CN113461800A - Synthesis method of liraglutide - Google Patents
Synthesis method of liraglutide Download PDFInfo
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- CN113461800A CN113461800A CN202010241108.5A CN202010241108A CN113461800A CN 113461800 A CN113461800 A CN 113461800A CN 202010241108 A CN202010241108 A CN 202010241108A CN 113461800 A CN113461800 A CN 113461800A
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Abstract
The invention provides a synthesis method of liraglutide, which comprises the steps of synthesizing three fragments through a solid phase, synthesizing two dipeptide fragments through a liquid phase, sequentially coupling each fragment and other raw materials in a solution system to obtain an N-Tfa protected liraglutide intermediate, and purifying to obtain an intermediate pure product; and after the palmitic acid is modified, removing the Tfa protecting group under the alkaline condition, and purifying and exchanging salts to obtain the required liraglutide. The method solves the problems of long synthesis period, high cost, low yield and difficult impurity removal of the existing synthesis method.
Description
Technical Field
The invention relates to chemical synthesis of medicinal polypeptide raw material medicines, in particular to a synthesis method of liraglutide.
Background
Compared with the natural GLP-1 molecular structure, the liraglutide has an amino acid difference, a 16-carbon palmitoyl fatty acid side chain is added, the liraglutide has 97 percent homology with the natural human GLP-1, and the difference from the natural GLP-1 is that the pharmacokinetic and pharmacodynamic characteristics of the liraglutide in a human body are both suitable for once-a-day administration schemes. Mechanisms for prolonging the duration of action following subcutaneous administration include: the self-association effect which slows absorption, binds to albumin, and has higher enzyme stability to dipeptidyl peptidase IV (DPP-IV) and Neutral Endopeptidase (NEP), thereby having longer plasma half-life.
The chemical formula of the liraglutide is C172H265N43O51The relative molecular mass is 3751.20, the CAS number is 204656-20-2, and the sequence is as follows:
NH2- (L-histidine-L-allyl-L-casein-L- α -aspartic-L-casein-L-lysine. The chemical structural formula is as follows:
aiming at the defects that the existing method for synthesizing liraglutide has more synthesis steps, long synthesis period, and simultaneously has low purity and yield and is not suitable for industrial scale production, the synthesis method which has high yield and is suitable for industrial scale production is urgently needed to be provided.
Disclosure of Invention
In order to solve the defects of the prior art, the invention provides a synthesis method of liraglutide.
The purpose of the invention is realized by the following technical scheme:
a synthesis method of liraglutide comprises the steps of synthesizing three fragments through a solid phase, synthesizing two dipeptide fragments through a liquid phase, sequentially coupling each fragment and other raw materials in a solution system to obtain an N-Tfa protected liraglutide intermediate, and purifying to obtain an intermediate pure product; and after the palmitic acid is modified, removing the Tfa protecting group under the alkaline condition, and purifying and exchanging salts to obtain the required liraglutide.
The synthesis process is as follows:
preferably, the three fragments of the solid phase synthesis are: polypeptide fragment a: NH (NH)2- (27-37AA) -Wang Resin, (27-37AA) comprising sequence EFIAWLVRGRG; fully protected peptide fragment B: Fmoc-NH (16-22AA) -OH, wherein 16-22AA comprises the sequence VSSYLEG; fully protected peptide fragment C: N-Tfa- (7-10AA) -OH, wherein 7-10AA comprises the sequence HAEG.
Preferably, the two dipeptide fragments synthesized in liquid phase are respectively: dipeptide fragment a: Fmoc-Lys (N-epsilon- (gamma-Glu (N-alpha-Boc) -OtBu) -OH; dipeptide fragment b Fmoc-NH- (24-25AA) -OH, wherein 24-25AA comprises the sequence AA and is Fmoc-Ala-Ala-OH.
Preferably, the synthesis of the N-Tfa protected liraglutide intermediate in the synthetic method comprises the following steps,
the polypeptide fragment A is firstly placed in a reaction column, and the dipeptide fragment a, the dipeptide fragment b, Fmoc-Gln (Trt) -OH, the polypeptide fragment B, Fmoc-Asp (OtBu) -OH, Fmoc-Ser (tBu) -OH, Fmoc-Thr (tBu) -OH, Fmoc-Phe-OH, Fmoc-Thr (tBu) -OH and the polypeptide fragment C are coupled in sequence according to the SPPS method and sequence, and a crude N-Tfa- (7-37AA) product, namely a liraglutide intermediate with N-Tfa protection, is obtained through cleavage.
Preferably, the liraglutide intermediate with N-Tfa protection is purified by dissolving the liraglutide intermediate with N-Tfa protection in a mixed solution of 10% acetonitrile and water, shaking for dissolution, and filtering for later use; purification by HPLC.
Preferably, the HPLC conditions employ: the mobile phase was a 0.1% TFA/water-0.1% TFA/acetonitrile system, loading 5.0 g/time, flow rate 300ml/min, gradient elution.
Preferably, the purified intermediate X is added into a three-mouth reaction bottle, 10% acetonitrile/water solution is added and stirred for dissolution, and 10% Na is slowly dripped into the three-mouth reaction bottle under the ice water bath2 CO3Mixing the solution with the aqueous solution mixed solution, adjusting the pH of the solution to 8, and stopping dripping;
dropwise adding a THF solution of Pal-OSu in an ice water bath, reacting at room temperature, adding glycine, and monitoring the reaction end point by HPLC; adding piperidine into the reaction solution under the condition of vigorous stirring, continuously stirring at room temperature, monitoring the alkaline hydrolysis end point by using HPLC (high performance liquid chromatography), stopping stirring after the reaction is finished, filtering insoluble substances, and washing the insoluble substances by using purified water; the removal of the Tfa protecting group is completed.
Preferably, the synthesis method further comprises a purification step of the liraglutide, which comprises combining the washing solution and the filtrate, diluting the peptide solution with 0.5% acetic acid aqueous solution until the pH value is reduced to 5, filtering the solution through a filter membrane, and purifying the solution through HPLC, wherein the HPLC condition is that; the mobile phase is a 20mM ammonium acetate water solution-acetonitrile system, the sample loading amount is 3.0 g/time, the flow rate is 300ml/min, and gradient elution is carried out; and (3) circularly injecting samples before and after peaks, intercepting a refined peptide solution with the central control analysis purity of more than 99.5 percent and the single impurity of less than 0.1 percent, desalting, concentrating and freeze-drying to obtain the liraglutide with the purity of more than 99.0 percent.
The invention has the beneficial effects that: solves the problems of long synthesis period, high cost, low yield and difficult impurity removal of the existing synthesis method.
Detailed Description
The technical scheme of the invention is specifically described in the following by combining with an embodiment, and the invention discloses a synthesis method of liraglutide. The synthesis process is as follows:
weighing 10g of queen resin with substitution degree of 1.0mmol/g, adding the queen resin into a solid phase reaction column, washing the queen resin with DMF for 2 times, swelling the resin with DCM for 30 minutes, weighing 5.94g of Fmoc-Gly-OH, 2.97g of HOBt and 0.21g of DMAP, dissolving the mixture with DMF, adding 3.42mL of DIC under ice-water bath, adding the mixture into the reaction column filled with resin, reacting for 3 hours, adding 10mL of pyridine and 12mL of acetic anhydride, and blocking for 6 hours. After 5 times of washing with DMF, 11.3g of Fmoc-Gly-Wang resin was obtained, and the detection substitution degree was 0.32 mmol/g. Sequentially coupling to 27 amino acid according to the SPPS method and sequence, removing Fmoc protecting group, and drying to obtain NH2- (27-37AA) -Wang resin (13.5g, 3.6mmol), designated polypeptide fragment A. Wherein 27-37AA comprises the sequence EFIAWLVRGRG.
Fmoc-Lys (Boc) -OH (50.0mmol) was dissolved in TFA/CH2Cl2(1: 1; 400ml) in a chamberStirred at room temperature for 2 hours. After TFA evaporation and ether extraction, 17.9g of Fmoc-Lys-OH was obtained as a white powder with a purity of > 99%. Rf＝0.5(CHCl2MeOH/AcOH, 6:3:1) or HPLC monitoring.
Boc-Glu-OtBu (27g, 90mmol), N-hydroxysuccinimide (11g, 91mmol) and dicyclohexylcarbodiimide (19g, 91.5mmol) were dissolved in 500ml THF and 0.9mmol DMAP was added to the reaction mixture from syringe. Stirring was maintained at room temperature for 24 hours. The mixture was filtered and the precipitate was washed with 3X 20ml of diethyl ether. The filtrate was concentrated and dried under high vacuum to give Boc-Glu (osu) -OtBu 35.8g as a white crystalline product with a purity of > 99%.
Fmoc-Lys-OH 11.0g (20mmol) was accurately weighed and dissolved in 300mL water (using Na)2CO3Adjusting pH to 8-8.5), stirring to clarify. Slowly adding THF solution (8.0g, 20mmol) of Boc-Glu (OSu) -OtBu into 100ml of THF at low temperature (2-8 ℃), stirring for reaction, monitoring the reaction end by TLC, after the reaction is completed, performing rotary evaporation to remove THF, adding 10% citric acid aqueous solution into ice water bath to adjust the pH value of the solution to 3, extracting 3 times by 100ml of ethyl acetate, combining organic phases, washing 3 times by 100ml of saturated saline, drying by anhydrous sodium sulfate, performing rotary evaporation and concentration to obtain solid Fmoc-Lys (N-epsilon- (gamma-Glu (N-alpha-Boc) -OtBu) -OH 15.2g with the purity of 98.6 percent, and naming the dipeptide fragment a as the dipeptide fragment.
A solution of Fmoc-Ala-OH (15.6g, 50mmol), N-hydroxysuccinimide (6.3g, 55mmol) and DCC (10.3g, 50mmol) in DCM (300ml) was stirred at 5 ℃ for 6 h. The DCU was filtered off and the filtrate was concentrated. The residue was redissolved in THF (30ml) and stored in the refrigerator (4 ℃ C.) overnight, more DCU was filtered off, the filter cake was washed with a small amount of THF, and the filtrate was collected for use. Alanine (5.3g, 60mmol) was weighed out and dissolved in 25% THF/H2O (80ml, using Na)2CO3Adjusting the pH to maintain the pH in the solution of 8-8.5). The above filtrate was slowly added at low temperature (2-8 deg.C) and the reaction mixture was stirred vigorously at 25 deg.C for 5 hours. The THF was removed by concentration and the aqueous suspension was adjusted to pH4 with concentrated hydrochloric acid. The aqueous suspension was stirred at 25 ℃ for a further 3 hours, the precipitate was collected by filtration, washed thoroughly with demineralized water and dried under vacuum over KOH to give the product Fmoc-Ala-OH (16.2g,purity > 98.5%), designated dipeptide fragment b.
40g of 2-CTC resin with a degree of substitution of 1.2mmol/g was weighed into a solid phase reaction column, washed 1 time with DMF, after swelling the resin with DCM for 30 minutes 28.5g of Fmoc-Gly-OH was weighed dissolved in DMF and 33ml of DIEA was added. After the solution is dissolved and clarified, the solution is added into the reaction column filled with the resin for reaction for 4 hours. The DMF was taken off and washed 3 times with DMF. The reaction was carried out twice for 15min each time with DCM: MeOH: DIEA: 17:2:1 (vol/vol). Washing with DMF 5 times gives 54g of Fmoc-Gly-CTC Resin with a detection substitution of 0.55 mmol/g. Coupling to 16 amino acids in sequence according to SPPS method and sequence gave 128g of Fmoc- (16-22AA) -CTC resin.
As TFA DCM ═ 1: 99 (volume ratio), preparing 430ml of mixed solution in a reaction bottle, and keeping the temperature at-5-0 ℃. 128g of Fmoc- (17-22AA) -CTC Resin was slowly added to the reaction flask and after stirring for 0.5h, the temperature was raised to 25 ℃ and stirring was continued for 1 h. The reaction was stopped, filtered through a sand funnel and the resin was washed 3 times with DCM and the filtrate was collected. Drying to a semi-solid state by rotary evaporation, beating with ether, filtering and vacuum drying gave the fully protected peptide (72g, > 97% purity) designated polypeptide fragment B, i.e. Fmoc-NH (16-22AA) -OH, wherein 16-22AA comprises the sequence VSSYLEG.
Using a similar solid phase synthesis reaction to that used to synthesize polypeptide fragment B, N-Tfa- (7-10AA) -CTC resin 93g, full protective peptide (52g, purity > 97%), named polypeptide fragment C, N-Tfa- (7-10AA) -OH, (7-10AA) contains sequence HAEG; .
Weighing a polypeptide fragment A (11.3g and 3mmol) according to a stoichiometric ratio, putting the polypeptide fragment A (11.3g and 3mmol) into a reaction column, sequentially coupling a dipeptide fragment a, a dipeptide fragment b, Fmoc-Gln (Trt) -OH, a polypeptide fragment B, Fmoc-Asp (OtBu) -OH, Fmoc-Ser (tBu) -OH, Fmoc-Thr (tBu) -OH, Fmoc-Phe-OH, Fmoc-Thr (tBu) -OH and a polypeptide fragment C according to an SPPS method and sequence, and obtaining crude N-Tfa- (7-37AA) (11.6g and purity of 82%) through cleavage.
11.6g of crude N-Tfa- (7-37AA) is dissolved in 10 percent acetonitrile/water solution (200ml), and after shaking dissolution, the crude N-Tfa- (7-37AA) is filtered by a 0.45um filter membrane for standby. The method comprises the steps of preparing a C18 preparation column with the inner diameter of 100mm, using a mobile phase of a 0.1% TFA/water-0.1% TFA/acetonitrile system, loading the sample at 5.0 g/time, carrying out gradient elution at a flow rate of 300ml/min, intercepting a fine peptide solution with the central control analysis purity of more than 99.5% and single impurity content of less than 0.1%, concentrating, and freeze-drying to obtain 6.7g of fine peptide with the purity of more than 99% and the single impurity content of less than 0.1%, wherein the product is named as an intermediate X.
Taking intermediate X6 g (about 1.7mmol, adding into a 250ml three-mouth reaction bottle, adding 100ml 10% acetonitrile/water solution, stirring for dissolving, slowly adding 10% Na dropwise in ice water bath2CO3Water solution, adjusting the pH value of the solution to 8, and stopping dripping; adding 0.94g (2.6mmol) of a THF solution of Pal-OSu/20 ml dropwise in an ice water bath, removing the ice bath after the dropwise addition, and reacting at room temperature for 3 h; adding 150mg (2.6mmol) of glycine, continuing to react for 30min, and monitoring the reaction end point by HPLC; adding 20ml of piperidine into the reaction solution under the condition of vigorous stirring, continuously stirring at room temperature, monitoring an alkaline hydrolysis endpoint by using HPLC (high performance liquid chromatography), stopping stirring after the reaction is finished, filtering insoluble substances by using a sand core funnel, and washing the insoluble substances by using purified water for three times; combining the washing solution and the filtrate, diluting the peptide solution with 0.5% acetic acid aqueous solution until the pH value is reduced to 5, and filtering the solution through a 0.45um filter membrane for later use.
C8 preparation column with inner diameter of 100mM, mobile phase of 20mM ammonium acetate water solution-acetonitrile system, sample loading amount of 3.0 g/time, flow rate of 300ml/min, gradient elution; performing cyclic sample injection before and after peaks, intercepting a refined peptide solution with the central control analysis purity of more than 99.5 percent and single impurity of less than 0.1 percent, desalting, concentrating and freeze-drying to obtain 4.1g of refined peptide, wherein the purity is more than 99.0 percent and the single impurity is less than 0.1 percent; the overall yield was 36.4%.
The amino acids involved in the present invention are shown below:
glycine (G), alanine (a), serine (S), leucine (L), arginine (R), tyrosine (Y), histidine (H), glutamic acid (E), phenylalanine (F), isoleucine (I), valine (V).
There are, of course, many other specific embodiments of the invention and these are not to be considered as limiting. All technical solutions formed by using equivalent substitutions or equivalent transformations fall within the scope of the claimed invention.
Claims (8)
1. A synthesis method of liraglutide is characterized by comprising the following steps: synthesizing three fragments through a solid phase, synthesizing two dipeptide fragments through a liquid phase, sequentially coupling each fragment and other raw materials in a solution system to obtain an N-Tfa protected liraglutide intermediate, and purifying to obtain an intermediate pure product; and after the palmitic acid is modified, removing the Tfa protecting group under the alkaline condition, and purifying and exchanging salts to obtain the required liraglutide.
2. The method of synthesizing liraglutide according to claim 1, wherein the peptide comprises the following steps: the three fragments of the solid phase synthesis are respectively: polypeptide fragment a: NH (NH)2- (27-37AA) -Wang resin, (27-37AA) comprising sequence EFIAWLVRGRG; fully protected peptide fragment B:
Fmoc-NH (16-22AA) -OH, wherein 16-22AA comprises the sequence VSSYLEG; fully protected peptide fragment C: N-Tfa- (7-10AA) -OH, wherein 7-10AA comprises the sequence HAEG.
3. A method of synthesizing liraglutide according to claim 2, wherein: the two dipeptide fragments synthesized by the liquid phase are respectively: dipeptide fragment a:
Fmoc-Lys (N- ε - (γ -Glu (N- α -Boc) -OtBu) -OH; dipeptide fragment b:
Fmoc-NH- (24-25AA) -OH, wherein 24-25AA comprises the sequence AA and is
Fmoc-Ala-Ala-OH。
4. A method of synthesizing liraglutide according to claim 3, wherein: the synthesis of the N-Tfa protected liraglutide intermediate in the synthesis method comprises the following steps,
the polypeptide fragment A is firstly placed in a reaction column, and the dipeptide fragment a, the dipeptide fragment B, the Fmoc-Gln (Trt) -OH, the polypeptide fragment B and the polypeptide fragment C are sequentially coupled according to the SPPS method and the sequence,
Fmoc-Asp(OtBu)-OH、Fmoc-Ser(tBU)-OH、Fmoc-Thr(tBu)-OH、
Fmoc-Phe-OH, Fmoc-Thr (tBu) -OH and polypeptide fragment C, and obtaining the polypeptide fragment by cleavage
And N-Tfa- (7-37AA) crude product, namely the liraglutide intermediate with N-Tfa protection.
5. A method of synthesizing liraglutide according to claim 4, wherein: the purification of the liraglutide intermediate with N-Tfa protection comprises the steps of dissolving the liraglutide intermediate with N-Tfa protection in a mixed solution of 10% acetonitrile and water, shaking for dissolution, and filtering for later use; purification by HPLC.
6. A method of synthesizing liraglutide according to claim 5, wherein: the HPLC conditions adopted are as follows: the mobile phase was a 0.1% TFA/water-0.1% TFA/acetonitrile system, loading 5.0 g/time, flow rate 300ml/min, gradient elution.
7. The method of synthesizing liraglutide according to claim 6, wherein the peptide comprises the following steps: adding the purified intermediate X into a three-mouth reaction bottle, adding 10% acetonitrile/water solution, stirring for dissolving, and slowly dropwise adding 10% Na in an ice water bath2 CO3Mixing the solution with the aqueous solution mixed solution, adjusting the pH of the solution to 8, and stopping dripping;
dropwise adding a THF solution of Pal-OSu in an ice water bath, reacting at room temperature, adding glycine, and monitoring the reaction end point by HPLC; adding piperidine into the reaction solution under the condition of vigorous stirring, continuously stirring at room temperature, monitoring the alkaline hydrolysis end point by using HPLC (high performance liquid chromatography), stopping stirring after the reaction is finished, filtering insoluble substances, and washing the insoluble substances by using purified water; the removal of the Tfa protecting group is completed.
8. The method of synthesizing liraglutide according to claim 7, wherein the peptide comprises the following steps: the synthesis method also comprises a purification step of liraglutide, which comprises combining washing liquor and filtrate, diluting the peptide solution by 0.5% acetic acid aqueous solution until the pH value is reduced to 5, filtering the solution by a filter membrane, and purifying by HPLC, wherein the HPLC condition is as follows; the mobile phase is a 20mM ammonium acetate water solution-acetonitrile system, the sample loading amount is 3.0 g/time, the flow rate is 300ml/min, and gradient elution is carried out; and (3) circularly injecting samples before and after peaks, intercepting a refined peptide solution with the central control analysis purity of more than 99.5 percent and the single impurity of less than 0.1 percent, desalting, concentrating and freeze-drying to obtain the liraglutide with the purity of more than 99.0 percent.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4345104A1 (en) | 2022-09-30 | 2024-04-03 | Bachem Holding AG | Method for preparing liraglutide |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4345104A1 (en) | 2022-09-30 | 2024-04-03 | Bachem Holding AG | Method for preparing liraglutide |
| WO2024068827A1 (en) | 2022-09-30 | 2024-04-04 | Bachem Holding Ag | Method for preparing liraglutide |
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