CN115521358A - Preparation method of destruxins B - Google Patents
Preparation method of destruxins B Download PDFInfo
- Publication number
- CN115521358A CN115521358A CN202211189862.4A CN202211189862A CN115521358A CN 115521358 A CN115521358 A CN 115521358A CN 202211189862 A CN202211189862 A CN 202211189862A CN 115521358 A CN115521358 A CN 115521358A
- Authority
- CN
- China
- Prior art keywords
- resin
- fmoc
- reaction
- methyl
- solvent
- 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.)
- Pending
Links
- GNBHVMBELHWUIF-UHFFFAOYSA-N destruxin-B Natural products O=C1C(CC(C)C)OC(=O)CCNC(=O)C(C)N(C)C(=O)C(C(C)C)N(C)C(=O)C(C(C)CC)NC(=O)C2CCCN21 GNBHVMBELHWUIF-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 239000011347 resin Substances 0.000 claims abstract description 110
- 229920005989 resin Polymers 0.000 claims abstract description 110
- 239000002904 solvent Substances 0.000 claims abstract description 56
- 238000000034 method Methods 0.000 claims abstract description 30
- 229920001184 polypeptide Polymers 0.000 claims abstract description 28
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 28
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 239000002253 acid Substances 0.000 claims abstract description 20
- JOFHWKQIQLPZTC-LBPRGKRZSA-N (2s)-2-[9h-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid Chemical compound C1=CC=C2C(COC(=O)N(C)[C@@H](C)C(O)=O)C3=CC=CC=C3C2=C1 JOFHWKQIQLPZTC-LBPRGKRZSA-N 0.000 claims abstract description 19
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 19
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims abstract description 16
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 14
- 239000011737 fluorine Substances 0.000 claims abstract description 14
- ZPGDWQNBZYOZTI-SFHVURJKSA-N (2s)-1-(9h-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 ZPGDWQNBZYOZTI-SFHVURJKSA-N 0.000 claims abstract description 12
- YCXXXPZNQXXRIG-IBGZPJMESA-N (2s)-2-[9h-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-methylbutanoic acid Chemical compound C1=CC=C2C(COC(=O)N(C)[C@@H](C(C)C)C(O)=O)C3=CC=CC=C3C2=C1 YCXXXPZNQXXRIG-IBGZPJMESA-N 0.000 claims abstract description 12
- LINBWYYLPWJQHE-UHFFFAOYSA-N 3-(9h-fluoren-9-ylmethoxycarbonylamino)propanoic acid Chemical compound C1=CC=C2C(COC(=O)NCCC(=O)O)C3=CC=CC=C3C2=C1 LINBWYYLPWJQHE-UHFFFAOYSA-N 0.000 claims abstract description 12
- GNBHVMBELHWUIF-VTSYCQLTSA-N (3R,10S,13S,16S,19S)-16-[(2S)-butan-2-yl]-10,11,14-trimethyl-3-(2-methylpropyl)-13-propan-2-yl-4-oxa-1,8,11,14,17-pentazabicyclo[17.3.0]docosane-2,5,9,12,15,18-hexone Chemical compound O=C1[C@@H](CC(C)C)OC(=O)CCNC(=O)[C@H](C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CCCN21 GNBHVMBELHWUIF-VTSYCQLTSA-N 0.000 claims abstract description 11
- 108010066170 destruxin B Proteins 0.000 claims abstract description 11
- 229940024606 amino acid Drugs 0.000 claims abstract description 10
- 150000001413 amino acids Chemical class 0.000 claims abstract description 10
- 239000000243 solution Substances 0.000 claims description 82
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 75
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 72
- 238000006243 chemical reaction Methods 0.000 claims description 44
- 239000003153 chemical reaction reagent Substances 0.000 claims description 35
- 239000000203 mixture Substances 0.000 claims description 27
- 230000008878 coupling Effects 0.000 claims description 25
- 238000010168 coupling process Methods 0.000 claims description 25
- 238000005859 coupling reaction Methods 0.000 claims description 25
- UZOFELREXGAFOI-UHFFFAOYSA-N 4-methylpiperidine Chemical compound CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 claims description 17
- 239000007821 HATU Substances 0.000 claims description 14
- 239000000047 product Substances 0.000 claims description 13
- 238000005406 washing Methods 0.000 claims description 11
- 230000005587 bubbling Effects 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 5
- 238000005086 pumping Methods 0.000 claims description 5
- 230000008961 swelling Effects 0.000 claims description 5
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 abstract description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 103
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 9
- 238000000520 microinjection Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- JFLSOKIMYBSASW-UHFFFAOYSA-N 1-chloro-2-[chloro(diphenyl)methyl]benzene Chemical compound ClC1=CC=CC=C1C(Cl)(C=1C=CC=CC=1)C1=CC=CC=C1 JFLSOKIMYBSASW-UHFFFAOYSA-N 0.000 description 7
- 241000223250 Metarhizium anisopliae Species 0.000 description 7
- 238000009833 condensation Methods 0.000 description 7
- 230000005494 condensation Effects 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 238000002390 rotary evaporation Methods 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- -1 tetramethyl chlorourea hexafluorophosphate Chemical compound 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- YVVXMBHAKNKELS-UHFFFAOYSA-N Leuconic acid Natural products O=C1C(=O)C(=O)C(=O)C1=O YVVXMBHAKNKELS-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 229910052710 silicon Inorganic materials 0.000 description 3
- 239000010703 silicon Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 241000233866 Fungi Species 0.000 description 2
- 239000004696 Poly ether ether ketone Substances 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229920002530 polyetherether ketone Polymers 0.000 description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 description 2
- LVRFTAZAXQPQHI-YFKPBYRVSA-N (S)-2-hydroxy-4-methylpentanoic acid Chemical compound CC(C)C[C@H](O)C(O)=O LVRFTAZAXQPQHI-YFKPBYRVSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- VQNDBXJTIJKJPV-UHFFFAOYSA-N 2h-triazolo[4,5-b]pyridine Chemical compound C1=CC=NC2=NNN=C21 VQNDBXJTIJKJPV-UHFFFAOYSA-N 0.000 description 1
- 108010069514 Cyclic Peptides Proteins 0.000 description 1
- 102000001189 Cyclic Peptides Human genes 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002981 blocking agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000000967 entomopathogenic effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention relates to a preparation method of destruxins B, which comprises the following steps: connecting the resin with Fmoc-N-methyl-L-alanine to obtain a first resin; connecting the amino acid end on the first resin with Fmoc-N-methyl-L-valine to obtain a second resin; connecting the amino acid end on the second resin with Fmoc-L-isoleucyl chloride, fmoc-L-proline, L-cerotic acid and Fmoc-beta-alanine in sequence to obtain a chain polypeptide compound; removing Fmoc protection from the chain polypeptide compound, treating with a fluorine-containing solvent, and performing cyclization reaction by using a continuous flow method to obtain destruxin B. The method comprises the steps of sequentially connecting Fmoc-N-methyl-L-alanine, fmoc-N-methyl-L-valine, fmoc-L-isoleucyl chloride, fmoc-L-proline, L-leuconic acid and Fmoc-beta-alanine on resin, removing Fmoc protection, treating with a fluorine-containing solvent, cutting off the resin, and performing cyclization reaction by adopting a continuous flow method to obtain destruxin B, wherein the reaction time can be effectively shortened by adopting the continuous flow method.
Description
Technical Field
The invention relates to the technical field of organic chemical synthesis, in particular to a preparation method of destruxins B.
Background
Metarhizium anisopliae B (Destruxin B) is a fungus isolated from entomopathogenic fungi (Metarhizium anisopliae), a cyclic peptide with insecticidal and anticancer activities.
At present, destrixin B has been synthesized for many times, wherein, 64 Destrixin B derivatives are synthesized by constructing ester bonds by a method of MNBA-DMAPO on the basis of Destrixin B by T.Doi team in 2016. However, the method reported in the document requires strictly anhydrous operation, and only 24 hours are needed for dropwise adding MNBA-DMAPO into the chain polypeptide precursor, and the total reaction time is 48 hours, so that the preparation efficiency of destruxin B is low.
Disclosure of Invention
Accordingly, there is a need for a method for preparing destruxins of Metarrhizium anisopliae B, which can improve the efficiency of preparing destruxins of Metarrhizium anisopliae B.
In order to achieve the above purpose, the present invention provides a technical solution:
a preparation method of destruxins of Metarrhizium anisopliae B comprises the following steps:
connecting the resin with Fmoc-N-methyl-L-alanine to obtain a first resin;
connecting the amino acid end on the first resin with Fmoc-N-methyl-L-valine to obtain a second resin;
connecting the amino acid end on the second resin with Fmoc-L-isoleucyl chloride, fmoc-L-proline, L-cerotic acid and Fmoc-beta-alanine in sequence to obtain a chain polypeptide compound;
and removing Fmoc protection from the chain polypeptide compound, treating by using a fluorine-containing solvent, and performing cyclization reaction by using a continuous flow method to obtain the destruxin B.
Preferably, the specific step of attaching the resin to Fmoc-N-methyl-L-alanine comprises:
swelling resin in a first solvent, and washing the resin swelled in the first solvent with a first washing solution to obtain swelled resin;
dissolving the Fmoc-N-methyl-L-alanine and diisopropylethylamine in a second solvent to obtain a first mixture;
and adding the first mixture into the swelled resin for reaction, bubbling the resin with an inert gas, and connecting the resin and Fmoc-N-methyl-L-alanine to obtain a first resin after the reaction is finished.
Preferably, the first solvent comprises dichloromethane.
Preferably, the specific step of attaching the amino acid terminus on the first resin to Fmoc-N-methyl-L-valine comprises:
adding an end-capping reagent into the first resin for reaction to obtain end-capped first resin after the reaction is finished;
treating the capped first resin with a 4-methylpiperidine solution to obtain a second resin;
dissolving Fmoc-N-methyl-L-valine, HATU and diisopropylethylamine in a third solvent to obtain a second mixture;
and adding a second resin into the second mixture for reaction, and obtaining a third resin after the reaction is finished.
Preferably, the specific steps for obtaining the chain polypeptide compound comprise:
and reacting the third resin with the Fmoc-L-isoleucyl chloride, the Fmoc-L-proline, the L-leucin and the Fmoc-beta-alanine in sequence, and finishing the reaction to obtain the chain polypeptide compound.
Preferably, the step of removing Fmoc protection from the chain polypeptide compound comprises:
and adding a 4-methylpiperidine solution into the chain polypeptide compound for treatment to obtain a fourth resin.
Preferably, the fluorine-containing solvent treatment comprises the following specific steps:
and adding a fluorine-containing solvent/dichloromethane mixed solution into the fourth resin for reaction, and obtaining a chain hexapeptide acid crude product after the reaction is finished.
Preferably, the specific steps of the cyclization reaction using the continuous flow method include:
dissolving the crude chain hexapeptide acid product in a fourth solvent to obtain a third mixture;
and pumping the third mixture and the coupling reagent solution into a continuous flow reactor through injection pumps respectively to carry out cyclization reaction, and obtaining the destruxins B after the reaction is finished.
Preferably, the condensation reagent in the coupling reagent solution comprises HATU, the base comprises DIPEA (N, N-diisopropylethylamine), and the solvent comprises DMF.
Preferably, the molar ratio of said resin to said Fmoc-N-methyl-L-alanine is 1: (1.1-5).
The invention has the beneficial effects that:
the method comprises the steps of sequentially connecting Fmoc-N-methyl-L-alanine, fmoc-N-methyl-L-valine, fmoc-L-isoleucyl chloride, fmoc-L-proline, L-leuconic acid and Fmoc-beta-alanine on resin, removing Fmoc protection, treating with a fluorine-containing solvent, cutting off the resin, and performing cyclization reaction by adopting a continuous flow method to obtain destruxin B, wherein the reaction time can be effectively shortened by adopting the continuous flow method.
Drawings
FIG. 1 is a schematic structural diagram of a tubular microreactor;
FIG. 2 is a hydrogen nuclear magnetic resonance spectrum of destruxins B;
FIG. 3 is a nuclear magnetic resonance carbon spectrum of destruxins B.
110, a first micro-injection pump; 120. a second micro-syringe pump; a model 200.T mixer; 300. a micro-pipe; 400. a sample outlet; 500. and (6) collecting the bottle.
Detailed Description
The present invention will be further described with reference to specific examples for better illustrating the objects, technical solutions and advantages of the present invention.
In the examples, the test methods used were all conventional methods unless otherwise specified, and the materials, reagents and the like used were commercially available unless otherwise specified.
A preparation method of destruxins of Metarrhizium anisopliae B comprises the following steps:
s100, connecting the resin with Fmoc-N-methyl-L-alanine.
The method comprises the following specific steps:
swelling the resin in a first solvent, and washing the resin swollen in the first solvent with a first washing solution to obtain a swollen resin; more specifically, the first solvent comprises dichloromethane; the swelling time is 0.5 to 2 hours; the first washing solution is dimethylformamide and dichloromethane;
dissolving Fmoc-N-methyl-L-alanine and diisopropylethylamine in a second solvent to obtain a first mixture; the second solvent is dimethylformamide;
adding the first mixture into the swelled resin for reaction for 2-5 h, bubbling with an inactive gas, connecting the resin with Fmoc-N-methyl-L-alanine after the reaction is finished, and obtaining a first resin, wherein the molar ratio of the resin to the Fmoc-N-methyl-L-alanine is 1: (1.1-5).
Specifically, the resin includes any one of 2-CTC resin, rinkamide-PS resin, rinkamide-PEG resin, and CM resin.
S200, connecting the amino acid end on the first resin with Fmoc-N-methyl-L-valine.
The method comprises the following specific steps:
adding an end-capping reagent into the first resin for reaction for 0.1-1 h to obtain the end-capped first resin after the reaction is finished; the end-capping reagent comprises a mixed solution of dichloromethane/diisopropylethylamine/methanol, and the volume ratio is (6-8): (5-10): (0.5-2).
Treating the blocked first resin with 4-methylpiperidine solution for 0.1-1 h to remove Fmoc protection, thereby obtaining a second resin; wherein the mass percent of the 4-methylpiperidine in the 4-methylpiperidine solution is 5-50%, and the solvent is dimethylformamide solution.
Dissolving Fmoc-N-methyl-L-valine, HATU {2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate } and diisopropylethylamine in a third solvent to obtain a second mixture; the third solvent comprises dimethylformamide;
and adding the end-capped first resin into the second mixture for reaction for 1-12 h, and obtaining a second resin after the reaction is finished.
S300, connecting the amino Acid end on the second resin with Fmoc-L-isoleucyl chloride, fmoc-L-proline, L-leuconic Acid (L-Leucic Acid) and Fmoc-beta-alanine in sequence to obtain a chain polypeptide compound. Specifically, the molar ratio of the second resin to Fmoc-L-isoleucyl chloride, fmoc-L-proline, L-leuconic acid and Fmoc-beta-alanine is 1: (1.5-5): (1.5-5): (1.5-5): (1.5-5).
The method comprises the following specific steps:
reacting the second resin with Fmoc-L-isoleucyl chloride, fmoc-L-proline, L-flash leuconic acid and Fmoc-beta-alanine in sequence, specifically, reacting the second resin with Fmoc-L-isoleucyl chloride, fmoc-L-proline, L-flash leuconic acid and Fmoc-beta-alanine in sequence according to condensation cycles, and referring to step S200, wherein each condensation cycle comprises two parts of condensation and Fmoc protection removal, and the L-flash leuconic acid does not need to remove Fmoc protection.
And (3) obtaining the chain polypeptide compound after all reactions are finished.
S400, removing Fmoc protection from the chain polypeptide compound, treating by using a fluorine-containing solvent, and performing cyclization reaction by using a continuous flow method to obtain destruxin B.
Specifically, the fluorine-containing solvent comprises any one of hexafluoroisopropanol, trifluoroacetic acid and a trifluoroacetic acid/water/silicon hydrogen mixed reagent, wherein the volume ratio of trifluoroacetic acid/water/silicon hydrogen in the trifluoroacetic acid/water/silicon hydrogen mixed reagent is (5-9): (1-3): (1 to 3)
The specific steps of removing Fmoc protection from the chain polypeptide compound comprise:
and adding a 4-methylpiperidine solution into the chain polypeptide compound for treatment to obtain a fourth resin, wherein the mass percent of 4-methylpiperidine in the 4-methylpiperidine solution is 20%, the solvent is a dimethylformamide solution, and the 4-methylpiperidine solution is added to remove Fmoc protection.
The fluorine-containing solvent treatment comprises the following specific steps:
and adding a fluorine-containing solvent/dichloromethane mixed solution into the fourth resin for reaction to cut off the resin on the fourth resin, and obtaining a chain hexapeptide acid crude product after the reaction is finished. Wherein the volume ratio of the fluorine-containing solvent to the dichloromethane is (1-10) to 20.
The method for carrying out the cyclization reaction by adopting the continuous flow method comprises the following specific steps:
and dissolving the crude chain hexapeptide acid product in a fourth solvent to prepare a 0.1-10 mmol/L chain polypeptide solution to obtain a third mixture.
And mixing the third mixture and the coupling reagent solution according to the volume ratio of 1: (1.1-3) respectively pumping the product into a continuous flow reactor through an injection pump to carry out cyclization reaction, wherein the reaction time is 1-20 min, the reaction temperature is room temperature, and the destruxins B is obtained after the reaction is finished. Specifically, the pumping speed is 10-1000. Mu.L/min. In particular, the continuous flow reactor is a tubular microreactor.
Specifically, the route for synthesizing the stiff rhzomorph B of one embodiment is as follows:
wherein the content of the first and second substances,
is a 2-CTC resin, and is prepared by mixing a raw material,
is a first resin which is a mixture of a first resin,
is a second resin, and is a first resin,
is a chain polypeptide compound, chainThe polypeptide compound is destruxins B.
Preferably, the solute in the coupling reagent solution comprises a condensation reagent comprising HATU, the base comprises DIPEA (N, N-diisopropylethylamine), and the solvent comprises DMF.
In one embodiment, the fourth solvent comprises DMF (N, N-dimethylformamide), and the step of preparing the coupling reagent solution comprises:
preparing HATU into a HATU solution with the concentration of 1-5 mmol/L by using DMF, preparing DIPEA into a DIPEA solution with the concentration of 4-20 mmol/L by using DMF, and mixing the HATU solution and the DIPEA solution according to the volume ratio of 1: (1-3) preparing a coupling reagent solution.
In one embodiment, the fourth solvent comprises MeCN (acetonitrile), and the step of preparing the solution of coupling reagent comprises:
preparing TCFH (tetramethyl chlorourea hexafluorophosphate) into a TCFH solution with the concentration of 1-5 mmol/L by using MeCN, preparing NMI (N-methylimidazole) into an NMI solution with the concentration of 4-20 mmol/L by using MeCN, wherein the volume ratio of the TCFH solution to the NMI solution is 1: (1-3) preparing a coupling reagent solution.
In one embodiment, the fourth solvent comprises DMF (N, N-dimethylformamide), and the step of preparing the coupling reagent solution comprises:
preparing PyAOP ((7-azabenzotriazole-1-oxygen) trispyrrolephosphonium hexafluorophosphate) into a PyAOP solution with the concentration of 1-5 mmol/L by using DMF, preparing DIPEA into a DIPEA solution with the concentration of 4-20 mmol/L by using DMF, and mixing the PyAOP solution and the DIPEA solution according to the volume ratio of 1: (1-3) preparing a coupling reagent solution.
More specifically, the tubular microreactor comprises a first microinjection pump 110, a second microinjection pump 120, a T-shaped mixer 200, a microchannel 300, a sample outlet 400 and a collection bottle 500, wherein the first microinjection pump 110, the second microinjection pump 120, the T-shaped mixer 200, the microchannel 300, the sample outlet 400 and the collection bottle 500 are sequentially connected, a third mixture and a coupling reagent solution are respectively pumped into the microchannel 300 by the first microinjection pump 110 and the second microinjection pump 120 for reaction, a product enters the collection bottle 500 through the sample outlet 400, the microchannel 300 is a pipe made of PTFE (polytetrafluoroethylene), PEEK (polyether ether ketone), PE (polyethylene) or PP (polypropylene) plastics, the inner diameter is 0.1-1 mm, and the length is 1-10 m.
It is to be noted that Fmoc in the present invention is fluorenylmethyloxycarbonyl.
Example 1
S100, placing 1.0g of 2-CTC resin (0.55 mmol) in a 50mL solid-phase polypeptide synthesis tube, adding 20mL dichloromethane into the polypeptide synthesis tube, swelling for 30min, and alternately washing the 2-CTC resin swelled in dichloromethane with dimethylformamide (3X 10 mL) and dichloromethane (3X 10 mL) to obtain the swelled 2-CTC resin.
0.358g of Fmoc-N-methyl-L-alanine (1.1 mmol) and 0.479mL of diisopropylethylamine (2.75 mmol) were dissolved in 10mL of dimethylformamide to give a first mixture.
And adding the first mixture into the swelled 2-CTC resin for reaction for 4h, bubbling with nitrogen, and connecting the 2-CTC resin with Fmoc-N-methyl-L-alanine to obtain a first resin after the reaction is finished.
S200, washing and alternately washing a first resin by using dimethylformamide (3X 10 mL) and dichloromethane (3X 10 mL), adding an end capping reagent into the first resin for reaction, bubbling by using nitrogen for 30min, and obtaining the first resin after end capping after the reaction is finished; the blocking agent comprises a dichloromethane/diisopropylethylamine/methanol mixture with a volume of 8mL/1.5mL/5mL.
The first resin after blocking is washed by dimethylformamide (3X 10 mL) and dioxymethane (3X 10 mL) alternately, then the second resin is treated by 10mL of 4-methylpiperidine solution for 20min, and then the second resin is washed by dimethylformamide (3X 10 mL) and dichloromethane (3X 10 mL) alternately to obtain a second resin; wherein the mass percent of the 4-methylpiperidine in the 4-methylpiperidine solution is 20 percent, and the solvent is dimethylformamide solution.
0.583g of Fmoc-N-methyl-L-valine (1.65 mmol), 0.628g of HATU (1.65 mmol) and 0.426g of diisopropylethylamine (3.30 mmol) were dissolved in 10mL of dimethylformamide to give a second mixture.
The second resin was added to the second mixture and the reaction was bubbled with nitrogen for 2h, the reaction was complete, the solvent was removed and the solute fractions were washed alternately with dimethylformamide (3X 10 mL) and dichloromethane (3X 10 mL) to give a third resin.
S300, reacting the third resin with 0.614g of Fmoc-L-isoleucyl chloride (1.65 mmol), 0.557g of Fmoc-L-proline (1.65 mmol), 0.218g of L-cerotic acid (1.65 mmol) and 0.565g of Fmoc-beta-alanine (1.65 mmol) in sequence.
Referring to the step S200, each condensation cycle includes two steps of condensation and Fmoc protection removal, wherein L-flash white acid does not need to remove Fmoc protection.
After the reaction, a chain polypeptide compound is obtained.
10mL of 4-methylpiperidine solution was added to the chain polypeptide compound and treated for 20min to obtain a fifth resin. Wherein the mass percent of the 4-methylpiperidine in the 4-methylpiperidine solution is 20 percent, and the solvent is dimethylformamide solution.
After the treatment, the fifth resin is washed by dimethylformamide (3X 10 mL) and dichloromethane (3X 10 mL) alternately, after the washing is finished, the fifth resin is transferred into a round-bottom flask from a synthesis tube, a hexafluoroisopropanol/dichloromethane mixed solution is added into the fifth resin for reaction, the reaction time is 2h, after the reaction is finished, the solid part is removed by filtration, and the solution is dried by nitrogen to obtain a crude product of the chain hexapeptide acid. The volumes of hexafluoroisopropanol/dichloromethane were 5mL and 20mL, respectively.
Dissolving 61.1mg of a crude chain hexapeptide acid product (0.1 mmol) in a fourth solvent to prepare a 1mmol/L chain polypeptide solution, thereby obtaining a fourth mixture;
and mixing the fourth mixture and the coupling reagent solution according to the volume ratio of 1:2 is pumped into the micro-pipeline 300 through the first micro-injection pump 110 and the second micro-injection pump 120 respectively for cyclization reaction, the reaction time is 10min, the reaction temperature is room temperature, and the pumping speed is 50 mu L/min, and the reaction is finished, thus obtaining the destruxins B (ee: 99%).
Specifically, the fourth solvent is DMF, and the preparation step of the coupling reagent solution comprises:
114mg of HATU (0.30 mmol) was made up into a 2mmol/L solution of HATU in DMF, 77mg of DIPEA (0.60 mmol) was made up into a 4mmol/L solution of DIPEA in DMF, and the volume ratio of the solution of HATU to the solution of DIPEA was 1:1 is configured as a coupling reagent solution.
The nuclear magnetic resonance hydrogen spectrum of the product destruxin B is shown in figure 2, the nuclear magnetic resonance carbon spectrum is shown in figure 3, and the nuclear magnetic resonance hydrogen spectrum data of the product destruxin B is as follows:
1 H NMR(400MHz,Chloroform-d)δ8.19(d,J＝8.2Hz,1H),7.19(d,J＝9.2Hz,1H),5.19(q,J＝6.9Hz,1H),4.94(d,J＝10.9Hz,1H),4.91–4.84(m,2H),4.67(d,J＝7.1Hz,1H),4.10–4.01(m,1H),3.96–3.86(m,1H),3.51–3.36(m,1H),3.22(s,3H),3.07(td,J＝11.3,10.8,1.9Hz,1H),2.72(s,3H),2.69–2.61(m,1H),2.61–2.53(m,1H),2.50(d,J＝6.1Hz,1H),2.37–2.26(m,1H),2.10–2.03(m,1H),1.94(tt,J＝6.8,3.7Hz,3H),1.88–1.82(m,1H),1.45–1.36(m,2H),1.36–1.33(m,1H),1.33–1.27(m,4H),0.99(d,J＝6.7Hz,3H),0.95–0.91(m,6H),0.88(d,J＝6.6Hz,3H),0.87–0.83(m,6H).
the nuclear magnetic resonance carbon spectrum data of the product destruxins B are as follows:
13 C-NMR(101MHz,CDCl3)δ173.8,173.5,171.1,170.9,169.7,169.7,71.9,60.7,58.1,55.4,53.7,46.5,38.9,37.5,34.4,33.2,30.8,28.9,28.1,27.2,24.4,24.4,24.1,23.4,21.4,20.0,19.7,15.4,15.2,11.4.
example 2
The other steps are the same as in example 1, with the following differences:
the fourth solvent is DMF, and the preparation steps of the coupling reagent solution comprise:
84.2mg of TCFH (0.30 mmol) was made up of MeCN into a 2mmol/L solution of TCFH and 49.2mg of NMI (0.60 mmol) was made up of MeCN into a 4mmol/L solution of NMI, the volume ratio of TCFH solution to NMI solution being 1:1 is configured as a coupling reagent solution. (product ee: 99%).
Example 3
The other steps are the same as in example 1, with the following differences:
the fourth solvent is DMF, and the preparation steps of the coupling reagent solution comprise:
156.1mg PyAOP (0.30 mmol) was made up in 2mmol/L PyAOP solution with DMF and 77mg DIPEA (0.60 mmol) was made up in 4mmol/L DIPEA solution with DMF, the ratio by volume of PyAOP solution to DIPEA solution was 1:1 configured as a coupling reagent solution. (product ee: 99%).
Comparative example 1
The other steps are the same as in example 1, with the following differences:
the fourth solvent is DMF, and the preparation steps of the coupling reagent solution comprise:
mixing 94.5mgT 3 P (1-Propylphosphoric anhydride) (0.30 mmol) was formulated with DMF to give a T concentration of 2mmol/L 3 Solution P, 77mg DIPEA (0.60 mmol) in DMF was prepared as a 4mmol/L solution of DIPEA, T 3 The volume ratio of the P solution to the DIPEA solution is 1:1 is configured as a coupling reagent solution. (product ee: 30%).
Comparative example 2
The other steps are the same as in example 1, with the following differences:
the fourth solvent is DMF, and the preparation steps of the coupling reagent solution comprise:
29.7mg of EDC (1, 2-dichloroethane) (0.30 mmol) were made up with DMF to give a 2mmol/L EDC solution, 77mg of DIPEA (0.60 mmol) were made up with DMF to give a 4mm ol/L DIPEA solution, EDC solution and DIPEA solution being mixed in a volume ratio of 1:1 is configured as a coupling reagent solution. (product ee: 37%).
Comparative example 3
The other steps are the same as in example 1, with the following differences:
61.1mg of the crude chain hexapeptide acid (0.1 mmol) was dissolved in 10mL of DMF, and when cooled to 0 ℃ 114mg of HATU (0.30 mmol) and 77mg of DIPEA (0.60 mmol) were added to conduct cyclization at room temperature for 18 hours. The solvent was removed by rotary evaporation under reduced pressure, and the residue was separated by silica gel column chromatography (methanol/dichloromethane = 1/25) to obtain destruxins B (ee: 74%) as a white solid.
Comparative example 4
The other steps were the same as in example 1, with the following differences:
61.1mg of the crude chain hexapeptide acid (0.1 mmol) was dissolved in 10mL of DMF, and when cooled to 0 ℃ 29.7mg of EDC (0.30 mmol) and 77mg of DIPEA (0.60 mmol) were added to conduct cyclization at room temperature for 18 hours. The solvent was removed by rotary evaporation under reduced pressure, and the residue was separated by silica gel column chromatography (methanol/dichloromethane = 1/25) to obtain destruxins B (ee: 35%) as a white solid.
Comparative example 5
The other steps are the same as in example 1, with the following differences:
61.1mg of crude chain hexapeptide acid (0.1 mmol) was dissolved in 10mL of DMF, and when cooled to 0 ℃ 156.1mg of PyAOP (0.30 mmol) and 77mg of DIPEA (0.60 mmol) were added to carry out cyclization at room temperature for 18h. The solvent was removed by rotary evaporation under reduced pressure, and the residue was separated by silica gel column chromatography (methanol/dichloromethane = 1/25) to obtain destruxins B (ee: 75%) as a white solid.
Comparative example 6
The other steps were the same as in example 1, with the following differences:
61.1mg of the crude chain hexapeptide acid (0.1 mmol) was dissolved in 10mL of DMF and 94.5mg of T was added after cooling to 0 deg.C 3 P (0.30 mmol) and 77mg DIPEA (0.60 mmol) were subjected to cyclization reaction and reacted at room temperature for 18h. The solvent was removed by rotary evaporation under reduced pressure, and the residue was separated by silica gel column chromatography (methanol/dichloromethane = 1/25) to obtain destruxins B (ee: 29%) as a white solid.
Comparative example 7
The other steps were the same as in example 1, with the following differences:
61.1mg of crude chain hexapeptide acid (0.1 mmol) was dissolved in 10mL of MeCN, and when cooled to 0 ℃, 42.1mg of TCFH (0.15 mmol) and 42.1mg of NMI (0.30 mmol) were added to carry out cyclization at room temperature for 18 hours. The solvent was removed by rotary evaporation under reduced pressure, and separated by silica gel column chromatography (methanol/dichloromethane = 1/25) to obtain destruxin B (ee: 80%) as a white solid.
Comparative example 8
61.1mg of the crude chain hexapeptide acid (0.1 mmol) was dissolved in 10mL of DMF and, after cooling to 0 deg.C, 42.1mg of TCFH (0.15 mmol) and 42.1mg of NMI (0.30 mmol) were added to effect cyclization reaction at room temperature for 18h. The solvent was removed by rotary evaporation under reduced pressure, and the residue was separated by silica gel column chromatography (methanol/dichloromethane = 1/25) to obtain destruxins B (ee: 79%) as a white solid.
According to the experimental data of the examples 1 to 3 and the comparative examples 1 to 8, the continuous flow method for preparing the destruxins B greatly reduces the reaction time, effectively improves the reaction yield and improves the preparation efficiency of the destruxins B.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention, and all equivalent structural changes made by using the contents of the present specification and the drawings, or any other related technical fields directly/indirectly applied to the present invention are included in the scope of the present invention.
Claims (10)
1. A preparation method of destruxins B is characterized by comprising the following steps:
connecting the resin with Fmoc-N-methyl-L-alanine to obtain a first resin;
connecting the amino acid end on the first resin with Fmoc-N-methyl-L-valine to obtain a second resin;
connecting the amino acid end on the second resin with Fmoc-L-isoleucyl chloride, fmoc-L-proline, L-leuconic acid and Fmoc-beta-alanine in sequence to obtain a chain polypeptide compound;
and removing Fmoc protection from the chain polypeptide compound, treating by using a fluorine-containing solvent, and performing cyclization reaction by using a continuous flow method to obtain the destruxin B.
2. The method of claim 1, wherein the step of coupling the resin to Fmoc-N-methyl-L-alanine comprises:
swelling resin in a first solvent, and washing the resin swelled in the first solvent with a first washing solution to obtain swelled resin;
dissolving the Fmoc-N-methyl-L-alanine and diisopropylethylamine in a second solvent to obtain a first mixture;
and adding the first mixture into the swelled resin for reaction, bubbling the resin with an inert gas, and connecting the resin and Fmoc-N-methyl-L-alanine to obtain a first resin after the reaction is finished.
3. The method of claim 2, wherein the first solvent comprises dichloromethane.
4. The method of claim 2, wherein the step of linking the amino acid terminus of the first resin to Fmoc-N-methyl-L-valine comprises:
adding an end-capping reagent into the first resin for reaction to obtain end-capped first resin after the reaction is finished;
treating the capped first resin with a 4-methylpiperidine solution to obtain a second resin;
dissolving Fmoc-N-methyl-L-valine, HATU and diisopropylethylamine in a third solvent to obtain a second mixture;
and adding a second resin into the second mixture for reaction, and obtaining a third resin after the reaction is finished.
5. The method for preparing destruxins B according to claim 4, wherein the specific steps of obtaining the chain polypeptide compound comprise:
and reacting the third resin with the Fmoc-L-isoleucyl chloride, the Fmoc-L-proline, the L-leucin and the Fmoc-beta-alanine in sequence, and finishing the reaction to obtain the chain polypeptide compound.
6. The method for preparing destruxins B according to claim 5, wherein the step of removing Fmoc protection from said chain polypeptide compound comprises:
and adding a 4-methylpiperidine solution into the chain polypeptide compound for treatment to obtain a fourth resin.
7. The method for preparing destruxins B according to claim 6, wherein the specific steps of the fluorine-containing solvent treatment comprise:
and adding a fluorine-containing solvent/dichloromethane mixed solution into the fourth resin for reaction, and obtaining a chain hexapeptide acid crude product after the reaction is finished.
8. The method for preparing destruxins B according to claim 7, wherein the cyclization reaction is carried out by a continuous flow method comprising the following steps:
dissolving the crude chain hexapeptide acid product in a fourth solvent to obtain a third mixture;
and pumping the third mixture and the coupling reagent solution into a continuous flow reactor through injection pumps respectively to carry out cyclization reaction, and obtaining the destruxins B after the reaction is finished.
9. The process of claim 8, wherein the condensing reagent in the coupling reagent solution comprises HATU.
10. The method of claim 1, wherein the molar ratio of the resin to the Fmoc-N-methyl-L-alanine is 1: (1.1-5).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211189862.4A CN115521358A (en) | 2022-09-28 | 2022-09-28 | Preparation method of destruxins B |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211189862.4A CN115521358A (en) | 2022-09-28 | 2022-09-28 | Preparation method of destruxins B |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115521358A true CN115521358A (en) | 2022-12-27 |
Family
ID=84698912
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211189862.4A Pending CN115521358A (en) | 2022-09-28 | 2022-09-28 | Preparation method of destruxins B |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115521358A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201544118A (en) * | 2014-05-16 | 2015-12-01 | Chi-Chiang Yang | Use of destruxin B |
| CN114106069A (en) * | 2021-11-26 | 2022-03-01 | 安徽农业大学 | Metarhizium anisopliae A and metarhizium anisopliae B with glycosidase activity inhibiting function and preparation method thereof |
| CN115521362A (en) * | 2022-09-30 | 2022-12-27 | 哈尔滨工业大学（深圳） | Preparation method of pseudodestruxinB |
-
2022
- 2022-09-28 CN CN202211189862.4A patent/CN115521358A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201544118A (en) * | 2014-05-16 | 2015-12-01 | Chi-Chiang Yang | Use of destruxin B |
| CN114106069A (en) * | 2021-11-26 | 2022-03-01 | 安徽农业大学 | Metarhizium anisopliae A and metarhizium anisopliae B with glycosidase activity inhibiting function and preparation method thereof |
| CN115521362A (en) * | 2022-09-30 | 2022-12-27 | 哈尔滨工业大学（深圳） | Preparation method of pseudodestruxinB |
Non-Patent Citations (8)
| Title |
|---|
| DOI等: "Combinatorial Solid-Phase Synthesis and Biological Evaluation of Cyclodepsipeptide Destruxin B as a Negative Regulator for Osteoclast Morphology", ACS COMBINATORIAL SCIENCE, vol. 18, no. 09, 4 August 2016 (2016-08-04), pages 591 * |
| DOI等: "Synthetic studies for destruxins and biological evaluation for osteoclast-like multinucleated cells: a review", THE JOURNAL OF ANTIBIOTICS, vol. 75, no. 08, 11 July 2022 (2022-07-11), pages 420 - 431, XP037903239, DOI: 10.1038/s41429-022-00540-8 * |
| FUSE等: "Recent Advances in the Solid- and Solution-Phase Synthesis of Peptides and Proteins Using Microflow Technology", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 26, no. 06, 27 May 2022 (2022-05-27), pages 1751 - 1765 * |
| LIAO等: "Rapid mild macrocyclization of depsipeptides under continuous flow: total syntheses of five cyclodepsipeptides", ORGANIC CHEMISTRY FRONTIERS, vol. 09, no. 23, 20 October 2022 (2022-10-20), pages 6640 - 6645 * |
| NAKAMURA等: "Rapid and Mild Lactamization Using Highly Electrophilic Triphosgene in a Microflow Reactor", CHEMISTRY-A EUROPEAN JOURNAL, vol. 27, no. 27, 12 May 2021 (2021-05-12), pages 8 - 9 * |
| 吴梧桐主编: "《生物化学》", vol. 2, 31 March 2010, 中国医药科技出版社, pages: 43 - 46 * |
| 姚其正主编: "《药物合成反应》", vol. 1, 30 September 2012, 中国医药科技出版社, pages: 559 - 560 * |
| 李海涛等: "腐败菌素研究进展――腐败菌素化合物的化学合成、生物合成、生物代谢降解和生物活性", 世界农药, vol. 27, no. 02, 25 April 2005 (2005-04-25), pages 15 - 17 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102216320B (en) | The solvent resistant diafiltration of peptide, PNA or oligonucleotide | |
| CN105777871B (en) | A kind of synthetic method of ring pentapeptide | |
| CN112940071B (en) | Method for realizing alkynyl functionalization of cysteine and polypeptide thereof by utilizing microchannel reactor | |
| CN115521362A (en) | Preparation method of pseudodestruxinB | |
| CN115298193A (en) | Peptide synthesizer of series resin reactor | |
| CN108218957B (en) | Method for preparing AMG416 by combining solid phase and liquid phase | |
| CN1923849B (en) | Preparation method of synthesizing octriotide from solid phase polypeptide | |
| CN106518966A (en) | Synthetic method of RGD cyclopeptide | |
| CN115521358A (en) | Preparation method of destruxins B | |
| CN103665115B (en) | The chemical preparation process of cyclic decapeptide compound GG-110824 | |
| CN106832324B (en) | Preparation method of cucurbituril polymer with multiple topological structures | |
| CN115626951A (en) | CladoamideA preparation method | |
| CN113861273B (en) | Synthesis method of myristoyl pentapeptide-4 | |
| CN112778402B (en) | Method for synthesizing oxytocin by utilizing micro-channel modularized reaction device | |
| CN110078798B (en) | Method for synthesizing leuprorelin by using microchannel modular reaction device | |
| CN106397572A (en) | Method for purifying sincalide | |
| CN112538103B (en) | Process for preparing somatostatin | |
| CN117285602A (en) | Preparation method of depsipeptide natural product Isaridin A | |
| CN101838355A (en) | Preparation method of 2-chloro trityl chloride resin | |
| CN108715605A (en) | A kind of chemical synthesis process of antibacterial cyclic peptides Thermoactinoamide A | |
| CN111378009A (en) | Preparation method of octreotide | |
| CN112010945B (en) | Preparation method of carbetocin impurity Gly9-OH | |
| CN116040673B (en) | Synthetic method of samarium diiodide | |
| CN109836470B (en) | Method for automatically synthesizing polypeptide intramolecular disulfide bond | |
| CN112778400A (en) | Preparation method of octreotide |
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 |