CN113214101B - Synthesis method of L-tert-leucine and L-cyclohexylalanine - Google Patents
Synthesis method of L-tert-leucine and L-cyclohexylalanine Download PDFInfo
- Publication number
- CN113214101B CN113214101B CN202110513523.6A CN202110513523A CN113214101B CN 113214101 B CN113214101 B CN 113214101B CN 202110513523 A CN202110513523 A CN 202110513523A CN 113214101 B CN113214101 B CN 113214101B
- Authority
- CN
- China
- Prior art keywords
- tert
- cyclohexylalanine
- leucine
- synthesizing
- compound
- 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
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
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Landscapes
- 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 method for synthesizing L-tert-leucine and L-cyclohexylalanine, belonging to the technical field of amino acid preparation. Pentafluorophenol- (dibenzyl amino) ester 1 and benzhydrol 2 are used as reactants, a compound 4 is obtained by dynamic kinetic resolution reaction under the catalysis of chiral PPY nitrogen oxide 3, and then the compound is subjected to Pd/C catalytic hydrogenation and debenzylation to obtain L-tert-leucine and L-cyclohexylalanine. In the invention, oxygen atoms in pyridine nitrogen and oxygen in the chiral PPY nitrogen and oxygen catalyst are used as nucleophilic sites to participate in dynamic kinetic resolution. The method has the advantages of good yield, high enantioselectivity and the like, the ee of the obtained product can reach more than 99.5 percent, and a new path is provided for the synthesis of chiral amino acid.
Description
Technical Field
The invention relates to a synthetic method of L-tert-leucine and L-cyclohexylalanine, belonging to the technical field of amino acid preparation.
Background
L-tert-leucine (CAS:20859-02-3) and L-cyclohexylalanine (CAS:27527-05-5) can be used as nutrition enhancer, animal feed additive and medicine. They are all non-proteinogenic, non-natural chiral amino acids, the origin of which is mainly by chemical synthesis, amino acid derivatives, such as L-tert-leucine, which, due to the greater steric hindrance of the tert-butyl group, serve as templates for the induction of asymmetry in asymmetric synthesis.
Unnatural amino acids will also play a key role in improving their chemical properties. L-tert-leucine and L-cyclohexylalanine are sweet raw materials of various anti-cancer drugs and dipeptides.
However, most previous reports on the synthesis of L-tert-leucine and L-cyclohexylalanine were made by Strecker amino acid synthesis followed by enzymatic resolution.
Therefore, the development of an effective synthetic method for dynamic chiral induction has important research significance.
Disclosure of Invention
In order to overcome the technical defects, pentafluorophenol- (dibenzyl amino) ester 1 and benzhydrol 2 are used as reactants, a compound 4 is obtained by dynamic kinetic resolution reaction under the catalysis of chiral PPY nitrogen oxide 3, and then L-tert-leucine and L-cyclohexylalanine are obtained by Pd/C catalytic hydrogenation debenzylation. In the invention, oxygen atoms in pyridine nitrogen and oxygen in the chiral PPY nitrogen and oxygen catalyst are used as nucleophilic sites to participate in dynamic kinetic resolution. The method has the advantages of good yield, high enantioselectivity and the like, the ee of the obtained product can reach more than 99.5 percent, and a new path is provided for the synthesis of chiral amino acid.
The invention relates to a method for synthesizing L-tert-leucine and L-cyclohexylalanine, which comprises the following steps:
the first step is as follows: using pentafluorophenol- (dibenzyl ammonia) ester 1 and benzhydrol 2 as raw materials, carrying out low-temperature reaction in an organic solvent in the presence of a chiral catalyst 3 and an inorganic base, and carrying out post-treatment to obtain a compound 4;
the second step is that: and mixing the compound 4 with an organic solvent, and carrying out catalytic hydrogenation on palladium carbon to obtain L-tert-leucine and L-cyclohexylalanine.
Further, in the above technical solution, in the first step, the organic solvent is selected from a mixed solvent of benzotrifluoride/dichloroethane, and the volume ratio thereof is 1: 1.
further, in the above technical scheme, in the first step, the low temperature is-20 ℃ to 0 ℃.
Further, in the above technical solution, in the first step, the inorganic base is selected from potassium tert-butoxide or sodium tert-amylate, preferably from a 20% potassium tert-butoxide/tetrahydrofuran solution or a 40% sodium tert-amylate/toluene solution.
Further, in the above technical scheme, in the first step, the molar ratio of the compound 1, the compound 2, the chiral catalyst and the inorganic base is 1: 1.3-1.2: 0.1-0.05: 1.4-1.3.
Further, in the above technical solution, in the second step, the organic solvent is selected from methanol or isopropanol, and Pd/C is selected from 5% or 10% Pd/C.
Furthermore, in the technical scheme, in the second step, the dosage of Pd/C is 5-20% of the weight of the raw materials, and the hydrogenation pressure is selected from 0.1-0.5 Mpa.
The synthesis method of pentafluorophenol- (dibenzyl ammonia) ester 1 comprises the following steps:
tert-butyl magnesium bromide or cyclohexylmethyl magnesium bromide is dropped into tetrahydrofuran solution containing oxalic acid bis (pentafluorophenyl) ester at low temperature for reaction, quenched with hydrochloric acid, and concentrated to obtain oily substance. Subsequently, dibenzylamine and sodium triacetoxyborohydride are reductively aminated to give pentafluorophenyl 2- (dibenzylamino) -3, 3-dimethylbutyric acid or pentafluorophenyl 3-cyclohexyl-2- (dibenzylamino) propionate.
Further, in the technical scheme, the low temperature is-40 ℃ to-50 ℃.
The PPY-type nitroxide chiral catalyst is a catalyst known in the literature, and the synthesis of the PPY-type nitroxide chiral catalyst is basically carried out according to the literature method.
Advantageous effects of the invention
1) Taking pentafluorophenol- (dibenzyl amino) ester and benzhydrol as reactants, obtaining a chiral dibenzyl amino acid ester product by one step through a dynamic kinetic resolution reaction, and then carrying out catalytic hydrogenation to synthesize corresponding L-tert-leucine and L-cyclohexylalanine; the reaction yield and the enantioselectivity are high and can respectively reach more than 78-80% and 99.5% ee.
2) In the invention, oxygen atoms in pyridine nitrogen oxygen in the PPY nitrogen oxygen chiral catalyst are used as nucleophilic sites to participate in dynamic kinetic resolution reaction, and the PPY nitrogen oxygen chiral catalyst is successfully applied to dynamic kinetic resolution of amino acid products.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
Synthesis of L-tert-leucine
Example 1
To a 500mL four-necked round bottom flask, a chiral catalyst (4.42g,0.01mol,0.1eq), benzhydrol (23.95g,0.13mol,1.3eq), and pentafluorophenyl 2- (dibenzylamino) -3, 3-dimethylbutyric acid (47.75g,0.1mol,1.0eq) were added in this order, followed by 340mL (1/1 vol.) of trifluorotoluene/dichloroethane, cooling to-5 deg.C, and a 20% potassium tert-butoxide/tetrahydrofuran solution (81.8g,0.135mol,1.35eq) was slowly added dropwise. After the dropwise addition, the reaction was carried out at 0 ℃ for 16 to 24 hours, and 1mL (after spin-drying the solution and direct flash column chromatography, HPLC 94.8% ee) was sampled and the reaction was detected to be complete. The mixture was distilled under reduced pressure to leave 3.5 volumes, 350mL of n-heptane was added, and the mixture was slurried at room temperature for 6 hours, filtered, and the filter cake was dried to give 40.41g of (S) -2- (dibenzylamino) -3, 3-dimethylbutyrate benzhydryl ester, HPLC 99.1%, yield 84.6%, 99.4% ee.1H NMR(CDCl3400MHz) 7.40-7.37(m,4H),7.29-7.18(m,17H),3.74(s,4H),3.24(s,1H),0.94(s, 9H.) the product conversion is 33-71% under the same conditions with triethylamine, diisopropylethylamine and DBU (1.35-6.0eq, reaction time 24-80H).
Example 2
To a 500mL single-necked flask, was added (S) -benzhydryl 2- (dibenzylamino) -3, 3-dimethylbutyrate (23.9g,0.05mol), 5% Pd/C2.4 g, and 200mL of methanol. After nitrogen replacement and hydrogen replacement, adding 0.1Mpa of hydrogen, controlling the temperature to be 20-35 ℃ for reaction for 8 hours, detecting 0.1 percent of the raw material residue by HPLC, filtering, concentrating the filtrate to a non-flowing liquid, adding MTBE and n-heptane for pulping, filtering, drying the filter cake to obtain 6g of L-tertiary leucine, 99.7 percent of HPLC, 91.8 percent of yield and 99.5 percent of ee.1HNMR(400MHz,D2O):3.40(s,1H),0.87(s,9H).
Synthesis of L-cyclohexylalanine
Example 3
To a 500mL four-necked round bottom flask, a chiral catalyst (4.42g,0.01mol,0.1eq), benzyl alcohol (23.95g,0.13mol,1.3eq), and pentafluorophenyl 3-cyclohexyl-2- (dibenzylamino) propionate (51.75g,0.1mol,1.0eq) were added in that order, followed by 340mL (1/1 vol.) of trifluorotoluene/dichloroethane, the temperature was reduced to-5 deg.C, and a 40% sodium tert-amylate/toluene solution (35.8g,0.13mol,1.3eq) was slowly added dropwise. After the dropwise addition, the reaction was carried out at 0 ℃ for 12 to 18 hours, and 1mL of the solution was sampled (after spin-drying, direct flash column chromatography, HPLC 95.9% ee) to complete the reaction. Reduced pressure distillation till the volume of the residue is 3.5 percent, 350mL of n-heptane is added, the mixture is pulped for 6 hours at room temperature, the filtration is carried out, and the filter cake is dried to obtain 45.4g of (S) -2- (dibenzylamino) -3-cyclohexylalanine benzhydryl ester, the HPLC (high performance liquid chromatography) content is 99.6 percent, the yield is 87.7 percent, and the optical purity is 99.7 percent.1H NMR(CDCl3400MHz) of 7.39 to 7.37(m,4H),7.27 to 7.14(m,17H),3.65(s,4H),3.31 to 3.28(m,1H),1.73 to 1.70(m,2H),1.63 to 1.46(m,11H), under the same conditions, triethylamine, diisopropylethylamine and DBU (1.30 to 6.0eq, reaction time 18 to 80H) are used, and the product conversion rate is 47 to 74 percent.
Example 4
To a 500mL single neck flask were added (S) -2- (dibenzylamino) -3-cyclohexylalanine benzhydryl ester (25.9g,0.05mol), 5% Pd/C5.18 g, and 200mL of isopropanol. After nitrogen replacement and hydrogen replacement, adding 0.1Mpa of hydrogen, controlling the temperature to be 20-35 ℃ for reaction for 14 hours, detecting 0.1 percent of the raw material residue by HPLC, filtering, concentrating the filtrate to a non-flowing liquid, adding MTBE and n-heptane for pulping, filtering, drying the filter cake to obtain 7.8g of L-cyclohexylalanine, 99.7 percent of HPLC, 90.9 percent of yield and 99.6 percent of ee.
Example 5
Under the protection of nitrogen, 42.2g of oxalic acid bis (pentafluorophenyl) ester and 200mL of tetrahydrofuran are added into a 500mL four-neck round-bottom flask, and the temperature is reduced to-40 to-50 ℃. Dropwise adding 53mL of 2.0mol/L tert-butyl magnesium chloride/tetrahydrofuran solution, reacting at-40 to-50 ℃ for 1 hour, naturally heating to 10 ℃, dropwise adding 1.0mol/L hydrochloric acid for quenching, demixing, extracting a water layer by using 2-methyltetrahydrofuran, combining organic phases, drying by anhydrous magnesium sulfate, and concentrating to about 40% of the original volume to obtain a light yellow solution. And then putting the mixture into a 500mL four-mouth reaction bottle again, adding 20g of dibenzylamine, adding 29.7g of sodium triacetoxyborohydride in batches at a controlled temperature of 20-30 ℃, controlling the temperature to be 25-28 ℃, reacting for 4 hours, cooling the system to 5-10 ℃, adding a small amount of methanol and hydrochloric acid for quenching, filtering, washing the filtrate with water, concentrating the organic phase to a non-flowing liquid, adding n-heptane to precipitate a solid, filtering to obtain 37.2g of white solid pentafluorophenyl 2- (dibenzylamino) -3, 3-dimethylbutyric acid, wherein the yield is 77.8%, and the HPLC yield is 98.5%.
Example 6
Under the protection of nitrogen, 42.2g of oxalic acid bis (pentafluorophenyl) ester and 200mL of tetrahydrofuran are added into a 500mL four-neck round-bottom flask, and the temperature is reduced to-40 to-50 ℃. 106mL of 1.0mol/L cyclohexylmethylmagnesium bromide tetrahydrofuran solution is dripped to react for 1 hour at the temperature of between 40 ℃ below zero and 50 ℃ below zero, then the temperature is naturally raised to 10 ℃,1.0 mol/L hydrochloric acid is dripped to quench, layering is carried out, a water layer is extracted by 2-methyltetrahydrofuran, organic phases are combined, anhydrous magnesium sulfate is dried, and the solution is concentrated to about 40 percent of volume to obtain a light yellow solution. And then putting the mixture into a 500mL four-mouth reaction bottle again, adding 20g of dibenzylamine, adding 30.0g of sodium triacetoxyborohydride in batches at the temperature of 20-30 ℃, controlling the temperature to be 25-28 ℃, reacting for 4 hours, cooling the system to 5-10 ℃, adding a small amount of methanol and hydrochloric acid for quenching, filtering, washing the filtrate with water, concentrating the organic phase to a non-flowing liquid, adding n-heptane to precipitate a solid, filtering to obtain 38.4g of white solid pentafluorophenyl 3-cyclohexyl-2- (dibenzylamino) propionate, wherein the yield is 74.1%, and the HPLC (high performance liquid chromatography) is 99.3%.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.
Claims (7)
1. A method for synthesizing L-tert-leucine and L-cyclohexylalanine, which is characterized by comprising the following steps:
the first step is as follows: reacting pentafluorophenol- (dibenzyl ammonia) ester 1 and benzhydrol 2 serving as raw materials in an organic solvent at the temperature of-20-0 ℃ in the presence of a chiral catalyst 3 and tert-butyl potassium alkoxide or tert-amyl alcohol sodium, and performing post-treatment to obtain a compound 4;
the second step is that: and mixing the compound 4 with an organic solvent, and carrying out catalytic hydrogenation on palladium carbon to obtain L-tert-leucine and L-cyclohexylalanine.
2. The method for synthesizing L-tert-leucine and L-cyclohexylalanine according to claim 1, wherein: in the first step, the organic solvent is selected from a mixed solvent of trifluorotoluene and dichloromethane.
3. The method for synthesizing L-tert-leucine and L-cyclohexylalanine according to claim 2, wherein: in the first step, the volume ratio of trifluorotoluene to dichloromethane was 1: 1.
4. the method for synthesizing L-tert-leucine and L-cyclohexylalanine according to claim 1, wherein: in the first step, the molar ratio of the compound 1, the compound 2, the chiral catalyst and the tert-butyl potassium alkoxide or the tert-amyl alcohol sodium is 1: 1.3-1.2: 0.1-0.05: 1.4-1.3.
5. The method for synthesizing L-tert-leucine and L-cyclohexylalanine according to claim 1, wherein: in the second step, the organic solvent is selected from methanol or isopropanol; the pressure of hydrogen is 0.1-0.5 Mpa.
6. The method for synthesizing L-tert-leucine and L-cyclohexylalanine according to claim 1, wherein: the Pd/C is selected from 5 percent or 10 percent of Pd/C, and the dosage is 5 to 20 percent of the weight of the raw material.
7. The method for synthesizing L-tert-leucine and L-cyclohexylalanine according to claim 1, wherein the pentafluorophenol- (dibenzylamino) ester 1 is synthesized by:
dropwise adding tert-butyl magnesium bromide or cyclohexyl methyl magnesium bromide into a tetrahydrofuran solution containing oxalic acid bis (pentafluorophenyl) ester at a temperature of between 40 ℃ below zero and 50 ℃ below zero to react, quenching by hydrochloric acid, and concentrating to obtain an oily substance; followed by reductive amination with dibenzylamine and sodium triacetoxyborohydride to give pentafluorophenyl-2- (dibenzylamino) -3, 3-dimethylbutanoic acid or pentafluorophenyl-3-cyclohexyl-2- (dibenzylamino) propionate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110513523.6A CN113214101B (en) | 2021-05-11 | 2021-05-11 | Synthesis method of L-tert-leucine and L-cyclohexylalanine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110513523.6A CN113214101B (en) | 2021-05-11 | 2021-05-11 | Synthesis method of L-tert-leucine and L-cyclohexylalanine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113214101A CN113214101A (en) | 2021-08-06 |
| CN113214101B true CN113214101B (en) | 2022-05-31 |
Family
ID=77095115
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110513523.6A Active CN113214101B (en) | 2021-05-11 | 2021-05-11 | Synthesis method of L-tert-leucine and L-cyclohexylalanine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113214101B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109400580B (en) * | 2018-12-24 | 2020-05-12 | 河南师范大学 | 3, 4-diaminopyridine nitrogen-oxygen chiral catalyst and application thereof in Steglich rearrangement |
| CN111170878B (en) * | 2020-02-09 | 2023-01-03 | 滨海瀚鸿生化有限公司 | Method for preparing D-type or L-type tert-leucine |
| CN111943929B (en) * | 2020-08-25 | 2023-04-07 | 河南师范大学 | 2,4-diaminopyridine nitroxides as catalysts and their use in the ring opening of azlactone alcohols |
-
2021
- 2021-05-11 CN CN202110513523.6A patent/CN113214101B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN113214101A (en) | 2021-08-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2019346118B2 (en) | Manufacture of compounds and compositions for inhibiting the activity of SHP2 | |
| US8471048B2 (en) | Ruthenium carbonyl complex having tridentate ligand, its production method and use | |
| KR20050091773A (en) | Processes for producing glutamic acid derivative and pyroglutamic acid derivative and novel intermediate for production | |
| US7754889B2 (en) | Optically active transition metal-diamine compound and process for producing optically active alcohol with the same | |
| CN112358379A (en) | Preparation method of optically pure S-configuration 1, 1-bis- (4-fluorophenyl) -2-propanol | |
| KR20130112707A (en) | Method for producing alcohol and/or amine from amide compound | |
| CN113214101B (en) | Synthesis method of L-tert-leucine and L-cyclohexylalanine | |
| CN113307812B (en) | Preparation method of broad-spectrum tumor drug erlotinib | |
| CN112174837B (en) | Method for synthesizing (R) -4-methoxy-alpha-methylphenethylamine | |
| CN109761956B (en) | Method for synthesizing cyclooctatriene indole derivatives under catalysis of manganese | |
| CN107827916B (en) | Synthesis method of (R) - (1-amino-3-methyl) butyl-1-pinanediol borate | |
| WO2021120953A1 (en) | Method for synthesizing 1,7-naphthyridine derivative | |
| EP1778627B1 (en) | Method for producing enantiomeric form of 2, 3-diaminopropionic acid derivatives | |
| CN111362854B (en) | Preparation method of ralotinib intermediate | |
| CN114853662B (en) | Process for preparing chiral hydrazinopiperidine derivatives | |
| CN103755624B (en) | A kind of synthetic method of piperidine derivative | |
| CN113214255B (en) | Synthesis method of 2, 6-diazaspiro [3.5] nonane-6-tert-butyl formate and salt thereof | |
| CN115784922B (en) | Preparation method of (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butyric acid | |
| CN114057668B (en) | Synthesis method of amino protecting group chiral 2-amino-3- (4-morpholinylphenyl) propionic acid | |
| CN117682981A (en) | Preparation method of gemagliptin prodrug | |
| CN107445879B (en) | Preparation method of Latricinib intermediate | |
| WO2022229820A1 (en) | Method for producing pyrrolidine compound | |
| KR20220066645A (en) | Aryl compounds containing tertiary amine | |
| WO2024077407A1 (en) | Chiral reducing agent and method for synthesizing chiral nicotine | |
| JP4314603B2 (en) | Process for producing optically active 3-alkoxycarbonylaminopyrrolidine derivative |
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 |