CN118164869A - Method for preparing N, N-dioctanoyl alanine ethyl ester and application thereof - Google Patents
Method for preparing N, N-dioctanoyl alanine ethyl ester and application thereof Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 77
- ROBXZHNBBCHEIQ-BYPYZUCNSA-N ethyl (2s)-2-aminopropanoate Chemical compound CCOC(=O)[C@H](C)N ROBXZHNBBCHEIQ-BYPYZUCNSA-N 0.000 title claims abstract description 30
- 239000002904 solvent Substances 0.000 claims abstract description 48
- 239000002994 raw material Substances 0.000 claims abstract description 42
- 239000012043 crude product Substances 0.000 claims abstract description 29
- 125000004494 ethyl ester group Chemical group 0.000 claims abstract description 21
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 20
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 20
- 238000004537 pulping Methods 0.000 claims abstract description 18
- 238000002156 mixing Methods 0.000 claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 105
- 239000012535 impurity Substances 0.000 claims description 66
- -1 N, N-bisoxalyl-alanine ethyl ester Chemical compound 0.000 claims description 56
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 33
- 238000004821 distillation Methods 0.000 claims description 32
- 238000002425 crystallisation Methods 0.000 claims description 30
- 230000008025 crystallization Effects 0.000 claims description 30
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 claims description 30
- 239000000243 solution Substances 0.000 claims description 26
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 20
- 229960003767 alanine Drugs 0.000 claims description 20
- 238000000746 purification Methods 0.000 claims description 20
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 claims description 19
- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 claims description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 18
- 239000000126 substance Substances 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 claims description 16
- 238000004064 recycling Methods 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 229940011671 vitamin b6 Drugs 0.000 claims description 15
- 239000011726 vitamin B6 Substances 0.000 claims description 14
- 235000019158 vitamin B6 Nutrition 0.000 claims description 14
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 claims description 13
- 238000010438 heat treatment Methods 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 12
- 235000006408 oxalic acid Nutrition 0.000 claims description 11
- 238000010009 beating Methods 0.000 claims description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 230000007062 hydrolysis Effects 0.000 claims description 9
- 239000003444 phase transfer catalyst Substances 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 8
- 230000002194 synthesizing effect Effects 0.000 claims description 8
- 238000009835 boiling Methods 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000010413 mother solution Substances 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims description 2
- 150000003242 quaternary ammonium salts Chemical group 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims 1
- 238000011084 recovery Methods 0.000 abstract description 24
- FWPDSAJKWKRRJD-UHFFFAOYSA-N 5-ethoxy-4-methyl-1,3-oxazole Chemical compound CCOC=1OC=NC=1C FWPDSAJKWKRRJD-UHFFFAOYSA-N 0.000 abstract description 18
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 235000019441 ethanol Nutrition 0.000 description 33
- 239000012452 mother liquor Substances 0.000 description 15
- 239000012065 filter cake Substances 0.000 description 14
- 238000004519 manufacturing process Methods 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 9
- 230000020477 pH reduction Effects 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 238000000967 suction filtration Methods 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- RBCOYOYDYNXAFA-UHFFFAOYSA-L (5-hydroxy-4,6-dimethylpyridin-3-yl)methyl phosphate Chemical compound CC1=NC=C(COP([O-])([O-])=O)C(C)=C1O RBCOYOYDYNXAFA-UHFFFAOYSA-L 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000001819 mass spectrum Methods 0.000 description 5
- 239000013558 reference substance Substances 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000012670 alkaline solution Substances 0.000 description 2
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- NHZMQXZHNVQTQA-UHFFFAOYSA-N pyridoxamine Chemical compound CC1=NC=C(CO)C(CN)=C1O NHZMQXZHNVQTQA-UHFFFAOYSA-N 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000002457 bidirectional effect Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000032798 delamination Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- PQRKGFMROBZFIM-UHFFFAOYSA-N ethyl 5-ethoxy-4-methyl-1,3-oxazole-2-carboxylate Chemical compound CCOC(=O)C1=NC(C)=C(OCC)O1 PQRKGFMROBZFIM-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- HKVLOZLUWWLDFP-UHFFFAOYSA-M hydron;tetrabutylazanium;carbonate Chemical compound OC([O-])=O.CCCC[N+](CCCC)(CCCC)CCCC HKVLOZLUWWLDFP-UHFFFAOYSA-M 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000003431 oxalo group Chemical group 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 235000008164 pyridoxal Nutrition 0.000 description 1
- 239000011674 pyridoxal Substances 0.000 description 1
- 229960003581 pyridoxal Drugs 0.000 description 1
- 235000008151 pyridoxamine Nutrition 0.000 description 1
- 239000011699 pyridoxamine Substances 0.000 description 1
- 235000008160 pyridoxine Nutrition 0.000 description 1
- 239000011677 pyridoxine Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- HRQDCDQDOPSGBR-UHFFFAOYSA-M sodium;octane-1-sulfonate Chemical compound [Na+].CCCCCCCCS([O-])(=O)=O HRQDCDQDOPSGBR-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
- G01N1/34—Purifying; Cleaning
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
- G01N2001/2893—Preparing calibration standards
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the field of synthesis of 4-methyl-5-ethoxy oxazole, and discloses a method for purifying N, N-dioxa-alanine ethyl ester, which is characterized by comprising the following steps: (1) Crystallizing a raw material containing N, N-dioxa-alanine ethyl ester; (2) Mixing the crude product of the N, N-dioxaoxalyl alanine ethyl ester obtained in the step (1) with a solvent for pulping; in the step (2), the solubility of the N, N-dioxazoylalanine ethyl ester in the solvent is less than or equal to 0.01g/100g of the solvent at 50 ℃. The method provided by the invention improves the purity and recovery rate of the N, N-bisoxalyl alanine ethyl ester, and has the advantages of low cost, low energy consumption, simple operation and convenience for industrial production.
Description
Technical Field
The invention relates to the field of synthesis of 4-methyl-5-ethoxy oxazole, in particular to a method for preparing N, N-dioxa-alanine ethyl ester and application thereof.
Background
Vitamin B 6 exists in nature in three forms, pyridoxine, pyridoxal and pyridoxamine. Under certain conditions, the three can mutually transform in vivo, and is one of vitamins necessary for human body. At present, vitamin B 6 is mainly prepared from 4-methyl-5-ethoxyoxazole industrially, and N-ethoxyoxalyl-L-alanine ethyl ester is an intermediate for synthesizing 4-methyl-5-ethoxyoxazole. The quality of the process for preparing N-ethoxyoxalyl-L-alanine ethyl ester indirectly determines the level of the process for producing vitamin B 6.
The synthesis process of the 4-methyl-5-ethoxy oxazole comprises the following steps:
In the process, the N-ethoxyoxalyl-L-alanine ethyl ester serving as a target intermediate is obtained through esterification reaction, the N-ethoxyoxalyl-L-alanine ethyl ester is obtained through reduced pressure distillation, and the residual solution of distillation equipment is identified by the inventor and mainly contains N, N-dioxaoxalyl alanine ethyl ester (figure 1), wherein the N, N-dioxaoxalyl alanine ethyl ester is formed by reacting two molecules of L-alanine ethyl ester with one molecule of diethyl oxalate. The existence of the impurity enables N, N-dioctanoyl ethyl ester to be dehydrated and cyclized in a bidirectional symmetry way in the next cyclization reaction to generate the impurity in the cyclization stage, thereby influencing the yield of 4-methyl-5-ethoxyoxazole, and the existence of the N, N-dioctanoyl ethyl ester leads to the increase of raw materials consumed in the cyclization process and the increase of production cost. In actual production, the yield of the impurity N, N-bisoxalyl alanine ethyl ester is 5-10%, and the impurity N, N-bisoxalyl alanine ethyl ester is often discarded, so that the environment is polluted, and the yield of the whole process is reduced.
Therefore, the impurity needs to be recycled to improve the production efficiency, and the pure N, N-bisoxaloacetate ethyl ester needs to be obtained as an impurity reference substance in the production process.
CN113214145A discloses a method for producing vitamin B6, wherein N, N-bisoxalyl-alanine ethyl ester is purified by distillation, but the method has the disadvantages of large energy consumption, long purification time, low purity of the obtained N, N-bisoxalyl-alanine ethyl ester, large loss in the purification process, and decomposition of the N, N-bisoxalyl-alanine ethyl ester caused by high temperature distillation. In addition, no other purification methods have been reported.
In view of the foregoing, there is a need for a method for separating and purifying ethyl N, N-dioxaoxalylalaninate to increase the purity of the ethyl N, N-dioxaoxalylalaninate and reduce losses during purification.
Disclosure of Invention
The inventors of the present invention have found in studies that, in comparison with a conventional distillation purification method, a plurality of crystallization can obtain N, N-bisoxalylalanine ethyl ester of higher purity, but a loss of N, N-bisoxalylalanine ethyl ester is caused in the process, in order to increase the purity of N, N-bisoxalylalanine ethyl ester while further increasing the recovery rate of purification, a first aspect of the present invention provides a method for purifying N, N-bisoxalylalanine ethyl ester, wherein the method comprises:
(1) Crystallizing a raw material containing N, N-dioxa-alanine ethyl ester;
(2) Mixing the crude product of the N, N-dioxaoxalyl alanine ethyl ester obtained in the step (1) with a solvent for pulping;
in step (2), the solvent is such that the solubility of ethyl N, N-dioxaoxalylalaninate in the solvent is below 0.01g/100g solvent at 50 ℃.
The second aspect of the invention provides a method for detecting impurities, which comprises the steps of purifying N, N-bisoxalylalanine ethyl ester by the method of the first aspect of the invention, and detecting impurities by taking the purified N, N-bisoxalylalanine ethyl ester as a standard substance and/or a reference substance.
The third aspect of the present invention provides a method for recycling N, N-bisoxalyl-alanine ethyl ester in a vitamin B6 synthesis process, the method comprising purifying a raw material containing N, N-bisoxalyl-alanine ethyl ester produced in the vitamin B6 synthesis process to obtain purified N, N-bisoxalyl-alanine ethyl ester, and then hydrolyzing the purified N, N-bisoxalyl-alanine ethyl ester for vitamin B6 synthesis;
wherein the purification method is the method according to the first aspect of the invention.
Through the technical scheme, the purification method provided by the invention has at least the following technical effects:
(1) The method prepares the high-purity N, N-dioxazoylalanine ethyl ester with high recovery rate through crystallization and pulping, and in some preferred embodiments, the purity of the N, N-dioxazoylalanine ethyl ester is more than 99 percent, and the N, N-dioxazoylalanine ethyl ester can be used as a standard substance or a reference substance in the production detection of 4-methyl-5-ethoxyoxazole; compared with the methods of distillation purification and crystallization purification, the method further improves the recovery rate and purity of the target product purification by pulping after crystallization, and has the advantages of low cost, low energy consumption, simple operation and convenient industrial production.
(2) The method for recycling the impurity can further improve the yield of the intermediate product 4-methyl-5-ethoxy oxazole in the vitamin B6 production process, improve the atom economy in the vitamin B6 synthesis process, reduce the production cost and reduce the impurity emission.
Drawings
FIG. 1 shows the structure of ethyl N, N-dioxaoxalylalaninate.
FIG. 2 is a mass spectrometry spectrum of ethyl N, N-dioxaoxalylalaninate.
FIG. 3 is a 1 H-NMR spectrum of ethyl N, N-dioxaalaninate.
Detailed Description
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
In the present invention, the impurity N and the diacyl are equivalent to N, N-dioxaalanin ethyl ester. Oxalyl is equivalent to N-ethoxyoxalyl-L-alanine ethyl ester.
In the present invention, purity= (content of the substance in the mixture/total amount of the mixture) ×100%.
In the present invention, the recovery rate refers to the ratio of the actual weight of the purified target compound (experimentally obtained weight) to the theoretical weight of the target compound that can be theoretically purified, expressed as a percentage, and the calculation formula is: recovery (%) = (weight of impurity N crystals×purity/theoretical weight of impurity N in impurity N-containing raw material) ×100%.
In the present invention, solubility refers to the mass of a substance dissolved when it reaches a saturated state in 100 g of a solvent at a certain temperature.
In a first aspect, the present invention provides a method for purifying ethyl N, N-dioxaoxalylalaninate, wherein the method comprises:
(1) Crystallizing a raw material containing N, N-dioxa-alanine ethyl ester;
(2) Mixing the crude product of the N, N-dioxaoxalyl alanine ethyl ester obtained in the step (1) with a solvent for pulping;
in step (2), the solvent is such that the solubility of ethyl N, N-dioxaoxalylalaninate in the solvent is below 0.01g/100g solvent at 50 ℃.
The method can improve the purity of the N, N-bisoxalyl alanine ethyl ester and improve the recovery rate.
In the present invention, preferably, in step (1), the step of crystallizing includes: a. dissolving a raw material containing N, N-bisoxalyl-alanine ethyl ester, performing first crystallization, and performing solid-liquid separation to obtain a crude product I and a mother solution I of the N, N-bisoxalyl-alanine ethyl ester; b. and (3) carrying out second crystallization on the mother solution I, carrying out solid-liquid separation to obtain a crude product II of the N, N-dioxaoxalyl alanine ethyl ester and a mother solution II, and combining the crude products I and II to obtain the crude product of the N, N-dioxaoxalyl alanine ethyl ester.
In the invention, the crude product of the N, N-dioxaoxalyl alanine ethyl ester is a crude product obtained in the step (2) after the crude products I and II are combined. The mother liquor II may be treated according to conventional means in the art, for example, the solvent of the mother liquor II may be recovered.
In the present invention, preferably, the dissolved solvent is an alcohol-containing solvent.
In the present invention, preferably, the alcohol is at least one selected from methanol, ethanol, butanol.
In the present invention, preferably, the dissolved solvent is ethanol, more preferably, absolute ethanol and/or 95 vol% ethanol.
In the present invention, the alcohol-containing solvent is preferably used in an amount of 1 to 10 times, more preferably 1 to 8 times, still more preferably 3 to 6 times the weight of the raw material containing ethyl N, N-bisoxalylalaninate.
In the present invention, the temperature of the dissolution is preferably a temperature of 50 ℃ or higher and less than the boiling point of the alcohol, more preferably 50 to 70 ℃, still more preferably 60 to 70 ℃.
In the present invention, the temperature of the first crystal is preferably 30 to 60 ℃, for example, 30℃、31℃、32℃、33℃、34℃、35℃、36℃、37℃、38℃、39℃、40℃、41℃、42℃、43℃、44℃、45℃、46℃、47℃、48℃、49℃、50℃、51℃、52℃、53℃、54℃、55℃、56℃、57℃、58℃、59℃、60℃ and any value within the above range and range of any value, more preferably 40 to 50 ℃, still more preferably 42 to 46 ℃.
In the present invention, the time of the first crystallization is preferably 1 to 10 hours, more preferably 3 to 6 hours.
Preferably, the temperature of the second crystallization is 2-10 ℃, more preferably 3-7 ℃.
Preferably, the second crystallization time is 1 to 10 hours, more preferably 2 to 5 hours.
In the present invention, all crude products obtained by crystallization are combined and pulped.
The inventors of the present invention found that in step (2), a solvent in which the solubility of N, N-bisoxalylalanine ethyl ester in the solvent is 0.01g/100g or less at 50℃is satisfied, which is advantageous for improving the purity and recovery rate of N, N-bisoxalylalanine ethyl ester, and found that when water is used as the solvent, it is advantageous for further improving the purity and recovery rate of N, N-bisoxalylalanine ethyl ester.
In the present invention, the solvent of step (2) is preferably water.
In order to further improve the purity and recovery rate of the ethyl N, N-dioxaalaninate, the solvent is preferably used in the step (2) in an amount of 1 to 8 times, for example, 1 to 2 times, 3 to 4 times, 5 to 6 times, 7 to 8 times, and any value within the range and range of any of the above-mentioned values, more preferably 1 to 5 times, the weight of the crude product.
In the present invention, the beating time may be adjusted according to the actual conditions (e.g., the quality of the raw material to be purified, the beating temperature, the solvent type, etc.), so that substances other than the N, N-bisoxaloalaninoethyl ester in the raw material may be dissolved, and in order to further improve the purity and recovery rate of the N, N-bisoxaloalaninoethyl ester, the beating time is preferably 0.1 to 5 hours, for example, may be 0.1 hour, 0.5 hour, 1 hour, 1.5 hour, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, and any value in the range of the foregoing, more preferably 0.5 to 1.5 hours.
In order to further improve the purity and recovery of the ethyl N, N-dioxaoxalylalaninate, the beating temperature is preferably 10-50 ℃, for example 10℃、15℃、20℃、25℃、29℃、30℃、31℃、32℃、33℃、34℃、35℃、36℃、37℃、38℃、39℃、40℃、41℃、42℃、43℃、44℃、45℃、46℃、47℃、48℃、49℃、50℃ and any value within the above range and range of any value, more preferably 29-42 ℃.
The crude product of the N, N-dioxaoxalylalanine ethyl ester obtained in the step (1) can be directly mixed with the solvent in the step (2) for pulping, and in order to further improve the purity and the recovery rate of the N, N-dioxaoxalylalanine ethyl ester, the solvent used for crystallization in the step (1) for residual product of the N, N-dioxaoxalylalanine ethyl ester can be removed before pulping, and preferably, the step (2) further comprises: and drying the crude product of the N, N-dioxanyl alanine ethyl ester before pulping. The drying is a conventional drying method, and the purpose of removing the solvent used for crystallization in the step (1) of the residual crude product of the N, N-dioxazoylalanine ethyl ester can be achieved.
In the present invention, the drying temperature is such that the solvent used for crystallization in step (1) is removed and the substance in the crude product of ethyl N, N-dioxaoxalylalaninate is not decomposed. In order to further improve the purity and recovery rate of the ethyl N, N-dioxaoxalylalaninate, the drying temperature is preferably 40 to 90 ℃, for example, 40 ℃, 45 ℃,50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃ and any value in the range of the above-mentioned values, more preferably 45 to 70 ℃.
In the present invention, the drying time is not particularly limited, and the solvent used for crystallization in step (1) can be removed without decomposing the substance in the crude N, N-diacetyl alanine ethyl ester, and in order to avoid delamination and further improve the purity and recovery rate of N, N-diacetyl alanine ethyl ester, the drying time is preferably 1 to 20 hours, for example, 1 hour, 3 hours, 5 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, and any value in the range and range of any value composition mentioned above, more preferably 1 to 10 hours.
In the present invention, the solid-liquid separation in the steps (1) and (2) is performed according to a conventional method in the art, and separation of the N, N-dioxalanin ethyl ester from the solvent can be achieved, and for example, centrifugation, suction filtration and the like can be used.
In some embodiments of the invention, preferably, the method further comprises: and (5) applying the beating mother liquor obtained by the solid-liquid separation. Preferably, the application comprises distillation recovery of the beating mother liquor, wherein the obtained solvent is returned and mixed into the beating solvent in the step (2), and the distilled N-ethoxyoxalyl-L-alanine ethyl ester is recycled, and can be used for synthesizing 4-methyl-5-ethoxyoxazole, for example. More preferably, the applying comprises boiling the pulping mother liquor before discharging to obtain ethanol and a solution containing N-ethoxyoxalyl-L-alanine ethyl ester, recycling the ethanol, standing and layering the solution to obtain N-ethoxyoxalyl-L-alanine ethyl ester and a pulping solvent, recycling the N-ethoxyoxalyl-L-alanine ethyl ester, returning the pulping solvent and mixing the pulping solvent into the pulping solvent in the step (2).
In the invention, the raw material containing the N, N-dioctanoyl-L-alanine ethyl ester is from a reaction system for preparing the N-ethoxyoxalyl-L-alanine ethyl ester by ester acylation reaction in a vitamin B6 synthesis process.
Preferably, the preparation method is as follows:
(I) Mixing L-alanine, oxalic acid, ethanol, diethyl oxalate and a water-carrying agent, and heating for reaction;
(II) distilling the reaction product of (I), wherein the residual solution in the distilled reaction system is the raw material containing N, N-dioxa-alanine ethyl ester.
In the present invention, preferably, the molar ratio of the L-alanine to the oxalic acid is 1: (1-5), for example, may be 1:1, 1:2, 1:3, 1:4, 1:5, and ranges and any values within ranges of any of the above values.
In the present invention, preferably, the molar ratio of the L-alanine to the diethyl oxalate is 1: (1-5), for example, may be 1:1, 1:2, 1:3, 1:4, 1:5, and ranges and any values within ranges of any of the above values.
In the present invention, the amount of ethanol is conventional in the art, and can meet the esterification requirement, preferably, the molar ratio of the L-alanine to the ethanol is 1: (1-10), for example, may be 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, and any value within the ranges and ranges of any of the values recited above. The ethanol can be mixed with water to prepare ethanol with any concentration such as 95 volume percent ethanol, 90 volume percent ethanol and the like, and the molar quantity of the ethanol in the prepared ethanol solution can meet the requirements.
In the present invention, the amount of the water-carrying agent is not particularly limited, and is a conventional amount in the art, and preferably, the mass ratio of the L-alanine to the water-carrying agent is 1: (1-6), for example, may be 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:55, 1:6, and ranges and any values within ranges of any of the above values.
In the present invention, preferably, the water-carrying agent is at least one of benzene, cyclohexane, chloroform and carbon tetrachloride.
In the present invention, the heating temperature is preferably 80 to 100 ℃, and may be, for example, 80 ℃, 83 ℃, 86 ℃, 89 ℃, 92 ℃, 95 ℃, 98 ℃, 100 ℃, and any value within the range and range of any value composition described above.
In the present invention, preferably, the rectification is performed in a rectification column to remove water.
In the present invention, preferably, the conditions of the rectification include: the temperature of the tower kettle is 85-95 ℃; the top temperature of the column is 60 to 70 ℃, for example, 60 ℃, 61 ℃, 62 ℃, 63 ℃, 64 ℃, 65 ℃, 66 ℃, 67 ℃, 68 ℃, 69 ℃,70 ℃, and any value in the range of the above-mentioned composition is more preferably 64 to 66 ℃.
In the present invention, the column bottom pressure and the column top pressure of the rectifying column are not particularly limited, and are conventional in the art, and for example, the column bottom pressure may be 0 to 0.2MPa (for example, 0MPa、0.01MPa、0.02MPa、0.03MPa、0.04MPa、0.05MPa、0.06MPa、0.07MPa、0.08MPa、0.09MPa、0.1MPa、0.11MPa、0.12MPa、0.13MPa、0.14MPa、0.15MPa、0.16MPa、0.17MPa、0.18MPa、0.19MPa、0.2MPa and any value within the above range and range of any value), the column top pressure may be 0 to 0.2MPa (for example, 0MPa、0.01MPa、0.02MPa、0.03MPa、0.04MPa、0.05MPa、0.06MPa、0.07MPa、0.08MPa、0.09MPa、0.1MPa、0.11MPa、0.12MPa、0.13MPa、0.14MPa、0.15MPa、0.16MPa、0.17MPa、0.18MPa、0.19MPa、0.2MPa and any value within the above range and range of any value), preferably, the column bottom pressure is 0.01 to 0.1MPa, and the column top pressure is 0.01 to 0.1MPa.
In the present invention, the pressure is gauge pressure.
In the present invention, the distillation is performed in a distillation apparatus, which may be an apparatus or device conventionally used in the art, as long as the distillation apparatus is capable of satisfying the distillation conditions of the present invention.
In the present invention, the conditions for the distillation are those conventional in the art, and the substances other than ethyl N, N-bisoxalylalaninate in the reaction system may be removed. Preferably, the conditions of the distillation include: (A) Distilling the reaction product for the first time to remove substances with boiling point less than 200 ℃; (B) And (3) carrying out second distillation to remove substances with boiling points of 200-260 ℃.
In the invention, the distillation conditions can be adjusted according to actual needs, and substances except N, N-bisoxalylalanine ethyl ester in a reaction system can be removed, preferably, in the step (A), the vacuum degree is 280-320Pa, and the distillation temperature is 25-130 ℃; more preferably, in step (A), the distillation may be carried out by gradient heating according to conventional means in the art, for example, the temperature after gradient heating may be 35 to 45℃and 55 to 60℃and 65 to 75℃and 120 to 130℃in this order.
In the present invention, preferably, in the step (B), the degree of vacuum is 280 to 320Pa and the distillation temperature is 135 to 155 ℃.
In the present invention, preferably, the content of N, N-dioxaoxalylalanine ethyl ester in the raw material containing N, N-dioxaoxalylalanine ethyl ester is not less than 60% by weight, preferably 75 to 85% by weight.
In the present invention, the raw material containing N, N-dioxaoxalyl alanine ethyl ester further contains other impurities, preferably, the other impurities include at least one of N-ethoxyoxalyl-L-alanine ethyl ester, diethyl oxalate and L-alanine ethyl ester.
In the present invention, the content of the N-ethoxyoxalyl-L-alanine ethyl ester is preferably 1 to 12w%, and more preferably 7 to 10 w%, based on the total weight of the raw materials.
In the present invention, preferably, the content of diethyl oxalate is 0.1 to 2wt%, preferably 0.5 to 1.5wt%, based on the total weight of the raw materials;
In the present invention, preferably, the content of L-alanine ethyl ester is 0.1 to 2% by weight, preferably 0.5 to 1.5% by weight, based on the total weight of the raw materials
In the invention, the content parameters of the N, N-bisoxalylalanine ethyl ester and other impurities are measured by adopting a gas chromatographic analysis method, and the quantitative method is an area normalization method. The second aspect of the invention provides a method for detecting impurities, which comprises the steps of purifying N, N-bisoxalylalanine ethyl ester by the method of the first aspect of the invention, and detecting impurities by taking the purified N, N-bisoxalylalanine ethyl ester as a standard substance and/or a reference substance.
In the invention, the N, N-bisoxalyl alanine ethyl ester prepared by the purification method can be used as a standard substance and/or a reference substance for impurity detection and impurity control in a process of preparing a compound by taking alanine and oxalic acid as raw materials, for example, for impurity detection in 4-methyl-5-ethoxyoxazole synthesis and vitamin B6 synthesis; the synthesis process of the compound taking the N-ethoxyoxalyl-L-alanine ethyl ester as an intermediate or a final product, or the synthesis process of the compound taking the N, N-dioxaoxalyl-alanine ethyl ester as the intermediate or the final product can be optimized through impurity detection.
The third aspect of the invention provides a method for recycling N, N-bisoxalyl-alanine ethyl ester in a vitamin B6 synthesis process, which is characterized in that the method comprises the steps of purifying raw materials containing N, N-bisoxalyl-alanine ethyl ester generated in the vitamin B6 synthesis process to obtain purified N, N-bisoxalyl-alanine ethyl ester, and then hydrolyzing the purified N, N-bisoxalyl-alanine ethyl ester for synthesizing vitamin B6;
wherein the purification method is the method according to the first aspect of the invention.
The method can improve the recycling effect of the N, N-dioxazoyl alanine ethyl ester, improve the yields of 4-methyl-5-ethoxyoxazole and N-ethoxyoxalyl-L-alanine ethyl ester in the vitamin B 6 production process, and reduce the production cost.
In the present invention, the reaction solvent for the hydrolysis is an inert solvent, preferably an inert solvent containing aromatic hydrocarbons, more preferably toluene.
In the present invention, the weight amount of the inert solvent is not particularly limited, and is a conventional amount in the art, and preferably, the weight amount of the inert solvent is 2 to 8 times that of ethyl N, N-bisoxalylalaninate.
In the present invention, the hydrolysis method is a conventional method in the art, and in order to further improve the recycling effect of the N, N-bisoxaloalaninoethyl ester, preferably, the hydrolysis reagent is a base, more preferably, the base is a hydroxide corresponding to an alkali metal and/or an alkaline earth metal, and further preferably, sodium hydroxide and/or potassium hydroxide.
In the present invention, in order to further improve the recycling effect of the N, N-dioxaoxalylalanine ethyl ester, preferably, the reaction conditions of the hydrolysis are: the pH is 13-15, preferably 14.3-14.6. The pH of the system may be controlled by an alkaline solution, which is an aqueous solution corresponding to the above-mentioned alkali, preferably the concentration of the alkaline solution is 10-40wt%, more preferably 15-30wt%.
In the present invention, preferably, the molar ratio of the N, N-bisoxalylalanine ethyl ester to the hydroxyl ion in the hydrolysis reagent is 1: (1-10), more preferably 1: (4-6).
In the present invention, preferably, the reaction conditions further include: the reaction temperature is 60 to 80 ℃, for example, 60 ℃, 65 ℃,70 ℃, 75 ℃, 80 ℃ and any value within the range and range of any value composition described above, more preferably 65 to 75 ℃; the reaction time is 0.1 to 8 hours (e.g., 0.1 hours, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, and ranges and any values within ranges of any of the above values), more preferably 0.1 to 3 hours.
In order to further improve the recycling effect of the N, N-dioxanylalanine ethyl ester, the reagent preferably further comprises a phase transfer catalyst.
In the present invention, the phase transfer catalyst is not particularly required, and may be a phase transfer catalyst conventionally used in the art. In order to further improve the recycling effect of the N, N-dioxanylalanine ethyl ester, preferably, the phase transfer catalyst is a quaternary ammonium salt phase transfer catalyst, and for example, at least one of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium bicarbonate and benzyltriethylammonium chloride can be used.
In order to further improve the recycling effect of the N, N-bisoxalylalanine ethyl ester, preferably, the mass ratio of the N, N-bisoxalylalanine ethyl ester to the phase transfer catalyst is 1: (0.0005-0.006), for example, 1:0.0005、1:0.001、1:0.0015、1:0.002、1:0.0025、1:0.003、1:0.0035、1:0.004、1:0.0045、1:0.005、1:0.0055、1:0.006 and any of the above ranges and ranges of values, more preferably 1: (0.001-0.003).
In the present invention, in order to reuse the ethyl N, N-bisoxalylalaninate after hydrolysis, preferably, the recycling method further includes acidification after hydrolysis, and then removing the salt formed by the solvent and the hydrolysis reagent.
In the present invention, preferably, the conditions of acidification include: the pH is below 2.5, preferably 2.4-2.5; wherein the pH of the system can be controlled by an acid solution, preferably the acid solution is sulfuric acid and/or hydrochloric acid, more preferably any one of sulfuric acid and hydrochloric acid.
In the present invention, preferably, the conditions of acidification further include: the acidification temperature is 3-10 ℃ higher than the hydrolysis reaction temperature, and the acidification time is 2-7h.
In the present invention, preferably, the molar ratio of the N, N-diacetylalanine ethyl ester to the hydrogen ions in the acid solution is 1: (1-8), more preferably 1: (2-6).
In the present invention, the concentration of the acid solution may be selected within a wide range, for example, may be 10 to 40wt%, preferably 20 to 40wt%.
In some embodiments of the invention, the solution obtained after acidification is used as a raw material for synthesizing the N-ethoxyoxalyl-L-alanine ethyl ester after solvent recovery and removal of the salt formed by the base.
In the present invention, in order to make L-alanine more soluble to be used as a raw material for synthesizing N-ethoxyoxalyl-L-alanine ethyl ester, it is preferable that the solution obtained after acidification is heated after adding oxalic acid and ethanol.
In the invention, the ethanol can be mixed with water to prepare ethanol solutions with any concentration, such as 95 volume percent ethanol, 90 volume percent ethanol and the like.
In the present invention, the heating temperature is preferably 90℃or higher as long as the L-alanine is dissolved and the substances in the reaction system are not decomposed, and more preferably 80 to 90℃for further reducing the cost and improving the recycling effect of the ethyl N, N-dioxazoylalaninate.
In the invention, the heating time can dissolve the L-alanine and the substances in the reaction system are not decomposed, and in order to reduce the cost and improve the recycling effect of the N, N-bisoxalyl alanine ethyl ester, the heating time is preferably 1-4 hours.
In the present invention, preferably, the molar ratio of the L-alanine to the oxalic acid added to the solution obtained after acidification is 1: (1-1.5).
In the present invention, preferably, the molar ratio of the L-alanine to the ethanol added to the solution obtained after acidification is 1: (1-2).
In the present invention, the purification method of the product obtained after heating is a conventional method in the art, for example, reduced pressure distillation, suction filtration, extraction, column separation, etc., and oxalic acid and L-alanine can be obtained.
The present invention will be described in detail by examples.
In the examples below, reagents and materials used, unless otherwise specified, are commercially available.
The meaning of the N, N-bisoxalylalanine ethyl ester is consistent with that of the impurity N.
The content of N, N-bisoxalylalanine ethyl ester and other impurities is measured by gas chromatography, the gas chromatography instrument model is GC-2014, the manufacturer is Shimadzu corporation, and the quantitative method is an area normalization method.
Purity= (content of the substance in the mixture/total amount of the mixture) ×100%.
Recovery (%) = (weight of impurity N crystals×purity/theoretical weight of impurity N in impurity N-containing raw material) ×100%.
Preparation example 1
The preparation example is used for explaining the production of N, N-bisoxalyl-alanine ethyl ester (impurity N for short) and the preparation of raw material containing impurity N in the conventional vitamin B 6 production process.
L-alanine and industrial oxalic acid (molar ratio is 1:4), 7 equivalents of ethanol (the molar amount of ethanol in 95 volume percent ethanol is 7 times of that of L-alanine) are sequentially added into a reaction kettle, after the temperature is raised to 83 ℃ for dissolution, 3 equivalents of diethyl oxalate and benzene (the mass of benzene is 0.3 times of that of ethanol) are added, and the mixture is heated to 85 ℃ for rectification and dehydration, wherein the rectification conditions are as follows: the temperature of the tower bottom is 85-95 ℃, the top temperature of the tower top is 64-66 ℃, until the moisture in the whole mixed system is less than 0.1 weight percent, the pressure of the tower bottom is 0.01-0.05MPa, and the pressure of the tower top is 0.01-0.05MPa.
After the reaction is finished, the product in the tank is in a black solution state;
Recovering benzene, absolute ethyl alcohol, diethyl oxalate and N-ethoxyoxalyl-L-alanine ethyl ester under reduced pressure, wherein the specific conditions are as follows: the distillation conditions were: the vacuum degree is 300Pa, the vacuum degree is 280-320Pa, the distillation temperature is 25-130 ℃, benzene, ethanol and diethyl oxalate are recovered, after no reflux is carried out on the top of the tower, the oxalyl compound is recovered, and the distillation conditions are as follows: the vacuum degree is 280-320Pa, and the distillation temperature is 145-155 ℃; the recovery under reduced pressure was stopped when the content of N-ethoxyoxalyl-L-alanine ethyl ester in the remaining solution was 10% by weight, and the remaining solution in the distillation apparatus was a raw material for purifying impurity N.
The content of impurity N in the raw material was 80% by weight, the content of N-ethoxyoxalyl-L-alanine ethyl ester was 10% by weight, and the contents of diethyl oxalate and propyl ester were 1% by weight, respectively.
Examples 1 to 8
420G of the raw material containing impurity N obtained in preparation example 1 was taken, and 4 times of 95% by volume of ethanol was added to dissolve at 65℃and then cooled to 45℃to conduct the first crystallization for 4 hours. And continuously cooling the primary mother liquor to 5 ℃ for crystallization for 4 hours, and carrying out suction filtration to obtain a secondary filter cake and a secondary mother liquor. Combining the primary filter cake and the secondary filter cake, drying, and obtaining a crude product with a mass of 320g, wherein the purity of the impurity N is 90%, and the recovery rate is 85.7% (320 multiplied by 0.9/336); this is crude impurity N.
The crude product was dried (6 h at 60 ℃) or not, and then beaten under different operating conditions (see table 1): adding water into the crude product, wherein the dosage of the water is X times of that of the crude impurity N before drying, stirring uniformly, carrying out suction filtration, drying the obtained filter cake to obtain impurity N crystals, detecting, calculating the weight of the obtained impurity N crystals, and calculating the yield and purity.
TABLE 1
Comprehensively considering the recovery rate and the purity, and finally determining the optimal pulping process as follows: the crude impurity N is dried at 60 ℃ for 6 hours, 3 times of water by weight is added, and pulping is carried out at 30 ℃ for 1 hour.
Examples 10 to 17
420G of the raw material containing impurity N obtained in preparation example 1 was taken, ethanol was added to dissolve at 65 ℃ in an amount Y times the weight of the raw material containing impurity N, and then the first crystallization was carried out under different operation conditions (see Table 2), and suction filtration was carried out to obtain a primary filter cake and a primary mother liquor. And continuously cooling the primary mother liquor to 5 ℃ for crystallization for 4 hours, and carrying out suction filtration to obtain a secondary filter cake and a secondary mother liquor. And combining the primary filter cake and the secondary filter cake to obtain the crude impurity N.
Drying the crude product at 60 ℃ for 6 hours, adding water, wherein the weight of the water is 3 times of that of the impurity N crude product before drying, pulping for 1 hour at 30 ℃, and carrying out suction filtration to obtain a filter cake and pulping mother liquor. And drying the filter cake at 60 ℃ for 6 hours to obtain impurity N crystals, detecting, calculating the weight of the obtained impurity N pure product, and calculating the yield and purity.
TABLE 2
Comparative example 1
This comparative example is used to illustrate a method of purifying impurity N by multiple crystallization.
420G of the solution containing impurity N obtained in preparation example 1 was crystallized: adding 4 times of 95 vol% ethanol to dissolve at 65 ℃, cooling to 45 ℃ for crystallization for 4 hours, and carrying out suction filtration to obtain a primary filter cake and a primary mother liquor. Continuously cooling the primary mother liquor to 5 ℃ for crystallization for 4 hours, and carrying out suction filtration to obtain a secondary filter cake and a secondary mother liquor; combining the secondary filter cake with the primary filter cake, drying, and measuring the purity of impurity N to be 90% and the recovery rate to be 85.7% by mass of the crude product to be 320 g;
Repeating the crystallization step for 1 time to obtain impurity N with purity of 98%, weight of mixture obtained after purification of 259g, and recovery rate of 75.5%;
the crystallization step was repeated 2 times to obtain impurity N having a purity of 99.0% and a weight of 210g as a mixture after purification, with a recovery rate of 61.2%.
Comparative example 2
This comparative example is used to illustrate the purification of impurity N by conventional distillation methods.
Taking 420g of raw material containing impurity N obtained in preparation example 1, and purifying by distillation under the conditions that the vacuum degree is 200Pa and the tank temperature is 160-170 ℃; the top temperature is 155-165 ℃;
The purity of the obtained impurity N was 88%, and the weight of the mixture obtained after purification was 357g; the product in the device is in a black solution state after distillation; after the distillation again, the mass of the residual solution in the device is slightly lower than 357g, the content of the impurity N in the residual solution is slightly lower than 88%, the purity of the impurity N cannot be obviously improved by the distillation again, and the impurities in the solution cannot be removed.
Application example 1
The application example is used for explaining the method for recycling the N, N-bisoxalyl-alanine ethyl ester in the vitamin B 6 synthesis process.
(1) The N, N-dioctanoyl alanine ethyl ester is recycled and used as a raw material for synthesizing the N-ethoxyoxalyl-L-alanine ethyl ester:
Taking 259.5g of impurity N obtained in the condition 1 of example 1, adding 1200ml of toluene and 0.52g of tetrabutylammonium chloride, heating to 70 ℃, dropwise adding 772g of NaOH with 20 mass percent after the solution solid is completely dissolved, taking 0.5h, adjusting the pH of a reaction system to 14.3-14.6, then continuously preserving heat for 1.5h, changing the toluene solution into colorless transparent, layering, washing the toluene layer with water once, and mixing with the water layer of the first layering. Adding 411g of 32 wt% hydrochloric acid into the water layer dropwise, adjusting the pH of the reaction system to 2.4-2.5, then reacting at 75 ℃ for 4 hours, spin-drying the solvent, adding 297ml of 95 vol% ethanol and 139g of oxalic acid, heating to 85 ℃ for reflux, preserving heat for 2 hours, cooling and suction filtering; the obtained 475g mother liquor is the raw material for synthesizing N-ethoxyoxalyl-L-alanine ethyl ester (the yield of L-alanine is 90%, and the yield of oxalic acid is 88%).
(2) The raw material obtained in (1) was used for synthesis of N-ethoxyoxalyl-L-alanine ethyl ester under the synthesis conditions described in preparation example 1, and 282g of N-ethoxyoxalyl-L-alanine ethyl ester was finally obtained.
(3) According to Zhou Houyuan et al, "vitamin B-6 oxazole Synthesis Process" (J.Endoconcha.of China, 1994,25 (9): 5) "Experimental section," 4-methyl-5-ethoxyoxazole was prepared from 297g N-ethoxyoxalyl-L-alanine ethyl ester obtained by a method from preparation of ethyl 4-methyl-5-ethoxy-2-oxazolecarboxylate to preparation of 4-methyl-5-ethoxyoxazole, 115g of 4-methyl-5-ethoxyoxazole was obtained, and the purity of 4-methyl-5-ethoxyoxazole was 99.88% as compared with 4-methyl-5-ethoxyoxazole standard, and the specific results are shown in the following Table.
The liquid phase detection method comprises the following steps:
high performance liquid chromatograph, model LC-20AT, manufacturer: shimadzu corporation's management Co.Ltd.
C18 chromatographic column, flow rate 1.0ml/min, wavelength 254nm, column temperature 35 ℃, run for 12min.
Mobile phase: 0.54g of sodium n-octane sulfonate is weighed, 500ml of purified water is added, 300ml of acetonitrile, 200ml of methanol and 50ml of glacial acetic acid are added after dissolution, and the mixture is uniformly mixed.
TABLE 3 Table 3
Therefore, the impurity N obtained by the purification method provided by the invention can be used for preparing the intermediate 4-methyl-5-ethoxyoxazole after being hydrolyzed. Further, after the impurity N was recovered and used, 115g of 4-methyl-5-ethoxyoxazole was obtained in large amount.
Test case
The test examples are used to illustrate the structural identification and results of ethyl N, N-dioxaoxalylalaninate.
The mass spectrum and nuclear magnetic resonance hydrogen spectrum of impurity N obtained in each of the examples and comparative examples were measured.
The mass spectrum and nuclear magnetic resonance hydrogen spectrum of impurity N obtained in condition 1 of example 1 are described below as examples, and the mass spectrum and nuclear magnetic resonance hydrogen spectrum of impurity N obtained in each of examples and comparative examples are similar to condition 1 of example 1 and are identified as N, N-bisoxalylalanine ethyl ester.
(1) Mass Spectrometry (MS):
The resulting sample was subjected to mass spectrometry using a mass spectrometer (ESI-MS, instrument model: waters ZQ2000 single quadrupole mass spectrometer), and the results are shown in FIG. 2.
As can be seen from FIG. 2, N-Dioxalylalaninate (molecular formula: C 12H20N2O6, molecular weight 288) has a molecular weight 288 as determined by the positive ion mass spectrum of the sample, in which the excimer ion peak [ M+2H ] + is M/z 289.93 and [ M+Na ] + is M/z 311.31. From this, it was confirmed that the molecular weight of the pure product obtained in condition 1 of example 1 was consistent with that of ethyl N, N-bisoxalylalaninate.
(2) Nuclear magnetic resonance hydrogen spectrum (1 H-NMR)
The pure product obtained in condition 1 of example 1 was analyzed by nuclear magnetic resonance using a nuclear magnetic resonance hydrogen spectrometer (Broker, 400 MHz), wherein the deuterated reagent was deuterated chloroform and tetramethylsilane was used as an internal standard, and the results are shown in FIG. 3.
As can be seen from fig. 3, five different types of hydrogen protons in the sample are measured. Wherein, the secondary amine group directly connected with the carbonyl has 1 proton (A), the methylene group directly connected with the carbonyl has 2 protons (C), the methyl group directly connected with the methylene has 3 protons (D), and the methyl group has 3 protons (E). With A-E, the proton absorption peak integration ratio is 1:1:2:3:3, and the corresponding proton numbers are 2,4, 6 and 6 respectively because of the symmetrical structure, and the structure of the compound deduced from the results is consistent with that of FIG. 1.
The mass spectrum is combined with nuclear magnetic resonance hydrogen spectrum to show that the purified impurity N is the target product N, N-bisoxalyl alanine ethyl ester.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, a number of simple variants of the technical solution of the invention are possible, including combinations of the individual technical features in any other suitable way, which simple variants and combinations should likewise be regarded as being disclosed by the invention, all falling within the scope of protection of the invention.
Claims (10)
1. A method of purifying ethyl N, N-dioxaoxalylalaninate, the method comprising:
(1) Crystallizing a raw material containing N, N-dioxa-alanine ethyl ester;
(2) Mixing the crude product of the N, N-dioxaoxalyl alanine ethyl ester obtained in the step (1) with a solvent for pulping;
In the step (2), the solubility of the N, N-dioxazoylalanine ethyl ester in the solvent is less than or equal to 0.01g/100g of the solvent at 50 ℃.
2. The method according to claim 1 or 2, wherein in step (1), the step of crystallizing comprises: a. dissolving a raw material containing N, N-bisoxalyl-alanine ethyl ester, performing first crystallization, and performing solid-liquid separation to obtain a crude product I and a mother solution I of the N, N-bisoxalyl-alanine ethyl ester; b. performing second crystallization on the mother solution I, performing solid-liquid separation to obtain an N, N-dioxaoxalyl alanine ethyl ester crude product II and a mother solution II, and combining the crude products I and II to obtain an N, N-dioxaoxalyl alanine ethyl ester crude product;
preferably, the crystallization solvent is an alcohol-containing solvent, more preferably ethanol, further preferably absolute ethanol and/or 95% by volume ethanol;
Preferably, the weight amount of the alcohol-containing solvent is 1 to 10 times, more preferably 1 to 8 times, still more preferably 3 to 6 times the weight of the raw material containing N, N-dioxaalanin ethyl ester;
Preferably, the temperature of dissolution is a temperature of 50 ℃ or higher and less than the boiling point of the alcohol in the alcohol-containing solvent, more preferably 50 to 70 ℃, still more preferably 60 to 70 ℃;
Preferably, the temperature of the first crystallization is 30 to 60 ℃, more preferably 40 to 50 ℃, still more preferably 42 to 46 ℃;
preferably, the time of the first crystallization is 1 to 10 hours, more preferably 3 to 6 hours;
preferably, the second crystallization temperature is 2-10 ℃, more preferably 3-7 ℃;
preferably, the second crystallization time is 1 to 10 hours, more preferably 2 to 5 hours;
Preferably, the content of N, N-dioxaoxalylalanine ethyl ester in the raw material containing N, N-dioxaoxalylalanine ethyl ester is not less than 60wt%, more preferably 75-85wt%.
3. The method according to claim 1 or 2, wherein in step (2), the solvent is water;
Preferably, in step (2), the solvent is used in an amount of 1 to 8 times, more preferably 1 to 5 times the weight of the crude product;
Preferably, the beating conditions include: the beating time is 0.1-5h, more preferably 0.5-1.5h; the beating temperature is 10-50 ℃, more preferably 29-42 ℃;
Preferably, the crude product of ethyl N, N-dioxaoxalylalaninate is dried before being mixed with the solvent of step (2);
More preferably, the drying conditions include: the drying temperature is 40-90deg.C, more preferably 45-70deg.C; the drying time is 1 to 20 hours, more preferably 1 to 10 hours.
4. The method according to claim 1 or 2, wherein the preparation method of the raw material containing N, N-dioxaalanin ethyl ester comprises:
(I) Mixing L-alanine, oxalic acid, ethanol, diethyl oxalate and a water-carrying agent, and heating for reaction;
(II) distilling the reaction product of (I), wherein the residual solution in the distilled reaction system is a raw material containing N, N-dioxaoxalyl alanine ethyl ester;
preferably, the molar ratio of the L-alanine to the oxalic acid is 1: (1-5);
Preferably, the molar ratio of the L-alanine to the diethyl oxalate is 1: (1-5);
preferably, the molar ratio of the L-alanine to the ethanol is 1: (1-10);
preferably, the mass ratio of the L-alanine to the water-carrying agent is 1: (1-6);
preferably, the water-carrying agent is at least one of benzene, cyclohexane, chloroform and carbon tetrachloride;
Preferably, the temperature of the heating is 80-100 ℃.
5. The process of claim 4, wherein the reaction in step (I) is performed in a rectification column to remove water;
preferably, the conditions of the rectifying column include: the temperature of the tower kettle is 85-95 ℃, and the pressure of the tower kettle is 0-0.2MPa; the top temperature of the column is 60-70 ℃, more preferably 64-66 ℃, and the pressure of the column top is 0-0.2MPa.
6. The method of claim 4, wherein the distillation conditions comprise: (A) Distilling the reaction product for the first time to remove substances with boiling point less than 200 ℃; (B) Distilling for the second time to remove substances with boiling point of 200-260 ℃;
Preferably, in the step (A), the vacuum degree is 280-320Pa, and the distillation temperature is 25-130 ℃;
preferably, in step (B), the vacuum is 280-320Pa and the distillation temperature is 135-155 ℃.
7. The method according to claim 1 or 2, wherein the raw material containing N, N-dioxaoxalyl alanine ethyl ester further contains other impurities including at least one of N-ethoxyoxalyl-L-alanine ethyl ester, diethyl oxalate and L-alanine ethyl ester;
preferably, the content of the N-ethoxyoxalyl-L-alanine ethyl ester is 1-12 wt%, preferably 7-10wt%, based on the total weight of the raw materials;
And/or the content of diethyl oxalate is 0.1-2wt%, preferably 0.5-1.5wt%, based on the total weight of the feedstock;
And/or the content of the L-alanine ethyl ester is 0.1-2 wt%, preferably 0.5-1.5wt%, based on the total weight of the raw materials.
8. A method for detecting impurities, comprising purifying N, N-bisoxalylalanine ethyl ester according to any one of claims 1 to 7, and detecting impurities using the purified N, N-bisoxalylalanine ethyl ester as a standard and/or a reference.
9. A method for recycling N, N-bisoxalyl-alanine ethyl ester in a vitamin B6 synthesis process is characterized by comprising the steps of purifying raw materials containing N, N-bisoxalyl-alanine ethyl ester generated in the vitamin B6 synthesis process to obtain purified N, N-bisoxalyl-alanine ethyl ester, and then hydrolyzing the purified N, N-bisoxalyl-alanine ethyl ester for synthesizing vitamin B6;
wherein the purification method is the method of any one of claims 1-7.
10. The method of claim 9, wherein the method of hydrolyzing comprises contacting a hydrolyzing reagent with the purified ethyl N, N-dioxaalaninate;
Preferably, the hydrolysis reagent is a base and/or a phase transfer catalyst;
More preferably, the base is an alkali metal hydroxide and/or an alkaline earth metal hydroxide, further preferably sodium hydroxide and/or potassium hydroxide;
more preferably, the phase transfer catalyst is a quaternary ammonium salt phase transfer catalyst.
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