CN113563214B - Synthesis method of glycine - Google Patents
Synthesis method of glycine Download PDFInfo
- Publication number
- CN113563214B CN113563214B CN202110764036.7A CN202110764036A CN113563214B CN 113563214 B CN113563214 B CN 113563214B CN 202110764036 A CN202110764036 A CN 202110764036A CN 113563214 B CN113563214 B CN 113563214B
- Authority
- CN
- China
- Prior art keywords
- glycine
- chloroacetic acid
- reaction
- ammonia water
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 title claims abstract description 110
- 239000004471 Glycine Substances 0.000 title claims abstract description 51
- 238000001308 synthesis method Methods 0.000 title claims abstract description 12
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims abstract description 64
- 229940106681 chloroacetic acid Drugs 0.000 claims abstract description 64
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 56
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 55
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- 239000003054 catalyst Substances 0.000 claims abstract description 37
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000012043 crude product Substances 0.000 claims abstract description 13
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- 150000001412 amines Chemical class 0.000 claims abstract description 8
- UTPOUAZEFGTYAY-UHFFFAOYSA-N azanium;2-chloroacetate Chemical compound [NH4+].[O-]C(=O)CCl UTPOUAZEFGTYAY-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 4
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 3
- 238000005576 amination reaction Methods 0.000 claims abstract 2
- 239000000243 solution Substances 0.000 claims description 36
- 239000000047 product Substances 0.000 claims description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- 238000001914 filtration Methods 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 18
- 239000013078 crystal Substances 0.000 claims description 16
- KKQBZNHBNPSGOP-UHFFFAOYSA-N azanium 2-aminoacetic acid chloride Chemical compound [NH4+].[Cl-].NCC(O)=O KKQBZNHBNPSGOP-UHFFFAOYSA-N 0.000 claims description 12
- 239000012295 chemical reaction liquid Substances 0.000 claims description 10
- 239000011259 mixed solution Substances 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 9
- 238000001291 vacuum drying Methods 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 5
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 2
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 claims description 2
- DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 claims description 2
- GNVRJGIVDSQCOP-UHFFFAOYSA-N n-ethyl-n-methylethanamine Chemical compound CCN(C)CC GNVRJGIVDSQCOP-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229960002449 glycine Drugs 0.000 abstract description 51
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 abstract description 17
- 239000006227 byproduct Substances 0.000 abstract description 15
- 235000013905 glycine and its sodium salt Nutrition 0.000 abstract description 4
- 150000003335 secondary amines Chemical class 0.000 abstract description 2
- 150000003512 tertiary amines Chemical class 0.000 abstract description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 37
- 235000019270 ammonium chloride Nutrition 0.000 description 18
- 238000001816 cooling Methods 0.000 description 16
- 238000010438 heat treatment Methods 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 8
- 229910021529 ammonia Inorganic materials 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 238000004448 titration Methods 0.000 description 7
- 238000005915 ammonolysis reaction Methods 0.000 description 5
- 238000004321 preservation Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 238000004176 ammonification Methods 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- NBZBKCUXIYYUSX-UHFFFAOYSA-N iminodiacetic acid Chemical compound OC(=O)CNCC(O)=O NBZBKCUXIYYUSX-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 3
- -1 amino acid compound Chemical class 0.000 description 2
- 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 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000010413 mother solution Substances 0.000 description 2
- 238000007344 nucleophilic reaction Methods 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003337 fertilizer Substances 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000003941 n-butylamines Chemical group 0.000 description 1
- MGFYIUFZLHCRTH-UHFFFAOYSA-N nitrilotriacetic acid Chemical compound OC(=O)CN(CC(O)=O)CC(O)=O MGFYIUFZLHCRTH-UHFFFAOYSA-N 0.000 description 1
- 238000013021 overheating Methods 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000007065 protein hydrolysis Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
-
- 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
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0235—Nitrogen containing compounds
- B01J31/0237—Amines
-
- 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
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0235—Nitrogen containing compounds
- B01J31/0237—Amines
- B01J31/0238—Amines with a primary amino group
-
- 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
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4277—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues
- B01J2231/4283—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues using N nucleophiles, e.g. Buchwald-Hartwig amination
Abstract
The invention relates to a synthesis method of glycine, belonging to the technical field of organic synthesis. The invention takes chloroacetic acid or ammonium chloroacetate as raw material, ammonia gas or ammonia water as amination agent, and synthesizes amino acetic acid under the catalysis of fatty amine. Compared with urotropine, the catalyst used in the invention has good thermal stability, and can not be decomposed when the reaction temperature is higher, thus ensuring higher effective amount of the catalyst; and the generation of secondary amine and tertiary amine byproducts can be effectively inhibited through the steric hindrance regulation and control of the catalyst, so that the glycine is selectively generated. The invention can obtain excellent reaction yield in a wider temperature range, and has less byproducts and high glycine content in the crude product.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a synthesis method of glycine.
Background
Glycine, also called glycine, is the amino acid compound with the simplest structure, is used as an important fine chemical intermediate and chemical raw material, and is widely used in various fields of medicines, pesticides, foods, fertilizers, feeds and the like. With the continuous improvement of the living standard of people, the demand of the glycine in the food and medicine industry is continuously expanding.
Currently, the synthesis methods of glycine mainly include chloroacetic acid ammonolysis, natural protein hydrolysis and Strecker. Most foreign uses Strecker method with sodium cyanide as main raw material to produce glycine, its advantage is that the product is easy to refine, the production cost is low; the disadvantages are that sodium cyanide is a serious poison, the condition is harsh, and the process route is long. Glycine is produced by chloroacetic acid ammonolysis, and technical schemes for preparing glycine by chloroacetic acid ammonolysis are reported in patents CN1058957, CN1136035, CN1803763, CN1896049B and the like, and urotropine is used as a catalyst. The glycine content in the glycine-ammonium chloride mixed crystal obtained by the traditional chloroacetic acid ammonolysis method is low and is only about 30% -50%. After the glycine-ammonium chloride mixed crystal is refined by an alcohol precipitation method, the yield of the obtained glycine is low, and is only about 80%. Although the yield of glycine can be increased by increasing the reaction temperature and increasing the amount of urotropine, the contents of iminodiacetic acid and aminotriacetic acid as by-products increase with the increase of the reaction temperature. In addition, due to poor heat stability of urotropine, the urotropine is decomposed to generate formaldehyde and ammonia along with the increase of the reaction temperature, so that the catalyst is lost, and the color of the reaction solution and the color of the product are deepened.
In order to solve the technical problem of the traditional catalyst urotropine in the preparation of glycine, the prior patent provides a corresponding technical scheme. The patent CN111196768A adopts a two-step method to synthesize the glycine. According to the technical scheme, pyridine base compounds are used for replacing urotropine catalysts, ammonium chloroacetate is firstly synthesized at a low temperature, and then pyridine base is used for catalyzing the ammonium chloroacetate to react with ammonia to produce glycine. The purity of the glycine generated by the technical scheme is higher, the recycling of the mixed solvent and the catalyst is realized, but the following problems still exist: the reaction steps are complicated, and the yield is low; methanol with high toxicity is used as a solvent; the pyridine base compound has high price, increases the production cost and is not beneficial to industrial production.
In the patent CN108558687A, chloroacetic acid and ammonia gas are used as raw materials, the chloroacetic acid is subjected to ammonification reaction in an alcohol phase in the presence of a substituted pyridine catalyst, and the obtained reaction liquid is subjected to operations such as multiple times of filtration, washing and the like to respectively obtain glycine and ammonium chloride. The technical scheme also solves the defects of poor thermal stability, easy loss and the like of the conventional catalyst urotropine, the purity of the synthesized glycine is higher, and the catalyst can be recycled. The following disadvantages still remain: the catalytic efficiency is still not ideal, and when the catalyst dosage is 3mol percent, the total reaction yield is only 78.5 percent; the reaction solvent is methanol, ethanol and the like, and the dosage is large, so that the cost of the recovery section is increased; the substituted pyridine catalyst has high price, increases the production cost and is not beneficial to industrial production.
The traditional chloroacetic acid ammonolysis method is split into three procedures of ammonia dissolution, salifying reaction and ammonification reaction by the patent CN 111187173A. (1) preparing ammonia water; (2) Mixing chloroacetic acid solution with prepared ammonia water to generate salt reaction to obtain solution A; (3) Adding the mixed solution containing urotropine and ammonia water into the solution A for ammoniation reaction, cooling, crystallizing and separating to obtain glycine-ammonium chloride mixed crystal and mother solution. The mother solution can be used for preparing ammonia water in the step (1) or chloroacetic acid solution in the step (2), and continuous glycine synthesis is realized by continuing the reaction. The technical scheme effectively avoids the defects of the traditional process scheme, and realizes the recycling of urotropine. Experimental results show that when the catalyst dosage is 10mol%, the glycine content in the mixed crystal is 50%, and the glycine yield is 96%. The technical scheme has the problems of large catalyst consumption, more byproducts in mixed crystals, low content of amino acetic acid, complex operation steps, high cost and the like.
The synthesis of glycine using an inexpensive, efficient and stable catalyst has not been reported. Peng Chunxue et al report methods for synthesizing glycine using triethylamine as an acid-binding agent (Peng Chunxue, zhan Zhiping, liu Sanliu, et al, experimental studies on glycine synthesis using triethylamine as an acid-binding agent [ J ]. Shandong chemical, 2017,46 (7): 44-47.). According to the method, triethylamine is used as an acid binding agent, paraformaldehyde is used as a catalyst, methanol is used as a solvent, and glycine is synthesized through ammonification reaction of chloroacetic acid. The highest yield of the reaction can reach 92%, and the main content of glycine can reach 98.5%. However, the catalyst in the method is still urotropine, and triethylamine is only used as an acid-binding agent, and the dosage is up to 115mol percent.
Disclosure of Invention
Aiming at the problems of high residue, low yield and the like of urotropine and ammonium chloride in products of most catalysts of chloroacetic acid and glycine in the prior art, the invention provides a synthesis method of glycine, and aims to solve the technical problems. The method takes chloroacetic acid as an initial raw material, adopts fatty amine as a catalyst, and prepares and generates glycine under the action of ammonia gas or ammonia water. Compared with urotropine, the catalyst used in the invention has good thermal stability, and can not be decomposed when the reaction temperature is higher, thus ensuring higher effective amount of the catalyst; and the generation of secondary amine and tertiary amine byproducts can be effectively inhibited through the steric hindrance regulation and control of the catalyst, so that the glycine is selectively generated. The invention can obtain excellent reaction yield in a wider temperature range, and has less byproducts and high glycine content in the crude product.
The technical scheme of the invention is as follows:
the synthesis process of glycine includes synthesizing glycine with chloroacetic acid or ammonium chloroacetate as material and ammonia or ammonia water as aminating agent under the catalysis of fatty amine; the reaction equation is as follows:
wherein R is 1 ，R 2 ，R 3 Each independently is H or C 1 ～C 4 Is a hydrocarbon group.
Preferably, the fatty amine is selected from n-butylamine, di-n-propylamine, diethylmethylamine, diisopropylethylamine, trimethylamine, triethylamine, tri-n-butylamine, or dimethylethylamine; preferably triethylamine, n-butylamine, di-n-butylamine or tri-n-butylamine.
The specific synthesis steps are as follows:
(1) Adding an aliphatic amine catalyst into a reaction vessel, and controlling the temperature for preheating;
(2) Preparing chloroacetic acid into a water solution with a certain concentration, and transferring the water solution into a chloroacetic acid water solution dropwise adding device;
(3) Taking a proper amount of ammonia water, and moving the ammonia water into an ammonia water dropwise adding device;
(4) Controlling the dropping speed of chloroacetic acid solution and ammonia water, and controlling the dropping temperature between 25 and 45 ℃;
(5) After the dripping is finished, controlling the reaction temperature to be between 40 and 85 ℃ and the reaction time to be between 1 and 4 hours;
(6) After the reaction is finished, carrying out reduced pressure distillation and filtration on the reaction liquid to obtain a glycine-ammonium chloride mixed crystal wet product, and carrying out vacuum drying on the wet product at 65 ℃ until the weight is constant to obtain a crude product; the filtrate can be directly used for synthesizing the glycine of the next batch or after a certain amount of catalyst is added;
(7) Recrystallizing the crude product by using 98% ethanol-water mixed solution at 50 ℃, filtering, washing with alcohol, and drying to obtain the glycine. Cooling, crystallizing and filtering the filtrate to obtain ammonium chloride, and reusing the filtrate;
preferably, in the step (1), the molar ratio of chloroacetic acid to catalyst is 1:0.005-0.05, preferably 1:0.02-0.05.
Preferably, in the step (1), the preheating temperature is 20 ℃ to 40 ℃.
Preferably, in the step (2), the chloroacetic acid aqueous solution concentration is 60% to 65%, preferably 62% to 63%.
Preferably, in the step (3), the concentration of the ammonia water is 25% -28%.
Preferably, in the step (4), the dropping speed of the ammonia water is 8.0g/min to 15.0g/min, preferably 10.0g/min to 13.0g/min, and the dropping speed of the chloroacetic acid solution is 13g/min to 22.0g/min, preferably 15.0g/min to 20.0g/min. The aim of controlling the dropping speed of chloroacetic acid and ammonia water is to: firstly, too fast dripping can cause too large local pH value of the reaction solution, and excessive side reaction products are generated; secondly, the dripping process is an exothermic process, and the control of the dripping speed is beneficial to controlling the temperature of a reaction system, so that the increase of impurity content caused by local overheating is avoided.
Preferably, in the step (4), the dropping time of the aqueous ammonia and chloroacetic acid solution is controlled to be 1 to 2 hours, preferably 1.5 hours.
Preferably, in the step (5), the reaction temperature is controlled between 50 and 80 ℃.
Preferably, in the step (6), the reduced pressure distillation pressure is-0.1 Mpa, and the temperature is controlled between 60 and 70 ℃.
Preferably, in the step (6), pure water obtained by distillation under reduced pressure can be used for preparing chloroacetic acid or an aqueous ammonia solution.
The beneficial effects of the invention are as follows:
(1) The invention uses fatty amine compound as catalyst for synthesizing amino acetic acid for the first time, the total yield of amino acetic acid can reach 99.0%, the content of ammonium chloride in mixed crystal is between 41.6% and 42.9%, and the content is close to theoretical value (theoretical content is 41.6%).
(2) The fatty amine catalyst used in the invention has good thermal stability, can efficiently catalyze the ammonification reaction of chloroacetic acid at 40-85 ℃, and the use temperature of the conventional catalyst urotropine is generally 60-75 ℃. In contrast, the catalyst used in the invention has better reaction adaptability than urotropine.
(3) The aliphatic amine catalyst used in the invention has high catalytic efficiency, and the catalyst dosage is between 0.5mol% and 5.0mol%, so that the ammoniation reaction of chloroacetic acid can be efficiently catalyzed. The dosage of the urotropine serving as a traditional catalyst is generally 3.0-10.0 mol percent or even higher.
(4) The invention can effectively inhibit the generation of byproducts such as iminodiacetic acid and the like and improve the product quality through the regulation and control of the steric hindrance of the catalyst.
(5) The catalyst of the invention can be recycled, the operation condition is milder and simpler than the prior art, the total reaction ammonia consumption is close to the theoretical equivalent, and the ammonia consumption is not more than 5% of the theoretical equivalent.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are required to be used in the description of the embodiments or the prior art will be briefly described below, and it will be obvious to those skilled in the art that other drawings can be obtained from these drawings without inventive effort.
FIG. 1 is a schematic diagram of the catalytic reaction mechanism of example 1 of the present invention.
Detailed Description
In order to make the technical solution of the present invention better understood by those skilled in the art, the technical solution of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the present invention without making any inventive effort, shall fall within the scope of the present invention.
Example 1
(1) Adding 39.7g (0.39 mol) of triethylamine into a reaction vessel provided with a thermometer, stirring, heating, cooling circulating water and dripping device, and controlling the preheating at 30 ℃;
(2) 1000.0g (10.6 mol) of chloroacetic acid is weighed, 600g of water is added for dissolution, and the mixture is transferred to a chloroacetic acid dripping device;
(3) Taking 160 mL of 25% ammonia water, and transferring to an ammonia water dropwise adding device;
(4) Controlling the drop speeds of the chloroacetic acid solution and the ammonia water to be 16.0g/min and 12.0g/min respectively, controlling the temperature to be 30 ℃, and controlling the dropwise adding of the chloroacetic acid solution to be completed within about 1.5 hours and the dropwise adding of the ammonia water to be completed within about 2 hours;
(5) Heating to 60 ℃ after the dripping is finished, and reacting for 2 hours with heat preservation;
(6) After the reaction is finished, the reaction liquid is distilled under reduced pressure to remove water and filtered to obtain a glycine-ammonium chloride mixed crystal wet product; vacuum drying the wet product at 65deg.C to constant weight, wherein the mass of the wet product is 1326.5g, and the content of byproduct ammonium chloride is 41.8%;
(7) The crude product is recrystallized at 50 ℃ by using 98% ethanol-water mixed solution, 741.2g of glycine is obtained through filtration and drying, the yield is 93.3%, and the content detected by a titration method is 98.9%. Slowly cooling the filtrate to 10 ℃, and filtering and separating to obtain ammonium chloride.
The catalytic mechanism of the invention is illustrated by way of example 1: firstly, carrying out addition reaction on triethylamine and chloroacetic acid to generate a quaternary ammonium salt intermediate, wherein the intermediate has larger steric hindrance; and ammonia and the quaternary ammonium salt intermediate undergo nucleophilic reaction to generate glycine and triethylamine hydrochloride. Because the steric hindrance of the glycine is large, nucleophilic reaction is not easy to occur with the quaternary ammonium salt intermediate, and thus, the generation of byproducts such as iminodiacetic acid can be effectively inhibited.
Example 2
(1) 72.7g (0.39 mol) of tri-n-butylamine is added into a reaction vessel provided with a thermometer, stirring, heating, circulating water cooling and dripping device, and preheating is controlled at 40 ℃;
(2) 1000.0g (10.6 mol) of chloroacetic acid is weighed, 600g of water is added for dissolution, and the mixture is transferred to a chloroacetic acid dripping device;
(3) Taking 160 mL of 25% ammonia water, and transferring to an ammonia water dropwise adding device;
(4) Controlling the drop speeds of the chloroacetic acid solution and the ammonia water to be 16.0g/min and 12.0g/min respectively, controlling the temperature to be 40 ℃, and controlling the dropwise adding of the chloroacetic acid solution to be completed within about 1.5 hours and the dropwise adding of the ammonia water to be completed within about 2 hours;
(5) Heating to 60 ℃ after the dripping is finished, and reacting for 2 hours with heat preservation;
(6) After the reaction is finished, the reaction liquid is distilled under reduced pressure to remove water and filtered to obtain a glycine-ammonium chloride mixed crystal wet product; vacuum drying the wet product at 65deg.C to constant weight, wherein the mass of the wet product is 1345.6g, and the content of byproduct ammonium chloride is 41.7%;
(7) The crude product is recrystallized at 50 ℃ by using 98% ethanol-water mixed solution, 761.1g of glycine is obtained through filtration and drying, the yield is 95.8%, and the content detected by a titration method is 99.0%. Slowly cooling the filtrate to 10 ℃, and filtering and separating to obtain ammonium chloride.
Example 3
(1) 68.5g (0.53 mol) of di-n-butylamine is added into a reaction vessel provided with a thermometer, stirring, heating, circulating water cooling and dripping device, and preheating is controlled at 40 ℃;
(2) 1000.0g (10.6 mol) of chloroacetic acid is weighed, 600g of water is added for dissolution, and the mixture is transferred to a chloroacetic acid dripping device;
(3) Taking 160 mL of 28% ammonia water, and transferring to an ammonia water dropwise adding device;
(4) Controlling the drop speeds of the chloroacetic acid solution and the ammonia water to be 15.0g/min and 10.0g/min respectively, controlling the temperature to be 40 ℃, and controlling the drop speed of the chloroacetic acid solution to be about 1.5 hours after the dropwise adding of the ammonia water is completed, and controlling the drop speed of the ammonia water to be about 2.5 hours after the dropwise adding of the chloroacetic acid solution is completed;
(5) Heating to 50 ℃ after the dripping is finished, and preserving heat for 4 hours;
(6) After the reaction is finished, the reaction liquid is distilled under reduced pressure to remove water and filtered to obtain a glycine-ammonium chloride mixed crystal wet product; vacuum drying the wet product at 65deg.C to constant weight, wherein the mass of the wet product is 1269.4g, and the content of byproduct ammonium chloride is 42.9%;
(7) The crude product is recrystallized at 50 ℃ by using 98% ethanol-water mixed solution, 737.3g of glycine is obtained through filtration and drying, the yield is 92.8%, and the content detected by a titration method is 98.1%. Slowly cooling the filtrate to 10 ℃, and filtering and separating to obtain ammonium chloride.
Example 4
(1) 38.8g (0.53 mol) of n-butylamine is added into a reaction vessel provided with a thermometer, stirring, heating, circulating water cooling and dripping device, and preheating is controlled at 35 ℃;
(2) 1000.0g (10.6 mol) of chloroacetic acid is weighed, 600g of water is added for dissolution, and the mixture is transferred to a chloroacetic acid dripping device;
(3) Taking 160 mL of 28% ammonia water, and transferring to an ammonia water dropwise adding device;
(4) Controlling the drop speeds of the chloroacetic acid solution and the ammonia water to be 15.0g/min and 10.0g/min respectively, controlling the temperature to be 40 ℃, and controlling the drop speed of the chloroacetic acid solution to be about 1.5 hours after the dropwise adding of the ammonia water is completed, and controlling the drop speed of the ammonia water to be about 2.5 hours after the dropwise adding of the chloroacetic acid solution is completed;
(5) Heating to 50 ℃ after the dripping is finished, and preserving heat for 4 hours;
(6) After the reaction is finished, the reaction liquid is distilled under reduced pressure to remove water and filtered to obtain a glycine-ammonium chloride mixed crystal wet product; vacuum drying the wet product at 65deg.C to constant weight, wherein the mass of the wet product is 1201.4g, and the content of byproduct ammonium chloride is 42.4%;
(7) The crude product is recrystallized at 50 ℃ by using 98% ethanol-water mixed solution, 684.0g of glycine is obtained through filtration and drying, the yield is 86.1%, and the content detected by a titration method is 97.8%. Slowly cooling the filtrate to 10 ℃, and filtering and separating to obtain ammonium chloride.
Example 5
(1) 6.85g (0.053 mol) of diisopropylethylamine is added into a reaction vessel equipped with a thermometer, stirring, heating, cooling with circulating water and dripping device, and preheating is controlled at 30 ℃;
(2) 1000.0g (10.6 mol) of chloroacetic acid is weighed, 600g of water is added for dissolution, and the mixture is transferred to a chloroacetic acid dripping device;
(3) Taking 160 mL of 28% ammonia water, and transferring to an ammonia water dropwise adding device;
(4) Controlling the drop speeds of the chloroacetic acid solution and the ammonia water to be 15.0g/min and 10.0g/min respectively, controlling the temperature to be 30 ℃, and controlling the drop speed of the chloroacetic acid solution to be 30 ℃ for about 1.5 hours after the dropwise addition of the ammonia water is completed, and controlling the drop speed of the ammonia water to be 2.5 hours after the dropwise addition of the ammonia water is completed;
(5) Heating to 80 ℃ after the dripping is finished, and reacting for 2 hours with heat preservation;
(6) After the reaction is finished, the reaction liquid is distilled under reduced pressure to remove water and filtered to obtain a glycine-ammonium chloride mixed crystal wet product; vacuum drying the wet product at 65deg.C to constant weight, wherein the mass of the wet product is 1023.1g, and the content of byproduct ammonium chloride is 42.6%;
(7) The crude product is recrystallized at 50 ℃ by using 98% ethanol-water mixed solution, 576.0g of glycine is obtained through filtration and drying, the yield is 72.5%, and the content detected by a titration method is 89.0%. Slowly cooling the filtrate to 10 ℃, and filtering and separating to obtain ammonium chloride.
Example 6
(1) 39.3g (0.21 mol) of tri-n-butylamine and 11.6g (0.16 mol) of n-butylamine are added into a reaction vessel provided with a thermometer, stirring, heating, circulating water cooling and dropwise adding device, and preheating is controlled at 40 ℃;
(2) 1000.0g (10.6 mol) of chloroacetic acid is weighed, 600g of water is added for dissolution, and the mixture is transferred to a chloroacetic acid dripping device;
(3) Taking 160 mL of 28% ammonia water, and transferring to an ammonia water dropwise adding device;
(4) Controlling the drop speeds of the chloroacetic acid solution and the ammonia water to be 16.0g/min and 12.0g/min respectively, controlling the temperature to be 40 ℃, and controlling the dropwise adding of the chloroacetic acid solution to be completed within about 1.5 hours and the dropwise adding of the ammonia water to be completed within about 2 hours;
(5) Heating to 60 ℃ after the dripping is finished, and reacting for 4 hours with heat preservation;
(6) After the reaction is finished, the reaction liquid is distilled under reduced pressure to remove water and filtered to obtain a glycine-ammonium chloride mixed crystal wet product; vacuum drying the wet product at 65deg.C to constant weight, wherein the mass of the wet product is 1236.7g, and the content of byproduct ammonium chloride is 42.0%;
(7) The crude product is recrystallized at 50 ℃ by using 98% ethanol-water mixed solution, 725.4g of glycine is obtained through filtration and drying, the yield is 91.3%, and the content detected by a titration method is 96.7%. Slowly cooling the filtrate to 10 ℃, and filtering and separating to obtain ammonium chloride.
Comparative example
(1) Adding 74.3g (0.53 mol) of urotropine into a reaction vessel equipped with a thermometer, stirring, heating, cooling circulating water and dripping device, and controlling the preheating at 40 ℃;
(2) 1000.0g (10.6 mol) of chloroacetic acid is weighed, 600g of water is added for dissolution, and the mixture is transferred to a chloroacetic acid dripping device;
(3) Taking 160 mL of 25% ammonia water, and transferring to an ammonia water dropwise adding device;
(4) Controlling the drop speeds of the chloroacetic acid solution and the ammonia water to be 16.0g/min and 12.0g/min respectively, controlling the temperature to be 40 ℃, and controlling the dropwise adding of the chloroacetic acid solution to be completed within about 1.5 hours and the dropwise adding of the ammonia water to be completed within about 2 hours;
(5) Heating to 60 ℃ after the dripping is finished, and reacting for 2 hours with heat preservation;
(6) After the reaction is finished, the reaction liquid is distilled under reduced pressure to remove water and filtered to obtain a glycine-ammonium chloride mixed crystal wet product; vacuum drying the wet product at 65deg.C to constant weight, wherein the mass of the wet product is 1073.5g, and the content of byproduct ammonium chloride is 46.7%;
(7) The crude product is recrystallized by using 98% ethanol-water mixed solution at 50 ℃, 630.0g of glycine is obtained by filtering and drying, the yield is 79.3%, and the content is 96.5% detected by a titration method. Slowly cooling the filtrate to 10 ℃, and filtering and separating to obtain ammonium chloride.
Although the present invention has been described in detail by way of preferred embodiments with reference to the accompanying drawings, the present invention is not limited thereto. Various equivalent modifications and substitutions may be made in the embodiments of the present invention by those skilled in the art without departing from the spirit and scope of the present invention, and it is intended that all such modifications and substitutions be within the scope of the present invention/be within the scope of the present invention as defined by the appended claims. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (9)
1. The synthesis method of the glycine is characterized in that chloroacetic acid or ammonium chloroacetate is used as a raw material, ammonia gas or ammonia water is used as an amination agent, and the glycine is synthesized under the catalysis of fatty amine; the reaction equation is as follows:
wherein R is 1 ，R 2 ，R 3 Each independently is C 1 ~C 4 Alkyl of (a);
the feeding molar ratio of chloroacetic acid to fatty amine is 1:0.005-0.05.
2. The method of synthesis according to claim 1, wherein the fatty amine is selected from at least one of n-butylamine, di-n-propylamine, diethylmethylamine, diisopropylethylamine, trimethylamine, triethylamine, tri-n-butylamine, or dimethylethylamine.
3. The synthesis method according to any one of claims 1-2, characterized by the specific synthesis steps as follows:
(1) Adding an aliphatic amine catalyst into a reaction vessel, and controlling the temperature for preheating;
(2) Preparing chloroacetic acid into a water solution with a certain concentration, and transferring the water solution into a chloroacetic acid water solution dropwise adding device;
(3) Taking a proper amount of ammonia water, and moving the ammonia water into an ammonia water dropwise adding device;
(4) Controlling the dropping speed of chloroacetic acid solution and ammonia water, and controlling the dropping temperature to be 25-45 ℃;
(5) After the dripping is finished, controlling the reaction temperature to be 40-85 ℃ and the reaction time to be 1-4 hours;
(6) After the reaction is finished, carrying out reduced pressure distillation and filtration on the reaction liquid to obtain a glycine-ammonium chloride mixed crystal wet product, and carrying out vacuum drying on the mixed crystal wet product at 65 ℃ until the weight is constant to obtain a crude product;
(7) Recrystallizing the crude product by using 98% ethanol-water mixed solution at 50 ℃, filtering, washing with alcohol, and drying to obtain the glycine.
4. The method according to claim 3, wherein in the step (1), the molar ratio of chloroacetic acid to the catalyst is 1:0.02-0.05.
5. The method according to claim 3, wherein in the step (2), the chloroacetic acid aqueous solution has a concentration of 60% -65%.
6. The synthesis method according to claim 3, wherein in the step (3), the concentration of ammonia water is 25% -28%.
7. The synthesis method according to claim 3, wherein in the step (4), the dropping speed of the ammonia water is 8.0g/min to 15.0g/min; the dropping speed of the chloroacetic acid solution is 13 g/min-22.0 g/min.
8. The synthesis method according to claim 3, wherein in the step (4), the dropping time is controlled to be 1 to 2 hours.
9. The synthesis method according to claim 3, wherein in the step (5), the reaction temperature is controlled to be 50-80 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110764036.7A CN113563214B (en) | 2021-07-06 | 2021-07-06 | Synthesis method of glycine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110764036.7A CN113563214B (en) | 2021-07-06 | 2021-07-06 | Synthesis method of glycine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113563214A CN113563214A (en) | 2021-10-29 |
| CN113563214B true CN113563214B (en) | 2024-02-02 |
Family
ID=78163870
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110764036.7A Active CN113563214B (en) | 2021-07-06 | 2021-07-06 | Synthesis method of glycine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113563214B (en) |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04112859A (en) * | 1990-09-04 | 1992-04-14 | Hakko Tsusho Kk | Improved method of synthesizing glycine |
| JPH0692917A (en) * | 1992-07-16 | 1994-04-05 | Hakko Tsusho Kk | Improved method of synthesizing glycine |
| CN1136035A (en) * | 1995-05-19 | 1996-11-20 | 河北东华化工总公司 | Preparation of amino-acetic acid |
| CN102030669A (en) * | 2009-09-25 | 2011-04-27 | 李其奎 | Clean production method for glycine |
| CN105130833A (en) * | 2015-09-28 | 2015-12-09 | 浙江汇能动物药品有限公司 | Preparation method of high-purity betain hydrochloride |
| CN107216262A (en) * | 2017-04-18 | 2017-09-29 | 中国科学院过程工程研究所 | A kind of method that homogeneous system intermediate ion liquid catalyst synthesizes glycine |
| CN108558687A (en) * | 2018-05-10 | 2018-09-21 | 四川福思达生物技术开发有限责任公司 | A kind of method that glycine is catalyzed and synthesized in homogeneous system |
| CN111517972A (en) * | 2019-02-03 | 2020-08-11 | 刘长飞 | Preparation method of environment-friendly betaine |
| CN112262139A (en) * | 2018-01-26 | 2021-01-22 | 百时美施贵宝公司 | Aminopyrrolotriazines as kinase inhibitors |
-
2021
- 2021-07-06 CN CN202110764036.7A patent/CN113563214B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04112859A (en) * | 1990-09-04 | 1992-04-14 | Hakko Tsusho Kk | Improved method of synthesizing glycine |
| JPH0692917A (en) * | 1992-07-16 | 1994-04-05 | Hakko Tsusho Kk | Improved method of synthesizing glycine |
| CN1136035A (en) * | 1995-05-19 | 1996-11-20 | 河北东华化工总公司 | Preparation of amino-acetic acid |
| CN102030669A (en) * | 2009-09-25 | 2011-04-27 | 李其奎 | Clean production method for glycine |
| CN105130833A (en) * | 2015-09-28 | 2015-12-09 | 浙江汇能动物药品有限公司 | Preparation method of high-purity betain hydrochloride |
| CN107216262A (en) * | 2017-04-18 | 2017-09-29 | 中国科学院过程工程研究所 | A kind of method that homogeneous system intermediate ion liquid catalyst synthesizes glycine |
| CN112262139A (en) * | 2018-01-26 | 2021-01-22 | 百时美施贵宝公司 | Aminopyrrolotriazines as kinase inhibitors |
| CN108558687A (en) * | 2018-05-10 | 2018-09-21 | 四川福思达生物技术开发有限责任公司 | A kind of method that glycine is catalyzed and synthesized in homogeneous system |
| CN111517972A (en) * | 2019-02-03 | 2020-08-11 | 刘长飞 | Preparation method of environment-friendly betaine |
Non-Patent Citations (2)
| Title |
|---|
| Optimization of2,4-diaminopyrimidines as GHS-R antagonists: Side chain exploration;Bo Liu等;Bioorganic & Medicinal Chemistry Letters;第16卷;1864-1868 * |
| 氯乙酸氨解法甘氨酸合成工艺研究;张汉铭;化学工业与工程技术;第31卷(第6期);1-3 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113563214A (en) | 2021-10-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8791302B2 (en) | Process for preparing an N,N-dialky-ethanolamine having high color stability | |
| US4140716A (en) | Process for making an amide of formic acid and forming nitrodiarylamine therefrom | |
| JP3041703B2 (en) | Production method of carbamate | |
| CN103665032A (en) | Preparation method of glufosinate | |
| KR20070087123A (en) | Method for the continuous production of silicon compounds carrying amino groups | |
| CN107325015B (en) | Method for continuously preparing glycine from hydroxyacetonitrile | |
| CN113698320A (en) | Preparation method of L-Carlactonitrile | |
| CN102503870B (en) | Preparation method of dialkyl thiodipropionate | |
| CN113563214B (en) | Synthesis method of glycine | |
| CN111170878B (en) | Method for preparing D-type or L-type tert-leucine | |
| CN108164423B (en) | Preparation method of naftifine hydrochloride | |
| US4571437A (en) | Process for preparing p-aminophenol and alkyl substituted p-aminophenol | |
| CN111320571B (en) | Method for preparing 4-dimethylaminopyridine | |
| JP3318992B2 (en) | Method for producing N- (α-alkoxyethyl) formamide | |
| CN113480588A (en) | Preparation method of estradiol mesilate | |
| AU2003267771A1 (en) | Process for the production of 3-methylthiopropanal | |
| CN102584612A (en) | Synthesis method of sarcosine | |
| CN113135841A (en) | Preparation method of Sacubitril intermediate | |
| JPH11209335A (en) | Production of substituted guanidine derivative | |
| CN112645824B (en) | Method for biosynthesizing isopropylamine hydrochloride by laccase | |
| CN115433081B (en) | Preparation method of diethyl dipropylmalonate | |
| CN115894182B (en) | Method for efficiently synthesizing 1, 4-tetramethoxy-2-butene | |
| CN112812029B (en) | Preparation method of crotonate compounds | |
| CN116273185B (en) | Immobilized bifunctional catalyst and method for preparing cyclic carbonate in outer loop reaction process | |
| US6333429B1 (en) | Process for preparing alkali metal salts of malonic monoalkyl esters |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |