DCC 74.3 g (0.36 mol) were added successively, then the temperature was raised to 60 degrees Celsius, and the reaction was carried out for 6-7 hours. The reaction liquid was detected by HPLC, and the peak of compound B disappeared. After the reaction system was cooled to room temperature, filtration was carried out, and the filtrate was concentrated and recrystallized with isopropyl ether 0.992 L (10 V). Solid compound C 111.5 g was obtained by filtration, with a purity of 98.7% and a yield of 96%.
[0063] (3) Compound C 111.5 g (0.290 mol) and acetonitrile 0.5575 L (5 V) were mixed in a reaction flask, and sodium hydroxide aqueous solution was added, wherein sodium hydroxide 23.2 g (0.58 mol) and water 0.5575 L (5 V). The reaction was carried out at room temperature for 3-4 hours. The peak of the raw material compound C disappeared by HPLC. The reaction system was concentrated to 5 V, dichloromethane 1.115 L (10 V) was added for extraction, and the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated to 2 V, and methyl tert-butyl ether 0.892 L (8 V) was added. Solid was precipitated, filtered, washed, and the filter cake was placed in a vacuum oven at 40 degrees Celsius until the weight was constant. Compound D monotert-butyl octadecanedioate 101.0 g was obtained, with a purity of 99.0% and a yield of 94%.
[0064] Comparative Example 1
[0065] The first step from A to B in this route utilizes lipase catalysis to protect the carboxyl group. The key difficulties of this step are: 1. the conversion rate of the reaction. If octadecanedioic acid is not completely consumed, a series of impurities will be generated in the next step. 2. the generation of dimethyl ester by-product. Since the catalytic efficiency of the enzyme is highly related to the type of enzyme and the solvent environment, single variable screening of enzymes and solvents was carried out, as shown in Table 1. According to the table, the reaction conditions of lipase Novozym 435 and tetrahydrofuran are better.
[0066] Table 1 Reaction results of different enzymes and solvents
[0067]
[0068] The above disclosed preferred embodiments of the present application are only used to help explain the present application, but the present application is not limited thereto. Those skilled in the art can understand that within the technical concept scope of the present application, the technical solutions of the present application can be modified, or some technical features can be combined in any other way. These modifications or combinations do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present application, and should be considered as the disclosed content of the present application, and all belong to the protection scope of the present application.
Claims
1. A method for producing an alkyl diacid mono-tert-butyl ester compound, characterized by, The method comprises the following steps: S1) reacting an alkyl diacid with methanol under the catalysis of immobilized lipase Novozym 435 to obtain an alkyl diacid monomethyl ester; S2) reacting the alkyl diacid monomethyl ester with tert-butyl alcohol in the presence of a condensing agent and an activating agent to obtain an intermediate; S3) hydrolyzing the intermediate under alkaline conditions to obtain an alkyl diacid mono-tert-butyl ester compound.
2. The production method according to claim 1, characterized by, The number of carbon atoms of the alkyl group in the alkyl diacid is 14-20; The molar ratio of the alkyl diacid to methanol is 1:(1-1.2).
3. The preparation method according to claim 1, characterized in that, The step S1) is carried out in an organic solvent; the polarity of the organic solvent is less than 4.
3.
4. The production method according to claim 3, characterized by, The alkyl diacid is octadecanedioic acid; The organic solvent is tetrahydrofuran.
5. The preparation method according to claim 1, characterized in that, The mass of the immobilized lipase Novozym 435 is 5%-20% of the mass of the alkyl diacid.
6. The method of claim 1, wherein, The condensing agent is selected from one or more of dicyclohexyl carbodiimide, diisopropyl carbodiimide and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide; The activating agent is selected from 4-N,N-dimethylpyridine and / or 1-hydroxybenzotriazole.
7. The preparation method according to claim 1, characterized in that, The ratio of the alkyl diacid monomethyl ester to tert-butyl alcohol is 100 g:(5-15) L; The molar ratio of the alkyl diacid monomethyl ester to the condensing agent is 1:(1-1.5); The molar ratio of the alkyl diacid monomethyl ester to the activating agent is 1:(0.01-0.1).
8. The method of claim 1, wherein, The temperature of the reaction in the step S1) is 36-40°C; the reaction time is 5-6 h; The temperature of the reaction in the step S2) is 40-60°C; the reaction time is 6-12 h.
9. The method of claim 1, wherein, The alkaline conditions in the step S3) are provided by an aqueous solution of an alkaline compound; the alkaline compound is selected from one or more of lithium hydroxide, sodium carbonate and sodium hydroxide; The molar ratio of the intermediate to the alkaline compound is 1:(1.5-2.5); the concentration of the aqueous solution of the alkaline compound is 0.5-1.5 mol / L.
10. The method of claim 1, wherein, After the hydrolysis in the step S3) is completed, the reaction system is concentrated to 2 / 3-1 / 3 of the volume, dichloromethane is added for extraction, the organic phase is concentrated to 1 / 4-1 / 6 of the volume of dichloromethane, methyl tert-butyl ether is added for precipitation, and an alkyl diacid mono-tert-butyl ester compound is obtained.