CN108676824B - Method for preparing methylbutylamine p-benzoquinone by lipase catalysis - Google Patents

Method for preparing methylbutylamine p-benzoquinone by lipase catalysis Download PDF

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CN108676824B
CN108676824B CN201810498564.0A CN201810498564A CN108676824B CN 108676824 B CN108676824 B CN 108676824B CN 201810498564 A CN201810498564 A CN 201810498564A CN 108676824 B CN108676824 B CN 108676824B
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benzoquinone
butylamine
methyl
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lipase
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CN108676824A (en
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唐慧
吕奎营
赵秋香
孙杨建
任文杰
赵嘉凯
张媛媛
杨丰科
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Qingdao University of Science and Technology
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Abstract

A method for preparing methylbutylamine p-benzoquinone by lipase catalysis is characterized in that immobilized candida antarctica lipase B is used for catalyzing butylamine to react with methyl-p-benzoquinone to prepare 2-methyl-5-butylamine p-benzoquinone. The 2-methyl-5-butylamine p-benzoquinone prepared by the enzyme catalysis method can avoid the difficulties of poor selectivity and product separation of a chemical synthesis process due to the high spatial selectivity of the enzyme, and is an environment-friendly and efficient synthesis method.

Description

Method for preparing methylbutylamine p-benzoquinone by lipase catalysis
Technical Field
The invention belongs to the technical field of pharmaceutical engineering, and particularly relates to an anti-tumor active substance 2-methyl-5-butylamine p-benzoquinone prepared by using Antarctic filamentous yeast lipase B as a catalyst.
Background
The 2-methyl-5-butylamine p-benzoquinone has strong antitumor activity, is expected to be capable of resisting tumors of various parts, and is developed into an antitumor drug with wide application. From the structural point of view, the 2 effective groups of benzoquinone and amino mainly enable the benzoquinone to have antitumor activity.
The synthesis of 2-methyl-5-butylamine p-benzoquinone by a chemical method can generate butylamine products substituted at 3-position and 6-position instead of only butylamine products substituted at 5-position due to poor space selectivity, and can obtain the following products with different substitutions: (1) a 3, 5-substituted dibutylamine product, (2) a 3, 5, 6-substituted tributylamine product, (3) a 3, 6-substituted dibutylamine product, (4) 2-methyl-5-butylamine p-benzoquinone, only such substitutions being products intended by the present invention. The products form a mixture, and the separation and purification of the products are difficult, so that the separation cost of the 2-methyl-5-butylamine p-benzoquinone is high, and the yield is low. The 2-methyl-5-butylamine p-benzoquinone is prepared by an enzyme catalysis method, and due to the high spatial selectivity of the enzyme, the 2-methyl-5-butylamine p-benzoquinone is specifically generated, and other substituted products are not generated, so that the difficulty of poor selectivity and product separation of a chemical synthesis process can be avoided by adopting an enzyme catalysis reaction, and the method is an environment-friendly and efficient synthesis method.
Disclosure of Invention
The invention adopts lipase to carry out catalytic reaction, in particular to immobilized Candida antarctica lipase B (trade name Novozme 435, namely CALB) produced by Novonid company as a catalyst, which catalyzes butylamine to react with methyl p-benzoquinone to generate 2-methyl-5-butylamine p-benzoquinone, wherein the reaction formula is as follows:
Figure 948864DEST_PATH_IMAGE001
the catalytic activity of the enzyme is greatly dependent on pH, the optimum pH of the lipase used in the present invention is 7.0 to 9.0, and the pH of the reaction system must be in an optimum range in order to maintain the catalytic activity of the enzyme, so that an appropriate buffer is selected, and it is considered that the pH of the system is affected by the addition of n-butylamine. A plurality of buffers are tested, including phosphate buffer, citric acid buffer, sodium acetate buffer and the like, and the test result shows that the effect of the citric acid buffer with the pH value of 7.0 is optimal, and the pH value is in the range of 7.0-9.0 after the butylamine with the corresponding concentration is added, so the citric acid buffer is adopted for the test.
The substrate of the methylbenzoquinone is insoluble in water, so that an enzyme catalytic reaction is carried out by using a non-aqueous medium. The non-aqueous medium includes a water-organic solvent single-phase system, a water-organic solvent 2-phase system, an organic solvent single-phase system, a micro-solution, an ionic liquid, and the like. The optimal reaction medium is an important link of the enzyme catalysis reaction, and a large number of experiments show that the reaction only has a good effect in a water-organic solvent single-phase system. The water-methanol single-phase system has the best effect, the methanol concentration is 3-5%, and the methyl benzoquinone can be dissolved in the medium, so that the enzyme inhibition is small.
The invention adopts lipase to carry out hydrolysis reaction. The lipase is a triacylglycerol hydrolase with wide application, and the lipase is of various types, including animal sources, plant sources and microorganism sources. For example, Pseudomonas lipase, Candida rugosa lipase, Candida antarctica lipase, Pseudomonas fluorescens lipase, lipase porcine pancreatic lipase, Penicillium lipase, Pseudomonas cepacia lipase, Candida cylindracea lipase, Aspergillus lipase, Alcaligenes lipase, etc. Since various lipases have different catalytic properties, a lipase having the best catalytic effect is selected for the catalytic reaction. A large number of experiments show that various lipases can catalyze the reaction, but the aspergillus lipase and the candida antarctica lipase B have good effects, but the immobilized candida antarctica lipase B has the best effect.
The enzyme adding amount is 5-10U/mL, the reaction temperature is 38-42 ℃, and the reaction time is 20-24 h.
The process for preparing 2-methyl-5-butylamine p-benzoquinone by enzyme catalysis reaction is as follows: stirring the reactor, adding citric acid buffer solution with pH of 7.0 containing 3-5% methanol, equimolar charges of methyl p-benzoquinone and butylamine with butylamine concentration of 0.05-0.1mM, adding immobilized Candida antarctica lipase B (trade name Novozme 435, Candida antarctica lipase B, CALB) from Novonid, adding 5-10U/mL of enzyme, reacting at 38-42 deg.C, and introducing N2The reaction is started, and the reaction time is 20-24 h. After the reaction is finished, sampling and performing liquid chromatography analysis, and filtering out the immobilized enzyme which can be reused. Extracting the filtrate with acetone, separating organic phase, and distilling off acetone to obtain 2-methyl-5-butylamine p-benzoquinone with reaction conversion rate of 99-100%, yield of 2-methyl-5-butylamine p-benzoquinone of 94-95% and yield of other substituted products less than 2.5%.
Liquid phase detection conditions: agilent 1200 liquid chromatograph, C18 reversed phase column, 250mm, mobile phase: methanol/water =80/20, product retention time 4.35 minutes.
Separation and purification of product 2-methyl-5-butylamine p-benzoquinone1H NMR (500 MHz, CDCl3) δ 7.07 (m,1H), 5.74 (m,1H), 4.94 (m,1H),3.41 (m,2H), 2.46 (d,J = 0.4 Hz,3H),1.51 (d,J = 7.7 Hz, 2H), 1.39 (d,J = 3.5 Hz, 2H), 0.98 (d,J = 6.4 Hz,3H). 13C NMR (125 MHz,CDCl3) δ 188.58 (s,1H), 172.84 (s,1H),153.25 (s, 1H), 121.22 (s, 1H),110.63 (s,1H),105.95 (s, 1H), 45.20 (s, 7H), 30.87 (s, 7H), 20.23 (s, 7H), 14.02 (s, 9H), 10.46 (s,3H)。
Detailed Description
Example 1
Stirring with magnetic particles in a 10mL brown reaction bottle, adding 2mL of citric acid buffer solution with pH of 7.0, wherein the citric acid buffer solution contains 3-5% of methanol, the equimolar feeding of methyl-p-benzoquinone and butylamine, the concentration of the butylamine is 0.05-0.1mM, adding immobilized candida antarctica lipase B and Novozme 435, the adding amount of the enzyme is 5-10U/mL, the reaction temperature is 38-42 ℃, and introducing N2 After 3 minutes, the bottle cap is closed, and the reaction is started, wherein the reaction time is 20-24 hours. After the reaction is finished, sampling and performing liquid chromatography analysis, wherein the liquid phase detection result is as follows: the reaction conversion rate is 99-100%, the yield of the product 2-methyl-5-butylamine-p-benzoquinone is 94-95%, and the yield of other substituted products is less than 2.5%.
Liquid phase detection conditions: agilent 1200 liquid chromatograph, C18 reversed phase column, 250mm, mobile phase: methanol/water =80/20, product 2-methyl-5-butylamine p-benzoquinone retention time 4.35 minutes.
Example 2
100mL brown reaction bottle, stirring with magnetic particles, adding 20mL of citric acid buffer solution with pH7.0, wherein the citric acid buffer solution contains 3-5% of methanol, the equimolar feeding of methyl-p-benzoquinone and butylamine, the concentration of the butylamine is 0.05-0.1mM, adding immobilized candida antarctica lipase B and Novozme 435, the adding amount of the enzyme is 5-10U/mL, the reaction temperature is 38-42 ℃, and introducing N2 After 5 minutes, the bottle cap is closed, and the reaction is started, wherein the reaction time is 20-24 hours. After the reaction is finished, sampling and performing liquid chromatography analysis, and filtering out the immobilized enzyme which can be reused. Extracting the filtrate with acetone, separating an organic phase, distilling out the acetone to obtain a product 2-methyl-5-butylamine p-benzoquinone, wherein the liquid phase detection result is as follows: the reaction conversion rate is 99-100%, the yield of the product 2-methyl-5-butylamine-p-benzoquinone is 94-95%, and the yield of other substituted products is less than 2.5%.
The liquid phase detection conditions were the same as in example 1.
Example 3
1000ml brown reaction bottle, magnetic stirring, adding pH7.0 citric acid buffer solution 500ml, which contains 3% methanol, methyl-p-benzoquinone and butylamine equimolar feed, butylamine concentration is 0.05mM,adding immobilized candida antarctica lipase B and Novozme 435 into the mixture, adding 5U/mL of enzyme, reacting at 42 ℃, and introducing N2 After 15 minutes, the bottle cap is closed, and the reaction is started, wherein the reaction time is 20 hours. After the reaction is finished, sampling and performing liquid chromatography analysis, and filtering out the immobilized enzyme which can be reused. Extracting the filtrate with acetone, separating an organic phase, distilling out the acetone to obtain a product 2-methyl-5-butylamine p-benzoquinone, wherein the liquid phase detection result is as follows: the reaction conversion rate is 99%, the yield of the product 2-methyl-5-butylamine p-benzoquinone is 94%, and the yield of other substituted products is less than 2.5%.
The liquid phase detection conditions were the same as in the examples. .
Separation and purification of product 2-methyl-5-butylamine p-benzoquinone1H NMR (500 MHz, CDCl3) δ 7.07 (m,1H), 5.74 (m,1H), 4.94 (m,1H),3.41 (m,2H), 2.46 (d,J = 0.4 Hz,3H),1.51 (d,J = 7.7 Hz, 2H), 1.39 (d,J = 3.5 Hz, 2H), 0.98 (d,J = 6.4 Hz,3H). 13C NMR (125 MHz,CDCl3) δ 188.58 (s,1H), 172.84 (s,1H),153.25 (s, 1H), 121.22 (s, 1H),110.63 (s,1H),105.95 (s, 1H), 45.20 (s, 7H), 30.87 (s, 7H), 20.23 (s, 7H), 14.02 (s, 9H), 10.46 (s,3H)。
Example 4
1000mL brown reaction bottle, magnetic stirring, adding 500mL of citric acid buffer solution with pH7.0, wherein the solution contains 5% of methanol, 0.1mM of butylamine, adding immobilized Candida antarctica lipase B and Novozme 435 at the enzyme adding amount of 10U/mL, reacting at the temperature of 40 ℃, and introducing N2 After 15 minutes, the bottle cap is closed, and the reaction is started, wherein the reaction time is 22 hours. After the reaction is finished, sampling and performing liquid chromatography analysis, and filtering out the immobilized enzyme which can be reused. Extracting the filtrate with acetone, separating an organic phase, distilling out the acetone to obtain a product 2-methyl-5-butylamine p-benzoquinone, wherein the liquid phase detection result is as follows: the reaction conversion rate is 100 percent, the yield of the product 2-methyl-5-butylamine p-benzoquinone is 94 percent, and the yield of other substituted products is less than 2.5 percent.
The liquid phase detection conditions were the same as in example 1. The nuclear magnetic data were as in example 3.
Example 5
1000mL brown reaction bottle, magnetic stirring, adding pH7.0 citric acid buffer solution 500mL, which contains 4% methanol, methyl p-benzoquinone and butylamine equimolar feed, butylamine concentration is 0.075mM, adding immobilized Candida antarctica lipase B, Novozme 435, enzyme adding amount is 7.5U/mL, reaction temperature is 38 ℃, introducing N2 After 15 minutes, the bottle cap is closed, and the reaction is started, wherein the reaction time is 24 hours. After the reaction is finished, sampling and performing liquid chromatography analysis, and filtering out the immobilized enzyme which can be reused. Extracting the filtrate with acetone, separating an organic phase, distilling out the acetone to obtain a product 2-methyl-5-butylamine p-benzoquinone, wherein the liquid phase detection result is as follows: the reaction conversion rate is 99%, the yield of the product 2-methyl-5-butylamine p-benzoquinone is 95%, and the yield of other substituted products is less than 2.5%.
The liquid phase detection conditions were the same as in example 1.

Claims (1)

1. A method for preparing methylbutylamine p-benzoquinone by lipase catalysis is characterized in that immobilized candida antarctica lipase B is used for catalyzing butylamine to react with methyl p-benzoquinone to prepare 2-methyl-5-butylamine p-benzoquinone; adding citric acid buffer solution with pH of 7.0 into brown reaction bottle, wherein the citric acid buffer solution contains 3-5% of methanol, equimolar feeds of methyl p-benzoquinone and butylamine, the concentration of the butylamine is 0.05-0.1mM, adding immobilized candida antarctica lipase B, the adding amount of the enzyme is 5-10U/mL, the reaction temperature is 38-42 ℃, and introducing N2 3-15 minutes later, closing the bottle cap, stirring, starting reaction, wherein the reaction time is 20-24 hours, and filtering out the immobilized enzyme after the reaction is finished; extracting the filtrate with acetone, separating organic phase, and distilling off acetone to obtain 2-methyl-5-butylamine p-benzoquinone with reaction conversion rate of 99-100%, yield of 2-methyl-5-butylamine p-benzoquinone of 94-95% and yield of other substituted products less than 2.5%.
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