CN111269137A - Method for preparing side chain of Somalutide by liquid phase method - Google Patents
Method for preparing side chain of Somalutide by liquid phase method Download PDFInfo
- Publication number
- CN111269137A CN111269137A CN202010047541.5A CN202010047541A CN111269137A CN 111269137 A CN111269137 A CN 111269137A CN 202010047541 A CN202010047541 A CN 202010047541A CN 111269137 A CN111269137 A CN 111269137A
- Authority
- CN
- China
- Prior art keywords
- condensation reaction
- dichloromethane
- hobt
- compound
- condensing agent
- 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
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
-
- 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
- C07C269/04—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 from amines with formation of carbamate groups
-
- 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
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
A method of preparing a somaglutide side chain: starting material 2- (2-aminoethoxy) ethanol amino with R1Protecting, nucleophilic substitution reaction with α haloester to elongate carbon chain, preparing fatty chain with two ends protected by one-pot method, removing protecting group from one end of said fatty chain, condensing to obtain compound 7, removing R1Protecting group to obtain compound 8, performing condensation reaction with fluorenylmethyloxycarbonyl-L-glutamic acid 1-tert-butyl ester to obtain compound 10, removing fluorenylmethyloxycarbonyl, performing amidation condensation reaction with 18- (tert-butoxy) -18 oxooctadecanoic acid to obtain compound 13, removing R2Protecting groups to obtain a target product chain 1; compared with solid phase synthesis, the method has the advantages of lower cost, wider selection of protecting groups and industrial production application prospect;
Description
Technical Field
The invention belongs to the field of polypeptide synthesis, and particularly relates to a liquid-phase synthesis method of a side chain of a polypeptide drug, namely somaglutide, for treating type II diabetes.
Background
Somaglutide is a new generation of glucagon-like peptide-1 (GLP-1) analogs developed by Novonide, Denmark, with a molecular formula of C187H291N45O59Molecular weight of4113.58, CAS number 910463-68-2. GLP-1 is a hormone inducing insulin secretion, and has beneficial effects on many important organs including pancreas, heart and liver. The somarutide medicine has the advantages of controlling blood sugar, obviously reducing the probability of occurrence of hypoglycemic events, obviously reducing weight and reducing the risk of cardiovascular events.
Somalutide was approved by the U.S. FDA in 2017 for marketing (0.5mg or 1mg injection) and was used clinically for the treatment of type II diabetes. The initial dose was 0.25mg weekly, once weekly, increased to 0.5mg weekly after four weeks, and the dose of 0.5mg increased to a maximum of 1mg weekly after four additional weeks.
Somaglutide oral insulin is officially approved by the U.S. FDA for marketing in 2019, 9, 20 days for improving glycemic control in type II diabetic patients in combination with diet and exercise. The once daily oral tablet of somaglutide with noh and nodel is the first oral glucagon-like peptide-1 (GLPR-1) to obtain FDA approval.
The molecular sequence of the somaglutide is:
His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys(AEEA-AEE-γ-Glu-Octadecanedioic Acid Mono-tert-butylester)-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-OH。
wherein the side chain Lys (AEEA-AEE-gamma-Glu-octanedioic Acid Mono-tert-butyl ester) is an essential part of the somaglutide, and the fatty chain to which Lys is attached comprises 2 molecules of 8-amino-3, 6-dioxaoctanoic Acid, one molecule of glutamic Acid and one molecule of Mono-tert-butyl octadecanedioate. The presence of this side chain allows for tighter binding of the somaglutide to the protein, thereby reducing renal clearance.
The invention adopts a liquid phase synthesis method to synthesize the side chain 1 connected with Lys.
Disclosure of Invention
The invention provides a liquid-phase synthesis method of a Somaloutide side chain, wherein the structural formula of the Somaloutide side chain synthesized by the method is as follows:
the technical scheme of the invention is as follows:
a method of making a somaglutide side chain, the method comprising the steps of:
(1) starting material 2- (2-aminoethoxy) ethanol amino with R1Protection, nucleophilic substitution reaction with α halogenated ester to extend the carbon chain, and one-pot method to obtain the fatty chain with two protected ends as shown below:
R1is Fmoc, Alloc, Boc, PMB, Cbz, Trt, Tos, Mtt, Mmt, Bom, Sem or MEM, preferably Fmoc, Trt or Boc, more preferably Trt or Boc; r1The reaction solvent used for protection is selected from one or a mixture of several of methanol, ethanol, ethyl acetate, dichloromethane, 1, 2-dichloroethane, DMF, DMSO, tetrahydrofuran, acetonitrile and N-methylpyrrolidone in any proportion, preferably ethanol or methanol, and more preferably methanol;
R2the reaction solvent used for nucleophilic substitution reaction with α halogenated ester is selected from one or a mixture of several of methanol, ethanol, ethyl acetate, dichloromethane, 1, 2-dichloroethane, DMF, DMSO, tetrahydrofuran, acetonitrile and N-methylpyrrolidone in any proportion, preferably tetrahydrofuran or acetonitrile, more preferably tetrahydrofuran;
(2) removing R from the fatty chain obtained in the step (1)1Protecting group compound and aliphatic chain removal R obtained in step (1)2Carrying out condensation reaction on the compound of the protecting group to obtain a compound 7;
removal of R1The protecting group is preferably in trifluoroacetic acid: volume ratio of dichloromethane 1:1 to 2 (more preferably 1: 1);
removal of R2The protecting group is carried out under the action of inorganic base, the inorganic base is selected from one or a mixture of several of sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, calcium hydroxide and barium hydroxide in any proportion, and sodium hydroxide is preferred; removal of R2The reaction solvent used for the protecting group is selected from one or a mixture of several of methanol, ethanol, ethyl acetate, dichloromethane, 1, 2-dichloroethane, DMF, DMSO, tetrahydrofuran, acetonitrile and N-methylpyrrolidone in any proportion, and preferably methanol or dichloromethane;
the solvent for condensation reaction is selected from one or more of methanol, ethanol, ethyl acetate, dichloromethane, 1, 2-dichloroethane, DMF, DMSO, tetrahydrofuran, acetonitrile and N-methylpyrrolidone, preferably 1, 2-dichloroethane or dichloromethane, more preferably dichloromethane; the condensation reaction is carried out under the action of a condensing agent selected from any single or multiple condensing agent of DIC, DCC, HBTU, PyBOP, BOP, HATU, TBTU, DIC/HOBT, DCC/DMAP, EDCI/HOBT, HATU/HOBT, preferably EDCI/DMAP, EDCI/HOBT or HATU, more preferably EDCI/HOBT, and the ratio of the amounts of EDCI and HOBT is 1: 0.5 to 2, preferably 1: 1; the condensation reaction temperature is 20-70 ℃, preferably 20-40 ℃, and more preferably 30 ℃;
(3) removal of R from Compound 71Protecting the group to obtain a compound 8;
removal of R1The protecting group is preferably in trifluoroacetic acid: volume ratio of dichloromethane 1:1 to 2 (more preferably 1: 1);
(4) carrying out condensation reaction on the compound 8 and fluorenylmethyloxycarbonyl-L-glutamic acid 1-tert-butyl ester to obtain a compound 10;
the solvent for condensation reaction is selected from one or more of methanol, ethanol, ethyl acetate, dichloromethane, 1, 2-dichloroethane, DMF, DMSO, tetrahydrofuran, acetonitrile and N-methylpyrrolidone, preferably 1, 2-dichloroethane or dichloromethane, more preferably dichloromethane; the condensation reaction is carried out under the action of a condensing agent selected from any single or multiple condensing agent of DIC, DCC, HBTU, PyBOP, BOP, HATU, TBTU, DIC/HOBT, DCC/DMAP, EDCI/HOBT, HATU/HOBT, preferably EDCI/DMAP, EDCI/HOBT or HATU, more preferably EDCI/HOBT, and the ratio of the amounts of EDCI and HOBT is 1: 0.5 to 2, preferably 1: 1; the condensation reaction temperature is 20-70 ℃, preferably 20-40 ℃, and more preferably 30 ℃;
(5) removing fluorenylmethyloxycarbonyl from the compound 10, and carrying out amidation condensation reaction with 18- (tert-butoxy) -18 oxooctadecanoic acid to obtain a compound 13;
the removal of fluorenylmethyloxycarbonyl is carried out under the action of an organic base selected from diethylamine, N-diisopropylethylamine, triethylamine, piperidine, imidazole, pyridine or DBU, preferably triethylamine, DBU or diethylamine, more preferably diethylamine; the reaction solvent used for removing the fluorenylmethyloxycarbonyl is one or a mixture of several of methanol, ethanol, ethyl acetate, dichloromethane, 1, 2-dichloroethane, DMF, DMSO, tetrahydrofuran, acetonitrile and N-methylpyrrolidone in any proportion, and acetonitrile is particularly preferred;
the solvent for amidation condensation reaction with 18- (tert-butoxy) -18 oxooctadecanoic acid is one or more of methanol, ethanol, ethyl acetate, dichloromethane, 1, 2-dichloroethane, DMF, DMSO, tetrahydrofuran, acetonitrile and N-methylpyrrolidone, preferably 1, 2-dichloroethane or dichloromethane, more preferably dichloromethane; the amidation condensation reaction is carried out under the action of a condensing agent selected from any single or multiple condensing agents of DIC, DCC, HBTU, PyBOP, BOP, HATU, TBTU, DIC/HOBT, DCC/DMAP, EDCI/HOBT, HATU/HOBT, preferably EDCI/DMAP, EDCI/HOBT or HATU, more preferably EDCI/HOBT, and the ratio of the amounts of EDCI and HOBT is 1: 0.5 to 2, preferably 1: 1; the temperature of the amidation condensation reaction is 20-70 ℃, preferably 20-40 ℃, and more preferably 30 ℃;
(6) removal of R from Compound 132Protecting groups to obtain a target product chain 1;
R2the removal of the protecting group is carried out under the action of an inorganic base selected from potassium hydroxide, barium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide or zinc hydroxide, preferably potassium hydroxide or lithium hydroxide, more preferably lithium hydroxide, and the inorganic base is preferably fed in the form of an aqueous solution, for example, 0.5 to 2M (preferably 1M) aqueous solution of lithium hydroxide; removal of R2The reaction solvent used for the protecting group is selected from one or a mixture of several of methanol, ethanol, ethyl acetate, dichloromethane, 1, 2-dichloroethane, DMF, DMSO, tetrahydrofuran, acetonitrile and N-methylpyrrolidone in any proportion, preferably ethanol or methanol, and more preferably methanol.
The final synthesized product of the invention can directly perform condensation reaction with free amino groups on the somaglutide Lys residues so as to be connected to the somaglutide main chain.
The invention has the beneficial effects that: compared with solid phase synthesis, the method has the advantages of lower cost, wider selection of protecting groups and application prospect, and is applied to industrial production.
The abbreviations used in the present invention have the following meanings:
his: histidine
Aib: 2-methylalanine
Glu: glutamic acid
Gly: glycine
Thr: threonine
Phe: phenylalanine
Thr: threonine
Ser: serine
Asp: aspartic acid
Val: valine
Leu: leucine
Gln: glutamine
Ala: alanine
Lys: lysine
Fmoc: fmoc group
And (3) Alloc: allyloxycarbonyl radical
Boc: tert-butyloxycarbonyl radical
PMB: p-methoxybenzyl
Trt: trityl radical
Tos: p-toluenesulfonyl group
Mtt: 4-methyl-trityl radical
Mmt: 4-Methoxytrityl group
And (5) Sem: trimethylsiloxyethylmethyl group
MEM: 2-methoxyethoxymethyl group
EDCI: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
HOBT: 1-hydroxybenzotriazoles
HATU: o- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea
DIC: n, N' -diisopropylcarbodiimide
DCC: dicyclohexylcarbodiimide
HBTU: benzotriazole-1-tetramethylhexafluorophosphate
DMAP: 4-dimethylaminopyridine
PyBOP: 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphates
BOP: benzotriazole-1-tris (trimethylamino) -trifluorophosphate
TBTU: o- (IH-benzotriazol-1-yl) -N, N, N ', N' -tetramethylisourea boron tetrafluoride
Drawings
FIG. 1 is a synthesis scheme of example 1 of the present invention.
FIG. 2 is a MS plot of Compound 1.
FIG. 3 is an IR spectrum of Compound 1
Detailed Description
The present invention is further illustrated by the following specific examples, but the scope of the invention is not limited thereto.
With R1＝Boc，R2With Bn as specific example 1, the somaglutide side chain was synthesized.
Example 1-1:
one-pot preparation
Dissolving 150mL of ethanol solution by using 2- (2-aminoethoxy) ethanol 2 as a starting material (100mmol, 10.5g), dropwise adding di-tert-butyl dicarbonate (100mmol, 23mL) under the ice bath condition, removing the ice bath, reacting at room temperature for 2h, and distilling under reduced pressure to remove the ethanol solvent; THF is redissolved, NaH (1.2-1.5eq) is added at 0-10 ℃, the temperature is kept and stirred for half an hour, ethyl bromoacetate 3(1.2-1.5eq) is slowly dripped into the reaction solution, the ice bath is removed after the dripping is finished, and the mixture is stirred at room temperature overnight. MeOH was added to the reaction, and MeOH: THF (1: 1) is added into the reaction solution, solid NaOH (1-2.2eq) is weighed, yellow, clear and transparent, and the reaction solution is heated and refluxed for 2 hours. And after the reaction is finished, distilling under reduced pressure to remove the solvent, re-dissolving the residue with water, extracting twice with ethyl acetate, collecting a water layer, adjusting the pH value to 1-3, extracting twice with ethyl acetate, collecting an organic layer, and distilling under reduced pressure to obtain a yellow oily liquid 4. The yield thereof was found to be 82%.
Examples 1 to 2:
(1) Dissolving 150mL of ethanol solution by using 2- (2-aminoethoxy) ethanol 2 as a starting material (100mmol, 10.5g), dropwise adding di-tert-butyl dicarbonate (100mmol, 23mL) under the ice bath condition, removing the ice bath, reacting at room temperature for 2h, and distilling under reduced pressure to remove the ethanol solvent; THF is redissolved, NaH (1.2-1.5eq) is added at the temperature of 0 to-10 ℃, the temperature is kept and the mixture is stirred for half an hour, benzyl bromoacetate 3' (1.2-1.5eq) is slowly dripped into the reaction solution, the ice bath is removed after the dripping is finished, and the mixture is transferred into an oil bath at the temperature of 50 DEG CThe pan was stirred overnight. TLC monitoring of the reaction (CH)2Cl2: EA 10: 1). After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was redissolved with ethyl acetate, extracted with 10% citric acid (75 mL. times.2) and saturated sodium bicarbonate solution (75 mL. times.2), washed with saturated brine (100mL), and the organic layer was collected and dried over anhydrous sodium sulfate. After concentration, the mixture is purified by column chromatography to obtain colorless oily liquid 5. The yield thereof was found to be 60%.
(2) Using TFA CH2Cl2Boc protection was removed 1:1 and dichloromethane was distilled off under reduced pressure to give yellow oily liquid 6 for use.
Examples 1 to 3:
The intermediate 4(10mmol, 2.63g) was dissolved in 25mL of dichloromethane, and N, N-diisopropylethylamine (3eq), EDCI (1.2eq), and HOBT (1.2eq) were added in this order, and after stirring for 30min, Compound 6(1.2eq) was added and stirred overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was redissolved with ethyl acetate, extracted with 1M hydrochloric acid solution (50 mL. times.2) and saturated sodium bicarbonate solution (50 mL. times.2), washed with saturated brine (75mL), and the organic layer was collected and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain yellow oily body 7. The yield thereof was found to be 79%.
Examples 1 to 4:
(1) Removing Boc protection; intermediate 7(1.56mmol, 780mg) was taken in 2mL CH2Cl2The mixture was dissolved in a solvent, and 2mL of TFA was added dropwise under ice-bath conditions, followed by reaction at room temperature for 2 hours. The solvent was distilled off under reduced pressure to obtain intermediate 8 for further use.
(2) Fluorenylmethoxycarbonyl-L-glutamic acid 1-tert-butyl ester 9(1.3mmol, 553mg) was weighed and dissolved in 10mL of dichloromethane solution, N-diisopropylethylamine (3eq), EDCI (2eq) and HOBT (2eq) were added in sequence, and after stirring for 30min, the above compound 8 was added, and the mixture was stirred at room temperatureOvernight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was redissolved with ethyl acetate, extracted with a 1M hydrochloric acid solution (20 mL. times.2) and a saturated sodium bicarbonate solution (20 mL. times.2), washed with a saturated saline solution (25mL), and the organic layer was collected and dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure and purified by column Chromatography (CH)2Cl2: MeOH ═ 20:1) gave yellow oily liquid 10. The yield thereof was found to be 93%.
Examples 1 to 5:
Compound 10(1.7mmol, 1.36g) above was dissolved in 30-40mL of anhydrous acetonitrile, diethylamine (3-4mL) was added dropwise, stirred at room temperature for 3h, and the reaction monitored by TLC. Purification by column Chromatography (CH)2Cl2: MeOH 10:1) gave 11 as a yellow oil. The yield thereof was found to be 86%.
Examples 1 to 6:
A25 mL round-bottomed flask was taken, and octadecanedioic acid mono-tert-butyl ester 12(0.83mmol, 308mg) was dissolved in 5mL of a dichloromethane solution, N-diisopropylethylamine (3eq), EDCI (1.2eq), and HOBT (1.2eq) were added in this order, and after stirring for 30min, the above intermediate 11(0.1mmol, 583mg) was added, and the reaction was monitored by TLC. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was redissolved with ethyl acetate, extracted with 10% citric acid (10 mL. times.2) and saturated sodium bicarbonate solution (10 mL. times.2), washed with saturated brine (20mL), and the organic layer was collected and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oily liquid 13 with a yield of 72%.
Examples 1 to 7:
A25 mL round-bottomed flask was taken, and the intermediate 13 was dissolved in 2mL MeOH, and the reaction mixture was addedDropwise adding 1mol/L LiOH aqueous solution, stirring at room temperature for 2h, distilling under reduced pressure to remove solvent, and purifying by column Chromatography (CH)2Cl2: MeOH ═ 5:1) to give final product 1. The yield thereof was found to be 90%.
This particular embodiment is provided to complement and illustrate the feasibility of the present invention, and many other variations and modifications may be made without departing from the spirit and scope of the present invention. Therefore, the scope of the appended claims should also encompass variations and modifications on the basis of the present invention.
Claims (7)
1. A method of preparing a somaglutide side chain, comprising the steps of:
(1) starting material 2- (2-aminoethoxy) ethanol amino with R1Protection, nucleophilic substitution reaction with α halogenated ester to extend the carbon chain, and one-pot method to obtain the fatty chain with two protected ends as shown below:
(2) removing R from the fatty chain obtained in the step (1)1Protecting group compound and aliphatic chain removal R obtained in step (1)2Carrying out condensation reaction on the compound of the protecting group to obtain a compound 7;
(3) removal of R from Compound 71Protecting the group to obtain a compound 8;
(4) carrying out condensation reaction on the compound 8 and fluorenylmethyloxycarbonyl-L-glutamic acid 1-tert-butyl ester to obtain a compound 10;
(5) removing fluorenylmethyloxycarbonyl from the compound 10, and carrying out amidation condensation reaction with 18- (tert-butoxy) -18 oxooctadecanoic acid to obtain a compound 13;
(6) removal of R from Compound 132Protecting groups to obtain a target product chain 1;
2. the method of preparing the somaglutide side chain of claim 1 wherein in step (1), R is1Is Fmoc, Alloc, Boc, PMB, Cbz, Trt, Tos, Mtt, Mmt, Bom, Sem or MEM; r1The reaction solvent used for protection is selected from one or a mixture of several of methanol, ethanol, ethyl acetate, dichloromethane, 1, 2-dichloroethane, DMF, DMSO, tetrahydrofuran, acetonitrile and N-methylpyrrolidone in any proportion;
R2the solvent used for nucleophilic substitution reaction with α halogenated ester is selected from one or a mixture of several of methanol, ethanol, ethyl acetate, dichloromethane, 1, 2-dichloroethane, DMF, DMSO, tetrahydrofuran, acetonitrile and N-methylpyrrolidone in any proportion.
3. The method for preparing the side chain of somaglutide of claim 1 wherein in step (2), R is removed1Protecting groups are described in trifluoroacetic acid: volume ratio of dichloromethane 1: 1-2 in the system;
removal of R2The protecting group is carried out under the action of inorganic base, and the inorganic base is one or a mixture of several of sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, calcium hydroxide and barium hydroxide in any proportion; removal of R2The reaction solvent used for the protecting group is selected from methanol, ethanol, ethyl acetate,One or a mixture of more of dichloromethane, 1, 2-dichloroethane, DMF, DMSO, tetrahydrofuran, acetonitrile and N-methylpyrrolidone in any proportion;
the solvent for condensation reaction is one or a mixture of several of methanol, ethanol, ethyl acetate, dichloromethane, 1, 2-dichloroethane, DMF, DMSO, tetrahydrofuran, acetonitrile and N-methylpyrrolidone in any proportion; the condensation reaction is carried out under the action of a condensing agent, and the condensing agent is any single condensing agent or composite condensing agent selected from DIC, DCC, HBTU, PyBOP, BOP, HATU, TBTU, DIC/HOBT, DCC/DMAP, EDCI/HOBT and HATU/HOBT; the temperature of the condensation reaction is 20-70 ℃.
4. The method for preparing the side chain of somaglutide of claim 1 wherein in step (3), R is removed1Protecting groups are described in trifluoroacetic acid: volume ratio of dichloromethane 1:1 to 2 in the system.
5. The method for preparing the side chain of the somaglutide as claimed in claim 1, wherein in the step (4), the solvent for the condensation reaction is selected from one or more of methanol, ethanol, ethyl acetate, dichloromethane, 1, 2-dichloroethane, DMF, DMSO, tetrahydrofuran, acetonitrile and N-methylpyrrolidone; the condensation reaction is carried out under the action of a condensing agent, and the condensing agent is any single condensing agent or composite condensing agent selected from DIC, DCC, HBTU, PyBOP, BOP, HATU, TBTU, DIC/HOBT, DCC/DMAP, EDCI/HOBT and HATU/HOBT; the temperature of the condensation reaction is 20-70 ℃.
6. The method for preparing the somaglutide side chain according to claim 1, wherein in step (5) the removal of fluorenylmethyloxycarbonyl group is performed under the action of an organic base selected from diethylamine, N-diisopropylethylamine, triethylamine, piperidine, imidazole, pyridine or DBU; the reaction solvent used for removing the fluorenylmethyloxycarbonyl is one or a mixture of several of methanol, ethanol, ethyl acetate, dichloromethane, 1, 2-dichloroethane, DMF, DMSO, tetrahydrofuran, acetonitrile and N-methylpyrrolidone in any proportion;
the solvent for amidation condensation reaction with 18- (tert-butoxy) -18 oxooctadecanoic acid is one or more of methanol, ethanol, ethyl acetate, dichloromethane, 1, 2-dichloroethane, DMF, DMSO, tetrahydrofuran, acetonitrile and N-methylpyrrolidone in any proportion; the amidation condensation reaction is carried out under the action of a condensing agent, wherein the condensing agent is any single condensing agent or composite condensing agent selected from DIC, DCC, HBTU, PyBOP, BOP, HATU, TBTU, DIC/HOBT, DCC/DMAP, EDCI/HOBT and HATU/HOBT; the temperature of the amidation condensation reaction is 20-70 ℃.
7. The method for preparing the side chain of somaglutide of claim 1, wherein in step (6), R is2The removal of the protecting group is carried out under the action of an inorganic base selected from potassium hydroxide, barium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide or zinc hydroxide; removal of R2The reaction solvent used for the protecting group is one or a mixture of several of methanol, ethanol, ethyl acetate, dichloromethane, 1, 2-dichloroethane, DMF, DMSO, tetrahydrofuran, acetonitrile and N-methylpyrrolidone in any proportion.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010047541.5A CN111269137A (en) | 2020-01-16 | 2020-01-16 | Method for preparing side chain of Somalutide by liquid phase method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010047541.5A CN111269137A (en) | 2020-01-16 | 2020-01-16 | Method for preparing side chain of Somalutide by liquid phase method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111269137A true CN111269137A (en) | 2020-06-12 |
Family
ID=70994821
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010047541.5A Pending CN111269137A (en) | 2020-01-16 | 2020-01-16 | Method for preparing side chain of Somalutide by liquid phase method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111269137A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113461591A (en) * | 2021-08-12 | 2021-10-01 | 浙江泽瑞生物医药有限公司 | Preparation method of precursor raw material Pht-AEEA-AEEA for side chain of Somalutide |
| CN114685646A (en) * | 2020-12-31 | 2022-07-01 | 厦门赛诺邦格生物科技股份有限公司 | Preparation method and application of polypeptide side chain analogue |
| CN114805543A (en) * | 2022-04-29 | 2022-07-29 | 四川普康药业有限公司 | Synthesis method of somaglutide side chain |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105154498A (en) * | 2007-12-28 | 2015-12-16 | 诺沃—诺迪斯克有限公司 | Semi-recombinant preparation of GLP-1 analogues |
| CN105683156A (en) * | 2013-08-29 | 2016-06-15 | 佩特雷化学和生物制药学实验室有限公司 | Amino diacids containing peptide modifiers |
| CN105745222A (en) * | 2013-10-17 | 2016-07-06 | 西兰制药公司 | Acylated glucagon analogues |
| CN110041219A (en) * | 2019-05-09 | 2019-07-23 | 南京工业大学 | A kind of liquid-phase synthesis process of Suo Malu peptide side chain |
-
2020
- 2020-01-16 CN CN202010047541.5A patent/CN111269137A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105154498A (en) * | 2007-12-28 | 2015-12-16 | 诺沃—诺迪斯克有限公司 | Semi-recombinant preparation of GLP-1 analogues |
| CN105683156A (en) * | 2013-08-29 | 2016-06-15 | 佩特雷化学和生物制药学实验室有限公司 | Amino diacids containing peptide modifiers |
| CN105745222A (en) * | 2013-10-17 | 2016-07-06 | 西兰制药公司 | Acylated glucagon analogues |
| CN110041219A (en) * | 2019-05-09 | 2019-07-23 | 南京工业大学 | A kind of liquid-phase synthesis process of Suo Malu peptide side chain |
Non-Patent Citations (1)
| Title |
|---|
| 东圆珍等: "索玛鲁肽的制备", 《中国医药工业杂志》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114685646A (en) * | 2020-12-31 | 2022-07-01 | 厦门赛诺邦格生物科技股份有限公司 | Preparation method and application of polypeptide side chain analogue |
| CN114685646B (en) * | 2020-12-31 | 2023-04-07 | 厦门赛诺邦格生物科技股份有限公司 | Preparation method and application of polypeptide side chain analogue |
| CN113461591A (en) * | 2021-08-12 | 2021-10-01 | 浙江泽瑞生物医药有限公司 | Preparation method of precursor raw material Pht-AEEA-AEEA for side chain of Somalutide |
| CN114805543A (en) * | 2022-04-29 | 2022-07-29 | 四川普康药业有限公司 | Synthesis method of somaglutide side chain |
| CN114805543B (en) * | 2022-04-29 | 2023-05-19 | 四川普康药业有限公司 | Synthesis method of cable Ma Lutai side chain |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111253287A (en) | Method for synthesizing side chain of Somalutide in liquid phase convergence manner | |
| CN111269137A (en) | Method for preparing side chain of Somalutide by liquid phase method | |
| US10239902B2 (en) | Stable peptide-conjugated ascorbic acid derivative, method for preparing same, and cosmetic composition comprising same | |
| US9434762B2 (en) | Macrocyclic cysteine protease inhibitors and compositions thereof | |
| CA1250398A (en) | Tri-tetra- and pentapeptides, their preparation, and pharmaceutical products containing same | |
| CN114685646B (en) | Preparation method and application of polypeptide side chain analogue | |
| CN111378028A (en) | Synthesis of acylated GLP-1 compounds and modified groups thereof | |
| CN112010961A (en) | Solid-liquid synthesis method of somaglutide | |
| CN112625087A (en) | Dipeptide fragment derivative for synthesizing semaglutide and preparation method thereof | |
| CN114213503A (en) | Synthesis method of snake venom-like tripeptide | |
| JPS61100596A (en) | Novel peptides | |
| CZ288529B6 (en) | Cyclic amino acids, process for preparing D- and L-enantiomers thereof and intermediates for their preparation | |
| CN108530518A (en) | 10 analog of aplysiatoxin and its preparation method and application | |
| CN111285780A (en) | Convergent liquid phase synthesis method of side chain of Somaloutide | |
| EP0485458A1 (en) | Thioacylating reagents and intermediates, thiopeptides, and methods for preparing and using same. | |
| CN105949279A (en) | Method for preparing proteasome inhibitor Oprozomib and analogs thereof | |
| JP5947821B2 (en) | Method for producing cereulide and derivatives thereof, intermediate for producing cereulide and cereulide derivatives | |
| CN114805543B (en) | Synthesis method of cable Ma Lutai side chain | |
| AU2021288365B2 (en) | Novel analogs of pterostilbene amino acid bearing carbonates for treating a non-alcoholic fatty liver disease and nonalcoholic steatohepatitis | |
| JPH0597789A (en) | Alpha-hydroxyglycinamide derivative and its production | |
| JPWO2015033781A1 (en) | Method for producing dipeptide derivatives containing disubstituted amino acid residues | |
| CN115515937A (en) | Dimers for the synthesis of peptidomimetics | |
| CN116496345A (en) | Polypeptide ceramide and synthesis method and application thereof | |
| CN117777231A (en) | Method for synthesizing itracin in liquid phase | |
| AU651557C (en) | Thioacylating reagents and intermediates, thiopeptides, and methods for preparing and using same |
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 | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200612 |