CN109704983B - Method for synthesizing 3-iodine-N-protected-L-tyrosine methyl ester by removing MOM protection - Google Patents
Method for synthesizing 3-iodine-N-protected-L-tyrosine methyl ester by removing MOM protection Download PDFInfo
- Publication number
- CN109704983B CN109704983B CN201910141309.5A CN201910141309A CN109704983B CN 109704983 B CN109704983 B CN 109704983B CN 201910141309 A CN201910141309 A CN 201910141309A CN 109704983 B CN109704983 B CN 109704983B
- Authority
- CN
- China
- Prior art keywords
- methyl ester
- tyrosine methyl
- iodine
- protected
- protection
- 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
Images
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing 3-iodine-N-protected-L-tyrosine methyl ester by MOM protection removal, belonging to the technical field of organic synthesis. Reacting N-protected-L-tyrosine methyl ester with MOMCl and an iodine reagent to obtain 3-iodine-N-protected-O-methyl ether-L-tyrosine methyl ester, and then removing MOM protection under normal pressure in a hydrogen atmosphere under the catalysis of palladium to obtain 3-iodine-N-protected-L-tyrosine methyl ester. The method for removing the MOM protecting group avoids the problem of group tolerance in conventional strong acid systems such as hydrochloric acid, acetic acid, trifluoroacetic acid or boron trifluoride diethyl etherate and the like, and has high reaction selectivity and simple post-treatment.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing 3-iodo-N-protected-L-tyrosine methyl ester through demethyl methyl ether groups.
Background
The cyclopeptide natural product has obvious effects on the activities of resisting tumors, resisting bacteria and the like, and is a hot field of the research of new drugs at present. The tyrosine skeleton is widely present in the natural products of cyclic peptides and has important significance for maintaining the antitumor or antibacterial activity. The selective protection and deprotection of amino acids in the synthesis of such natural products is crucial to control the reaction sites and improve the reaction efficiency. MOM (methyl ether) is a commonly used hydroxyl protecting group and is widely applied to peptide synthesis, but the MOM removal method reported in the literature is mostly carried out under acidic conditions, and specific examples are as follows:
the Hidenori Watanabe research group used trifluoroacetic acid in the tyrosochelin synthesis process to reflux remove MOM, Boc (tert-butyloxycarbonyl) and TBS (tert-butyldimethylsilyl) groups in the presence of tetrahydrofuran, methanol and water to obtain the target product [ Tetrahedron,2009,65: 3629-:
hitoshi KAGAWA et al, in the synthesis of flavone derivatives, reacted with 17.8% methanol hydrochloride in methanol at 100 ℃ to give the ring-closed flavone compounds in 66% yield, together with 24.8% of the MOM-removed product [ chem.Pharm.Bull.,2005,53:547-554], the equation is as follows:
oghale Obaro-Best et al used bismuth chloride to react in acetonitrile-water solvent at 50 ℃ for 2 hours to give demetomom p-benzyloxyphenol [ Synth. Commun.,2016, DOI:10.1080/00397911.2016.1158270] in 90% yield.
Taking the above examples as representative examples, most of the methods for removing MOM reported in the literature at present use strong acids such as hydrochloric acid and trifluoroacetic acid or strong lewis acids such as boron tribromide and boron trifluoride diethyl etherate, and the main disadvantages of these conditions are that the acidity is too strong, side reactions are easily caused, the post-treatment is complicated, and the method is not suitable for synthesis of molecules containing acid-intolerant groups.
Disclosure of Invention
In order to overcome the defects, the invention adopts N-protection-L-tyrosine methyl ester to react with chloromethyl methyl ether and iodine simple substance in sequence to obtain 3-iodine-N-protection-O-methyl ether-L-tyrosine methyl ester, and demethyl methyl ether is carried out under the conditions of palladium catalyst and hydrogen to obtain 3-iodine-N-protection-L-tyrosine methyl ester.
The invention provides a method for synthesizing 3-iodine-N-protection-L-tyrosine methyl ester by demethyl methyl ether group, which is characterized by comprising the following steps:
the method comprises the following steps:
the first step, carrying out MOM protection of hydroxyl and 3-bit iodination reaction on N-protection-L-tyrosine methyl ester in sequence to obtain 3-iodine-N-protection-O-methyl ether-L-tyrosine methyl ester;
and secondly, removing MOM protection from the 3-iodine-N-protection-O-methyl ether-L-tyrosine methyl ester under the catalysis of palladium and in a hydrogen atmosphere to obtain the 3-iodine-N-protection-L-tyrosine methyl ester.
Further, in the above technical scheme, the protecting group P is selected from tert-butoxycarbonyl, benzyloxycarbonyl, acetyl or benzoyl.
Further, in the above technical scheme, in the first step, the raw material of formula I reacts with chloromethyl methyl ether and alkali in a chlorinated solvent, and then reacts with elemental iodine and silver reagent to obtain the intermediate of formula II. The chlorinated solvent is selected from dichloromethane, chloroform, 1, 2-dichloroethane, etc.
Further, in the above technical solution, in the first step, the base is selected from sodium hydride, triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide; the silver agent is selected from silver nitrate, silver sulfate or silver trifluoroacetate. By controlling the equivalent of silver reagent to not more than 1.2 times the starting material I, it was ensured that the reaction was free of a clearly visible diiodo impurity.
Further, in the above technical scheme, in the second step, the intermediate of formula II is dissolved in an alcohol solution, a palladium catalyst is added, the reaction is performed under a hydrogen atmosphere, the solvent is filtered and evaporated, and the product of formula III is obtained by recrystallization. The recrystallization solvent is preferably ethyl acetate. The preferred pressure range is 1-2 atm. Above 3atm, the deiodinated by-products increase significantly with longer reaction times or increased temperatures.
Further, in the above technical solution, in the second step, the palladium catalyst is selected from palladium carbon or palladium hydroxide; either 5% or 10% palladium on carbon of common commercial specifications can be used. The alcoholic solution is selected from methanol, ethanol or isopropanol.
Further, in the above technical scheme, the molar ratio of the intermediate of the formula II to the palladium catalyst in the second step is 1000:1 to 5: 1.
Advantageous effects of the invention
The method comprises the steps of taking N-protection-L-tyrosine methyl ester as a raw material, reacting with chloromethyl methyl ether and iodine simple substance in sequence to obtain 3-iodine-N-protection-O-methyl ether-L-tyrosine methyl ester, and then demethylating methyl ether under the conditions of palladium catalyst and hydrogen to obtain the 3-iodine-N-protection-L-tyrosine methyl ester. The two-step reaction has high yield, the deprotection is carried out under a neutral condition, the reaction is relatively mild, and no influence is caused on acid-intolerant groups, so the method is very suitable for peptide synthesis. Meanwhile, the post-treatment only needs filtration and recrystallization, so that the reaction yield is improved, the post-treatment process is simplified, and a simple, convenient and feasible way is provided for the synthesis of the compounds.
Drawings
FIG. 1 is a drawing showing the preparation of 3-iodo-N-benzyloxycarbonyl-L-tyrosine methyl ester in example 11H-NMR;
FIG. 2 is the preparation of methyl 3-iodo-N-benzyloxycarbonyl-L-tyrosine in example 113C-NMR;
FIG. 3 shows the preparation of methyl 3-iodo-N-tert-butoxycarbonyl-L-tyrosine in example 31H-NMR;
FIG. 4 shows the preparation of methyl 3-iodo-N-tert-butoxycarbonyl-L-tyrosine in example 313C-NMR。
Detailed Description
Example 1
Preparation of 3-iodo-N-benzyloxycarbonyl-L-tyrosine methyl ester
1) Weighing 1.0mmol of N-benzyloxycarbonyl-L-tyrosine methyl ester, dissolving the N-benzyloxycarbonyl-L-tyrosine methyl ester by using 20mL of dichloromethane, then adding 3.0mmol of triethylamine and 1.0mmol of MOMCl (chloromethyl methyl ether), then reacting for 3 hours, evaporating to dryness under reduced pressure, adding 25mL of ethyl acetate and 10mL of water for extraction, washing an organic phase by using 10mL of water and saturated saline water respectively, drying the organic phase by using anhydrous sodium sulfate, evaporating to remove an organic solvent under reduced pressure, then dissolving by using 10mL of methanol, then adding 1.0mmol of silver nitrate and 1.0mmol of iodine, reacting for 1 hour, evaporating to dryness under reduced pressure, adding 25mL of ethyl acetate and 10mL of water for extraction, evaporating to dryness under reduced pressure an organic extract to obtain 0.51g of a crude product, recrystallizing by using 50mL of ethyl acetate to obtain 0.44g of 3-iodine-N-benzyloxycarbonyl-O-methyl ether-.1H-NMR(300MHz,CDCl3):δ(ppm)7.53(1H,d),7.39-7.29(5H,m),7.02-6.92(2H,m),5.33-5.28(1H,m),5.20(2H,s),5.15-5.05(2H,m),4.63-4.57(1H,m),3.73(3H,s),3.49(3H,s),3.05-2.94(2H,m).13C-NMR(75MHz,CDCl3):δ(ppm)171.83,155.69,155.37,140.22,136.29,131.25,130.40,128.66,128.30,128.17,114.85,95.09,87.30,67.14,56.52,54.91,52.51,36.94.
2) 0.5mmol of 3-iodine-N-benzyloxycarbonyl-O-methyl ether-L-tyrosine methyl ester is weighed, dissolved in 5mL of methanol, added with 0.005mmol of 5% palladium carbon, reacted at room temperature for 1 hour under a hydrogen atmosphere (1atm), and after the reaction is detected to be finished, no iodine product and other impurities are found (TLC). Filtering to remove solid, evaporating organic solvent under reduced pressure, recrystallizing with ethyl acetate to obtain 0.2g of 3-iodo-N-benzyloxycarbonyl-L-tyrosine methyl ester with yield of 88%;1H-NMR(300MHz,CDCl3):δ(ppm)7.22(5H,s),6.82(1H,d),6.68(1H,d),6.61(1H,d),5.36(1H,dd),4.99(2H,s),4.52-4.48(1H,m),3.60(3H,s),2.93-2.84(2H,m).13C-NMR(75MHz,CDCl3):δ(ppm)172.38,172.03,156.00,155.47,154.58,139.21,136.08,130.72,130.34,129.49,128.58,128.54,128.23,128.05,126.96,115.65,115.16,85.02,67.22,55.10,52.43,37.39,36.88.
example 2
Preparation of 3-iodo-N-benzyloxycarbonyl-L-tyrosine methyl ester
1) Weighing 1.0mmol of N-benzyloxycarbonyl-L-tyrosine methyl ester, dissolving with 30mL of dichloromethane, adding 3.0mmol of diisopropylethylamine and 1.1mmol of MOMCl, reacting for about 5 hours, evaporating the liquid under reduced pressure, adding 25mL of ethyl acetate and 10mL of water for extraction, washing the separated organic phase once with 10mL of water and saturated saline water respectively, drying with anhydrous sodium sulfate, and evaporating the organic solvent under reduced pressure to obtain an intermediate. Dissolving the intermediate by using 10mL of methanol, adding 1.1mmol of silver trifluoroacetate and 1.1mmol of iodine, reacting for 1 hour, evaporating the solvent to dryness under reduced pressure, adding 25mL of ethyl acetate and 10mL of water for extraction, evaporating the organic extract to dryness under reduced pressure to obtain a crude product, recrystallizing 45mL of ethyl acetate to obtain 0.42g of 3-iodine-N-benzyloxycarbonyl-O-methyl ether-L-tyrosine methyl ester, wherein the yield is 85%;
2) 0.7mmol of 3-iodine-N-benzyloxycarbonyl-O-methyl ether-L-tyrosine methyl ester is weighed, dissolved in 10mL of methanol, added with 0.07mmol of palladium hydroxide, reacted at room temperature for 1 hour under a hydrogen atmosphere (1atm), and after the detection reaction is finished, no iodine product or other impurities are found (TLC). Filtering to remove solid, evaporating organic solvent under reduced pressure, and recovering ethyl acetate0.27g of 3-iodo-N-benzyloxycarbonyl-L-tyrosine methyl ester was obtained in 86% yield.1H-NMR(300MHz,CDCl3):δ(ppm)7.23(5H,s),6.83(1H,d),6.68(1H,d),6.61(1H,d),5.36(1H,dd),4.99(2H,s),4.52-4.48(1H,m),3.60(3H,s),2.94-2.84(2H,m).13C-NMR(75MHz,CDCl3):δ(ppm)172.40,172.04,156.01,155.48,154.59,139.22,136.09,130.72,130.34,129.49,128.59,128.55,128.24,128.06,126.96,115.66,115.17,85.03,67.17,55.10,52.43,37.39,36.88.
Example 3
Preparation of 3-iodo-N-tert-butoxycarbonyl-L-tyrosine methyl ester
1) 1.0mmol of N-t-butoxycarbonyl-L-tyrosine methyl ester was weighed, dissolved in 25mL of dichloromethane, then 3.0mmol of sodium hydride and 1.2mmol of MOMCl were added, then the reaction was carried out for about 1 hour, 10mL of a water-saturated aqueous ammonium chloride solution was added, then 25mL of ethyl acetate and 10mL of water were added for extraction, the separated organic phase was washed once with 10mL of water and saturated brine, then dried over anhydrous sodium sulfate, and the organic solvent was evaporated under reduced pressure to give an intermediate. Dissolving the intermediate by using 15mL of methanol, adding 1.1mmol of silver sulfate and 1.1mmol of iodine, reacting for 1 hour, evaporating the solvent to dryness under reduced pressure, adding 25mL of ethyl acetate and 10mL of water for extraction, evaporating the organic extract to dryness under reduced pressure to obtain a crude product, and recrystallizing ethyl acetate to obtain 0.4g of 3-iodine-N-tert-butoxycarbonyl-O-methyl ether-L-tyrosine methyl ester with the yield of 87%;1H-NMR(300MHz,CDCl3):δ(ppm)7.54(1H,s),7.06-6.97(2H,m),5.21(s,2H),5.03(d,1H),4.53(m,1H),3.74(s,3H),3.50(s,3H),3.08-2.91(m,2H),1.43(s,9H);13C-NMR(75MHz,CDCl3):δ(ppm)172.09,155.20,140.21,131.50,130.32,114.74,95.00,87.08,80.01,56.43,54.39,52.24,36.92,28.32.
2) 0.6mmol of 3-iodo-N-tert-butoxycarbonyl-O-methyl ether-L-tyrosine methyl ester was weighed, dissolved in 10mL of methanol, and then 0.003mmol of palladium hydroxide was added to the solution to react under a hydrogen atmosphere at room temperature for 1 hour. The solid was removed by filtration, and after the organic solvent was evaporated under reduced pressure, ethyl acetate was recrystallized to give 0.22g of 3-iodo-N-tert-butoxycarbonyl-L-tyrosine methyl ester in 89% yield.1H-NMR(300MHz,CDCl3):δ(ppm)7.43(1H,s),6.96(1H,dd),6.81(1H,d),6.63(1H,s),5.13(1H,d),4.50(1H,m),3.73(3H,s),3.04-2.87(2H,m),1.42(9H,s).13C-NMR(75MHz,CDCl3):δ(ppm)172.29,155.24,154.49,139.94,139.22,130.71,129.67,115.07,84.99,80.31,54.53,52.40,36.93,28.32.
The foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.
Claims (6)
1. The method for synthesizing 3-iodine-N-protected-L-tyrosine methyl ester by removing MOM protection is characterized in that the reaction equation is as follows:
the method comprises the following steps: step one, carrying out MOM protection of hydroxyl and 3-bit iodination reaction on N-protection-L-tyrosine methyl ester in sequence, and recrystallizing ethyl acetate to obtain 3-iodine-N-protection-O-methyl ether-L-tyrosine methyl ester; secondly, removing MOM protection from 3-iodine-N-protection-O-methyl ether-L-tyrosine methyl ester in a hydrogen atmosphere under the catalysis of palladium, and recrystallizing ethyl acetate to obtain 3-iodine-N-protection-L-tyrosine methyl ester; the protecting group P is selected from tert-butyloxycarbonyl, benzyloxycarbonyl, acetyl or benzoyl; in the first step, the raw material of formula I reacts with chloromethyl methyl ether and alkali in a chlorinated solvent, and then reacts with elemental iodine and a silver reagent to obtain an intermediate of formula II, wherein the equivalent of the silver reagent is not more than 1.2 times of that of the initial raw material I; in the second step, the hydrogen pressure is in the range of 1-2 atm.
2. A process for the synthesis of 3-iodo-N-protected-L-tyrosine methyl ester according to claim 1, characterized in that: in the first step, the base is selected from sodium hydride, triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide; the silver agent is selected from silver nitrate, silver sulfate or silver trifluoroacetate.
3. A process for the synthesis of 3-iodo-N-protected-L-tyrosine methyl ester according to claim 1, characterized in that: and in the second step, dissolving the intermediate in the formula II in an alcohol solution, adding a palladium catalyst, reacting under a hydrogen atmosphere, filtering and evaporating the solvent, and recrystallizing to obtain the product in the formula III.
4. A process for the synthesis of 3-iodo-N-protected-L-tyrosine methyl ester according to claim 3, characterized in that: in the second step, the palladium catalyst is selected from palladium carbon or palladium hydroxide; the alcoholic solution is selected from methanol, ethanol or isopropanol.
5. The method of synthesizing 3-iodo-N-protected-L-tyrosine methyl ester according to claim 4, wherein: in the second step, the palladium carbon is selected from two specifications of 5% or 10%.
6. A process for the synthesis of 3-iodo-N-protected-L-tyrosine methyl ester according to claim 3, characterized in that: in the second step, the molar ratio of the intermediate of formula II to the palladium catalyst is 1000:1 to 5: 1.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910141309.5A CN109704983B (en) | 2019-02-26 | 2019-02-26 | Method for synthesizing 3-iodine-N-protected-L-tyrosine methyl ester by removing MOM protection |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910141309.5A CN109704983B (en) | 2019-02-26 | 2019-02-26 | Method for synthesizing 3-iodine-N-protected-L-tyrosine methyl ester by removing MOM protection |
Publications (2)
Publication Number | Publication Date |
---|---|
CN109704983A CN109704983A (en) | 2019-05-03 |
CN109704983B true CN109704983B (en) | 2021-06-04 |
Family
ID=66263913
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910141309.5A Active CN109704983B (en) | 2019-02-26 | 2019-02-26 | Method for synthesizing 3-iodine-N-protected-L-tyrosine methyl ester by removing MOM protection |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN109704983B (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108659086A (en) * | 2017-03-29 | 2018-10-16 | 杭州源昶医药科技有限公司 | A kind of synthetic method of Austria's shellfish cholic acid |
-
2019
- 2019-02-26 CN CN201910141309.5A patent/CN109704983B/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108659086A (en) * | 2017-03-29 | 2018-10-16 | 杭州源昶医药科技有限公司 | A kind of synthetic method of Austria's shellfish cholic acid |
Non-Patent Citations (3)
Title |
---|
Platinum-Catalyzed α,β –Unsaturated Carbene Formation in the Formal Syntheses of Frondosin B and Liphagal;Khoi Q. Huynh et al.;《Organic Letters》;20161220;第19卷;第294-297页 * |
Synthesis and conformation studies of rubiyunnanin B analogs;Na-Na Liu et al.;《Terahedron》;20140630;第70卷;第6630-6640页 * |
ynthesis of F-18 labeled fluoroalkyltyrosine derivatives and their biological evaluation in rat bearing 9L tumor;Byung Seok Moon et al.;《Bioorganic & Medicinal Chemistry Letters》;20061010;第200-204页 * |
Also Published As
Publication number | Publication date |
---|---|
CN109704983A (en) | 2019-05-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN112125805B (en) | Water-soluble magnolol derivative, preparation method of honokiol derivative and intermediate thereof, and related monohydroxy protected intermediate | |
CN112321395B (en) | Application of metalate/palladium compound catalytic reduction system in allyl removal reaction of allyl allyloxy naphthalene | |
JP2546659B2 (en) | Method for producing podophyllotoxin type compound | |
CA2919317A1 (en) | Synthesis of biphenylalaninol via novel intermediates | |
CN112645982B (en) | Preparation and purification method of key intermediate of Rudexiluwei | |
CN107011404A (en) | A kind of method using cholic acid as Material synthesis lithocholic acid | |
CN108358760B (en) | Application of metalate/palladium compound catalytic reduction system in debenzylation reaction and deuteration reaction | |
CN1513836A (en) | Method of preparing 4-hydroxy pyrrolidone-2-acetamine | |
CN109704983B (en) | Method for synthesizing 3-iodine-N-protected-L-tyrosine methyl ester by removing MOM protection | |
CN114716331A (en) | Preparation method of dopamine hydrochloride | |
CN114717280A (en) | Synthesis method of monopilavir | |
CN104513241A (en) | New regadenoson intermediate, preparation method and application thereof | |
CN109704996B (en) | Method for preparing 3-halogenated-N-protected-L-tyrosine methyl ester | |
US6384201B1 (en) | Synthetic method for the preparation of the antineoplastic agent etoposide | |
CN111100042B (en) | Preparation method of 2-methoxy-5-sulfonamide benzoic acid | |
CN111217709A (en) | Preparation method of (1-fluorocyclopropyl) methylamine hydrochloride | |
CN111233685B (en) | Preparation method of racemic D/L-tert-leucine | |
CN104803846A (en) | Method for the preparation of bis[4-(6-acryloyloxy-hexyl)-phenyl]cyclohexane-1,4-dicarboxylate | |
CN113603630B (en) | Synthesis method of 4-phenylpiperidine hydrochloride | |
CN108976182A (en) | A method of preparing Dapagliflozin five-membered ring impurity | |
CN113683574B (en) | Method for synthesizing 1-methyl-1H-1, 2, 4-triazole-3-methyl formate | |
CN109438243B (en) | Preparation method of electronic grade octyl gallate | |
CN114478324B (en) | Active compound and application thereof in side chain carboxyl compound protection | |
CN111978188B (en) | Preparation method of mexiletine hydrochloride impurity C | |
CN108084049B (en) | Preparation method of posaconazole intermediate |
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 |