CN103275209A - Liraglutide preparation method - Google Patents
Liraglutide preparation method Download PDFInfo
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Abstract
The invention belongs to the technical field of polypeptide medicament preparation methods, particularly relates to a liraglutide preparation method, and aims to solve the technical problems of complex operation process, high purification difficulty of a crude product and low product yield in the existing method. The technical scheme for solving the technical problems is as follows: the liraglutide preparation method comprises the following steps: performing coupling reaction on an N-protected GLP1(7-37) peptide segment and N-alpha-PAL-gamma-Glu(OtBu)-ONSu under the action of alkali to obtain a liraglutide-protected peptide, removing the N-protection, and performing acidolysis to obtain a liraglutide crude product; and purifying to obtain a liraglutide pure product, wherein the sequence of the used GLP1(7-37) peptide segment is as follows: R-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-OH; and R is Fmoc, Dde or ivDde. The new liraglutide preparation method provided by the invention has the advantages that the method is simple to operate, the crude product is easy to purify and the product is high in yield.
Description
Technical field
The invention belongs to polypeptide drugs preparation method technical field, particularly prepare the method for Li Lalu peptide.
Background technology
The Li Lalu peptide has following structure:
His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-
Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys(N
α-PAL-γ-Glu)-
Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-OH。
The Li Lalu peptide is a kind of GLP-1(glucagon-like peptide) analogue, have 97% sequence homology with people GLP-1, people GLP-1 can in conjunction with and activate the GLP-1 acceptor.The GLP-1 acceptor is the target spot of natural GLP-1, and GLP-1 is a kind of endogenous incretin hormone, can promote pancreatic beta cell glucose concn dependency ground excreting insulin.Different with big right GLP-1 is, pharmacokinetics and the pharmacodynamic characteristics of Li Lalu peptide in human body all is fit to once a day dosage regimen.After the subcutaneous injection administration, the mechanism that prolong its action time comprises: make to absorb the self association that slows down; With albumin bound; DPP IV (DPP-IV) and neutral endopeptidase (NEP) are had higher enzyme stability, thereby have long plasma half-life.
The activity of Li Lalu peptide causes the increase of cyclic monophosphate (cAMP) by the specific mediation that interacts between itself and GLP-1 acceptor.The Li Lalu peptide can be with the pattern stimuli secretion of insulin of glucose concn dependence, and the pattern that relies on glucose concn reduces the secretion of too high glicentin simultaneously.Therefore, when blood sugar increasing, insulin secretion is upset, and glicentin secretion simultaneously is suppressed.In contrast, the Li Lalu peptide can reduce insulin secretion when hypoglycemia, and does not influence the secretion of glicentin.The hypoglycemic mechanism of Li Lalu peptide also comprises the mild prolonged gastric emptying time.The Li Lalu peptide can be taken in reduction body weight and BFM by alleviating hunger sensation and energy.
The acting duration of Li Lalu peptide is 24 hours, can improve glycemic control by empty stomach and the postprandial blood sugar that reduces the diabetes B patient.In the diabetes B patient, single gives the Li Lalu peptide can observe the pattern increase that insulin secretion rate relies on glucose concn.
The specific absorption of Li Lalu peptide after subcutaneous injection is slower, reaches peak concentration after administration in 8-12 hour.After the single subcutaneous injection Li Lalu peptide 0.6mg, the peak concentration estimated value of Li Lalu peptide is 9.4nmol/L.Under the Li Lalu of 1.8mg peptide dosage level, the average steady state concentration (AUC1/24) of Li Lalu peptide reaches about 34nmol/L.The degree of exposure of Li Lalu peptide is with the proportional increase of dosage.Single gives Li Lalu peptide, and (the intraindividual variation coefficient of (AUC) is 11% to area under the drug-time curve.Absolute bioavailability after the subcutaneous injection of Li Lalu peptide is about 55%.Apparent volume of distribution after the distribution subcutaneous injection is 11-17L.The Li Lalu peptide volume that is evenly distributed after the arteries and veins injection silently is 0.07L/kg.The Li Lalu peptide can with plasma proteins broad incorporation (〉 98%).
This product is used for adult's diabetes B patient and controls blood sugar: be applicable to and singly still control not good patient with N1,N1-Dimethylbiguanide or the maximum tolerable dose treatment of sulfonylurea drugs back blood sugar, with N1,N1-Dimethylbiguanide or sulfonylurea drugs combined utilization.
Report about Li Lalu peptide preparation report is a lot of both at home and abroad, provide a kind of solid-phase synthesis as Chinese patent CN201110271342.3, be starting raw material with the Wang resin, amino acid with the Fmoc protection is monomer, connect amino acid successively one by one and obtain linear Li Lalu peptide resin, adopt the TFA cracking to obtain crude product, adopt the reversed-phased high performace liquid chromatographic purifying at last, obtain the Li Lalu peptide, not regulation+Gly and-Gly impurity; Chinese patent 201210369966.3 adopts the synthetic preparation method of fragment.
Above-mentioned preparation method has the following disadvantages, in preparation Li Lalu peptide process, because Gly constructional feature, when inserting Gly Gly of multiple access can take place or miss the side reaction of a Gly, so can produce [+1Gly]-Li Lalu peptide and [1Gly]-Li Lalu peptide impurity when inserting Gly, thereby reduce crude product purity, these impurity polarity and Li Lalu peptide are very approaching, increase the purifying crude difficulty, reduced product yield.
Summary of the invention
The technical problem to be solved in the present invention is that existing method complex operation, crude product are difficult for purifying, product yield is low.
The technical scheme that the present invention solves the problems of the technologies described above provides a kind of method of the Li Lalu of preparation peptide, comprising: GLP1 (7-37) the peptide section of N end protection under the effect of alkali with N
αLinked reaction takes place in-PAL-γ-Glu (OtBu)-ONSu, obtains Li Lalu peptide protection peptide; Li Lalu peptide protection peptide obtains Li Lalu peptide crude product after going the protection of N end after acidolysis; Li Lalu peptide purifying crude is got profit and is drawn the pure product of Shandong peptide; Described GLP1 (7-37) peptide section sequence is:
R-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-
Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-
Leu-Val-Arg-Gly-Arg-Gly-OH；
Wherein R is Fmoc, Dde or ivDde.
In the above-mentioned method for preparing the Li Lalu peptide, described alkali is NaOH, Na
2CO
3, ammoniacal liquor, monoethylamine, a kind of in diethylamine, triethylamine, azanol, diisopropyl ethyl amine or the piperidines; Preferred alkali is diisopropyl ethyl amine.
In the above-mentioned method for preparing the Li Lalu peptide, be 10～11 with the pH value of alkali control reaction soln.
In the above-mentioned method for preparing the Li Lalu peptide, described N
αThe consumption of-PAL-γ-Glu (OtBu)-ONSu is 1.5～6 times of GLP1 (7-37) peptide section total mole number; Be preferably 2.5～3.5 times.
In the above-mentioned method for preparing the Li Lalu peptide, the time of described linked reaction is 20～240 minutes; Preferably 60～90 minutes.
Preferably, Li Lalu peptide protection peptide goes the protection of N end to obtain Li Lalu peptide crude product by acidolysis:
His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-
Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys(N
α-PAL-γ-Glu)-
Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-OH。
Further preferred, the acidolysis agent that described Li Lalu peptide adopts when protecting the peptide acidolysis is the mixed solvent of trifluoracetic acid (TFA) and water, and the volume proportion of mixed solvent is: 85～100% TFA, surplus is water.Preferably, the volume proportion of described mixed solvent is: 90～98% TFA, surplus is water.Optimum, the volume proportion of described mixed solvent is: 95% TFA, surplus is water.
Further preferred, the consumption of described acidolysis agent is that every Ke Lilalu peptide protection peptide needs 4～15mL acidolysis agent; Preferably, every Ke Lilalu peptide protection peptide needs 9～11mL acidolysis agent.
Further preferred, the described time of using acidolysis is under the room temperature condition 1～6 hour; Preferably 2～4 hours.
Further, Li Lalu peptide crude product obtains the pure product of Li Lalu peptide through high-efficient liquid phase chromatogram purification, freeze-drying.
The invention provides a kind of GLP1 (7-37) peptide section of protection of having used and be the method for feedstock production Li Lalu peptide; that this method has is simple to operate, because to have adopted purified GLP1 (7-37) peptide section be raw material; prepared crude product purity is greater than more than 90%; and the crude product purity that obtains according to a conventional method is generally about 50%; so the crude product that the inventive method obtains is easy to purifying, the product yield height.Compared with the prior art, technology of the present invention has more practical value and application prospect widely.
Embodiment
The corresponding Chinese of the english abbreviation that relates among the present invention is shown in Table 1:
Table 1
Prepare the method for Li Lalu peptide, may further comprise the steps:
GLP1 (7-37) the peptide section of a, N end protection under the alkali effect with N
αLinked reaction takes place and obtains Li Lalu peptide protection peptide in-PAL-γ-Glu (OtBu)-ONSu;
After b, Li Lalu peptide protection peptide are sloughed the protection of N end, after acidolysis, obtain Li Lalu peptide crude product;
C, high performance liquid chromatography are carried out purifying and are got profit and draw the pure product of Shandong peptide;
Described GLP1 (7-37) peptide section sequence is:
R-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-
Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-
Leu-Val-Arg-Gly-Arg-Gly-OH；
Wherein R is Fmoc, Dde or ivDde.
In the above-mentioned method for preparing the Li Lalu peptide, the described alkali of step a is NaOH, Na
2CO
3, ammoniacal liquor, monoethylamine, a kind of in diethylamine, triethylamine, azanol, diisopropyl ethyl amine or the piperidines; Preferred alkali is diisopropyl ethyl amine.
In the above-mentioned method for preparing the Li Lalu peptide, be 10～11 with the pH value of alkali control reaction soln.
In the above-mentioned method for preparing the Li Lalu peptide, the described N of step a
αThe consumption of-PAL-γ-Glu (OtBu)-ONSu is 1.5～6 times of GLP1 (7-37) peptide section total mole number; Be preferably 2.5～3.5 times.
In the above-mentioned method for preparing the Li Lalu peptide, the time of the described linked reaction of step a is 20～240 minutes; Preferably 60～90 minutes.
In the above-mentioned method for preparing the Li Lalu peptide, after the described linked reaction of step a finishes, add excess of ammonia base acid termination reaction.Described amino acid is preferably glycine.
In the above-mentioned method for preparing the Li Lalu peptide, Li Lalu peptide protection peptide goes the protection of N end to obtain Li Lalu peptide crude product by acidolysis among the step b:
His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-
Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys(N
α-PAL-γ-Glu)-
Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-OH。
In the above-mentioned method for preparing the Li Lalu peptide, the N end protection reagent of sloughing described in the step b is general Fmoc, Dde or the ivDde reagent of going.
In the above-mentioned method for preparing the Li Lalu peptide, the acidolysis agent of adopting during the acidolysis of the described Li Lalu peptide protection of step b peptide is the mixed solvent of trifluoracetic acid (TFA) and water, and the volume proportion of mixed solvent is: 85～100% TFA, surplus is water.Preferably, the volume proportion of described mixed solvent is: 90～98% TFA, surplus is water.Optimum, the volume proportion of described mixed solvent is: 95% TFA, surplus is water.
In the above-mentioned method for preparing the Li Lalu peptide, the consumption of the described acidolysis agent of step b is that every Ke Lilalu peptide protection peptide needs 4～15mL acidolysis agent; Preferably, every Ke Lilalu peptide protection peptide needs 9～11mL acidolysis agent.
In the above-mentioned method for preparing the Li Lalu peptide, the time of step b acidolysis is under the room temperature condition 1～6 hour; Preferably 2～4 hours.
In the above-mentioned method for preparing the Li Lalu peptide, the described Li Lalu peptide of step c crude product obtains the pure product of Li Lalu peptide through high-efficient liquid phase chromatogram purification, freeze-drying, and concrete grammar is:
Get Li Lalu peptide crude product, add water and stir, transfer pH8.5 to dissolving fully with ammoniacal liquor, solution is equipped with purifying and uses with 0.45 μ m mixing filtering with microporous membrane;
Adopt high performance liquid chromatography to carry out purifying, the purifying chromatograph packing material is the anti-phase C18 of 10 μ m, flow phase system is the 0.1%TFA/ aqueous solution-0.1%TFA/ acetonitrile solution, the chromatographic column flow velocity of 77mm*250mm is 90mL/min, adopts the gradient system wash-out, circulation sample introduction purifying, getting crude product solution is splined in the chromatographic column, start the moving phase wash-out, after the collection main peak boils off acetonitrile, get profit and draw Shandong peptide purification intermediate concentrated solution;
Get Li Lalu peptide purification intermediate concentrated solution, filter standby with 0.45 μ m filter membrane;
Adopt high performance liquid chromatography to change salt, flow phase system is the 1% acetic acid/aqueous solution-acetonitrile, the purifying chromatograph packing material is the anti-phase C18 of 10 μ m, and the chromatographic column flow velocity of 77mm*250mm is 90mL/min (can adjust corresponding flow velocity according to the chromatographic column of different size).Adopt gradient elution, quadrat method in the circulation is splined in the chromatographic column, starts the moving phase wash-out, gather collection of illustrative plates, the variation of observation optical density is collected and is changed the salt main peak and change salt main peak solution with analyzing Liquid Detection purity, merging, concentrating under reduced pressure, obtain Li Lalu peptide aqueous acetic acid, lyophilize is got profit and is drawn the pure product of Shandong peptide.
Synthesizing of embodiment 1 Li Lalu peptide protection peptide
GLP1 (7-37) peptide section sequence is:
R-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-
Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-
Leu-Val-Arg-Gly-Arg-Gly-OH；
Wherein R is Fmoc.
Get 3.6g GLP1 (7-37), the acetonitrile solution dissolving with 50% is transferred pH10.5 with DIEA, stirs to drip down to contain 1.6gN
αThe acetonitrile solution of-PAL-γ-Glu (OtBu)-ONSu keeps pH10.5 with DIEA simultaneously, and stirring reaction 1.5 hours adds 50% the acetonitrile solution contain 0.6g Gly, continues stirring reaction 0.5 hour, pressure reducing and steaming acetonitrile, the centrifugal N that goes
a-Pal-Glu-(ONSu)-OtBu transfers pH5.0, gets profit and draws Shandong peptide protection peptide.
The preparation of embodiment 2 Li Lalu peptide crude products
Get the Li Lalu peptide protection peptide that embodiment 1 makes; earlier with containing 25%(V) the DMF(10mL/g Li Lalu peptide protection peptide of piperidines) solution-treated 25 minutes; the gained solid is joined in the lytic reagent that volume ratio is TFA ︰ water=95 ︰ 5 (lytic reagent 10mL/g resin); stir; stirring at room reaction 3 hours; reaction mixture uses sand core funnel to filter; collect filtrate; resin is again with a small amount of TFA washing 3 times; concentrating under reduced pressure behind the merging filtrate adds the anhydrous diethyl ether precipitation, washes precipitation 3 times with anhydrous diethyl ether again; drain to such an extent that off-white powder is Li Lalu peptide crude product, crude product purity is 92.3%.
The purifying of embodiment 3 Li Lalu peptide crude products
Get the Li Lalu peptide crude product that embodiment 2 makes, add water and stir, transfer pH8.5 to dissolving fully with ammoniacal liquor, solution is equipped with purifying and uses with 0.45 μ m mixing filtering with microporous membrane.Adopt high performance liquid chromatography to carry out purifying, the purifying chromatograph packing material is the anti-phase C18 of 10 μ m, flow phase system is the 0.1%TFA/ aqueous solution-0.1%TFA/ acetonitrile solution, the chromatographic column flow velocity of 77mm*250mm is 90mL/min, adopts the gradient system wash-out, circulation sample introduction purifying, getting crude product solution is splined in the chromatographic column, start the moving phase wash-out, after the collection main peak boils off acetonitrile, get profit and draw Shandong peptide purification intermediate concentrated solution.
Get Li Lalu peptide purification intermediate concentrated solution, filter standby with 0.45 μ m filter membrane.Adopt high performance liquid chromatography to change salt, flow phase system is the 1% acetic acid/aqueous solution-acetonitrile, the purifying chromatograph packing material is the anti-phase C18 of 10 μ m, and the chromatographic column flow velocity of 77mm*250mm is 90mL/min (can adjust corresponding flow velocity according to the chromatographic column of different size).Adopt gradient elution, quadrat method in the circulation is splined in the chromatographic column, start the moving phase wash-out, gather collection of illustrative plates, the variation of observation optical density is collected and is changed the salt main peak also with analyzing Liquid Detection purity, merge and change salt main peak solution, concentrating under reduced pressure obtains Li Lalu peptide aqueous acetic acid, lyophilize, get product 2.52g, total recovery is 67.2%.
Molecular weight: 3749.8 (100%M+H); Purity: 99.2%; Maximum single impurity 0.2%.
Above-described embodiment shows that method provided by the invention is simple to operate, and crude product is easy to purifying, the product yield height, and products obtained therefrom purity has practical value and application prospect widely greater than 99.0%.
Claims (9)
1. prepare the method for Li Lalu peptide, comprising: GLP1 (7-37) the peptide section of N end protection under the effect of alkali with N
αLinked reaction takes place in-PAL-γ-Glu (OtBu)-ONSu, obtains Li Lalu peptide protection peptide; Li Lalu peptide protection peptide obtains Li Lalu peptide crude product after going the protection of N end after acidolysis; Li Lalu peptide purifying crude is got profit and is drawn the pure product of Shandong peptide; Described GLP1 (7-37) peptide section sequence is:
R-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-
Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-
Leu-Val-Arg-Gly-Arg-Gly-OH；
Wherein R is Fmoc, Dde or ivDde.
2. the method for preparing the Li Lalu peptide according to claim 1, it is characterized in that: described alkali is NaOH, Na
2CO
3, ammoniacal liquor, monoethylamine, a kind of in diethylamine, triethylamine, azanol, diisopropyl ethyl amine or the piperidines; Preferred alkali is diisopropyl ethyl amine.
3. the method for preparing the Li Lalu peptide according to claim 2 is characterized in that: the pH value with alkali control reaction soln is 10～11.
4. the method for preparing the Li Lalu peptide according to claim 1 is characterized in that: described N
αThe consumption of-PAL-γ-Glu (OtBu)-ONSu is 1.5～6 times of GLP1 (7-37) peptide section total mole number; Be preferably 2.5～3.5 times.
5. the method for preparing the Li Lalu peptide according to claim 1, it is characterized in that: the time of described linked reaction is 20～240 minutes; Preferably 60～90 minutes.
6. the method for preparing the Li Lalu peptide according to claim 1 is characterized in that: Li Lalu peptide protection peptide goes the protection of N end to obtain Li Lalu peptide crude product by acidolysis:
His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-
Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys(N
α-PAL-γ-Glu)-
Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-OH。
7. the method for preparing the Li Lalu peptide according to claim 6 is characterized in that: the acidolysis agent of adopting during described Li Lalu peptide protection peptide acidolysis is the mixed solvent of trifluoracetic acid and water; Wherein, the volume proportion of mixed solvent is: 85～100% TFA, and surplus is water; Preferably, the volume proportion of described mixed solvent is: 80～100% TFA, and surplus is water; Optimum, the volume proportion of described mixed solvent is: 95% TFA, surplus is water.
8. the method for preparing the Li Lalu peptide according to claim 7 is characterized in that: the consumption of described acidolysis agent is every Ke Lilalu peptide protection peptide needs 4～15mL acidolysis agent; Preferably, every Ke Lilalu peptide protection peptide needs 6～8mL acidolysis agent.
9. the method for preparing the Li Lalu peptide according to claim 6 is characterized in that: the time of acidolysis is under the room temperature condition 1～6 hour; Preferably 2～4 hours.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017381A (en) * | 2015-07-20 | 2015-11-04 | 吉尔生化（上海）有限公司 | Purification method of liraglutide |
| CN105111303A (en) * | 2015-06-23 | 2015-12-02 | 济南康和医药科技有限公司 | Solid-liquid combined preparation method for liraglutide |
| WO2017162650A1 (en) | 2016-03-23 | 2017-09-28 | Bachem Holding Ag | Method for preparing glucagon-like peptides |
| CN109438569A (en) * | 2018-09-28 | 2019-03-08 | 苏州纳微科技股份有限公司 | A kind of process for separation and purification of Liraglutide |
| WO2021017793A1 (en) * | 2019-07-27 | 2021-02-04 | 深圳市健元医药科技有限公司 | Method for preparing chemically synthesized acidic polypeptide |
| CN114031681A (en) * | 2022-01-11 | 2022-02-11 | 浙江湃肽生物有限公司深圳分公司 | Liraglutide analogue and preparation method thereof |
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| US20010011071A1 (en) * | 1996-08-30 | 2001-08-02 | Liselotte Bjerre Knudsen | Derivatives of glp-1 analogs |
| CN102408471A (en) * | 2011-06-23 | 2012-04-11 | 成都圣诺科技发展有限公司 | Preparation method of Terlipressin |
| CN102875665A (en) * | 2012-09-28 | 2013-01-16 | 深圳翰宇药业股份有限公司 | Method for synthesizing liraglutide |
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| US20010011071A1 (en) * | 1996-08-30 | 2001-08-02 | Liselotte Bjerre Knudsen | Derivatives of glp-1 analogs |
| CN102408471A (en) * | 2011-06-23 | 2012-04-11 | 成都圣诺科技发展有限公司 | Preparation method of Terlipressin |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105111303A (en) * | 2015-06-23 | 2015-12-02 | 济南康和医药科技有限公司 | Solid-liquid combined preparation method for liraglutide |
| CN105111303B (en) * | 2015-06-23 | 2019-07-26 | 济南康和医药科技有限公司 | A kind of method that solid-liquid combination prepares Liraglutide |
| CN105017381A (en) * | 2015-07-20 | 2015-11-04 | 吉尔生化（上海）有限公司 | Purification method of liraglutide |
| WO2017162650A1 (en) | 2016-03-23 | 2017-09-28 | Bachem Holding Ag | Method for preparing glucagon-like peptides |
| US11117946B2 (en) | 2016-03-23 | 2021-09-14 | Bachem Holding Ag | Method for preparing glucagon-like peptides |
| CN109438569A (en) * | 2018-09-28 | 2019-03-08 | 苏州纳微科技股份有限公司 | A kind of process for separation and purification of Liraglutide |
| WO2021017793A1 (en) * | 2019-07-27 | 2021-02-04 | 深圳市健元医药科技有限公司 | Method for preparing chemically synthesized acidic polypeptide |
| CN114031681A (en) * | 2022-01-11 | 2022-02-11 | 浙江湃肽生物有限公司深圳分公司 | Liraglutide analogue and preparation method thereof |
| CN114031681B (en) * | 2022-01-11 | 2022-04-12 | 浙江湃肽生物有限公司深圳分公司 | Liraglutide analogue and preparation method thereof |
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Application publication date: 20130904 |