CN112375055A - Preparation method of eptifibatide key raw material L-high arginine - Google Patents
Preparation method of eptifibatide key raw material L-high arginine Download PDFInfo
- Publication number
- CN112375055A CN112375055A CN202011285045.XA CN202011285045A CN112375055A CN 112375055 A CN112375055 A CN 112375055A CN 202011285045 A CN202011285045 A CN 202011285045A CN 112375055 A CN112375055 A CN 112375055A
- Authority
- CN
- China
- Prior art keywords
- eptifibatide
- raw material
- guanidine
- tert
- toluenesulfonyl
- 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.)
- Withdrawn
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
-
- 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
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/18—Fluorenes; Hydrogenated fluorenes
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of an eptifibatide key raw material L-high arginine, belonging to the field of synthesis of medical intermediates. Reacting 1, 3-di (tert-butoxycarbonyl) guanidine with p-toluenesulfonyl chloride to obtain 1, 3-di-Boc-2- (p-toluenesulfonyl) guanidine, then reacting with N-fluorenylmethyloxycarbonyl-N' -tert-butoxycarbonyl-L-lysine Fmoc-hArg (Boc2) -OH, de-Boc protecting, and adding Pbf-Cl to obtain N- (9-fluorenylmethyloxycarbonyl) -2,2,4,6, 7-pentamethyl-2H-benzofuran-5-sulfonyl-L-arginine. The p-toluenesulfonyl polypeptide guanylating agent is adopted in the route of the invention, the ultralow temperature reaction and the use of trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride with strong corrosivity are avoided, and a simple and efficient way is provided for the synthesis of the intermediate.
Description
Technical Field
The invention relates to a preparation method of an unnatural amino acid, and particularly relates to (S) -11- (tert-butyloxycarbonylamino) -1- (9H-fluoren-9-yl) -15, 15-dimethyl-3, 13-dioxa-2, 14-dioxa-4, 10, 12-triazacyclohexadecyl-11-ene-5-carboxylic acid.
Background
Eptifibatide, alias Eptifibatide, english name epifibatide, CAS: 188627-80-7. First developed by COR therapeutics in the United states, first marketed in the United states under the trade name Integrelin in 7 months of 1998.
The eptifibatide is a synthetic cyclic peptide containing mercaptopropionic acid and six amino acid residues, has a specific and targeted platelet glycoprotein GP IIb/IIIa receptor antagonist, selectively and reversibly inhibits a final common pathway of platelet aggregation (blood coagulation of plasma is caused by binding of blood coagulation factor I and GP IIb/IIIa), and can reverse an ischemic state caused by thrombosis. The traditional Chinese medicine composition is mainly used for treating unstable angina and acute myocardial infarction clinically, the main adverse reaction is bleeding, most of the bleeding is mild and moderate bleeding, the most main bleeding part is a blood vessel puncture part when the blood vessel puncture part is PCI, and cerebral hemorrhage is rare.
N- (9-fluorenylmethoxycarbonyl) -2,2,4,6, 7-pentamethyl-2H-benzofuran-5-sulfonyl-L-arginine (CAS: 154445-77-9) is a key intermediate of polypeptide drug eptifibatide, belongs to non-natural amino acid polypeptide, and has the structure as follows:
the intermediate is synthesized by taking N-fluorenylmethyloxycarbonyl-N ', N' -di-tert-butyloxycarbonyl-L-homoarginine (Fmoc-hArg (Boc2) -OH, CAS: 158478-81-0) as a raw material, and the reaction equation is as follows:
US8524659 reports the reflux reaction of 1, 3-di-Boc-2- (trifluoromethylsulfonyl) guanidine with Fmoc-lysine to give the target product (Fmoc-hagg (Boc2) -OH). However, the method has a long reaction route, the raw material 1, 3-di-BOC-2- (trifluoromethyl sulfonyl) guanidine has high cost, the obtained product has low purity, the product needs to be purified by a column chromatography method, and industrial scale-up production cannot be realized.
Disclosure of Invention
The invention aims to overcome the technical problems of complexity, low yield, high cost and the like in the prior art, and provides a preparation method of (S) -11- (tert-butyloxycarbonylamino) -1- (9H-fluoren-9-yl) -15, 15-dimethyl-3, 13-dioxa-2, 14-dioxa-4, 10, 12-triazacyclohexadecyl-11-ene-5-carboxylic acid and a key intermediate N- (9-fluorenylmethoxycarbonyl) -2,2,4,6, 7-pentamethyl-2H-benzofuran-5-sulfonyl-L-arginine for subsequent synthesis of eptifibatide.
The reaction route is as follows:
the invention relates to a preparation method of eptifibatide key raw material L-high-grade arginine, which adopts the technical scheme that N-fluorenylmethyloxycarbonyl-N' -tert-butyloxycarbonyl-L-lysine and 1, 3-di-Boc-2- (p-toluenesulfonyl) guanidine are adopted as raw materials to react to obtain Fmoc-hArg (Boc2) -OH, and N- (9-fluorenylmethyloxycarbonyl) -2,2,4,6, 7-pentamethyl-2H-benzofuran-5-sulfonyl-L-arginine is obtained after Boc protection removal and Pbf-Cl reaction.
A preparation method of an eptifibatide key raw material L-higher arginine comprises the following operations: in the first step, 1, 3-di (tert-butoxycarbonyl) guanidine is reacted with p-toluenesulfonyl chloride in the presence of an organic base in an organic solvent to give 1, 3-di-Boc-2- (p-toluenesulfonyl) guanidine. In the second step, 1, 3-di-Boc-2- (p-toluenesulfonyl) guanidine was reacted with N-fluorenylmethoxycarbonyl-N' -tert-butoxycarbonyl-L-lysine in the presence of an organic base at room temperature to give Fmoc-hArg (Boc2) -OH.
Further, in the first step of the above technical solution, the organic solvent is selected from common organic solvents such as dichloromethane, tetrahydrofuran, ethyl acetate, 2-methyltetrahydrofuran, cyclopentyl methyl ether, and the like.
Further, in the first step of the above technical solution, the organic base is selected from triethylamine, pyridine, diisopropylethylamine, etc.
Further, in the first step of the above technical scheme, the reaction is carried out at 0-30 ℃, preferably at room temperature.
Further, in the first step of the above technical scheme, the molar ratio of 1, 3-bis (tert-butoxycarbonyl) guanidine to p-toluenesulfonylchloride is 1: 1-1.2.
Further, in the second step of the above technical scheme, the organic base is selected from triethylamine and diisopropylethylamine.
Further, in the second step of the above technical scheme, the molar ratio of 1, 3-di-Boc-2- (p-toluenesulfonyl) guanidine to N-fluorenylmethoxycarbonyl-N' -tert-butoxycarbonyl-L-lysine is 1.2-1.3: 1.
the intermediate is adopted to synthesize N- (9-fluorenylmethyloxycarbonyl) -2,2,4,6, 7-pentamethyl-2H-benzofuran-5-sulfonyl-L-arginine, and the reaction is as follows:
further, in the third step of the above technical scheme, the organic solvent is selected from dichloromethane or ethyl acetate.
Further, in the fourth step of the above technical solution, the organic base is selected from tertiary amines such as triethylamine, triisopropylamine, diisopropylethylamine, and the like.
Further, in the fourth step of the above technical means, the reaction is carried out at 0 to 30 ℃, preferably at room temperature.
Further, in the fourth step of the technical scheme, the molar ratio of the Fmoc-arginine hydrochloride to the Pbf-Cl is 1: 1.1-1.15.
Advantageous effects of the invention
The method synthesizes the target product more simply and conveniently, obtains the product with the liquid phase purity of 99 percent by a TBD crystallization method, has low cost in the route, and is suitable for industrial large-scale production.
Drawings
FIG. 1 is an HPLC chromatogram of the product of example 1.
The specific implementation mode is as follows:
example 1
Synthesis of (S) -11- (tert-butyloxycarbonylamino) -1- (9H-fluoren-9-yl) -15, 15-dimethyl-3, 13-dioxa-2, 14-dioxa-4, 10, 12-triazahexadecyl-11-ene-5-carboxylic acid
2L of tetrahydrofuran is added into a 5L reaction kettle, 680g (2.622mol,1eq) of 1, 3-di (tert-butoxycarbonyl) guanidine and 291g (2.884mol,1.2eq) of triethylamine are added under stirring, stirring is carried out to dissolve the mixture after the addition is finished, then 500g (2.623mol,1eq) of p-toluenesulfonyl chloride solution in tetrahydrofuran is added dropwise, the temperature is controlled to be 20-25 ℃, after stirring and reacting for 2 hours, sampling TLC detects that no raw material is left, solvent is concentrated under reduced pressure and then dichloromethane is used for extraction, a large amount of solid is separated out after the dichloromethane is concentrated, the filtration is carried out, a filter cake is washed by 500mL of water, and 950g of a product is obtained after drying. The yield was 87.6%, and the content of the liquid phase was 99.61%.
Adding 75Kg of DMF into a reaction kettle, adding 7.5Kg (16mol,1eq) of N-fluorenylmethoxycarbonyl-N' -tert-butoxycarbonyl-L-lysine into the reaction kettle under stirring, stirring and dissolving the mixture after the addition is finished, then dropwise adding 8Kg (72.3mol) of concentrated hydrochloric acid, controlling the temperature to be 20-25 ℃, stirring and reacting the mixture for 2 hours, dropwise adding 3.789Kg (37.45mol,2.34eq) of TEA, batchwise adding 7.92Kg (19.2mol,1.2eq) of 1, 3-di-Boc-2- (p-toluenesulfonyl) guanidine, reacting the mixture for 6 hours at the temperature of 20-25 ℃ after the addition is finished, then cooling the diluent to 5-10 ℃, slowly dropwise adding 6.24Kg of 1mol/L hydrochloric acid solution, adjusting the pH to 4-5, precipitating a large amount of solid, centrifuging, washing the filter cake with 15L of water to obtain 10Kg of a product, and drying the filter cake to obtain 8.01Kg, the yield thereof was found to be 81.9%. The liquid phase (HPLC) content was 99.47%.
Example 2
Synthesis of (S) -11- (tert-butyloxycarbonylamino) -1- (9H-fluoren-9-yl) -15, 15-dimethyl-3, 13-dioxa-2, 14-dioxa-4, 10, 12-triazahexadecyl-11-ene-5-carboxylic acid
3.4L of dichloromethane is added into a 5L reaction kettle, 680g (2.622mol,1eq) of 1, 3-di (tert-butoxycarbonyl) guanidine and 372.8g (2.884mol,1.2eq) of diisopropylethylamine are added under stirring, after the addition is finished, the mixture is stirred and dissolved, then 0.5L of dichloromethane solution containing 500g (2.623mol,1eq) of p-toluenesulfonyl chloride is added dropwise, the temperature is controlled at 15-20 ℃, after stirring and reacting for 2 hours, TLC sampling is carried out to detect that no raw material is left, solvent is concentrated under reduced pressure and then extracted by dichloromethane, after the dichloromethane is concentrated, a large amount of solid is separated out, the filter cake is washed by 500mL of water, and after the drying, 1020.2g of the product is obtained. The yield is 94.1 percent, and the content of the liquid phase UPLC is 99.9 percent.
Adding 75Kg of DCM into a reaction kettle, adding 7.5Kg (16mol,1eq) of N-fluorenylmethoxycarbonyl-N' -tert-butoxycarbonyl-L-lysine into the reaction kettle under stirring, stirring to dissolve the mixture, cooling to 0 ℃, introducing 2.9Kg (79.45mol,4.97eq) of dried hydrogen chloride gas in two batches, controlling the temperature to be 20-25 ℃, stirring to react for 2 hours, concentrating dichloromethane under vacuum to a non-flowing liquid, adding 25Kg of isopropyl ether to solidify to obtain 6.8Kg (LOD 10) of Fmoc-L-lysine hydrochloride wet product, putting 6.8Kg of Fmoc-L-lysine hydrochloride into the kettle, adding 60L of ethyl acetate, dropwise adding 4.846Kg (37.49mol,2.34eq) of diisopropylethylamine, cooling to 0-10 ℃, adding 7.452Kg (18.07mol,1.2eq) of 1, 3-di-Boc-2- (p-toluenesulfonyl) guanidine in batches, after the addition is finished, the reaction is carried out for 6 hours at the temperature of 20-25 ℃, then the diluent is cooled to 5-10 ℃, 5.875Kg of 1mol/L hydrochloric acid solution is slowly dripped, the pH value is adjusted to be 4-5, a large amount of solid is separated out, the centrifugation is carried out, the filter cake is washed by 15L of water, and the product 7.91Kg is obtained after the filter cake is dried. The yield was 80.93%, and the content of the liquid phase was 99.67%.
Example 3
Synthesis of N- (9-fluorenylmethoxycarbonyl) -2,2,4,6, 7-pentamethyl-2H-benzofuran-5-sulfonyl-L-arginine
Adding 3Kg of ethyl acetate into a reaction kettle, adding 500g (0.819mol,1eq) of Fmoc-hArg (Boc2) -OH under stirring, after the addition is finished, stirring and dissolving, then cooling to 0 ℃, dropwise adding 620mL of 4mol/L ethyl acetate hydrochloric acid solution, controlling the temperature at 20-25 ℃, stirring and reacting for 2 hours, concentrating the ethyl acetate under vacuum till the solution does not flow, adding 1Kg of acetone for solidification to obtain 395g (LOD 10) of Fmoc-L-arginine hydrochloride wet product, adding 395g of Fmoc-L-arginine hydrochloride wet product into the kettle, adding 3L of acetone, cooling to 0 ℃, dropwise adding 8% sodium bicarbonate aqueous solution to adjust the pH to 7-7.5, adding 147.6g (1.142mol,1.5eq) of DIPEA, adding 4g (0.836mol,1.1eq) of Pbf-Cl in batches, heating to 20-25 ℃ after the addition is finished, reacting for 3 hours, detecting raw material by HPLC (high performance liquid chromatography) with the content of less than 0.2%, adding saturated ammonium chloride aqueous solution for quenching, concentrating to remove acetone, adding 4L dichloromethane for extracting water phase, concentrating organic phase to obtain non-flowing liquid, replacing with ethanol, and adding ethanol after concentrating to obtain non-flowing liquid: recrystallization from a mixed solvent of 1:3 methyl t-butyl ether, filtration and drying gave 441.2g of product, 81.3% yield, and 99.67% liquid phase content.
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 (8)
1. A preparation method of an eptifibatide key raw material L-high arginine is characterized by comprising the following steps: adopting N-fluorenylmethoxycarbonyl-N' -tert-butyloxycarbonyl-L-lysine and 1, 3-di-Boc-2- (p-toluenesulfonyl) guanidine as raw materials, reacting to obtain Fmoc-hArg (Boc2) -OH, removing Boc protection, and then reacting with Pbf-Cl to obtain N- (9-fluorenylmethoxycarbonyl) -2,2,4,6, 7-pentamethyl-2H-benzofuran-5-sulfonyl-L-arginine.
2. The method of preparing eptifibatide key starting material L-higher arginine of claim 1, wherein the Fmoc-hArg (Boc2) -OH is prepared by: the first step, 1, 3-di (tert-butoxycarbonyl) guanidine reacts with p-toluenesulfonyl chloride in the presence of organic base in an organic solvent to obtain 1, 3-di-Boc-2- (p-toluenesulfonyl) guanidine; in the second step, 1, 3-di-Boc-2- (p-toluenesulfonyl) guanidine was reacted with N-fluorenylmethoxycarbonyl-N' -tert-butoxycarbonyl-L-lysine in the presence of an organic base to give Fmoc-hArg (Boc2) -OH.
3. The method for preparing the eptifibatide key raw material L-higher arginine according to claim 2, wherein the method comprises the following steps: in the first step, the organic solvent is selected from dichloromethane, tetrahydrofuran, ethyl acetate, 2-methyltetrahydrofuran, cyclopentyl methyl ether.
4. The method for preparing the eptifibatide key raw material L-higher arginine according to claim 2, wherein the method comprises the following steps: in the first step, the organic base is selected from triethylamine, pyridine, diisopropylethylamine.
5. The method for preparing the eptifibatide key raw material L-higher arginine according to claim 2, wherein the method comprises the following steps: in the first step, the reaction temperature is 0-30 ℃.
6. The method for preparing the eptifibatide key raw material L-higher arginine according to claim 2, wherein the method comprises the following steps: the molar ratio of the 1, 3-di (tert-butoxycarbonyl) guanidine to the p-toluenesulfonyl chloride is 1: 1-1.2.
7. The method for preparing the eptifibatide key raw material L-higher arginine according to claim 2, wherein the method comprises the following steps: in the second step, the organic base is selected from triethylamine, diisopropylethylamine.
8. The method for preparing the eptifibatide key raw material L-higher arginine according to claim 2, wherein the method comprises the following steps: in the second step, the mol ratio of 1, 3-di-Boc-2- (p-toluenesulfonyl) guanidine to N-fluorenylmethoxycarbonyl-N' -tert-butyloxycarbonyl-L-lysine is 1.2-1.3: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011285045.XA CN112375055A (en) | 2020-11-17 | 2020-11-17 | Preparation method of eptifibatide key raw material L-high arginine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011285045.XA CN112375055A (en) | 2020-11-17 | 2020-11-17 | Preparation method of eptifibatide key raw material L-high arginine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112375055A true CN112375055A (en) | 2021-02-19 |
Family
ID=74584945
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011285045.XA Withdrawn CN112375055A (en) | 2020-11-17 | 2020-11-17 | Preparation method of eptifibatide key raw material L-high arginine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112375055A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115572251A (en) * | 2022-10-18 | 2023-01-06 | 苏州爱玛特生物科技有限公司 | Preparation method of (4S) -1-fluorenylmethyloxycarbonyl-4-tert-butyloxycarbonyl-D-proline |
-
2020
- 2020-11-17 CN CN202011285045.XA patent/CN112375055A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115572251A (en) * | 2022-10-18 | 2023-01-06 | 苏州爱玛特生物科技有限公司 | Preparation method of (4S) -1-fluorenylmethyloxycarbonyl-4-tert-butyloxycarbonyl-D-proline |
| CN115572251B (en) * | 2022-10-18 | 2024-03-22 | 苏州爱玛特生物科技有限公司 | Preparation method of (4S) -1-fluorenylmethoxycarbonyl-4-tert-butoxycarbonylamino-D-proline |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10577394B2 (en) | Ganirelix precursor and method for preparing ganirelix acetate by using the same | |
| CN114031543A (en) | Preparation method of intermediate of palovaried | |
| CN110194724A (en) | A kind of compound containing diphenyl-methane structure and its application | |
| EP4212509A1 (en) | Method for preparing water-soluble magnolol derivative and honokiol derivative, methods for preparing intermediates of water-soluble magnolol derivative and honokiol derivative, and related monohydroxy protected intermediate | |
| CN107674062B (en) | Anti-hepatitis C drug intermediate, preparation method and application | |
| CN112375055A (en) | Preparation method of eptifibatide key raw material L-high arginine | |
| CN104387299A (en) | Method for preparing 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-benzene butyl]-N-isobutyl benzsulfamide | |
| EP4071135A1 (en) | Etelcalcetide intermediate and method for synthesizing etelcalcetide | |
| CN110551144B (en) | Preparation method of amoxicillin | |
| US10399927B2 (en) | Method for preparing long-chain compound | |
| CN114409727A (en) | Preparation method of anti-coronavirus 3CLPRO inhibitor | |
| DesMarteau et al. | Easy Preparation of Bioactive Peptides from the Novel N α-Trifluoroethyl Amino Acids | |
| EP3708561B1 (en) | Polyethylene glycol derivative and preparation method thereof | |
| CN112920053A (en) | Preparation method of chiral alpha-methyl aromatic ethylamine | |
| CN112876502A (en) | Preparation method of N-trimethylsiloxyethoxycarbonyl-N-methyl-L/D-leucine | |
| CN110878098B (en) | Preparation method of BCL-2 inhibitor-vetila | |
| CN107474108B (en) | Preparation method of Suc-Ile-Glu (gamma-Pip) -Gly-Arg-pNA & HCl | |
| CN112358423A (en) | Preparation and application of novel polypeptide guanidizing agent | |
| CN112430235A (en) | Preparation method of PF-06651600 intermediate | |
| CN116082361B (en) | Method for preparing Marbalo Sha Wei intermediate and Marbalo Sha Wei | |
| CN115490626B (en) | Key chiral compound of PF-07321332 and preparation method thereof | |
| CN109384734B (en) | Preparation method of Selsemipa intermediate | |
| CN109251150B (en) | Preparation method of 2, 3-diamino methyl propionate | |
| WO2004035657A1 (en) | Process for the preparation of polyethylene glycol bis amine | |
| CN116554040A (en) | Preparation method of aminotetraglycol for chemical 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 | ||
| WW01 | Invention patent application withdrawn after publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20210219 |