CN111285780A - Convergent liquid phase synthesis method of side chain of Somaloutide - Google Patents
Convergent liquid phase synthesis method of side chain of Somaloutide Download PDFInfo
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Abstract
A synthesis method of a side chain 1 of Somaloutide comprises the following steps: the amino end group of the raw material diglycolamine 2 is R1Protection, nucleophilic substitution with α haloester, and hydrolyzing the ester in one pot to obtain compound 4, wherein the free carboxyl of compound 4 is substituted by R2Protection and removal of R1Protecting group to obtain compound 6, condensation reaction of compound 7 and compound 6 to obtain compound 8, removing fluorenylmethyloxycarbonyl group of compound 8, amidation condensation coupling reaction with 18- (tert-butoxy) -18 oxooctadecanoic acid to obtain compound 11, removing R from compound 112Protecting group, condensation coupling reaction with compound 6 to obtain compound 13, and removing R from compound 132Protecting groups to give chain 1; the invention uses the convergent synthesis method to reduce the reaction cost and shorten the reaction time, and the synthesis process is effective, controllable, low in cost and high in yield, and is suitable for large-scale production;
Description
Technical Field
The invention belongs to the field of polypeptide synthesis, and particularly relates to a convergent liquid-phase synthesis method of a side chain of a polypeptide drug, namely somaglutide, for treating type II diabetes.
Background
According to statistics, the number of diabetes patients in 2017 reaches 4.25 hundred million worldwide. Due to incurability and accelerated aging of the population, the worldwide population of diabetics in 2045 years is expected to reach 6.29 billion. The marketing of both the somaglutide (glucagon-like peptide-1 (GLP-1)) injection and oral formulations (for controlling blood glucose and reducing the risk probability of cardiovascular events) will undoubtedly bring about a good news to the diabetic. 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
the side chain to which Lys at position 26 is attached can be seen as consisting of the following four units: 2 molecules of 8-amino-3, 6-dioxaoctanoic acid, one molecule of glutamic acid and one molecule of mono-tert-butyl octadecanedioate, the existence of side chains can enhance the combination of the somaglutide drug and the protein, thereby reducing the renal clearance rate. At present, the soxhlet peptide and the side chain thereof are synthesized by a linear solid-phase synthesis method commonly used in industry, and the development of a new synthesis method and the reduction of the synthesis cost and the synthesis period are urgent because the raw materials of the soxhlet peptide side chain are relatively expensive.
The present invention adopts a liquid phase synthesis method to synthesize the side chain 1 to which Lys is attached in a convergent manner.
Disclosure of Invention
The invention aims to provide a convergent liquid phase synthesis method of a Somaloutide side chain, which can reduce the cost of liquid phase synthesis, shorten the reaction period, improve the reaction yield and has industrial application prospect.
The structural formula of the side chain of the Somalutide is shown as follows:
the technical scheme of the invention is as follows:
a method of synthesizing a somaglutide side chain 1, the method comprising the steps of:
(1) the amino end group of the raw material diglycolamine 2 is R1Protecting, then carrying out nucleophilic substitution reaction with α halogenated ester, and preparing a compound 4 by ester hydrolysis in one pot;
the R is1Is 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;
the α halogenated ester is ethyl bromoacetate or benzyl bromoacetate, preferably ethyl bromoacetate, and the reaction solvent used for nucleophilic substitution reaction with α halogenated ester 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, preferably tetrahydrofuran or acetonitrile, more preferably tetrahydrofuran;
ester hydrolysis is carried out under the action of inorganic base, wherein the inorganic base is selected from one or a mixture of more of sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, calcium hydroxide and barium hydroxide in any proportion, and preferably sodium hydroxide; the mass ratio of the inorganic base to the diglycolamine 2 is 0.5-4: 1, preferably 0.5 to 2: 1, more preferably 2: 1;
(2) r for free carboxyl group of compound 42Protection and removal of R1Protecting group to give compound 6;
the R is2Bn, Pfp, Me, Allyl, t-Bu, PMB, MEM or TBS, preferably Bn or Me, more preferably Bn;
removal of R1The protecting group is carried out under the action of an acid reagent, wherein the acid reagent is hydrochloric acid, acetic acid or trifluoroacetic acid, and preferably the trifluoroacetic acid; removal of R1The protecting group is prepared with the solvent selected from methanol, ethanol and ethanolOne or more of ethyl acetate, dichloromethane, 1, 2-dichloroethane, DMF, DMSO, tetrahydrofuran, acetonitrile and N-methylpyrrolidone, preferably methanol or dichloromethane, and more preferably dichloromethane; particularly preferably, R is removed1Protecting groups are described in trifluoroacetic acid: volume ratio of dichloromethane 1: 1-2 (preferably 1: 1);
(3) condensation reaction of fluorenylmethyloxycarbonyl-L-glutamic acid 1-tert-butyl ester 7 and a compound 6 to obtain a compound 8;
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 ℃; the solvent for the condensation reaction is selected from one or a mixture of more than one of methanol, ethanol, ethyl acetate, dichloromethane, 1, 2-dichloroethane, DMF, DMSO, tetrahydrofuran, acetonitrile and N-methylpyrrolidone in any proportion, preferably 1, 2-dichloroethane or dichloromethane, more preferably dichloromethane;
(4) removing fluorenylmethyloxycarbonyl of the compound 8, and then carrying out amidation condensation coupling reaction with 18- (tert-butoxy) -18 oxooctadecanoic acid to obtain a compound 11;
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 a plurality of solvents in any proportion selected from methanol, ethanol, ethyl acetate, dichloromethane, 1, 2-dichloroethane, DMF, DMSO, tetrahydrofuran, acetonitrile and N-methylpyrrolidone, preferably acetonitrile or methanol, more preferably acetonitrile;
the amidation condensation coupling reaction with 18- (tert-butoxy) -18 oxooctadecanoic acid is carried out under the action of a condensing agent selected from any single condensing agent or a complex 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 substances is 1: 0.5 to 2, preferably 1: 1; the solvent for condensation coupling 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 temperature of the condensation coupling reaction is 20-70 ℃, preferably 20-40 ℃, and more preferably 30 ℃;
(5) removal of R from Compound 112Protecting group, and then carrying out condensation coupling reaction with a compound 6 to obtain a compound 13;
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 condensation coupling reaction with compound 6 is carried out under the action of a condensing agent selected from any single or complex 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 solvent for the condensation coupling reaction 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 1, 2-dichloroethane or dichloromethane, more preferably dichloromethane; the temperature of the condensation coupling 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 advantages that: the convergent synthesis method is used for reducing the reaction cost and shortening the reaction time. The synthesis process is effective and controllable, has low cost and high yield, and is suitable for large-scale production. The use of flammable and expensive palladium on carbon reagents is avoided.
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 2 of the present invention.
FIG. 2 is a MS plot of Compound 1.
FIG. 3 is an infrared spectrum of Compound 1.
Detailed Description
The invention will be further illustrated with reference to specific examples, without restricting its scope.
Example 1
R1Preferably Trt, R2Preferably Bn
Example 1-1:
preparation of
Taking a 500mL round-bottom flask, dissolving 10mL diglycolamine 2(100mmol) in a dichloromethane solution, slowly adding 14mL triethylamine (1eq) dropwise at 0 ℃, stirring for 30min, slowly adding Trt-Cl (1.2eq) dropwise, removing an ice bath, and reacting at room temperature for 1 h. The solvent was distilled off under reduced pressure, the residue was redissolved with tetrahydrofuran, 28g of potassium carbonate were added under ice-bath, after stirring for 30min benzyl bromoacetate (1.5eq) was added dropwise, the ice-bath was removed, and the reaction was warmed to 50 ℃ and stirred overnight. The solvent was distilled off under reduced pressure, extracted twice with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. And carrying out reduced pressure distillation to obtain a target product. The yield thereof was found to be 90%.
Examples 1 to 2: preparation of compound 6.
The product was dissolved in dichloromethane and trifluoroacetic acid: dichloromethane (v: v) ═ 1:1, the reaction was monitored by TLC, and trifluoroacetic acid was distilled off under reduced pressure to give yellow oily liquid 6 for use.
Examples 1 to 3: preparation of compound 8.
A50 mL round-bottomed flask was charged with 3g of fluorenylmethoxycarbonyl-L-glutamic acid 1-tert-butyl ester (7mmol) using dichloro chlorideAfter methane was dissolved, 3.6mL of DIPEA, 1.6g of EDCI and 1.1g of HOBT were added, and the mixture was stirred for 30min, then Compound 6(1.1eq) was added to the reaction mixture, and the mixture was stirred at 30 ℃ and monitored by TLC. The solvent was removed by distillation under the reduced pressure, the residue was redissolved with ethyl acetate, extracted with 10% citric acid (50 mL. times.2) and saturated sodium bicarbonate solution (50 mL. times.2), washed with saturated brine, the organic layer was collected, 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 a yellow oil, 8. The yield thereof was found to be 82%.
Examples 1 to 4: preparation of Compound 9
3.3g of Compound 8 are dissolved in 22mL of acetonitrile solution, 11.6mL of diethylamine are added dropwise, stirred at room temperature for 2h and the reaction is monitored by TLC. Removing solvent by rotation, and purifying by column Chromatography (CH)2Cl2: MeOH 10:1) gave 9 as a yellow oil in 86% yield.
Examples 1 to 5: preparation of compound 11.
A50 mL round-bottomed flask was taken, 1.11g of 18- (tert-butoxy) -18 oxooctadecanoic acid was dissolved in dichloromethane, 1.5mL of DIPEA, 691mg of EDCI and 486mg of HOBT were added, respectively, and after stirring at 30 ℃ for 30min, 1.57g of Compound 9 was added, and the reaction was monitored by TLC. The solvent was distilled off under reduced pressure, and the residue was redissolved with ethyl acetate, extracted with 10% citric acid, saturated sodium bicarbonate solution, washed with saturated brine, and the organic layer was collected and dried over anhydrous sodium sulfate. Distilling under reduced pressure to remove solvent, and purifying by column Chromatography (CH)2Cl2: MeOH: 30:1) gave a yellow oily substance 11. The yield thereof was found to be 89%.
Examples 1 to 6: preparation of compound 12.
Taking a round-bottomed flask, dissolving 791g (1mmol) of compound 11 in 10mL of methanol solution, dropwise adding 4mL of 1mol/L aqueous LiOH solution to the reaction solution, stirring at room temperature for 2h, distilling off the solvent under reduced pressure, and purifying by column Chromatography (CH)2Cl2: MeOH: HCOOH ═ 30:1:1), compound 12 was obtained. The yield thereof was found to be 77%.
Examples 1 to 7: preparation of compound 13.
A25 mL round-bottomed flask was taken, the above compound 12(0.77mmol, 539mg) was dissolved in 5mL of dichloromethane, DIPEA (3eq, 0.4mL) and EDCI/HOBT (1.2eq) were added in this order, and after stirring for 30min, compound 6(1.2eq) was added and the reaction was monitored by TLC. After the reaction, the solvent was distilled off under reduced pressure, the residue was redissolved with ethyl acetate, extracted with 10% citric acid, saturated sodium bicarbonate solution, washed with saturated brine, 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 in a yield of 82%.
Examples 1 to 8: preparation of compound 1.
Taking a 25mL round-bottom flask, dissolving the compound 13 in 2mL MeOH, dropwise adding 1mol/L LiOH aqueous solution to the reaction solution, stirring at room temperature for 2h, removing the solvent by distillation under reduced pressure, and purifying by column Chromatography (CH)2Cl2: MeOH ═ 5:1) to give final product 1. The yield thereof was found to be 90%.
Example 2:
the specific experimental route can be seen in FIG. 1
R1Preferably Boc, R2Preferably Bn.
Example 2-1: preparation of compound 4.
The preparation method comprises the following steps: taking a 250mL round-bottom flask, dissolving 10mL of 2- (2-aminoethoxy) ethanol in 150mL of ethanol, slowly dropwise adding 23mL of di-tert-butyl dicarbonate under an ice bath condition, removing the ice bath after dropwise adding is finished, reacting for 2h at room temperature, and removing the ethanol solvent by reduced pressure distillation; the residue was redissolved with THF, NaH (1.2-1.5eq) was added while maintaining the temperature at 0-10 deg.C, the mixture was stirred for 30min, 16.6mL of ethyl bromoacetate 3 was slowly added dropwise to the reaction mixture, the mixture was stirred at room temperature overnight, and the reaction was monitored by TLC. MeOH was added to the reaction, and MeOH: THF (v: v) ═ 1:1, 8g of NaOH was weighed into the reaction solution, and the reaction was refluxed for 2 hours. And (3) distilling under reduced pressure to remove the solvent, re-dissolving the residue with water, extracting with ethyl acetate twice, collecting a water layer, adjusting the pH value to 1-3, extracting with ethyl acetate twice, collecting an organic layer, and distilling under reduced pressure to obtain a yellow oily liquid 4. The yield thereof was found to be 82%.
Example 2-2: preparation of compound 6.
(1) Under the ice-bath condition, benzyl chloroformate 5(100mmol, 12) is slowly dropped into a dichloromethane (100mL) solution of the above raw material 4(1-1.2eq) and triethylamine (1-1.2eq)9mL) was stirred for 5min, DMAP (0.1-0.3eq) was added to the reaction mixture, the mixture was reacted at room temperature overnight, and the reaction was monitored by TLC (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. The solvent was distilled off under reduced pressure to obtain a colorless oily liquid. The yield thereof was found to be 63%.
(2) The above colorless oily liquid was dissolved in a dichloromethane solution using trifluoroacetic acid: dichloromethane (v: v) ═ 1:1 was deprotected, and trifluoroacetic acid was distilled off under reduced pressure to give yellow oily liquid 6 for use.
The subsequent procedure for the preparation of the final product 1 was the same as in example 1.
The above specific embodiments are intended 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 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 for synthesizing a side chain 1 of Somalutide, which comprises the following steps:
(1) the amino end group of the raw material diglycolamine 2 is R1Protecting, then carrying out nucleophilic substitution reaction with α halogenated ester, and preparing a compound 4 by ester hydrolysis in one pot;
(2) r for free carboxyl group of compound 42Protection and removal of R1Protecting group to give compound 6;
(3) condensation reaction of fluorenylmethyloxycarbonyl-L-glutamic acid 1-tert-butyl ester 7 and a compound 6 to obtain a compound 8;
(4) removing fluorenylmethyloxycarbonyl of the compound 8, and then carrying out amidation condensation coupling reaction with 18- (tert-butoxy) -18 oxooctadecanoic acid to obtain a compound 11;
(5) removal of R from Compound 112Protecting group, and then carrying out condensation coupling reaction with a compound 6 to obtain a compound 13;
(6) removal of R from Compound 132Protecting groups to obtain a target product chain 1;
2. the method for synthesizing the somaglutide side chain 1 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;
the α halogenated ester is ethyl bromoacetate or benzyl bromoacetate, and the reaction solvent used for nucleophilic substitution reaction with α halogenated ester 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;
ester hydrolysis is carried out under the action of inorganic base, wherein the inorganic base is one or a mixture of more of sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, calcium hydroxide and barium hydroxide in any proportion; the mass ratio of the inorganic base to the diglycolamine 2 is 0.5-4: 1.
3. the method for synthesizing the somaglutide side chain 1 of claim 1, wherein in step (2), R is2Bn, Pfp, Me, Allyl, t-Bu, PMB, MEM or TBS;
removal of R1The protecting group is carried out under the action of an acid reagent, wherein the acid reagent is hydrochloric acid, acetic acid or trifluoroacetic acid; removal of R1The 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.
4. The method for synthesizing the somaglutide side chain 1 of claim 1 wherein in step (3) the condensation reaction is performed by 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; the temperature of the condensation reaction is 20-70 ℃; the solvent for the 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.
5. The method for synthesizing the somaglutide side chain 1 according to claim 1, wherein in the step (4), the removal of the fluorenylmethyloxycarbonyl group is performed under the action of an organic base, wherein the organic base is 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;
carrying out amidation condensation coupling reaction with 18- (tert-butoxy) -18 oxooctadecanoic acid 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 solvent for condensation coupling reaction is selected from one or more of methanol, ethanol, ethyl acetate, dichloromethane, 1, 2-dichloroethane, DMF, DMSO, tetrahydrofuran, acetonitrile and N-methylpyrrolidone in any proportion; the temperature of the condensation coupling reaction is 20-70 ℃.
6. The method for synthesizing the somaglutide side chain 1 of claim 1, wherein in step (5), 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 by 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;
the condensation coupling reaction with the compound 6 is carried out under the action of a condensing agent, wherein the condensing agent is any single condensing agent or a composite condensing agent selected from DIC, DCC, HBTU, PyBOP, BOP, HATU, TBTU, DIC/HOBT, DCC/DMAP, EDCI/HOBT and HATU/HOBT; the solvent of the condensation coupling reaction is one or a mixture of several solvents in any proportion selected from methanol, ethanol, ethyl acetate, dichloromethane, 1, 2-dichloroethane, DMF, DMSO, tetrahydrofuran, acetonitrile and N-methylpyrrolidone; the temperature of the condensation coupling reaction is 20-70 ℃.
7. The method for synthesizing the somaglutide side chain 1 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 the group consisting of potassium hydroxide, barium hydroxide, calcium hydroxide, and calcium hydroxideAluminum, 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.
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