CN112574049A - Novel method for preparing phenylglycine by using hydrocyanic acid - Google Patents
Novel method for preparing phenylglycine by using hydrocyanic acid Download PDFInfo
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- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 title claims abstract description 58
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 title claims abstract description 44
- 238000000034 method Methods 0.000 title claims abstract description 43
- 238000006243 chemical reaction Methods 0.000 claims abstract description 53
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims abstract description 44
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 43
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 23
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims abstract description 22
- GOOUUOYVIYFDBL-UHFFFAOYSA-N 2-hydroxy-3-phenylpropanenitrile Chemical compound N#CC(O)CC1=CC=CC=C1 GOOUUOYVIYFDBL-UHFFFAOYSA-N 0.000 claims abstract description 18
- NXQJDVBMMRCKQG-UHFFFAOYSA-N 5-phenylimidazolidine-2,4-dione Chemical compound O=C1NC(=O)NC1C1=CC=CC=C1 NXQJDVBMMRCKQG-UHFFFAOYSA-N 0.000 claims abstract description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002994 raw material Substances 0.000 claims abstract description 13
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 12
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 12
- 230000008569 process Effects 0.000 claims abstract description 11
- 238000001035 drying Methods 0.000 claims abstract description 9
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 9
- 238000002156 mixing Methods 0.000 claims abstract description 8
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 5
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 20
- 239000001099 ammonium carbonate Substances 0.000 claims description 20
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 claims description 16
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 16
- 235000012538 ammonium bicarbonate Nutrition 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000012295 chemical reaction liquid Substances 0.000 claims description 13
- 238000002425 crystallisation Methods 0.000 claims description 11
- 230000008025 crystallization Effects 0.000 claims description 11
- 238000003786 synthesis reaction Methods 0.000 claims description 10
- 239000001569 carbon dioxide Substances 0.000 claims description 8
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 8
- 238000001704 evaporation Methods 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 4
- 239000012452 mother liquor Substances 0.000 claims description 4
- 238000004064 recycling Methods 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- 229910001069 Ti alloy Inorganic materials 0.000 claims description 2
- 229910001093 Zr alloy Inorganic materials 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- 229910000856 hastalloy Inorganic materials 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 12
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 230000035484 reaction time Effects 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 2
- 231100000167 toxic agent Toxicity 0.000 abstract description 2
- 239000003440 toxic substance Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- -1 amido compound Chemical class 0.000 description 8
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- ZGUNAGUHMKGQNY-UHFFFAOYSA-N alpha-phenylglycine Chemical compound OC(=O)C(N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-UHFFFAOYSA-N 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000010924 continuous production Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- NNICRUQPODTGRU-UHFFFAOYSA-N mandelonitrile Chemical compound N#CC(O)C1=CC=CC=C1 NNICRUQPODTGRU-UHFFFAOYSA-N 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 229960003424 phenylacetic acid Drugs 0.000 description 3
- 239000003279 phenylacetic acid Substances 0.000 description 3
- ZGUNAGUHMKGQNY-SSDOTTSWSA-N D-alpha-phenylglycine Chemical compound OC(=O)[C@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-SSDOTTSWSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- RZVNMMLXLKRPFA-UHFFFAOYSA-N 2-amino-2-phenylacetic acid;sodium Chemical compound [Na].OC(=O)C(N)C1=CC=CC=C1 RZVNMMLXLKRPFA-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical class O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- KHWHYHFZHBCYDB-UHFFFAOYSA-N 6,7-dihydrocyclopenta[c]pyridin-5-one Chemical compound N1=CC=C2C(=O)CCC2=C1 KHWHYHFZHBCYDB-UHFFFAOYSA-N 0.000 description 1
- 235000011437 Amygdalus communis Nutrition 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- VKDFZMMOLPIWQQ-VIFPVBQESA-N N-acetyl-L-alpha-phenylglycine Chemical compound CC(=O)N[C@H](C(O)=O)C1=CC=CC=C1 VKDFZMMOLPIWQQ-VIFPVBQESA-N 0.000 description 1
- 241000220304 Prunus dulcis Species 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000004996 alkyl benzenes Chemical class 0.000 description 1
- 229910045601 alloy Inorganic materials 0.000 description 1
- 239000000956 alloy Substances 0.000 description 1
- 235000020224 almond Nutrition 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- KLOHDWPABZXLGI-YWUHCJSESA-M ampicillin sodium Chemical compound [Na+].C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C([O-])=O)(C)C)=CC=CC=C1 KLOHDWPABZXLGI-YWUHCJSESA-M 0.000 description 1
- 229960001931 ampicillin sodium Drugs 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- HCZAKYJSJQYXQM-UHFFFAOYSA-N azanium 2-acetamido-2-phenylacetate Chemical compound [NH4+].CC(=O)NC(C([O-])=O)C1=CC=CC=C1 HCZAKYJSJQYXQM-UHFFFAOYSA-N 0.000 description 1
- KKTCWAXMXADOBB-UHFFFAOYSA-N azanium;hydrogen carbonate;hydrate Chemical compound [NH4+].O.OC([O-])=O KKTCWAXMXADOBB-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 description 1
- 229960005361 cefaclor Drugs 0.000 description 1
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 description 1
- 229960002129 cefixime Drugs 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000003754 machining Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000003408 phase transfer catalysis Methods 0.000 description 1
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 description 1
- 150000005331 phenylglycines Chemical class 0.000 description 1
- IVBHGBMCVLDMKU-GXNBUGAJSA-N piperacillin Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 IVBHGBMCVLDMKU-GXNBUGAJSA-N 0.000 description 1
- 229960002292 piperacillin Drugs 0.000 description 1
- 239000003910 polypeptide antibiotic agent Substances 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000004065 wastewater treatment Methods 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/24—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from hydantoins
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a novel method for preparing phenylglycine by using hydrocyanic acid, which comprises the steps of synthesizing alpha-hydroxybenzyl acetonitrile by using benzaldehyde and hydrogen cyanide as initial raw materials, mixing the alpha-hydroxybenzyl acetonitrile with an excessive carbon source and an ammonia source, preparing phenylhydantoin by a Bucherer-Begrs cyclization reaction in a microchannel reactor, carrying out hydrolysis reaction, and distilling, crystallizing, separating and drying a product to obtain the phenylglycine. Compared with the current domestic mainstream process, the method realizes the rapid and continuous preparation of the phenylglycine by taking the benzaldehyde and the hydrocyanic acid as raw materials, and simultaneously avoids the use of a highly toxic substance sodium cyanide. The invention adopts a combination mode of the microchannel reactor and the high-pressure reaction kettle, can shorten the reaction time, can effectively avoid easy blockage of the microchannel reactor, and has the advantages of short reaction time, less by-products, high product yield and low production cost.
Description
Technical Field
The invention relates to the field of fine chemical engineering, and particularly relates to a novel method for preparing phenylglycine by using hydrocyanic acid.
Background
Phenylglycine (phenylglycine, alpha-aminobenzeneacetic acid or 2-amino-2-phenylacetic acid) also known as phenylglycine, alpha-aminophenylacetic acid or 2-amino-2-Phenylacetic acid, molecular formula: c8H9NO2White or off-white crystalline powder with a molecular weight of 151.2, insoluble in common organic solvents. Has optical isomerism, and is divided into L-phenylglycine (formula I) and D-phenylglycine (formula II), wherein the former is important intermediate for synthesizing beta-lactam antibiotics such as penicillin, cefixime, cefaclor, ampicillin sodium, piperacillin, cefotrozine, and phenimidazole penicillin; the latter is mainly used as a resolving agent for organic synthesis, and a small amount of the resolving agent is also used as an intermediate for pesticide synthesis.
With the development of the antibiotic industry in China, the demand of phenylglycine intermediates is continuously increased, and the sources of phenylglycine intermediates are rare and mainly exist in molecular structures of natural glycopeptide antibiotics and lactam antibiotics, so that the development of the synthesis of phenylglycine derivatives is of great significance.
At present, a plurality of methods for preparing phenylglycine exist, but several phenylglycine production methods in the prior art have some defects. Wherein: (1) sodium cyanide process: benzaldehyde and ammonium bicarbonate water solution are used as initial raw materials, and reacted with excessive potassium cyanide (or sodium cyanide) water solution to prepare phenylhydantoin, then the phenylhydantoin is generated through pressure hydrolysis, and finally the phenylglycine sodium is obtained through neutralization and centrifugal separation until the pH value is about 7. The method is an inelegant production method because a large amount of virulent sodium cyanide is required to be used in raw materials, the pollution is serious, and strict measures are required for equipment, safe operation and environmental protection. (2) A phenylacetic acid method: taking phenylacetic acid as a starting material, heating and melting or dissolving solid phenylacetic acid in an inert aprotic solvent, and carrying out chlorination reaction under the conditions of normal pressure and reflux and under the action of a catalyst to prepare the alpha-halogenated phenylacetic acid. After the halogenation reaction is finished, impurities are separated, and the pH value is adjusted, so that crystals with higher purity, namely the monohalogenated phenylacetic acid, can be obtained. And (3) ammoniating the purified alpha-halogenated phenylacetic acid in an aqueous solution of methanol or ethanol under the action of a catalyst to obtain a phenylglycine crude product, and recrystallizing to obtain a product with higher purity. The method has the disadvantages of complicated operation steps and harsh reaction conditions. (3) A glyoxylic acid method: under the acidic condition, glyoxylic acid is condensed with ammonium salt or amido compound or low-carbon chain nitrile, and the condensed product is reacted with alkylbenzene to prepare the N-acetic acid phenylglycine. Adding ammonia into purified N-acetylphenylglycine for reaction to obtain N-acetylphenylglycine ammonium salt, adding D-phenylglycine ammonium salt (seed crystal) into the ammonium salt, dissolving the ammonium salt in a mixed solution of water and ethanol, cooling to separate out D-phenylglycine ammonium salt, adding DL-phenylglycine ammonium salt into a filtered solution, heating for dissolving, cooling to obtain crystal L-phenylglycine ammonium salt, adding the crystal L-phenylglycine ammonium salt into a sodium hydroxide solution, heating for dissolving, and cooling to separate out DL-phenylglycine ammonium salt. And adding hydrochloric acid into solid D-phenylglycine ammonium salt obtained by filtering for acidification, heating and refluxing, and then adjusting the pH to 5 by using a sodium hydroxide solution to obtain D-phenylglycine. The process has high yield, but requires a catalyst with high selectivity, large wastewater treatment capacity and difficult glyoxylate recovery, thereby causing high production cost. (4) A chloroform method: the chloroform method is to produce phenylglycine by using benzaldehyde and chloroform as main raw materials. The solid potassium hydroxide method and the urea method are classified according to the main reaction raw materials used in the reaction. However, the chloroform method has a large number of reaction steps and thus the yield is not high. In addition, phase transfer catalysis and biological enzyme methods are also being studied.
Patent CN106380415A discloses a method for preparing D, L-phenylglycine and its analogues, which can significantly and effectively reduce pollution compared with the existing process. However, the reaction process needs a catalyst, and acid and alkali are used in the hydrolysis reaction, so the cost is high, the environment is not friendly, and a large amount of byproducts are generated. In view of the above, a new method needs to be found to solve the above technical problems.
Disclosure of Invention
One aspect of the invention provides a novel method for preparing phenylglycine by using hydrocyanic acid, aiming at the defects of high cost, more byproducts, environmental friendliness and incapability of continuous production in the prior art for preparing phenylglycine by using hydrocyanic acid.
The technical scheme provided by the invention is as follows:
a new method for preparing phenylglycine by using hydrocyanic acid comprises the steps of taking benzaldehyde and hydrogen cyanide as initial raw materials, synthesizing alpha-hydroxybenzyl acetonitrile, mixing the alpha-hydroxybenzyl acetonitrile with an excessive carbon source and an excessive ammonia source, performing Bucherer-Begrs cyclization reaction in a microchannel reactor to obtain phenylhydantoin, performing hydrolysis reaction, and distilling, crystallizing, separating and drying a product to obtain the phenylglycine.
The synthetic route in the technical scheme of the invention can be as follows:
the invention creatively adopts the microchannel reactor to carry out the phenylhydantoin synthesis and hydrolysis reaction, and optimizes the reaction parameters on the basis, thereby realizing the purpose of continuous production. Compared with other common reaction devices, the microchannel reactor has the advantages of high heat exchange efficiency and mixing efficiency, no amplification effect, high safety and the like. In order to better achieve the purpose of continuous production, the invention also considers the reactors of the high-pressure reaction kettles connected in series, so that the hydrolysis reaction time is further prolonged, and the yield of the glycine is improved.
Therefore, as a preference, in one embodiment of the present invention, the hydrolysis reaction is carried out in an autoclave.
More preferably, in one embodiment of the present invention, the autoclave is an autoclave connected in series, and the reactor assembly comprises at least two sub-reactors connected in series.
The microchannel reactor of the present invention can be any commercially available microchannel reactor for industrial use, for example, a microchannel GramFlow reactor from Chemtrix BV., the netherlands. Preferably, in an embodiment of the present invention, the microchannel reactor has an inner diameter of 0.1mm to 1mm and a wall thickness of 0.1mm to 1.0 mm.
The reactor of the autoclave of the present invention may be any commercially available industrial reactor, for example, MC250 autoclave of Senlang in Beijing century. The pressure can be in the range of 0 to 20 MPa.
Preferably, in an embodiment of the present invention, the method of the present invention specifically comprises the steps of:
step 1) synthesizing alpha-hydroxybenzyl acetonitrile by using benzaldehyde and hydrocyanic acid as raw materials;
step 2) mixing the alpha-hydroxybenzyl acetonitrile synthesized in the step 1) with an excessive carbon source and an excessive ammonia source, inputting the mixture into a microchannel reactor, and performing a synthesis reaction through a Bucherer-Begrs cyclization reaction at the temperature of 60-90 ℃ and the pressure of 0.5-2 Mpa to prepare a phenylhydantoin reaction mixed solution;
step 3) conveying the phenylhydantoin reaction mixed solution obtained in the step 2) to a high-pressure reaction kettle reactor connected in series, controlling the temperature at 100-150 ℃ and the pressure at 0.5-5 Mpa, and carrying out hydrolysis reaction to obtain hydrolysis reaction liquid;
the series high-pressure reaction kettle reactor component is formed by connecting at least two sub-reactors in series, and the reaction temperature is increased gradually among the kettles;
step 4) sending the hydrolysis reaction liquid obtained in the step 3) to a stripping tower, separating carbon dioxide, recycling the carbon dioxide as a carbon source, and separating ammonia gas, recycling the ammonia gas as an ammonia source, so as to obtain a phenylglycine aqueous solution;
and 5) evaporating, concentrating, crystallizing, separating, decoloring and drying the phenylglycine aqueous solution obtained in the step 4) to obtain the phenylglycine.
The carbon source and the ammonia source in the step 2) may be preheated carbon source and ammonia source.
The reaction temperature in the step 3) may be increased in sequence between the reactors, and the reaction temperature may be increased in sequence between each reactor at 10 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃ or 50 ℃.
Preferably, in an embodiment of the present invention, the reaction pressure in the step 3) is 2.1 to 5 MPa.
Preferably, in an embodiment of the present invention, the carbon source is one or more of ammonium carbonate, ammonium bicarbonate or carbon dioxide, and the ammonia source is one or more of ammonium carbonate, ammonium bicarbonate, ammonia gas, ammonia water or liquid ammonia.
Preferably, in an embodiment of the present invention, the molar ratio of the benzaldehyde, the hydrocyanic acid, the ammonium bicarbonate and the water is 1:1 to 2: 2-10: 60-100. More preferably, the molar ratio of the benzaldehyde and the hydrocyanic acid to the ammonium bicarbonate and the water is 1: 2: 8: 100.
preferably, in an embodiment of the present invention, the residence time of the microchannel reactor in the step 2) is 15 to 40 minutes; and 3) the residence time of the high-pressure reaction kettle reactors connected in series is 60-120 minutes.
Preferably, in the embodiment of the invention, the materials of the microchannel reactor and the reactor of the serially connected high-pressure reaction kettle are one or more of titanium alloy, zirconium alloy and hastelloy alloy.
Preferably, in the embodiment of the present invention, the ammonia gas and the carbon dioxide separated in the stripping tower in the step 4) are returned to the blending kettle and recycled as raw materials.
Preferably, in the embodiment of the present invention, the primary crystallization mother liquor in step 5) is returned to the primary high-pressure reaction kettle reactor described in step 3), the generated solid is heated and dissolved, decolorized by activated carbon, filtered, and then subjected to secondary crystallization, and the secondary crystallization mother liquor is returned to the evaporator.
The invention has the beneficial effects that:
compared with the current domestic mainstream process, the novel method for preparing phenylglycine and derivatives thereof by using hydrocyanic acid provided by the invention realizes the rapid and continuous preparation of phenylglycine by using benzaldehyde and hydrocyanic acid as raw materials, and simultaneously avoids the use of a highly toxic substance sodium cyanide. The invention adopts a combination mode of the microchannel reactor and the high-pressure reaction kettle, can shorten the reaction time, can effectively avoid easy blockage of the microchannel reactor, and has the advantages of short reaction time, less by-products, high product yield and low production cost.
Drawings
FIG. 1 is a process flow diagram in an embodiment of the invention.
Detailed Description
The invention discloses a novel method for preparing phenylglycine by using hydrocyanic acid, which can be realized by appropriately improving process parameters by referring to the content. It is expressly intended that all such alterations and modifications which are obvious to those skilled in the art are deemed to be incorporated herein by reference, and that the techniques of the invention may be practiced and applied by those skilled in the art without departing from the spirit, scope and range of equivalents of the invention.
In the present invention, unless otherwise specified, scientific and technical terms used herein have the meanings that are commonly understood by those skilled in the art. Some terms appearing in the present invention are explained below.
The term "α -hydroxyphenylacetonitrile" is also known as Mandelonitrile, phenylethanenitrile, English Mandelionitrile, formula C8H7NO, yellow liquid.
The term "Benzaldehyde", an organic compound of formula C7H6O, is a colorless liquid. It is a colorless liquid at room temperature with a distinctive almond odor.
The term "phenylglycine", english-language phenylglycine, α -aminobenzeneacetic acid or 2-amino-2-phenylacetic acid, also known as phenylglycine, α -aminophenylacetic acid or 2-amino-2-phenylacetic acid, has the formula: c8H9NO2White or off-white crystalline powder with a molecular weight of 151.2, insoluble in common organic solvents.
The term "excess" means that the material remains after complete reaction in the chemical reaction.
The term "microchannel reactor" is a microreactor fabricated using precision machining techniques with feature sizes between 10 and 300 microns (or 1000 microns). the term "microchannel" of a microreactor refers to channels for process fluids on the order of microns and does not mean that the overall dimensions of the microreactor are small or that the product yield is small. The microreactors can contain millions of microchannels and thus achieve high throughput.
In order to make those skilled in the art better understand the technical solution of the present invention, the following detailed description of the present invention is provided with reference to specific embodiments.
Example 1
The molar ratio of benzaldehyde, hydrocyanic acid, ammonium bicarbonate and water is 1: 1: 5: 80, synthesizing alpha-hydroxybenzyl acetonitrile from benzaldehyde and hydrocyanic acid, conveying the synthesized alpha-hydroxybenzyl acetonitrile, ammonium bicarbonate and water to a microchannel reactor by a metering pump to perform a phenylhydantoin synthesis reaction at the reaction temperature of 80 ℃, the pressure of 2MPa and the residence time of 30min, and then performing a phenylhydantoin hydrolysis reaction on the synthesized reaction liquid in serially connected high-pressure reaction kettles, wherein the reaction temperature of the kettle 1 is 100 ℃, the pressure of 4MPa and the residence time of 60min, and the reaction temperature of the kettle 2 is 120 ℃, the pressure of 4MPa and the residence time of 60 min. The hydrolysis reaction liquid is subjected to steam stripping, evaporation concentration, crystallization, separation, decoloration and drying to obtain the phenylglycine product with the content of 98.8 percent and the yield of 97.5 percent.
Example 2
The molar ratio of benzaldehyde, hydrocyanic acid, ammonium bicarbonate and water is 1: 2: 10:60 mixing, namely synthesizing alpha-hydroxybenzyl acetonitrile from benzaldehyde and hydrocyanic acid, conveying the synthesized alpha-hydroxybenzyl acetonitrile, ammonium bicarbonate and water to a micro-channel reactor by a metering pump to perform a phenylhydantoin synthesis reaction at the reaction temperature of 90 ℃, the pressure of 2MPa and the residence time of 40min, and then performing a phenylhydantoin hydrolysis reaction on the synthesized reaction liquid in serially connected high-pressure reaction kettles, wherein the reaction temperature of the kettle 1 is 120 ℃, the pressure of the kettle 1 is 4MPa and the residence time of 40min, and the reaction temperature of the kettle 2 is 120 ℃, the pressure of the kettle 2 is 4MPa and the residence time of 60 min. The hydrolysis reaction liquid is subjected to steam stripping, evaporation concentration, crystallization, separation, decoloration and drying to obtain the phenylglycine product with the content of 98.3 percent and the yield of 97.9 percent.
Example 3
The molar ratio of benzaldehyde, hydrocyanic acid, ammonium bicarbonate and water is 1: 2: 8: 100, synthesizing alpha-hydroxybenzyl acetonitrile from benzaldehyde and hydrocyanic acid, conveying the synthesized alpha-hydroxybenzyl acetonitrile, ammonium bicarbonate and water to a microchannel reactor by a metering pump to perform a phenylhydantoin synthesis reaction at a reaction temperature of 80 ℃, a pressure of 2MPa and a residence time of 20min, and then performing a phenylhydantoin hydrolysis reaction on the synthesized reaction liquid in serially connected high-pressure reaction kettles, wherein the reaction temperature of the kettle 1 is 120 ℃, the pressure of 4MPa and the residence time of 40min, the reaction temperature of the kettle 2 is 120 ℃, the pressure of 3MPa and the residence time of 40min, and the reaction temperature of the kettle 3 is 140 ℃, the pressure of 3MPa and the residence time of 40 min. The hydrolysis reaction liquid is subjected to steam stripping, evaporation concentration, crystallization, separation, decoloration and drying to obtain the phenylglycine product with the content of 99.3 percent and the yield of 98.5 percent.
Example 4
The molar ratio of benzaldehyde, hydrocyanic acid, ammonium bicarbonate and water is 1: 1.5: 2: 100, synthesizing alpha-hydroxybenzyl acetonitrile from benzaldehyde and hydrocyanic acid, conveying the synthesized alpha-hydroxybenzyl acetonitrile, ammonium bicarbonate and water to a microchannel reactor by a metering pump to perform a phenylhydantoin synthesis reaction at a reaction temperature of 60 ℃, a pressure of 0.5MPa and a residence time of 15min, and then performing a phenylhydantoin hydrolysis reaction on the synthesized reaction liquid in a series-connected high-pressure reaction kettle, wherein the reaction temperature of a kettle 1 is 120 ℃, the pressure of 5MPa and the residence time of 40min, the reaction temperature of a kettle 2 is 150 ℃, the pressure of 5MPa and the residence time of 20min, the reaction temperature of a kettle 3 is 140 ℃, the pressure of 4MPa and the residence time of 40 min. The hydrolysis reaction liquid is subjected to steam stripping, evaporation concentration, crystallization, separation, decoloration and drying to obtain the phenylglycine product with the content of 99.6 percent and the yield of 98.9 percent.
Comparative example:
benzaldehyde, hydrocyanic acid, ammonium bicarbonate and water are mixed according to a molar ratio of 1: 1.5: 2: 100 is mixed in a reaction kettle, the temperature is increased to 60 ℃ at the speed of 5 ℃/min, the stirring speed is 500r/min, the temperature is kept for 1h, the temperature is continuously increased to 120 ℃ at the speed of 5 ℃/min, the temperature is increased to 140 ℃ after 1h of heat preservation, and the temperature is reduced after 1h of heat preservation. The obtained reaction liquid is subjected to steam stripping, evaporation concentration, crystallization, separation, decoloration and drying to obtain a phenylglycine product with the content of 96.1 percent and the yield of 95.9 percent.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A novel method for preparing phenylglycine by using hydrocyanic acid is characterized in that benzaldehyde and hydrogen cyanide are used as initial raw materials to synthesize alpha-hydroxybenzyl acetonitrile, the alpha-hydroxybenzyl acetonitrile is mixed with an excessive carbon source and an ammonia source, a Bucherer-Begrs cyclization reaction is carried out in a microchannel reactor to prepare phenylhydantoin, hydrolysis reaction is carried out, and the product is distilled, crystallized, separated and dried to obtain the phenylglycine.
2. The novel process according to claim 1, characterized in that the hydrolysis reaction is carried out in an autoclave;
preferably, the high-pressure reaction kettle is a high-pressure reaction kettle connected in series, and the reactor component is composed of at least two sub-reactors connected in series.
3. The new method according to claim 1 or 2, characterized in that it comprises in particular the following steps:
step 1) synthesizing alpha-hydroxybenzyl acetonitrile by using benzaldehyde and hydrocyanic acid as raw materials;
step 2) mixing the alpha-hydroxybenzyl acetonitrile synthesized in the step 1) with an excessive carbon source and an excessive ammonia source, inputting the mixture into a microchannel reactor, and performing a synthesis reaction through a Bucherer-Begrs cyclization reaction at the temperature of 60-90 ℃ and the pressure of 0.5-2 Mpa to prepare a phenylhydantoin reaction mixed solution;
step 3) conveying the phenylhydantoin reaction mixed solution obtained in the step 2) to a high-pressure reaction kettle reactor connected in series, controlling the temperature at 100-150 ℃ and the pressure at 0.5-5 Mpa, and carrying out hydrolysis reaction to obtain hydrolysis reaction liquid; the series high-pressure reaction kettle reactor component is formed by connecting at least two sub-reactors in series, and the reaction temperature is increased gradually among the kettles;
step 4) sending the hydrolysis reaction liquid obtained in the step 3) to a stripping tower, separating carbon dioxide, recycling the carbon dioxide as a carbon source, and separating ammonia gas, recycling the ammonia gas as an ammonia source, so as to obtain a phenylglycine aqueous solution;
and 5) evaporating, concentrating, crystallizing, separating, decoloring and drying the phenylglycine aqueous solution obtained in the step 4) to obtain the phenylglycine.
4. The new method according to claim 1 or 2, characterized in that the carbon source is one or more of ammonium carbonate, ammonium bicarbonate or carbon dioxide, and the ammonia source is one or more of ammonium carbonate, ammonium bicarbonate, ammonia gas, ammonia water or liquid ammonia.
5. The novel method of claim 4, wherein the molar ratio of the benzaldehyde, the hydrocyanic acid, the ammonium bicarbonate and the water is 1: 1-2: 2-10: 60-100.
6. The novel process of claim 3, wherein the microchannel reactor residence time of step 2) is 15 to 40 minutes; and 3) the residence time of the high-pressure reaction kettle reactors connected in series is 60-120 minutes.
7. The novel method as claimed in claim 3, wherein the microchannel reactor and the reactor of the high-pressure reaction kettle connected in series are made of one or more of titanium alloy, zirconium alloy or hastelloy.
8. The novel process of claim 3 wherein the microchannel reactor has an internal diameter of 0.1mm to 1mm and a wall thickness of 0.1mm to 1.0 mm.
9. The new method as claimed in claim 3, characterized in that the ammonia gas and the carbon dioxide separated in the stripping tower in the step 4) are returned to the blending kettle and recycled as raw materials.
10. The new method as claimed in claim 3, characterized in that the primary crystallization mother liquor in step 5) is returned to the primary high-pressure reaction kettle reactor in step 3), the generated solid is heated and dissolved, decolored by active carbon, filtered and then subjected to secondary crystallization, and the secondary crystallization mother liquor is returned to the evaporator.
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