CN117924142A - Liquid phase synthesis method of semaglutin side chain and synthesis method of semaglutin - Google Patents
Liquid phase synthesis method of semaglutin side chain and synthesis method of semaglutin Download PDFInfo
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- CN117924142A CN117924142A CN202410080071.0A CN202410080071A CN117924142A CN 117924142 A CN117924142 A CN 117924142A CN 202410080071 A CN202410080071 A CN 202410080071A CN 117924142 A CN117924142 A CN 117924142A
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- compound
- semaglutin
- side chain
- dichloromethane
- liquid phase
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- 230000004580 weight loss Effects 0.000 description 1
Abstract
The invention relates to the technical field of organic synthesis, in particular to a liquid phase synthesis method of a side chain of semaglutin and a synthesis method of semaglutin. The liquid phase synthesis method of the semaglutin side chain comprises the following steps: the synthesis was performed with reference to the following synthesis route: Wherein R 1 is selected from any one of N-hydroxysuccinimide, 1-hydroxybenzotriazole, p-nitrophenol and pentafluorophenol; r 2 is selected from any one of N-hydroxysuccinimide and 2-succinimidyl-1, 3-tetramethylurea tetrafluoroborate. The method has the advantages of simple and controllable reaction process, low cost, high yield, mild process conditions, easy removal of reaction byproducts and high operation safety, and is suitable for large-scale production of the Ste-Glu-AEEa-aEEA-OSU of the side chain of the semeglutide.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a liquid phase synthesis method of a side chain of semaglutin and a synthesis method of semaglutin.
Background
Diabetes mellitus (diabetes mellitus) is a group of clinical syndromes caused by the interaction of genetic and environmental factors. A series of metabolic disorders of sugar, protein, fat, water and electrolytes are caused by absolute or relative inadequate insulin secretion and reduced sensitivity of target tissue cells to insulin.
The semaglutin is GLP-1 receptor agonist drug marketed in 6 th place after exenatide, liraglutide, abirudin, dulragide and lixisenatide, and is long-acting GLP-1 hypoglycemic drug 1 time per week 3. Semaglutin is a novel long-acting GLP-1 analogue, and subcutaneous injection is carried out 1 time per week, so that the blood sugar level of type 2 diabetics can be greatly improved, and the risk of hypoglycemia is low. Meanwhile, the semaglutin can induce weight loss by reducing appetite and food intake, and can also obviously reduce the major cardiovascular event risk of type 2 diabetics. The danish and nod company publishes the latest clinical research results, and the semaglutinin is superior to the GLP-1 hypoglycemic novel drug, namely the duloxetine, which is the best in the market at present, whether the blood sugar is reduced or the weight is reduced.
The lysine position at the 26 th position of the peptide chain is connected with the 18 carbon fatty diacid side chain, so that the modification of PEG is added, the PEG can mediate and promote the strong combination of the semaglutin and albumin, the renal clearance rate is reduced, and compared with the liraglutide with the C16 side chain, the affinity of the semaglutin side chain to albumin is enhancedThe binding with albumin can increase the molecular weight of the product, increase the molecular size of the product, and the product can also carry a large amount of water molecules, and one PEG-protein is increased by 5-10 times. Second, PEG modification allows not only the previously insoluble proteins to be readily solubilized, but also to have a high degree of mobility. In addition, PEG modification can reduce the filtration of the drug by the kidney, reduce its pyrogenicity, and reduce its digestion by proteases, improving its delivery by protecting the molecule from attack by the human immune system. Meanwhile, because it evades the human body defensive mechanism, the residence time at the action part is much longer, and the rapid clearance by the kidney and the metabolic degradation can be avoided, and the half-life in vivo is prolonged.
The synthesis of the side chain Ste-Glu-AEEA-AEEA-OSU is extremely important in the preparation process of the semaglutin, but most of the prior art adopts a solid phase synthesis mode for coupling, and the coupling is obtained by cutting, for example: US2019309040A1. However, the solid phase synthesis has poor atom economy, relatively expensive side chain raw materials, low yield and high cost, and is unfavorable for commercial use. Or the benzyl ester is adopted to protect the side chain, and then Pb/C hydrogenolysis protecting group is selected to obtain the target product, which not only increases the danger in the process engineering, but also has higher cost and is unfavorable for commercial use.
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims to provide a liquid phase synthesis method of a side chain of semaglutin and a synthesis method of semaglutin. The embodiment of the invention provides a novel liquid phase synthesis method for synthesizing a side chain of the semaglutin, which has the advantages of simple and feasible reaction process, controllability, low cost, high yield, mild process conditions, easy removal of reaction byproducts and high operation safety, and is suitable for mass production of the side chain of the semaglutin Ste-Glu-AEEA-AEEA-OSU.
The invention is realized in the following way:
in a first aspect, the present invention provides a liquid phase synthesis method of a semaglutin side chain, comprising: the synthesis was performed with reference to the following synthesis route:
Wherein R 1 is selected from any one of N-hydroxysuccinimide, 1-hydroxybenzotriazole, p-nitrophenol and pentafluorophenol;
R 2 is selected from any one of N-hydroxysuccinimide and 2-succinimidyl-1, 3-tetramethylurea tetrafluoroborate.
In an alternative embodiment, the operations of (1) include: mixing a compound A, R 1, a condensing agent and a solvent for reaction;
Wherein the molar ratio of the compound A to the R 1 is 1:0.9-1.3; the molar ratio of the compound A to the condensing agent is 1:1-1.5.
In an alternative embodiment, the condensing agent is selected from any one of N, N "-diisopropylcarbodiimide, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, N" -dicyclohexylcarbodiimide, 2-succinimidyl-1, 3-tetramethylurea tetrafluoroborate and O-benzotriazol-N, N "-tetramethylurea tetrafluoroborate;
Preferably 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride;
Preferably, the solvent is selected from any one or a combination of at least 2 of C2-C6 ester solvents, C1-C5 halogenated alkane solvents, furan solvents, nitrile solvents, amide solvents, C1-C5 monohydric alcohol solvents and water;
Preferably any one or a mixture of a plurality of ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile, DMF, dichloromethane, chloroform, methanol and water in any proportion;
More preferably any one or a mixture of a plurality of dichloromethane, DMF and tetrahydrofuran in any proportion; preferably dichloromethane;
Preferably, the reaction temperature is 5-15 ℃;
Preferably, the R 1 is selected from the group consisting of N-hydroxysuccinimide and pentafluorophenol, most preferably N-hydroxysuccinimide.
In an alternative embodiment, the step of (2) comprises: mixing a compound B, a compound C, alkali and an organic solvent for reaction;
Wherein the molar ratio of the compound B to the compound C is 1:1-1.2;
The molar ratio of the compound B to the base is 1:1.3-2.
In alternative embodiments, the base is selected from a weak base, preferably any one or a combination of at least 2 of N, N-diisopropylethylamine, triethylamine, N-methylmorpholine, pyridine and sodium bicarbonate;
preferred are N, N-diisopropylethylamine and triethylamine; most preferably N, N-diisopropylethylamine;
preferably, the organic solvent is selected from any one or a combination of at least 2 of C2-C6 ester solvents, C1-C5 halogenated alkane solvents, furan solvents, nitrile solvents, amide solvents, C1-C5 monohydric alcohol solvents and water;
Preferably ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile, N-dimethylformamide, dichloromethane, chloroform, methanol, water or a mixture of any one or more of the above, preferably dichloromethane, N-dimethylformamide, tetrahydrofuran, preferably dichloromethane;
Preferably, the reaction temperature is 0-40 ℃ and the time is 10-20 hours; preferably at 20℃for 15 hours.
In an alternative embodiment, the step of (3) comprises: mixing a compound D, R 2, a condensing agent and a solvent for reaction;
Wherein the molar ratio of the compound D to the R 2 is 1:0.9-1.3; the molar ratio of the compound D to the condensing agent is 1:1-1.5.
In an alternative embodiment, the R 2 is selected from 2-succinimidyl-1, 3-tetramethylurea tetrafluoroborate;
Preferably, the condensing agent is selected from an organic weak base, more preferably any one of N, N-diisopropylethylamine, triethylamine, N-methylmorpholine and pyridine, preferably N, N-diisopropylethylamine and triethylamine, most preferably N, N-diisopropylethylamine.
In an alternative embodiment, the step of (4) comprises: mixing the compound E with trifluoroacetic acid for reaction; wherein the molar ratio of the compound E to the trifluoroacetic acid is 1:3-10.
In an alternative embodiment, the reaction temperature is 15-25 ℃.
In a second aspect, the present invention provides a method for synthesizing semaglutin, which comprises the liquid phase synthesis method of semaglutin side chain according to the previous embodiment.
The invention has the following beneficial effects: the synthesis method provided by the embodiment of the invention has the advantages of low cost, high yield, mild process conditions and easily available raw materials; the operation safety is high, the method is suitable for large-scale production, and can stably provide qualified products, and the quality purity of the produced products is more than or equal to 99.0 percent (without counting free acid and HOSu).
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the embodiments will be briefly described below, it being understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and other related drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a high-resolution spectrum of Compound B provided in example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance spectrum of the compound B provided in example 1 of the present invention;
FIG. 3 is a high-resolution spectrum of an isomer impurity of Compound B provided in example 1 of the present invention;
FIG. 4 is a high-resolution spectrum of compound D provided in example 1 of the present invention;
FIG. 5 is a nuclear magnetic spectrum of compound D according to example 1 of the present invention;
FIG. 6 is a high-resolution spectrum of an isomer impurity of Compound D provided in example 1 of the present invention;
FIG. 7 is a high-resolution spectrum of the side chain of semaglutin provided in example 1 of the present invention;
fig. 8 is a nuclear magnetic spectrum of a side chain of semaglutin provided in example 1 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The embodiment of the invention provides a liquid phase synthesis method of a semaglutin side chain, which comprises the following steps:
(1) Compound B was synthesized with reference to the following synthetic route;
Wherein R 1 is selected from any one of N-hydroxysuccinimide, 1-hydroxybenzotriazole, p-nitrophenol and pentafluorophenol; r 1 is selected from the group consisting of N-hydroxysuccinimide and pentafluorophenol, most preferably N-hydroxysuccinimide.
Specifically, compound A, R 1, condensing agent and solvent are mixed for reaction; wherein the molar ratio of the compound A to the R 1 is 1:0.9-1.3; for example, 1:0.9, 1:1.0, 1:1.1, 1:1.2 and 1:1.3 etc. 1: any value between 0.9 and 1.3 or a range of values between any two values. The molar ratio of the compound A to the condensing agent is 1:1-1.5. For example, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4 and 1:1.5, etc. 1:1-1.5, or a range of values between any two values.
The condensing agent is selected from N, N '-Diisopropylcarbodiimide (DIC), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCL), N, N' -Dicyclohexylcarbodiimide (DCC), 2-succinimidyl-1, 3-tetramethyluronium tetrafluoroborate (TSTU), O-benzotriazol-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) preferably EDC. HCL.
The solvent is selected from any one or at least 2 of C2-C6 ester solvent, C1-C5 halogenated alkane solvent, furan solvent, nitrile solvent, amide solvent, C1-C5 monohydric alcohol solvent and water; preferably any one or a mixture of a plurality of ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile, DMF, dichloromethane, chloroform, methanol and water in any proportion; more preferably any one or a mixture of a plurality of dichloromethane, DMF and tetrahydrofuran in any proportion; dichloromethane is preferred.
The reaction temperature is 5-15 ℃, and the reaction is complete by adopting an LC point plate for observation.
And after the reaction is finished, carrying out post-treatment, such as cooling crystallization, filtering and drying.
(2) Synthesizing a compound D;
Compound D was synthesized with reference to the following synthetic route:
Specifically, a compound B, a compound C, a base and an organic solvent are mixed for reaction; wherein the molar ratio of the compound B to the compound C is 1:1-1.2; for example, 1:1.0, 1:1.1 and 1:1.2, etc. 1: any value between 1 and 1.2 or a range of values between any two values. The molar ratio of compound B to the base is 1:1.3-2, for example 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 and 1:2.0, etc. 1: any value between 1.3 and 2.0 or a range of values between any two values.
The base is selected from weak base, preferably any one or at least 2 of N, N-diisopropylethylamine, triethylamine, N-methylmorpholine, pyridine and sodium bicarbonate; preferred are N, N-diisopropylethylamine and triethylamine; most preferred is N, N-diisopropylethylamine.
Preferably, the organic solvent is selected from any one or a combination of at least 2 of C2-C6 ester solvents, C1-C5 halogenated alkane solvents, furan solvents, nitrile solvents, amide solvents, C1-C5 monohydric alcohol solvents and water; preferably ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile, N-dimethylformamide, dichloromethane, chloroform, methanol, water, or a mixture of any one or more of them in any ratio, preferably dichloromethane, N-dimethylformamide, tetrahydrofuran, preferably dichloromethane.
The reaction temperature is 0-40deg.C, such as 0 deg.C, 5 deg.C, 10 deg.C, 15 deg.C, 20 deg.C, 25 deg.C, 30 deg.C, 35 deg.C, 40 deg.C, etc., or any value or range between any two values. The preferred temperature is 20 ℃. The time is 10-20 hours; for example, the time is preferably 15 hours, and the time is any value or a range of values between 10 and 20 hours, such as 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, and 20 hours.
(3) Synthesizing a compound E;
The reaction was performed with reference to the following synthetic route:
Wherein R 2 is selected from any one of N-hydroxysuccinimide and 2-succinimidyl-1, 3-tetramethylurea tetrafluoroborate, preferably R 2 is selected from 2-succinimidyl-1, 3-tetramethylurea tetrafluoroborate.
Specifically, compound D, R 2, condensing agent and solvent are mixed for reaction; wherein the molar ratio of the compound D to the R 2 is 1:0.9-1.3; for example, 1:0.9, 1:1.0, 1:1.1, 1:1.2 and 1:1.3 etc. 1: any value between 0.9 and 1.3 or a range of values between any two values. The molar ratio of the compound D to the condensing agent is 1:1-1.5. For example, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4 and 1:1.5, etc. 1:1-1.5, or a range of values between any two values.
The condensing agent is selected from the group consisting of organic weak bases, more preferably N, N-Diisopropylethylamine (DIEA), triethylamine (Et 3N), N-methylmorpholine, pyridine, preferably N, N-Diisopropylethylamine (DIEA), triethylamine (Et 3N), and most preferably N, N-Diisopropylethylamine (DIEA).
(4) Synthesizing a target product;
The synthesis is performed with reference to the following path:
Specifically, the compound E is mixed with trifluoroacetic acid for reaction; wherein the molar ratio of the compound E to the trifluoroacetic acid is 1:3-10, for example 1:3. 1:4, 1:5, 1:6, 1:7, 1: 8. 1:9 and 1:10, etc. 1: any number between 3 and 10, or a range of values between any two.
The reaction temperature is 15-25deg.C, such as 15 deg.C, 16 deg.C, 17 deg.C, 18 deg.C, 19 deg.C, 20 deg.C, 21 deg.C, 22 deg.C, 23 deg.C, 24 deg.C, 25 deg.C, etc., or any value or range between any two values.
In the synthetic method provided by the embodiment of the invention, no genotoxic impurities such as DCC, DIC, byproducts DCU and DIU are used in the condensation reaction, EDC.HCl and the generated byproduct EDCU are adopted, the hydrophilicity is good, the removal is easy, and the safety of the side chain of the cable marlutide is greatly improved. Meanwhile, the synthetic method has simple production process, the impurities are mostly removed by crystallization and beating, the reaction process is easy to control, and the repeatability of the production process is high.
In a second aspect, the present invention provides a method for synthesizing semaglutin, which comprises the liquid phase synthesis method of semaglutin side chain according to the previous embodiment.
The features and capabilities of the present invention are described in further detail below in connection with the examples.
Example 1
The embodiment provides a liquid phase synthesis method of a semaglutin side chain, which comprises the following steps:
(1) Synthesizing a compound B;
5.00g of compound A (9.00 mmol) is added into a 100ml reaction bottle, 25ml of acetonitrile is added, 1.90g of EDC.HCl (9.90 mmol) is slowly added into the mixture at the temperature of 10 ℃ after 1.24g of HOSu (10.80 mmol) is added, the reaction is completed after the addition, the temperature is kept for 6 hours, and the reaction is complete by TLC (thin layer chromatography) plate observation; cooling the reaction to 0 ℃, crystallizing for 6 hours, filtering, and drying to obtain 5.45g of compound B with the yield of 93%; purity 99.47% (high-liquid spectrum see fig. 1), nuclear magnetic spectrum see fig. 2; its corresponding isomer impurity was 0.04%, see fig. 3.
(2) Forming compound D;
5g of free AEEA-AEEA (16.2 mmol) was added to a 100ml reaction flask, 25ml of DCM was added, 3.28g of triethylamine (32.43 mmol) was slowly added dropwise to 9.53g of Compound B (14.59 mmol) at 20℃and the reaction was completed after the addition, incubated for 10h and observed on a TLC plate; the reaction product was washed with acid, washed with water, dried, filtered and concentrated to give 9.87g of compound D in 89% yield, 99.64% purity, with either single impurity being less than 0.2% (see fig. 4 for high-resolution spectra of compound D), with nuclear magnetism as shown in fig. 5, isomer 0.0118%, see fig. 6.
(3) Synthesizing a compound E;
5.00g of compound D (9.00 mmol) is added into a 100ml reaction bottle, 25ml of dichloromethane is added, 1.24g TsTu (10.80 mmol) and 1.90g of DIEA (9.90 mmol) are added, the reaction is carried out for 12h after the addition, and the reaction is complete by a TLC (thin layer chromatography) plate; concentrating under reduced pressure at 45deg.C to obtain compound E.
(4) Synthesizing a side chain of the semaglutin;
Adding 40g of trifluoroacetic acid into a 100ml reaction bottle of the compound E, reacting at normal temperature for 6h, observing a TLC (thin layer chromatography) spot plate, and completely reacting; concentrating at 40deg.C until there is no fraction, adding acetonitrile, cooling, crystallizing, suction filtering, pulping the solid with acetonitrile for 1 time, suction filtering to obtain solid with low Wen Lagan, to obtain target product with 89% yield and 99.78% purity (high liquid diagram of target product is shown in figure 7, HOSu and free acid are not counted), and nuclear magnetism is shown in figure 8.
Example 2
In this example, the results of the investigation of the compound A as a standard substrate, the activator for the synthetic compound B and the corresponding condensing agent, and the reaction solvent are shown in Table 1.
TABLE 1
| Sequence number | Activating agent | Condensing agent | Solvent(s) | Time of | Temperature (temperature) | Purity of |
| 1 | HOSu | EDCI | Dichloromethane (dichloromethane) | 6 | 20℃ | 98％ |
| 2 | HOSu | DCC/DIC | Dichloromethane (dichloromethane) | 6 | 20℃ | 91.93％ |
| 3 | TsTu | DIEA | Dichloromethane (dichloromethane) | 6 | 20℃ | 54％ |
Example 3
In this example, other reaction conditions for synthesizing compound B were studied using compound A, HOSu, EDCI as a standard substrate, and the results are shown in table 2.
TABLE 2
Example 4
In this example, other reaction conditions for synthesizing compound D were examined using compound B and compound C as standard substrates, and the results are shown in table 3.
TABLE 3 Table 3
Example 5
In this example, the reaction time of the compound D was examined using the compound B and the compound C as standard substrates, and the results are shown in Table 4.
TABLE 4 Table 4
Example 6
In this example, the temperature of the synthetic compound D was examined using the compound B and the compound C as standard substrates, and the results are shown in table 5.
TABLE 5
| Sequence number | Alkali | Solvent(s) | Time of | Temperature (temperature) | Purity of |
| 1 | DIEA | Dichloromethane (dichloromethane) | 15h | 0℃ | 91.54％ |
| 2 | DIEA | Dichloromethane (dichloromethane) | 15h | 10℃ | 94.10％ |
| 3 | DIEA | Dichloromethane (dichloromethane) | 15h | 20℃ | 99.5％ |
| 4 | DIEA | Dichloromethane (dichloromethane) | 15h | 30℃ | 96.7％ |
| 5 | DIEA | Dichloromethane (dichloromethane) | 15h | 40℃ | 95.3％ |
Example 7
In this example, the results of examining an activator and a condensing agent for the synthetic compound E using the compound D as a standard substrate are shown in Table 6.
TABLE 6
| Sequence number | Activating agent | Condensing agent | Solvent(s) | Time of | Temperature (temperature) | Yield of target product | Purity of |
| 1 | TsTu | DIEA | Dichloromethane (dichloromethane) | 12h | 0℃ | 89％ | 99.65％ |
| 2 | HOSu | EDCI | Dichloromethane (dichloromethane) | 12h | 0℃ | Incomplete reaction | 85.6％ |
| 3 | TsTu | NMM | Dichloromethane (dichloromethane) | 12h | 0℃ | 76％ | 90.78％ |
| 4 | TsTu | Et3N | Dichloromethane (dichloromethane) | 12h | 0℃ | 73％ | 97.23％ |
| 5 | TsTu | Pyridine compound | Dichloromethane (dichloromethane) | 12h | 0℃ | 55％ | 95.16％ |
Note that: since compound E is a dichloromethane solution, the yield of the target product is taken as a reference
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A liquid phase synthesis method of a semaglutin side chain, which is characterized by comprising the following steps: the synthesis was performed with reference to the following synthesis route:
Wherein R 1 is selected from any one of N-hydroxysuccinimide, 1-hydroxybenzotriazole, p-nitrophenol and pentafluorophenol;
R 2 is selected from any one of N-hydroxysuccinimide and 2-succinimidyl-1, 3-tetramethylurea tetrafluoroborate.
2. The method for liquid phase synthesis of a semaglutin side chain according to claim 1, wherein the operation of (1) comprises: mixing a compound A, R 1, a condensing agent and a solvent for reaction;
Wherein the molar ratio of the compound A to the R 1 is 1:0.9-1.3; the molar ratio of the compound A to the condensing agent is 1:1-1.5.
3. The liquid phase synthesis method of a semaglutin side chain according to claim 2, wherein the condensing agent is selected from any one of N, N ' -diisopropylcarbodiimide, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, N ' -dicyclohexylcarbodiimide, 2-succinimidyl-1, 3-tetramethylurea tetrafluoroborate and O-benzotriazol-N, N ' -tetramethylurea tetrafluoroborate;
Preferably 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride;
Preferably, the solvent is selected from any one or a combination of at least 2 of C2-C6 ester solvents, C1-C5 halogenated alkane solvents, furan solvents, nitrile solvents, amide solvents, C1-C5 monohydric alcohol solvents and water;
Preferably any one or a mixture of a plurality of ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile, DMF, dichloromethane, chloroform, methanol and water in any proportion;
More preferably any one or a mixture of a plurality of dichloromethane, DMF and tetrahydrofuran in any proportion; preferably dichloromethane;
Preferably, the reaction temperature is 5-15 ℃;
Preferably, the R 1 is selected from the group consisting of N-hydroxysuccinimide and pentafluorophenol, most preferably N-hydroxysuccinimide.
4. The liquid phase synthesis method of a semaglutin side chain according to claim 1, wherein the step of (2) comprises: mixing a compound B, a compound C, alkali and an organic solvent for reaction;
Wherein the molar ratio of the compound B to the compound C is 1:1-1.2;
The molar ratio of the compound B to the base is 1:1.3-2.
5. The liquid phase synthesis method of a semaglutin side chain according to claim 4, wherein the base is selected from weak base, preferably any one or a combination of at least 2 of N, N-diisopropylethylamine, triethylamine, N-methylmorpholine, pyridine and sodium bicarbonate;
preferred are N, N-diisopropylethylamine and triethylamine; most preferably N, N-diisopropylethylamine;
preferably, the organic solvent is selected from any one or a combination of at least 2 of C2-C6 ester solvents, C1-C5 halogenated alkane solvents, furan solvents, nitrile solvents, amide solvents, C1-C5 monohydric alcohol solvents and water;
Preferably ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile, N-dimethylformamide, dichloromethane, chloroform, methanol, water or a mixture of any one or more of the above, preferably dichloromethane, N-dimethylformamide, tetrahydrofuran, preferably dichloromethane;
Preferably, the reaction temperature is 0-40 ℃ and the time is 10-20 hours; preferably at 20℃for 15 hours.
6. The method for liquid phase synthesis of a semaglutin side chain according to claim 1, wherein the step of (3) comprises: mixing a compound D, R 2, a condensing agent and a solvent for reaction;
Wherein the molar ratio of the compound D to the R 2 is 1:0.9-1.3; the molar ratio of the compound D to the condensing agent is 1:1-1.5.
7. The liquid phase synthesis method of a semaglutin side chain according to claim 6, wherein R 2 is selected from 2-succinimidyl-1, 3-tetramethylurea tetrafluoroborate;
Preferably, the condensing agent is selected from an organic weak base, more preferably any one of N, N-diisopropylethylamine, triethylamine, N-methylmorpholine and pyridine, preferably N, N-diisopropylethylamine and triethylamine, most preferably N, N-diisopropylethylamine.
8. The method for liquid phase synthesis of a semaglutin side chain according to claim 1, wherein the step of (4) comprises: mixing the compound E with trifluoroacetic acid for reaction; wherein the molar ratio of the compound E to the trifluoroacetic acid is 1:3-10.
9. The method for liquid phase synthesis of a semaglutin side chain according to claim 8, wherein the reaction temperature is 15-25 ℃.
10. A method for synthesizing semaglutin, comprising the method for liquid-phase synthesis of semaglutin side chain according to claim 1.
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