CN101104862B - Method for synthesizing D-arylglycine by using heterogeneous enzyme to catalytically hydrolyzing 5-arylhydantoin - Google Patents
Method for synthesizing D-arylglycine by using heterogeneous enzyme to catalytically hydrolyzing 5-arylhydantoin Download PDFInfo
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Abstract
The invention relates to a chemical pharmaceutical field, in particular to an approach on synthesis of D-aryl glycine by heterogeneous enzyme catalytic hydrolysis of 5-aryl hydantoin. The invention takes an enzyme preparation fermented by a mutant bacteria UV-LZ98 of a hydantoin producing strain Arthrobacter aurescens LZ-98 and a mutant bacteria UV-LZ99 of an ammonia methyl amidohydrolase producing strain Agrobacterium radiobacter LZ99 as a catalyst, and has a heterogeneous catalytic reaction with an input of more than three to ten times of 5-aryl hydantoin than homogeneous reaction to make the D-aryl glycine produced precipitate directly in a solid way during the substrate hydrolysis process, which improves the synthesis efficiency and lowers the evaporation energy consumption with a stable quality.
Description
Technical field
The present invention relates to the chemical pharmaceutical field, relate in particular to the method for the synthetic D-aryl glycine of a kind of heterogeneous enzyme catalysis hydrolysis 5-aryl glycolylurea.
Background technology
The D-aryl glycine is the crucial alpha-non-natural amino acid of a class, because its configuration just in time is mainly used in the synthetic of medicine, peptide and sweeting agent etc. mutually on the contrary with natural amino acid and prepares, along with the further exploitation to its using value, the demand in market is at rapid growth in recent years.
The preparation method of traditional D-aryl glycine, chemosynthesis and Split Method and biocatalysis D-aryl glycolylurea hydrolysis method have been comprised, wherein the technology of all reports is liquid-liquid homogenous process, and reaction volume is huge, production capacity is low, energy consumption is high and the synthetic D-aryl glycine of homogeneous phase biocatalysis hydrolysis method causes because of its solubleness is little.
Summary of the invention
The technical problem to be solved in the present invention provides the method that a kind of heterogeneous enzyme catalysis hydrolysis 5-aryl glycolylurea prepares the D-aryl glycine, to overcome problems of the prior art.
Design of the present invention is such:
Prepare in applied chemistry synthetic method on the basis of substrate 5-aryl glycolylurea, produce the mutant bacteria UV-LZ98 of bacterium Arthrobacter aurescens LZ98 and zymin that carboxamide amine lytic enzyme produces the mutant bacteria UV-LZ99 mixed fermentation preparation of bacterium Agrobacterium radiobacter LZ99 is a catalyzer with the glycolylurea enzyme, input exceeds the doubly above 5-aryl glycolylurea of measuring of homogeneous reaction 3-10 and carries out heterogeneous catalytic reaction, make product D-aryl glycine be hydrolyzed direct acquisition with substrate, to enhance productivity and to reduce the evaporation energy consumption in the solid mode.
The D-aryl glycine comprises the D-phenylglycine among the present invention, the D-fluorophenyl glycine, the D-chlorobenzene glycine, D-bromobenzene glycine, D-iodobenzene glycine, D-alcoxyl phenylglycine, the D-pyridine glycine, D-naphthalene glycine, D-quinoline glycine, D-pyrimidine glycine, D-pyrazine glycine, D-pyridazine glycine, D-indoles glycine, D-thiophene glycine, D-furans glycine, D-pyrroles's glycine, D-pyrazoles glycine, D-imidazoles glycine, D-thiazole glycine, D-oxazole glycine and D-isoxazole glycine etc., wherein major part is a new compound in the D-quinoline glycine series, and glycine α carbon can be connected on the different rings carbon of aromatic ring.
The height that the present invention lives according to the zymin enzyme is adjusted temperature of reaction and reaction pressure, can controls reaction speed and product crystallization velocity, and avoid the substrate glycolylurea by double team.
Technical solution of the present invention is:
The method of the synthetic D-aryl glycine of heterogeneous enzyme catalysis hydrolysis 5-aryl glycolylurea of the present invention may further comprise the steps:
1. in the biocatalysis hydrolysis reactor, drop into aqueous solvent, 5-aryl glycolylurea, zymin, acid or alkali etc. successively, stir and form suspension, the input amount of 5-aryl glycolylurea is 5～21% (w/w) of reaction system material total amount, and adding sour adjust pH is 6.5～7.8;
2. by reaction solution quality total amount 2～8%, enzyme lives and to put in the above-mentioned biocatalysis hydrolysis reactor for the zymin more than the 0.28U/mL, controlled temperature is at 25～40 ℃, the beginning stirring reaction;
3. in reaction process, the control reacting system pressure is between 0.09～0.03Mpa, 6h sampling at interval, with liquid phase chromatography detection reaction situation, when reaction proceeds to the 8h left and right sides, then have D-aryl glycine crystal to begin to separate out, when can't check substrate 5-aryl glycolylurea in the question response system, reaction finishes substantially;
4. screening separates the coarse-grain obtain and just can obtain product D-aryl glycine through recrystallization.
The preparation method of described enzymes soln is: the mutant bacteria UV-LZ99 mixed fermentation of the mutant bacteria UV-LZ98 of Arthrobacter aurescens LZ98 and Agrobacterium radiobacter LZ99 makes the zymin that contains glycolylurea enzyme and carboxamide amine lytic enzyme, i.e. " two bacterium, two enzymes ".
Further, described D-aryl glycine is the D-phenylglycine, the D-fluorophenyl glycine, the D-chlorobenzene glycine, D-bromobenzene glycine, D-iodobenzene glycine, D-methoxy phenylglycine, the D-pyridine glycine, D-naphthalene glycine, D-quinoline glycine, D-pyrimidine glycine, D-pyrazine glycine, D-pyridazine glycine, D-indoles glycine, D-thiophene glycine, D-furans glycine, D-pyrroles's glycine, D-pyrazoles glycine, D-imidazoles glycine, D-thiazole glycine, a kind of in the D-amino acid such as D-oxazole glycine and D-isoxazole glycine, wherein glycine α carbon can be connected on the carbon atom of aromatic ring different positions.
Further, described D-aryl glycine is the D-phenylglycine, and its synthetic method may further comprise the steps:
1. in 10L enzymic catalytic reaction jar, add entry 7kg, 5-phenyl hydantoin because of 0.9～1kg, add hydrochloric acid or sulfuric acid is adjusted pH to 6.8;
2. add wet enzyme again and live in living for the enzymes soln enzyme of 0.62U/ml and be 0.3L under stirring condition, controlled temperature is under 25～38 ℃, stirring reaction;
3. 6h sampling at interval is with liquid phase chromatography detection reaction situation, when reaction proceeds to the 8h left and right sides, then there is D-phenylglycine crystal to begin to separate out, can't check in the question response system substrate 5-phenyl hydantoin because of, and N-carboxamide phenylglycine 0.25% is when following, reaction finishes substantially;
4. separate the coarse-grain that obtains and just can obtain qualified product D-phenylglycine through recrystallization;
5. the dialysed feed liquid of sieve aperture, extractive process can obtain another part D-phenylglycine in the solution to adopt membrane filtration respectively, concentrate etc.
Further, described D-aryl glycine is the D-pyridine glycine, and its synthetic method may further comprise the steps:
1. in 10L enzymic catalytic reaction jar, add entry 6.5kg, stir and drop into 5-pyridyl glycolylurea 1kg down, add hydrochloric acid or sulfuric acid and adjust pH to 6.5;
2. add wet enzyme work again and be that the about 0.4L of enzymes soln of 0.58U/ml, controlled temperature are 28～36 ℃ of following stirring reactions;
3. 8h sampling at interval with liquid phase chromatography detection reaction situation, when reaction proceeds to the 9h left and right sides, then has D-pyridine glycine crystal to begin to separate out.Can't check substrate 5-pyridyl glycolylurea in the question response system, when and N-carboxamide-D-pyridine glycine 0.20% was following, reaction finished substantially;
4. separate the coarse-grain that obtains and just can obtain qualified product D-pyridine glycine through recrystallization.
5. the dialysed feed liquid of sieve aperture, extractive process can obtain another part D-pyridine glycine in the solution to adopt membrane filtration respectively, concentrate etc.
Further, described D-aryl glycine is a D-naphthalene glycine, and its synthetic method may further comprise the steps:
1. in 10L enzymic catalytic reaction jar, add entry 7.5kg, stir and drop into 5-naphthyl glycolylurea 0.8kg down, add hydrochloric acid or sulfuric acid adjustment pH to 7.0;
2. add wet enzyme again and live in living for the enzymes soln enzyme of 0.62U/ml and be 0.4L under stirring condition, controlled temperature is under 30～40 ℃, stirring reaction;
3. 8h sampling at interval with liquid phase chromatography detection reaction situation, when reaction proceeds to the 7h left and right sides, then has D-naphthalene glycine crystal to begin to separate out, and when can't check the intermediate of substrate 5-naphthyl glycolylurea and correspondence in the question response system, reaction finishes substantially;
4. screening separates the coarse-grain obtain and just can obtain qualified product D-naphthalene glycine through recrystallization.
5. the dialysed feed liquid of sieve aperture, extractive process can obtain another part D-naphthalene glycine in the solution to adopt membrane filtration respectively, concentrate etc.
Further, described D-aryl glycine is a D-quinoline glycine, and its synthetic method may further comprise the steps:
1. in 10L enzymic catalytic reaction jar, add entry 8kg, under stirring condition, drop into 5-quinoline glycolylurea 0.85kg, adjust pH to 6.5;
2. add wet enzyme work then and be the about 0.35L of enzymes soln of 0.68U/ml, in 35～38 ℃ of following stirring reactions;
3. 6h sampling at interval is with liquid phase chromatography detection reaction situation, when reaction proceeds to the 8h left and right sides, then there is D-quinoline glycine crystal to begin to separate out, can't check substrate 5-quinoline glycolylurea in the question response system, and N-carboxamide-D-quinoline glycine is lower than at 0.30% o'clock, reaction finishes substantially;
4. screening separates the coarse-grain obtain and just can obtain qualified product D-2-quinoline glycine through recrystallization.
5. the dialysed feed liquid of sieve aperture, extractive process can obtain another part D-quinoline glycine in the solution to adopt membrane filtration respectively, concentrate etc.
Heterogeneous catalysis of the present invention is to realize under microorganism is the prerequisite of catalyzer, the more important thing is that reactant and most product are solid phase in whole process, has avoided the solid double team by the control of condition, and transformation efficiency has been reached more than 99.5%.
Among the present invention, 5-aryl glycolylurea biocatalysis prepares the D-aryl glycine through two-step reaction.The first step is that substrate 5-aryl glycolylurea is hydrolyzed to intermediate product D-N-carboxamide-aryl glycine under the glycolylurea enzyme catalysis; Second step was that intermediate product is hydrolyzed to product D-aryl glycine under the catalysis of carboxamide amine lytic enzyme.
The katalysis of enzyme is the process of a complexity, be subjected to the chirality of orienting effect, the enzyme-to-substrate of structure, enzyme-to-substrate interaction of molecules, the enzyme-to-substrate of enzyme molecule select combination and with the influence of effect such as combining of reaction transition state.Metal ion is producing important effect to the enzyme catalysis ability in actual applications, and divalent ions such as Ni, Cu have restraining effect, and divalent ions such as Mn, Mg then have tangible activation.
The dynamics research that the hydrolysis of enzyme catalysis 5-aryl glycolylurea prepares the D-aryl glycine shows, under the prerequisite of fix in enzyme concn, primary condition is constant, when concentration of substrate is low, reaction shows first order reaction substantially, yet when reactant concn increase to saturated after, it is constant that speed of response is tending towards, and reaches maximum.If the concentration of substrate 5-aryl glycolylurea is in state of saturation in the energy guarantee system in the long duration, so just can make enzymic catalytic reaction speed in considerable time, keep maximum value.Enzyme work in zymin reaches under the sufficiently high prerequisite, in the reactive system that water exists, when solid-state (not being completed into solution) substrate 5-aryl glycolylurea is generated product along with solute substrate in the solution by catalytic hydrolysis fast dissolving guarantee that so that solution is in saturated mode all the time enzymatic reaction at full throttle carries out.Meanwhile, the product that generates will crystallize out with the crystalline form along with after the increase of concentration reaches capacity, and break dissolution equilibrium, enzymatic reaction can successfully be carried out, thereby realize the process of the synthetic D-aryl glycine of heterogeneous biocatalysis hydrolysis 5-aryl glycolylurea.
Method can be finished whole conversion, hydrolytic process to traditional " bacterium two enzymes " in a cell, and " two bacterium, two enzymes " rule is finished in two different cells.Therefore, substrate, intermediate and the product mass transfer process between different cells is the key of present technique.In order to reduce the influence of mass transfer, add cats product and then can obtain good result in reaction system to speed of response.
Heterogeneous biocatalysis process is different from the chemical catalysis process, but the catalytic activity of biological catalyst is equally along with there is the problem that descends in the prolongation in reaction times.Therefore, total charging capacity of control substrate is necessary.The amount of determining substrate 5-aryl glycolylurea among the present invention accounts for the 5～18% proper of reaction system total amount, and different aryl has different ideal values.The value ratio here is a mass ratio, and reactant system comprises water, zymin, acid (sulfuric acid or hydrochloric acid, phosphoric acid etc.), alkali (sodium hydroxide, potassium hydroxide, yellow soda ash or other carbonate etc.), 5-aryl glycolylurea and other auxiliary agents etc.
In the process that the heterogeneous method of two bacterium, two enzymes is implemented, unreacted solid substrate 5-aryl glycolylurea, intermediate product N-carboxamide-aryl glycine solid and product D-aryl glycine solid coexist in the same reactor, and whole process exists heterogeneous.And solid intermediate product D-N-carboxamide-aryl glycine and solid phase prod D-aryl glycine be to form under the condition that a large amount of substrates exist, and mutual parcel or double team very easily occur and the problem that causes transformation efficiency to reduce.But advantageously the solid of substrate is a powder, and the sweet amino acid of D-aryl then is crystal.The speed that the sweet amino acid crystal of control D-aryl is separated out can avoid solid to wrap up mutually, and transformation efficiency can reach more than 99.6%.Concrete method is the adjustment that optimization, control and the zymin enzyme of reaction conditions lived.
The influence of pH.According to the catalyzed reaction principle, in conversion process, there are ammonia, carbonic acid gas and D-aryl glycine to produce.The ammonia that generates easily forms salt with amino acid and accumulates in reactive system, makes the pH that reacts the later stage be elevated to 8.5 fast, thereby has suppressed the catalytic activity of N-carboxamide amine lytic enzyme consumingly, causes speed of response to slow down, even stops.So it is very important to reaction to control acid-basicity in good time, 6.5-7.8 is the pH that suits.
Temperature is to the influence of reaction.Under concentration, pH fixed condition, temperature also has bigger influence to enzymic catalytic reaction speed.Temperature is in the time of 25 ℃, and speed of response is slower, but the product crystal speed of separating out is also slower, helps growing up of nucleus, and the parcel phenomenon does not almost observe; Along with the raising speed of response of temperature of reaction is also accelerated, when reaching 41 ℃, speed of response is very fast, and nucleus formation speed is also along with quickening in the supersaturation system, and the parcel phenomenon is tending towards obvious.Suitable temperature is 25-40 ℃.
The present invention compared with prior art has following remarkable advantage:
1, select the different bacterium of two strains for use, make it respectively produce a kind of enzyme, form " two bacterium, two enzymes " catalyst system, not only fast reaction speed to greatest extent simultaneously also makes the two-step catalysis hydrolysis once finish.More original " bacterium two enzymes " technology has greatly improved speed of response.
2, the input amount of 5-aryl glycolylurea be traditional technology 3-10 doubly, and far above its solubleness.Along with the carrying out of reaction, product D-aryl glycine will accumulate until crystal and separate out, and a crystal output capacity can reach the 40-75% (w/w) of gross product amount, has reduced the consumption of concentration and evaporation steam, and fractional energy savings is more than 40%.
3, constant product quality, the consumption of a water of minimizing, productive rate exceeds original technology more than 4 percentage points.
Description of drawings
Fig. 1 is the amino acid whose structure iron of D-;
Fig. 2 prepares the reaction principle figure of D-aryl glycine for 5-aryl glycolylurea enzymatic hydrolysis.
Illustrate: the R among Fig. 1 is an aryl; R is identical with R among Fig. 1 among Fig. 2.
Embodiment
Below the present invention is further illustrated.
At first be prepared into zymin with the mutant bacteria UV-LZ98 of glycolylurea enzyme generation bacterium Arthrobacter aurescens LZ98 and the mutant bacteria UV-LZ99 mixed fermentation of carboxamide amine lytic enzyme generation bacterium Agrobacterium radiobacter LZ99.Finish process of the present invention then.
In 10L enzymic catalytic reaction jar, add 7kg water earlier, drop into the 5-phenyl hydantoin then because of 1kg, add hydrochloric acid or sulfuric acid and adjust pH to 6.8, add wet enzyme work again and be the about 0.3L of enzymes soln of 0.62U/ml under stirring condition, controlled temperature is 28 ℃, stirring reaction.6h sampling at interval with liquid phase chromatography detection reaction situation, when reaction proceeds to the 8h left and right sides, then has D-phenylglycine crystal to begin to separate out, and product concentration is substantially constant at 2.45% in the reaction solution.Can't check in the question response system substrate 5-phenyl hydantoin because of, and N-carboxamide phenylglycine 0.25% is when following, reaction finishes substantially, its transformation efficiency is more than 99.6%.Screening separates the coarse-grain that obtains, and just can obtain qualified product D-phenylglycine 446.2g through recrystallization; Extractive processes such as the material of sieve aperture of dialysing then adopts membrane filtration, concentrate obtain another part D-phenylglycine product 240.2g.Obtain product 686.4g altogether, yield is 80%.
D-can be obtained the hydrolysis of fluorophenyl glycolylurea by 5-fluorophenyl glycine, and method for making is similar to embodiment 1, yield 77%.
The D-p-chlorophenylglycine can be obtained by the hydrolysis of 5-rubigan glycolylurea, and method for making is identical with embodiment 1, yield 81%.
D-can be obtained the hydrolysis of bromophenyl glycolylurea by 5-the bromobenzene glycine, and method for making is similar to embodiment 1, and is identical, yield 73%.
D-can be obtained the hydrolysis of iodophenyl glycolylurea by 5-iodobenzene glycine system, and method for making is similar to embodiment 1, yield 69%.
D-can be obtained the hydrolysis of iodophenyl glycolylurea by 5-methoxy phenylglycine method for making, and method for making is identical with embodiment 1, yield 75%.
Embodiment 2, the preparation of D-3-pyridine glycine
In the enzymic catalytic reaction jar of 10L, add 6.5kg water earlier, under stirring condition, drop into 5-(3-pyridyl) glycolylurea 1kg, adjust pH to 6.5, the wet enzyme of adding is lived and is the about 0.4L of enzymes soln of 0.58U/ml then, in 32～36 ℃ of following stirring reactions.8h sampling at interval with liquid phase chromatography detection reaction situation, when reaction proceeds to the 9h left and right sides, then has D-pyridine glycine crystal to begin to separate out.Can't check substrate 5-(3-pyridyl) glycolylurea in the question response system, and N-carboxamide pyridine glycine 0.20% is when following, reaction finishes substantially, and its transformation efficiency is about 99.5%.Screening separates the coarse-grain that obtains just can obtain qualified product D-3-pyridine glycine 391.6g through recrystallization; Extractive processes such as the material of sieve aperture of dialysing then adopts membrane filtration, concentrate obtain another part product 261.1g.Amount to product 652.7g, yield is 76%.
Other D-pyridine glycine method for making is basic identical.
Embodiment 3, the preparation of D-2-naphthalene glycine
In the enzymic catalytic reaction jar of 10L, add 7.5kg water earlier, under stirring condition, drop into 5-(2-naphthyl) glycolylurea 0.8kg, adjust pH to 7.0, the wet enzyme of adding is lived and is the about 0.4L of enzymes soln of 0.65U/ml then, in 30-40 ℃ of following stirring reaction.8h sampling at interval with liquid phase chromatography detection reaction situation, when reaction proceeds to the 7h left and right sides, then has D-2-naphthalene glycine crystal to begin to separate out.When can't check the intermediate of 5-(2-naphthyl) glycolylurea and correspondence in the question response system, reaction finishes substantially, and its transformation efficiency is about 99%.Screening separates the coarse-grain that obtains just can obtain qualified product D-2-naphthalene glycine 327.3g through recrystallization; Extractive processes such as the material of sieve aperture of dialysing then adopts membrane filtration, concentrate obtain another part D-2-naphthalene glycine 192.2g.Product amounts to 519.5g, and yield is 73%.
Other D-naphthalene glycine method for making is basic identical.
Embodiment 4, the preparation of D-2-quinoline glycine
In the enzymic catalytic reaction jar of 10L, add 8kg water earlier, under stirring condition, drop into 5-(2-quinolyl) glycolylurea 0.85kg, adjust pH to 6.5, the wet enzyme of adding is lived and is the about 0.35L of enzymes soln of 0.68U/ml then, in 35～38 ℃ of following stirring reactions.6h sampling at interval with liquid phase chromatography detection reaction situation, when reaction proceeds to the 8h left and right sides, then has D-2-quinoline glycine crystal to begin to separate out.Can't check substrate 5-(2-quinolyl) glycolylurea in the question response system, and N-carboxamide-D-2-quinoline glycine is lower than at 0.30% o'clock, reaction finishes substantially, and its transformation efficiency is about 99%.Screening separates the coarse-grain that obtains just can obtain qualified product D-2-quinoline glycine 346.1g through recrystallization; Extractive processes such as the material of sieve aperture of dialysing then adopts membrane filtration, concentrate obtain another part product D-2-quinoline glycine 221.2g.Product amounts to 567.3g, and yield is 75%.
Other D-quinoline glycine method for making is basic identical with it.
Claims (1)
1. the method for the synthetic D-aryl glycine of heterogeneous enzyme catalysis hydrolysis glycolylurea is characterized in that described D-aryl glycine is a D-naphthalene glycine, and its synthetic method may further comprise the steps:
1. in the enzymic catalytic reaction jar, add entry 7.5kg, stir and drop into 5-naphthyl glycolylurea 0.8kg down, add hydrochloric acid or sulfuric acid and adjust pH to 7.0;
2. under stirring condition, add the wet enzyme work that contains glycolylurea enzyme and carboxamide amine lytic enzyme again and be that the enzymes soln 0.4L of 0.62U/ml, controlled temperature are 36～40 ℃ of following stirring reactions;
3. 8h sampling at interval with liquid phase chromatography detection reaction situation, when reaction proceeds to 7h, then has D-naphthalene glycine crystal to begin to separate out, and when can't check the intermediate of substrate 5-naphthyl glycolylurea and correspondence in the question response system, reaction finishes;
4. screening separates the coarse-grain that obtains, and just can obtain qualified product D-naphthalene glycine through recrystallization.
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| EP1275723A1 (en) * | 2001-07-10 | 2003-01-15 | Ajinomoto Co., Inc. | Recombinant D-hydantoin hydrolases and N-carbamyl-D-amino acid hydrolases, and DNA encoding them; uses thereof for producing D-amino acids |
| CN1431295A (en) * | 2002-12-30 | 2003-07-23 | 南京工业大学 | Method for producing D-a amino acid series by using De's bacterium of Bakehuo in onions |
| CN1928103A (en) * | 2006-08-30 | 2007-03-14 | 石家庄经济技术开发区中天化工有限责任公司 | Method of producing D-p-hydroxy-phenyl glycine by heterogeneous enzyme catalysis method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP1275723A1 (en) * | 2001-07-10 | 2003-01-15 | Ajinomoto Co., Inc. | Recombinant D-hydantoin hydrolases and N-carbamyl-D-amino acid hydrolases, and DNA encoding them; uses thereof for producing D-amino acids |
| CN1431295A (en) * | 2002-12-30 | 2003-07-23 | 南京工业大学 | Method for producing D-a amino acid series by using De's bacterium of Bakehuo in onions |
| CN1928103A (en) * | 2006-08-30 | 2007-03-14 | 石家庄经济技术开发区中天化工有限责任公司 | Method of producing D-p-hydroxy-phenyl glycine by heterogeneous enzyme catalysis method |
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