CN117776947A - Preparation method of sodium and calcium raceme isoleucine - Google Patents
Preparation method of sodium and calcium raceme isoleucine Download PDFInfo
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- CN117776947A CN117776947A CN202311639344.2A CN202311639344A CN117776947A CN 117776947 A CN117776947 A CN 117776947A CN 202311639344 A CN202311639344 A CN 202311639344A CN 117776947 A CN117776947 A CN 117776947A
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- Prior art keywords
- isoleucine
- sodium
- raceme
- temperature
- calcium
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- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 title claims abstract description 61
- 229960000310 isoleucine Drugs 0.000 title claims abstract description 61
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 title claims abstract description 61
- 239000011734 sodium Substances 0.000 title claims abstract description 57
- 229910052708 sodium Inorganic materials 0.000 title claims abstract description 57
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 title abstract description 10
- 239000011575 calcium Substances 0.000 title abstract description 10
- 229910052791 calcium Inorganic materials 0.000 title abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 61
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims abstract description 42
- 238000004321 preservation Methods 0.000 claims abstract description 36
- 238000003756 stirring Methods 0.000 claims abstract description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 229940091173 hydantoin Drugs 0.000 claims abstract description 27
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 22
- 230000001105 regulatory effect Effects 0.000 claims abstract description 17
- 238000010438 heat treatment Methods 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims abstract description 15
- 239000003513 alkali Substances 0.000 claims abstract description 14
- 159000000007 calcium salts Chemical class 0.000 claims abstract description 14
- 238000001816 cooling Methods 0.000 claims abstract description 14
- 238000002156 mixing Methods 0.000 claims abstract description 12
- 238000002425 crystallisation Methods 0.000 claims abstract description 5
- 230000008025 crystallization Effects 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 48
- 238000001914 filtration Methods 0.000 claims description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- HAKYTLKBERZBAM-FHAQVOQBSA-N [Ca].CC[C@H](C)[C@H](N=O)C(O)=O Chemical compound [Ca].CC[C@H](C)[C@H](N=O)C(O)=O HAKYTLKBERZBAM-FHAQVOQBSA-N 0.000 claims description 15
- -1 isoleucine calcium salt Chemical compound 0.000 claims description 12
- 239000008213 purified water Substances 0.000 claims description 12
- UCEVWHLQENWBLK-FHAQVOQBSA-N [Ca].CC[C@H](C)[C@H](N)C(O)=O Chemical compound [Ca].CC[C@H](C)[C@H](N)C(O)=O UCEVWHLQENWBLK-FHAQVOQBSA-N 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 11
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 9
- 239000001110 calcium chloride Substances 0.000 claims description 9
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 9
- 235000011148 calcium chloride Nutrition 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 238000002474 experimental method Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 claims description 3
- 239000001639 calcium acetate Substances 0.000 claims description 3
- 235000011092 calcium acetate Nutrition 0.000 claims description 3
- 229960005147 calcium acetate Drugs 0.000 claims description 3
- 239000004227 calcium gluconate Substances 0.000 claims description 3
- 229960004494 calcium gluconate Drugs 0.000 claims description 3
- 235000013927 calcium gluconate Nutrition 0.000 claims description 3
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000012266 salt solution Substances 0.000 claims description 3
- 229960002713 calcium chloride Drugs 0.000 claims description 2
- 238000012824 chemical production Methods 0.000 claims description 2
- 102000004879 Racemases and epimerases Human genes 0.000 claims 8
- 108090001066 Racemases and epimerases Proteins 0.000 claims 8
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 9
- 239000000126 substance Substances 0.000 abstract description 9
- 230000007062 hydrolysis Effects 0.000 abstract description 7
- 238000006297 dehydration reaction Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000005815 base catalysis Methods 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 21
- 239000007864 aqueous solution Substances 0.000 description 9
- 239000012295 chemical reaction liquid Substances 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 8
- 229960005069 calcium Drugs 0.000 description 8
- VKDSQMAMKKIKGQ-FHAQVOQBSA-N (2s,3s)-2-amino-3-methylpentanoic acid;sodium Chemical compound [Na].CC[C@H](C)[C@H](N)C(O)=O VKDSQMAMKKIKGQ-FHAQVOQBSA-N 0.000 description 6
- 150000003385 sodium Chemical class 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 3
- JVQYSWDUAOAHFM-UHFFFAOYSA-N 3-methyl-2-oxovaleric acid Chemical compound CCC(C)C(=O)C(O)=O JVQYSWDUAOAHFM-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- VOTJRUMOYQHLFS-UHFFFAOYSA-N 5-hydroxy-5-(2-methylpropyl)imidazolidine-2,4-dione Chemical compound CC(C)CC1(O)NC(=O)NC1=O VOTJRUMOYQHLFS-UHFFFAOYSA-N 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- ICUUWNSKLVVRHQ-WFGSYIHQSA-L calcium (2S,3S)-3-methyl-2-nitrosopentanoate Chemical compound CC[C@H](C)[C@@H](C(=O)[O-])N=O.CC[C@H](C)[C@@H](C(=O)[O-])N=O.[Ca+2] ICUUWNSKLVVRHQ-WFGSYIHQSA-L 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- NQZACQYNHPSSFV-FHAQVOQBSA-M sodium;(2s,3s)-2-amino-3-methylpentanoate Chemical compound [Na+].CC[C@H](C)[C@H](N)C([O-])=O NQZACQYNHPSSFV-FHAQVOQBSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of chemical preparation, and discloses a preparation method of raceme sodium isoleucine, which specifically comprises the following steps: s1, mixing 100-200 parts by weight of hydantoin, 100-200 parts by weight of alkali, 50-100 parts by weight of butanone, 50-100 parts by weight of water and 200-400 parts by weight of alcohol; s2, stirring by using stirring equipment, heating to 10-50 ℃, and carrying out heat preservation reaction for 5h; s3, gradually increasing the temperature and concentrating the mixture at normal pressure to obtain alcohol, and increasing the temperature to 60-100 ℃; s4, after the heat preservation reaction is carried out for 15 hours, the temperature of the reaction solution is reduced and cooled to 10-50 ℃; s5, regulating the pH value to 5-7, and cooling to 0-20 ℃ for crystallization; the invention adopts low-temperature base catalysis, after the intermediate 5-sec-butyl-5-hydroxy hydantoin is generated by reaction, the temperature is continuously increased to carry out hydrolysis and dehydration reaction, so that the high-purity and high-yield sodium dehydroketoisoleucine can be obtained, and then the sodium dehydroketoisoleucine reacts with calcium salt to obtain calcium dehydroketoisoleucine. The synthesis process has the advantages of easily available raw materials, simple and convenient operation, environmental protection and suitability for industrial production.
Description
Technical Field
The invention relates to the technical field of chemical preparation, and in particular discloses a preparation method of sodium and calcium raceme isoleucine.
Background
Chemical preparation is to prepare the required substances through a series of chemical reactions by utilizing the properties of various chemical substances. The number of chemicals available worldwide is up to 700 ten thousand, and more than 7 ten thousand are often used. Chemicals come in a variety of forms, mostly gaseous, liquid and solid.
According to literature reports, the preparation method of the raceme isoleucine calcium one-pot method is found, and mainly comprises the following two methods: in the scheme 1, butanone and hydantoin are used as raw materials, reacted under the action of organic alkali to generate 5-sec-butylidene hydantoin, hydrolyzed under the condition of adding strong alkali, and reacted with calcium salt to generate the raceme ketoisoleucine calcium. In the scheme 2, 5-sec-butylidene hydantoin is produced through reaction under the action of ammonia water or inorganic base, hydrolysis is carried out under the condition of adding strong alkali, and racemization ketone isoleucine calcium is produced through reaction with calcium salt.
Experiments show that under the condition that organic alkali exists in the system, the organic alkali can interfere the hydrolysis process, so that the raceme isoleucine is excessively hydrolyzed into isobutyric acid, and the raceme isoleucine calcium cannot be prepared. The catalytic effect of ammonia water and inorganic base used alone is poor, and the reaction is basically avoided. Therefore, a preparation method of the raceme sodium isoleucine and the raceme calcium isoleucine is designed.
Disclosure of Invention
The invention provides a preparation method of raceme sodium isoleucine and raceme calcium isoleucine, which can solve the problems in the prior art.
In order to solve the technical problems, according to one aspect of the present invention, more specifically, a preparation method of racemic ketoisoleucine sodium is provided, hydantoin and butanone react at a low temperature under the action of a solvent, then the temperature is raised for reaction, and the pH is adjusted to obtain the racemic ketoisoleucine sodium, which specifically comprises the following steps:
s1, mixing 100-200 parts by weight of hydantoin, 100-200 parts by weight of alkali, 50-100 parts by weight of butanone, 50-100 parts by weight of water and 200-400 parts by weight of alcohol;
s2, stirring by using stirring equipment, heating to 10-50 ℃, and carrying out heat preservation reaction for 5h;
s3, gradually increasing the temperature and concentrating the mixture at normal pressure to obtain alcohol, and increasing the temperature to 60-100 ℃;
s4, after the heat preservation reaction is carried out for 15 hours, the temperature of the reaction solution is reduced and cooled to 10-50 ℃;
s5, regulating the pH value to 5-7, and cooling to 0-20 ℃ for crystallization;
s6, filtering after 1-3 h to obtain the raceme sodium isoleucine.
Further, the solvent is one or more of methanol, ethanol and water.
Further, in the step S1, the alcohol is methanol, ethanol or isopropanol.
Further, in the step S1, sodium hydroxide is used as the base.
Furthermore, the molar ratio of the hydantoin to the butanone to the alkali is 1:1-2:2-4.
Further, in the step S6, filter paper may be used for filtration in the experiment, and industrial solid-liquid filter may be used in the chemical production.
According to one aspect of the present invention, there is further provided a method for preparing a racemic ketoisoleucine calcium salt, which is based on a method for preparing a racemic ketoisoleucine sodium salt as defined in any one of claims 1 to 6, comprising the steps of:
s1, adding sodium raceme isoleucine into purified water with the weight being 5 times that of the sodium raceme isoleucine, and heating to 20-30 ℃;
s2, adding 400 parts by weight of 10-20% calcium salt solution, uniformly stirring, and carrying out heat preservation reaction for 1-3 h;
s3, filtering to obtain the raceme isoleucine calcium.
Further, in the step S2, the calcium salt is one or a mixture of two or three of calcium chloride, calcium acetate or calcium gluconate.
Furthermore, the raceme sodium isoleucine reacts with calcium salt under the condition of normal temperature and normal pressure.
Furthermore, the dosage mole ratio of the raceme isoleucine sodium salt to the calcium salt is 1:0.4-1.
The preparation method of the raceme sodium isoleucine and the raceme calcium isoleucine has the beneficial effects that:
the invention adopts low-temperature base catalysis, after the intermediate 5-sec-butyl-5-hydroxy hydantoin is generated by reaction, the temperature is continuously increased to carry out hydrolysis and dehydration reaction, so that the high-purity and high-yield sodium dehydroketoisoleucine can be obtained, and then the sodium dehydroketoisoleucine reacts with calcium salt to obtain calcium dehydroketoisoleucine. The synthesis process has the advantages of easily available raw materials, simple and convenient operation, environmental protection and suitability for industrial production.
Drawings
The invention will be described in further detail with reference to the accompanying drawings and detailed description.
FIG. 1 shows the chemical equation of hydantoin in the present invention in alcohol and water solvent with strong alkali to produce 5-isobutyl-5-hydroxy hydantoin;
FIG. 2 is a chemical equation of the hydrolysis and dehydration reaction of 5-isobutyl-5-hydroxyhydantoin to form sodium isoleucine racemate in the present invention;
FIG. 3 shows the calcification equation of the substitution of sodium and calcium salts of racemic ketoisoleucine into racemic ketoisoleucine in the present invention.
Detailed Description
The invention will be described in detail hereinafter with reference to the drawings in conjunction with embodiments. It should be noted that, in the case of no conflict, the embodiments and features in the embodiments may be combined with each other.
According to the attached figures 1-3, a preparation method of the raceme sodium isoleucine is provided, hydantoin and butanone react at a low temperature under the action of a solvent, then the temperature is raised for reaction, and the pH is regulated to obtain the raceme sodium isoleucine. The method is realized based on the preparation method of the sodium raceme isoleucine according to any one of claims 1-6, the sodium raceme isoleucine is added into purified water with the weight of 5, the temperature is raised to 20-30 ℃, 400 parts by weight of 10-20% calcium salt solution is added, the heat preservation reaction is carried out for 1-3 hours, and then the filtration is carried out to obtain the calcium raceme isoleucine.
Example 1
The preparation method of the raceme sodium isoleucine specifically comprises the following steps:
s1, adding 100g of hydantoin, 65g of water, 200g of methanol, 110g of sodium hydroxide and 80g of butanone into a 1L three-necked flask and mixing;
s2, stirring and heating to 35 ℃ by using stirring equipment, and carrying out heat preservation reaction for 5 hours;
s3, gradually increasing the temperature and concentrating the mixture at normal pressure to obtain alcohol, and increasing the temperature to 95 ℃;
s4, after the heat preservation reaction is carried out for 15 hours, the temperature of the reaction liquid is reduced and cooled to 20-40 ℃;
s5, regulating the pH value to 6.5 by using 31% hydrochloric acid, continuously cooling to 0-15 ℃, and preserving heat and crystallizing for 2 hours;
s6, filtering to obtain 143.4g of raceme sodium isoleucine, and obtaining 94.3% of yield and 99.62% of HPLC purity.
The preparation method of the racemic ketoisoleucine calcium specifically comprises the following steps:
s1, adding 717g of purified water and 143.4g of alpha-racemization ketoisoleucine sodium into a 2L three-mouth bottle, stirring the solution, and filtering;
s2, slowly dripping 400g of filtered calcium chloride aqueous solution with the weight percentage of 10%, and carrying out heat preservation reaction for 2 hours at room temperature;
s3, filtering, washing and drying to obtain 139.9g of alpha-racemic ketoisoleucine calcium, with a yield of 97.6% and an HPLC purity of 99.95%.
Example 2
The preparation method of the raceme sodium isoleucine specifically comprises the following steps:
s1, adding 100g of hydantoin, 65g of water, 400g of methanol, 110g of sodium hydroxide and 80g of butanone into a 1L three-necked flask and mixing;
s2, stirring and heating to 35 ℃ by using stirring equipment, and carrying out heat preservation reaction for 5 hours;
s3, gradually increasing the temperature and concentrating the mixture at normal pressure to obtain alcohol, and increasing the temperature to 95 ℃;
s4, after the heat preservation reaction is carried out for 15 hours, the temperature of the reaction liquid is reduced and cooled to 20-40 ℃;
s5, regulating the pH value to 6.5 by using 31% hydrochloric acid, continuously cooling to 0-15 ℃, and preserving heat and crystallizing for 2 hours;
s6, filtering to obtain 141.2g of raceme sodium isoleucine, wherein the yield is 92.9%, and the HPLC purity is 99.41%.
The preparation method of the racemic ketoisoleucine calcium specifically comprises the following steps:
s1, adding 706g of purified water and 141.2g of alpha-racemization ketoisoleucine sodium into a 2L three-mouth bottle, stirring the solution, and filtering;
s2, slowly dripping 400g of filtered calcium acetate aqueous solution with the weight percentage of 14.2%, and carrying out heat preservation reaction at room temperature for 2 hours;
s3, filtering, washing and drying to obtain 135.7g of racemic ketoisoleucine calcium with 96.1 percent of yield and 99.91 percent of HPLC purity.
Example 3
The preparation method of the raceme sodium isoleucine specifically comprises the following steps:
s1, adding 100g of hydantoin, 65g of water, 200g of ethanol, 110g of sodium hydroxide and 80g of butanone into a 1L three-necked flask and mixing;
s2, stirring and heating to 35 ℃ by using stirring equipment, and carrying out heat preservation reaction for 5 hours;
s3, gradually increasing the temperature and concentrating the mixture at normal pressure to obtain alcohol, and increasing the temperature to 95 ℃;
s4, after the heat preservation reaction is carried out for 15 hours, the temperature of the reaction liquid is reduced and cooled to 20-40 ℃;
s5, regulating the pH value to 6.5 by using 31% hydrochloric acid, continuously cooling to 0-15 ℃, and preserving heat and crystallizing for 2 hours;
s6, filtering to obtain 139.9g of raceme sodium isoleucine, wherein the yield is 92.0%, and the HPLC purity is 99.38%.
The preparation method of the racemic ketoisoleucine calcium specifically comprises the following steps:
s1, adding 699.5g of purified water and 139.9g of raceme isoleucine sodium into a 2L three-mouth bottle, stirring the solution, and filtering;
s2, slowly dripping 400g of filtered calcium gluconate aqueous solution with the weight percentage of 20 percent into the mixture at the temperature of 20-30 ℃ and carrying out heat preservation reaction at room temperature for 2 hours;
s3, filtering, washing and drying to obtain 131.8g of the raceme isoleucine calcium, wherein the yield is 94.3% and the HPLC purity is 99.89%.
Example 4
The preparation method of the raceme sodium isoleucine specifically comprises the following steps:
s1, adding 100g of hydantoin, 65g of water, 200g of isopropanol, 110g of sodium hydroxide and 80g of butanone into a 1L three-necked flask and mixing;
s2, stirring and heating to 35 ℃ by using stirring equipment, and carrying out heat preservation reaction for 5 hours;
s3, gradually increasing the temperature and concentrating the mixture at normal pressure to obtain alcohol, and increasing the temperature to 95 ℃;
s4, after the heat preservation reaction is carried out for 15 hours, the temperature of the reaction liquid is reduced and cooled to 20-40 ℃;
s5, regulating the pH value to 6.5 by using 31% hydrochloric acid, continuously cooling to 0-15 ℃, and preserving heat and crystallizing for 2 hours;
s6, filtering to obtain 135.4g of raceme sodium isoleucine, wherein the yield is 89.1%, and the HPLC purity is 99.86%.
The preparation method of the racemic ketoisoleucine calcium specifically comprises the following steps:
s1, adding 677g of purified water and 135.4g of raceme isoleucine sodium into a 2L three-mouth bottle, stirring the solution, and filtering;
s2, slowly dripping 400g of filtered calcium chloride aqueous solution with the weight percentage of 10%, and carrying out heat preservation reaction for 2 hours at room temperature;
s3, filtering, washing and drying to obtain 132.4g of the raceme isoleucine calcium, wherein the yield is 97.6%, and the HPLC purity is 99.93%.
Example 5
The preparation method of the raceme sodium isoleucine specifically comprises the following steps:
s1, adding 100g of hydantoin, 100g of water, 200g of methanol, 110g of sodium hydroxide and 80g of butanone into a 1L three-necked flask and mixing;
s2, stirring and heating to 35 ℃ by using stirring equipment, and carrying out heat preservation reaction for 5 hours;
s3, gradually increasing the temperature and concentrating the mixture at normal pressure to obtain alcohol, and increasing the temperature to 95 ℃;
s4, after the heat preservation reaction is carried out for 15 hours, the temperature of the reaction liquid is reduced and cooled to 20-40 ℃;
s5, regulating the pH value to 6.5 by using 31% hydrochloric acid, continuously cooling to 0-15 ℃, and preserving heat and crystallizing for 2 hours;
s6, filtering to obtain 140.8g of sodium racemate isoleucine, wherein the yield is 92.6%, and the HPLC purity is 99.56%.
The preparation method of the racemic ketoisoleucine calcium specifically comprises the following steps:
s1, adding 700g of purified water, 140.8g of raceme isoleucine sodium into a 2L three-mouth bottle, stirring the solution, and filtering;
s2, slowly dripping 400g of filtered calcium chloride aqueous solution with the weight percentage of 10%, and carrying out heat preservation reaction for 2 hours at room temperature;
s3, filtering, washing and drying to obtain 134.2g of the raceme isoleucine calcium, wherein the yield is 95.3% and the HPLC purity is 99.92%.
Example 6
The preparation method of the raceme sodium isoleucine specifically comprises the following steps:
s1, adding 100g of hydantoin, 65g of water, 200g of methanol, 200g of sodium hydroxide and 80g of butanone into a 1L three-necked flask and mixing;
s2, stirring and heating to 35 ℃ by using stirring equipment, and carrying out heat preservation reaction for 5 hours;
s3, gradually increasing the temperature and concentrating the mixture at normal pressure to obtain alcohol, and increasing the temperature to 95 ℃;
s4, after the heat preservation reaction is carried out for 15 hours, the temperature of the reaction liquid is reduced and cooled to 20-40 ℃;
s5, regulating pH to 7.0 by using 31% hydrochloric acid, continuously cooling to 0-15 ℃, and preserving heat and crystallizing for 2 hours;
s6, filtering to obtain 126.5g of raceme sodium isoleucine, with a yield of 83.2% and an HPLC purity of 98.53%.
The preparation method of the racemic ketoisoleucine calcium specifically comprises the following steps:
s1, adding 632.5g of purified water and 126.5g of raceme isoleucine sodium into a 2L three-mouth bottle, stirring the solution, and filtering;
s2, slowly dripping 400g of filtered calcium chloride aqueous solution with the weight percentage of 10%, and carrying out heat preservation reaction for 2 hours at room temperature;
s3, filtering, washing and drying to obtain 123.8g of racemic ketoisoleucine calcium with 97.3% yield and 99.90% HPLC purity.
Example 7
The preparation method of the raceme sodium isoleucine specifically comprises the following steps:
s1, adding 100g of hydantoin, 50g of water, 200g of methanol, 110g of sodium hydroxide and 50g of butanone into a 1L three-necked flask and mixing;
s2, stirring and heating to 10 ℃ by using stirring equipment, and carrying out heat preservation reaction for 5 hours;
s3, gradually increasing the temperature and concentrating the mixture at normal pressure to obtain alcohol, and increasing the temperature to 60 ℃;
s4, after the heat preservation reaction is carried out for 15 hours, the temperature of the reaction liquid is reduced and cooled to 20-40 ℃;
s5, regulating the pH value to 5.0 by using 31% hydrochloric acid, continuously cooling to 0-15 ℃, and preserving heat and crystallizing for 2 hours;
s6, filtering to obtain 109.6g of raceme sodium isoleucine, with a yield of 72.1% and an HPLC purity of 95.96%.
The preparation method of the racemic ketoisoleucine calcium specifically comprises the following steps:
s1, adding 548g of purified water and 109.6g of raceme sodium isoleucine into a 2L three-port bottle, stirring the solution, and filtering;
s2, slowly dripping 400g of filtered calcium chloride aqueous solution with the weight percentage of 10%, and carrying out heat preservation reaction for 2 hours at room temperature;
s3, filtering, washing and drying to obtain 102.3g of the raceme isoleucine calcium with the yield of 93.4% and the HPLC purity of 99.79%.
Example 8
The preparation method of the raceme sodium isoleucine specifically comprises the following steps:
s1, adding 100g of hydantoin, 65g of water, 200g of methanol, 110g of sodium hydroxide and 100g of butanone into a 1L three-necked flask and mixing;
s2, stirring and heating to 35 ℃ by using stirring equipment, and carrying out heat preservation reaction for 5 hours;
s3, gradually increasing the temperature and concentrating the mixture at normal pressure to obtain alcohol, and increasing the temperature to 95 ℃;
s4, after the heat preservation reaction is carried out for 15 hours, the temperature of the reaction liquid is reduced and cooled to 20-40 ℃;
s5, regulating pH to 7.0 by using 31% hydrochloric acid, continuously cooling to 0-15 ℃, and preserving heat and crystallizing for 2 hours;
s6, filtering to obtain 135.3g of raceme sodium isoleucine, wherein the yield is 89.0%, and the HPLC purity is 99.60%.
The preparation method of the racemic ketoisoleucine calcium specifically comprises the following steps:
s1, adding 676.5g of purified water and 135.3g of alpha-racemic ketoisoleucine sodium into a 2L three-necked flask, stirring the solution, and filtering;
s2, slowly dripping 400g of filtered calcium chloride aqueous solution with the weight percentage of 10%, and carrying out heat preservation reaction for 2 hours at room temperature;
s3, filtering, washing and drying to obtain 121.3g of racemic ketoisoleucine calcium with the yield of 89.6% and the HPLC purity of 99.69%.
Example 9
The preparation method of the raceme sodium isoleucine specifically comprises the following steps:
s1, adding 100g of hydantoin, 100g of water, 400g of methanol, 100g of sodium hydroxide and 100g of butanone into a 1L three-necked flask and mixing;
s2, stirring and heating to 50 ℃ by using stirring equipment, and carrying out heat preservation reaction for 5 hours;
s3, gradually increasing the temperature and concentrating the mixture at normal pressure to obtain alcohol, and increasing the temperature to 100 ℃;
s4, after the heat preservation reaction is carried out for 15 hours, the temperature of the reaction liquid is reduced and cooled to 20-40 ℃;
s5, regulating pH to 7.0 by using 31% hydrochloric acid, continuously cooling to 0-15 ℃, and preserving heat and crystallizing for 2 hours;
s6, filtering to obtain 118.3g of sodium racemate isoleucine, wherein the yield is 77.8%, and the HPLC purity is 99.10%.
The preparation method of the racemic ketoisoleucine calcium specifically comprises the following steps:
s1, adding 591.5g of purified water and 118.3g of raceme isoleucine sodium into a 2L three-mouth bottle, stirring the solution, and filtering;
s2, slowly dripping 400g of filtered calcium chloride aqueous solution with the weight percentage of 10%, and carrying out heat preservation reaction for 2 hours at room temperature;
s3, filtering, washing and drying to obtain 114.4g of the raceme isoleucine calcium with the yield of 96.7% and the HPLC purity of 99.63%.
Comparison experiment:
in the prior art, monoethanolamine is used as a catalyst to prepare sub-sec-butylhydantoin firstly and then is hydrolyzed under strong alkali to prepare the raceme isoleucine calcium, but organic alkali exists in the hydrolysis reaction process to cause excessive hydrolysis of a product, and compared with the experiment, the molar ratio hydantoin is used: monoethanolamine=1:0.8 is used as a catalyst for synthesis, the reaction is carried out for 5 hours at low temperature, then sodium hydroxide is added, the reaction is carried out for 15 hours at high temperature, and the yield of the sodium dehydroketoisoleucine is compared.
Examples: a. Preparation method of sodium racemate isoleucine in example 1.
Comparative example 1: 100g of hydantoin, 65g of water, 61.2g of ethanolamine and 80g of butanone are added into a 1L three-necked flask and mixed, stirred and heated to 35 ℃, the temperature is kept for reaction for 5 hours, 110kg of sodium hydroxide is added into the system, the temperature is gradually raised to 95 ℃, and the temperature is kept for reaction for 15 hours. After the reaction is finished, the temperature is reduced to 20-40 ℃, the pH value is regulated to 6.5 by 31% hydrochloric acid, the temperature is reduced to 0-15 ℃, the temperature is kept for crystallization for 2 hours, 99.6g of the raceme sodium isoleucine is obtained by filtration, the yield is 65.5%, and the HPLC purity is 94.98%.
Examples: the preparation of sodium racemate isoleucine in example 7.
Comparative example 2: 100g of hydantoin, 50g of water, 61.2g of ethanolamine and 50g of butanone are added into a 1L three-necked flask and mixed, stirred and heated to 10 ℃, the temperature is kept for reaction for 5 hours, 100kg of sodium hydroxide is added into the system, the temperature is gradually raised to 60 ℃, and the temperature is kept for reaction for 2 hours. After the reaction is finished, the temperature is reduced to 20-40 ℃, the pH value is regulated to 5.0 by 31% hydrochloric acid, the temperature is reduced to 0-15 ℃, the temperature is kept for crystallization for 2 hours, 60.5g of the raceme isoleucine sodium is obtained by filtration, the yield is 39.8%, and the HPLC purity is 88.49%.
Examples: a. Preparation of sodium racemate isoleucine in example 9.
Comparative example 3: 100g of hydantoin, 100g of water, 61.2g of ethanolamine and 100g of butanone are added into a 1L three-necked flask and mixed, the mixture is stirred and heated to 50 ℃, the temperature is kept for reaction for 5 hours, 200kg of sodium hydroxide is added into the system, the temperature is gradually raised to 100 ℃, and the reaction is kept for 2 hours. After the reaction, cooling to 20-40 ℃, regulating pH7.0 with 31% hydrochloric acid, continuously cooling to 0-15 ℃, preserving heat and crystallizing for 2 hours, and filtering to obtain 94.3g of raceme sodium isoleucine, the yield is 62.0%, and the HPLC purity is 91.94%.
The comparative experiment proves that sodium hydroxide is used as a catalyst, intermediate state can be generated in an alcohol and water system by reaction at low temperature, and then high-yield sodium ketoisoleucine is obtained by heating, hydrolyzing and dehydrating, the sub-sec-butyl hydantoin is not needed to be prepared at high temperature, the hydrolysis of hydantoin is avoided, and the high-yield and high-purity sodium ketoisoleucine can be obtained by the method provided by the invention, and the method has obvious superiority.
The working principle of the device is as follows: the method is characterized in that the starting raw materials of the marine product are subjected to low-temperature condensation reaction to generate an intermediate state, then the intermediate state is subjected to high-temperature hydrolysis reaction and dehydration, so that the high-purity and high-yield raceme sodium isoleucine can be obtained, and then the raceme sodium isoleucine can be prepared from the raceme sodium isoleucine, and the high-purity and high-yield raceme calcium isoleucine can also be obtained.
Wherein the electrical components presented herein are all electrical components that are present in reality.
Of course, the above description is not intended to limit the invention, but rather the invention is not limited to the above examples, and variations, modifications, additions or substitutions within the spirit and scope of the invention will be within the scope of the invention.
Claims (10)
1. The preparation method of the raceme sodium isoleucine comprises the steps of firstly carrying out low-temperature reaction on hydantoin and butanone under the action of a solvent, then carrying out temperature-rising reaction, and regulating pH to obtain the raceme sodium isoleucine, and is characterized in that: the method specifically comprises the following steps:
s1, mixing 100-200 parts by weight of hydantoin, 100-200 parts by weight of alkali, 50-100 parts by weight of butanone, 50-100 parts by weight of water and 200-400 parts by weight of alcohol;
s2, stirring by using stirring equipment, heating to 10-50 ℃, and carrying out heat preservation reaction for 5h;
s3, gradually increasing the temperature and concentrating the mixture at normal pressure to obtain alcohol, and increasing the temperature to 60-100 ℃;
s4, after the heat preservation reaction is carried out for 15 hours, the temperature of the reaction solution is reduced and cooled to 10-50 ℃;
s5, regulating the pH value to 5-7, and cooling to 0-20 ℃ for crystallization;
s6, filtering after 1-3 h to obtain the raceme sodium isoleucine.
2. The method for preparing the sodium racemase isoleucine as defined in claim 1, which is characterized in that: the solvent is one or more of methanol, ethanol and water.
3. The method for preparing the sodium racemase isoleucine as defined in claim 1, which is characterized in that: in the step S1, the alcohol is methanol, ethanol or isopropanol.
4. The method for preparing the sodium racemase isoleucine as defined in claim 1, which is characterized in that: in the step S1, sodium hydroxide is used as the alkali.
5. The method for preparing the sodium racemase isoleucine as defined in claim 1, which is characterized in that: the molar ratio of the hydantoin to the butanone to the alkali is 1:1-2:2-4.
6. The method for preparing the sodium racemase isoleucine as defined in claim 1, which is characterized in that: in the step S6, filter paper may be used for filtration in the experiment, and an industrial solid-liquid filter may be used in the chemical production.
7. A preparation method of racemic ketoisoleucine calcium is characterized by comprising the following steps: the method is realized based on the preparation method of the raceme sodium isoleucine according to any one of claims 1-6, and specifically comprises the following steps:
s1, adding sodium raceme isoleucine into purified water with the weight being 5 times that of the sodium raceme isoleucine, and heating to 20-30 ℃;
s2, adding 400 parts by weight of 10-20% calcium salt solution, uniformly stirring, and carrying out heat preservation reaction for 1-3 h;
s3, filtering to obtain the raceme isoleucine calcium.
8. The method for preparing the racemase isoleucine calcium salt as defined in claim 7, wherein: in the step S2, the calcium salt adopts one or two or three of calcium chloride, calcium acetate or calcium gluconate.
9. The method for preparing the racemase isoleucine calcium salt as defined in claim 8, wherein: the raceme sodium isoleucine reacts with calcium salt under normal temperature and normal pressure.
10. The method for preparing the racemase isoleucine calcium salt as defined in claim 9, wherein: the dosage molar ratio of the raceme sodium isoleucine to the calcium salt is 1:0.4-1.
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