CN107540727B - Preparation method of buserelin or goserelin - Google Patents
Preparation method of buserelin or goserelin Download PDFInfo
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Abstract
The invention relates to a preparation method of buserelin or goserelin, which comprises the following steps: 1) preparing Fmoc-Pro-resin by using 2-CTC resin as a carrier; 2) preparing full-protection 9 peptide resin by a solid-phase synthesis method; 3) cracking the full-protection 9 peptide resin to obtain full-protection 9 peptide; 4) fully-protected buserelin is obtained by fully-protected 9 peptide and monoethylamine hydrochloride under the action of a coupling agent, or fully-protected goserelin is obtained by fully-protected 9 peptide and semicarbazide hydrochloride under the action of the coupling agent; 5) carrying out hydrogenolysis reaction of palladium-carbon catalysis on the fully protected buserelin or the fully protected goserelin in a solvent Z, and filtering off palladium-carbon after the reaction is finished to obtain a buserelin solution or a goserelin solution; 6) purifying the buserelin solution or the goserelin solution, and freeze-drying to obtain buserelin or goserelin; wherein the solvent Z in the step 5) is a methanol solution of 5% pyridine hydrochloride or an acetic acid aqueous solution of 85-95%.
Description
Technical Field
The invention relates to a preparation method of a compound, in particular to a preparation method of buserelin or goserelin.
Background
Buserelin (Buserelin) and Goserelin (Goserelin) both belong to the gonadotropin releasing hormone (GnRH) analogues, the structures of which are indicated by amino acid abbreviations as: Pyr-His-Trp-Ser-Tyr-D-Ser (tBu) -Leu-Arg-Pro-R, when R is NHEt in buserelin and R is Azgly-NH in goserelin2The structural formula is as follows:
the current synthesis methods for buserelin and goserelin include solid phase synthesis and liquid phase synthesis. Liquid phase synthesis processes are well known from earlier literature, for example WO97/48726 and EP 1008656. However, the liquid phase synthesis operation is complex, purification is required in each synthesis step, the industrial production is not facilitated, and the application value is not high. Because D-Ser side chain tBu in buserelin and goserelin is not compatible with the Fmoc/tBu protection strategy widely used in the solid-phase synthesis method, the modified Fmoc/tBu solid-phase reaction system is adopted in the literature for preparation.
The patents which adopt solid phase synthesis at present are mainly a plurality of domestic patents, each patent method centers on a protecting group strategy and a deprotection method, and the patents are summarized that a full protection peptide is firstly synthesized, and then the protecting group is removed by different methods. Depending on the structure, there may be protecting groups at positions with side chains of His, Ser, Tyr and Arg. The Hanyu pharmaceutical preparation buserelin patent (application No. 201010256054.6) employs a protection strategy of His (Trt), Ser (Trt), Arg (HCl), and the deprotection agent is 5% TFA in dichloromethane; the Hanyu pharmaceutical industry, Gosrelin (application No. 201210155366.7), uses His (Trt), Ser (Trt), Tyr (Bzl), Arg (NO)2) The deprotection method is a hydrogen transfer reaction; the protection strategies adopted by the buserelin preparation patent (application No. 201310557778.8) of Ningbo Sansheng pharmaceutical industry are His (Trt), Ser (Bzl), Tyr (Bzl) and Arg (NO)2) The removal condition is the catalytic hydrogenolysis of palladium-carbon in a methanol or ethanol solution; the patent (application No. 201410185283.1) of Chenorelin preparation by Chengde medical college adopts protection strategies of His (Trt), Tyr (Bzl) and Arg (NO2), and the deprotection comprises two steps of firstly removing Bzl and NO by adopting hydrogen transfer reaction2Then removing Trt by using an about 15% TFA dichloromethane solution; the patent of preparation of goserelin by Tianma, Suzhou (application No. 201510005951.2) uses His (Trt), Tyr (Bzl), Arg (NO)2) The deprotection method also comprises two steps of firstly removing Trt by using 20% TFA dichloromethane solution, and then removing Bzl and NO by using hydrogen transfer reaction2。
His (Trt) in the latter two patents is not removed with hydrogen transfer but is removed with TFA alone. This is consistent with our specific experimental phenomenon. We have found that the Trt protecting group in His (Trt) is difficult to remove or slow to remove by conventional hydrogen transfer reaction or catalytic hydrogenolysis, and the content of impurities can be obviously increased by heating or pressurizing and the like. So the TFA solution in dichloromethane is used for removing in the actual production at present, but the method has two inevitable problems: (1) the tertiary butyl ether of D-Ser which needs to be retained in the molecule is also a group sensitive to acid, so that the side reaction of removing the tertiary butyl ether can be generated; (2) when the reaction solvent is removed by reduced pressure distillation after the reaction is finished, the TFA composition proportion of the reaction system can be continuously changed, the distillation time can be influenced by factors such as equipment state and the like and is difficult to accurately control, and the factors can influence the side reaction of removing the tertiary butyl ether, so that the production process is unstable, and uncertainty is brought to actual production.
Furthermore, in practical experiments, we found that the solubility of fully protected buserelin and goserelin in methanol and ethanol was very low, and Bzl and NO were removed by the conventional method since the solvents commonly used for the conventional hydrogen transfer reaction and hydrogenolysis reaction were methanol and ethanol2The protective group is slow in reaction or has a large amount of catalyst, which brings about many potential safety hazards due to the problem of solubility.
Therefore, the development of a deprotection method with high selectivity, mild reaction conditions, simple operation and easy realization of industrial production is necessary for the scale-up production of buserelin and goserelin.
Disclosure of Invention
In order to overcome the defects, the invention provides a preparation method of buserelin or goserelin, which comprises the following steps:
1) preparing Fmoc-Pro-resin by using 2-CTC resin as a carrier;
2) preparing a full-protection 9 peptide resin Pyr-His (Trt) -Trp-Ser (Trt) -Tyr (Bzl) -D-Ser (tBu) -Leu-Arg (NO2) -Pro-resin by a solid phase synthesis method;
3) cracking the full-protection 9 peptide resin to obtain the full-protection 9 peptide Pyr-His (Trt) -Trp-Ser (Trt) -Tyr (Bzl) -D-Ser (tBu) -Leu-Arg (NO2) -Pro-OH;
4) fully-protected buserelin is obtained by fully-protected 9 peptide and monoethylamine hydrochloride under the action of a coupling agent, or fully-protected goserelin is obtained by fully-protected 9 peptide and semicarbazide hydrochloride under the action of the coupling agent;
5) carrying out hydrogenolysis reaction of palladium-carbon catalysis on the fully protected buserelin or the fully protected goserelin in a solvent Z, and filtering off palladium-carbon after the reaction is finished to obtain a buserelin solution or a goserelin solution;
6) purifying the buserelin solution or the goserelin solution, and freeze-drying to obtain buserelin or goserelin;
wherein the solvent Z in the step 5) is a methanol solution of 5% pyridine hydrochloride or an acetic acid aqueous solution of 85-95%.
Wherein the reaction temperature in the step 5) is 58-65 ℃; preferably, the reaction time is 2 to 5 hours.
The Fmoc-Pro-resin prepared in the step 1) is obtained by activating Fmoc-Pro-OH and DIPEA, adding the activated Fmoc-Pro-OH and DIPEA into 2-CTC resin with the substitution degree of 0.6-1.0 mmol/g for coupling, and sealing the resin with methanol for 20 minutes after the reaction is finished.
Wherein, the solid phase synthesis method in the step 2) is an Fmoc solid phase polypeptide synthesis method, and amino acids with amino protected by Fmos are synthesized one by one;
preferably, the coupling agent selected by the Fmoc solid-phase polypeptide synthesis method is DIPCDI + A or DIPEA + A + B, wherein A is selected from HOBt, HOAt or a combination thereof, and B is selected from PyBOP, PyAOP, HATU, HBTU, TBTU or a combination of at least two of the same;
more preferably, the ratio of the components in the coupling agent is, in molar ratio, DIPCDI: a ═ 1: 0.8-1.5(1.2:1.1), DIPEA: a: B ═ 2: 0.8-1.5: 0.8-1.5(2.0:1.1: 1.0); the amino acids of the Fmoc protected amino group are Fmoc-Arg (NO2) -OH, Fmoc-Leu-OH, Fmoc-D-Ser (tBu) -OH, Fmoc-Tyr (Bzl) -OH, Fmoc-Ser (Trt) -OH, Fmoc-Trp-OH, Fmoc-His (Trt) -OH and Pyr-OH.
Wherein the reagent used in the step 3) is 1-3% TFA/DCM solution, and the cracking time is 2-3 hours;
preferably, the volume ratio of TFA to DCM is 1: 45-55 (1: 48-50, 1: 49);
more preferably, the method further comprises the steps of precipitating with glacial acetic acid, separating the precipitate, and washing with diethyl ether after the cleavage is completed.
Wherein, the coupling agent in the step 4) is EDCI and NMM.
Wherein the purification method in the step 6) is a high performance liquid phase method.
Compared with the prior art, the method has the advantages of mild reaction conditions, simple operation, good selectivity, high purity of the obtained crude peptide, high yield and contribution to large-scale production.
Buserelin synthesis scheme:
Detailed Description
EXAMPLE 1 Synthesis of fully protected peptide resin
55.0g (50mmol) of 2-CTC resin with a degree of substitution of 0.91mmol/g was weighed into a solid phase reaction column, washed 2 times with DMF and the resin swollen with DMF for 30 min. Weighing 33.7g (100mmol) of Fmoc-Pro-OH, adding a proper amount of DMF (dimethyl formamide) for dissolving, adding 12.9g (100mmol) of DIPEA under an ice-water bath, stirring for 4-6 minutes, adding into the resin, performing coupling reaction for 5 minutes, supplementing 12.9g (100mmol) of DIPEA, performing coupling reaction for 1 hour, adding 55ml of methanol into the reaction solution, performing sealing reaction for 20 minutes, removing the reaction solution, and washing the resin with DMF for three times to obtain the Fmoc-Pro-CTC resin.
DBLK was added for deprotection for 5+7 min and the resin was washed 6 times with DMF. 66.2g (150mmol) of Fmoc-Arg (NO) were weighed2) -OH and 22.5g (165mmol) HOAt, dissolved in DMF. Adding 22.6g (180mmol) of DICPDI in an ice water bath, stirring for 4-6 minutes, adding into the resin, reacting for 2 hours at room temperature, and detecting the reaction end point with ninhydrin (if the resin is colorless and transparent, the reaction is terminated, and if the resin is colored, the reaction is prolonged for 1 hour). After the reaction, the reaction solution was removed by suction and the resin was washed with DMF three times.
Following coupling Fmoc-Arg (NO)2) Fmoc-Leu-OH, Fmoc-D-Ser (tBu) -OH, Fmoc-Tyr (Bzl) -OH, Fmoc-Ser (Trt) -OH, Fmoc-Trp-OH, Fmoc-His (Trt) -OH and Pyr-OH were coupled in sequence in the same manner as described for OH. Obtaining the full protection peptide resin.
After the coupling is finished, the resin is contracted by methanol for 3 times, the solvent is drained off, and the vacuum pumping is carried out overnight, so that 138.9g of dry full-protection peptide resin is obtained, the weight of the resin is increased by 83.9g, the theoretical weight is increased by 89.75, and the weight increase rate is 93.5%.
EXAMPLE 2 Synthesis of fully protected peptide resin
48.4g (30mmol) of 2-CTC resin with a degree of substitution of 0.62mmol/g was weighed into a solid phase reaction column, washed 2 times with DMF and the resin swollen with DMF for 30 min. Weighing 20.2g (60mmol) of Fmoc-Pro-OH, adding a proper amount of DMF (dimethyl formamide) for dissolving, adding 7.7g (60mmol) of DIPEA (diethylene glycol Ether-Ether) in an ice-water bath, stirring for 4-6 minutes, adding the mixture into resin, performing coupling reaction for 5 minutes, then supplementing 7.7g (60mmol) of DIPEA, performing coupling reaction for 1 hour, adding 45ml of methanol into the reaction solution, performing sealing reaction for 20 minutes, removing the reaction solution.
DBLK was added for deprotection for 5+7 min and the resin was washed 6 times with DMF. 39.7g (90mmol) Fmoc-Arg (NO) were weighed2) OH and 13.5g (99mmol) of HOAt, dissolved in DMF. Adding 13.6g (108mmol) of DICPDI in an ice water bath, stirring for 4-6 minutes, adding into the resin, reacting for 2 hours at room temperature, and detecting the reaction end point with ninhydrin (if the resin is colorless and transparent, the reaction is stopped, and if the resin is colored, the reaction is prolonged for 1 hour). After the reaction, the reaction solution was removed by suction and the resin was washed with DMF three times.
Following coupling Fmoc-Arg (NO)2) Fmoc-Leu-OH, Fmoc-D-Ser (tBu) -OH, Fmoc-Tyr (Bzl) -OH, Fmoc-Ser (Trt) -OH, Fmoc-Trp-OH, Fmoc-His (Trt) -OH and Pyr-OH were coupled in sequence in the same manner as described for OH. Obtaining the full protection peptide resin.
After the coupling is finished, the resin is contracted by methanol for 3 times, the solvent is drained, and the vacuum pumping is carried out overnight, so that 101.5g of dry full-protection peptide resin is obtained, the weight is increased by 53.1g, the theoretical weight is increased by 53.85g, and the weight increase rate is 98.6%.
EXAMPLE 3 preparation of fully protected crude peptide by cleavage
101.5g of the fully protected peptide resin from example 2 was added to a 2000ml round bottom flask. Add pre-formulated TFA: 1015ml of DCM 2:98(V: V), reacted at room temperature for 2.5 hours, and the resin was filtered to collect the filtrate. The resin was washed with a small amount of DCM and the filtrates combined. The filtrate was slowly added to 10.15L of glacial ethyl ether for precipitation, centrifuged, washed with ethyl ether 2 times, and dried under reduced pressure to give 50.2 g of the fully protected crude peptide with an HPLC purity of 93.9%. Theoretical yield 55.0g, weight yield 91.4%.
EXAMPLE 4 preparation of fully protected buserelin
18.31g (10mmol) of the fully protected crude peptide from example 3 were weighed into a 500ml round-bottom flask and dissolved by magnetic stirring with 183ml of DCM. 1.64g (20mmol) of monoethylamine hydrochloride is weighed, dissolved with 5ml DMF by ultrasound and added into the reaction system. 2.88g (15mmol) of EDCI and 3.54g (35mmol) of NMM were weighed into the system and stirred at room temperature for 16 hours. After the reaction, the reaction solution was poured into a separatory funnel, washed three times with a saturated sodium chloride solution, once with a saturated sodium bicarbonate solution, and once with a saturated sodium chloride solution. The organic phase is decompressed and the organic solvent is removed by rotation to obtain 18.68g of full protection buserelin. Theoretical yield 18.59 g.
Example 5 preparation of fully protected goserelin
18.31g (10mmol) of the fully protected crude peptide from example 3 were weighed into a 500ml round-bottom flask and dissolved by magnetic stirring with 183ml of DCM. 2.23g (20mmol) of semicarbazide hydrochloride is weighed, ultrasonically dissolved by 7ml of DMF, and then added into a reaction system. 2.88g (15mmol) of EDCI and 3.54g (35mmol) of NMM were weighed into the system and stirred at room temperature for 16 hours. After the reaction, the reaction solution was poured into a separatory funnel, washed three times with a saturated sodium chloride solution, once with a saturated sodium bicarbonate solution, and once with a saturated sodium chloride solution. The organic phase obtained is decompressed and the organic solvent is removed by rotation to obtain 19.05g of the fully protected goserelin. Theoretical yield 18.89 g.
EXAMPLE 6 deprotection to prepare crude buserelin peptide
9g (4.84mmol) of the fully protected buserelin crude peptide obtained in example 4 was taken and added into a 250ml three-neck flask, 81ml of a 5% pyridine hydrochloride methanol solution prepared in advance was uniformly stirred, 2.1g of 5% palladium carbon (containing 57.6% of water) was added, vacuum pumping and nitrogen gas pumping were carried out for three times, vacuum pumping and hydrogen gas pumping were carried out for three times, and hydrogen balloon hydrogenation was carried out. Heating in oil bath at 63 ℃, reacting for 4 hours, sampling and detecting by HPLC, and stopping stirring, wherein the raw materials disappear, and each intermediate is less than 2%. The solid is filtered off, and the filtrate is dried by spinning to obtain 6.2g of buserelin crude peptide, 89.5 percent of HPLC and 6.0g of theoretical yield.
Example 7 deprotection to give goserelin crude peptide
9g (4.76mmol) of the fully protected goserelin crude peptide obtained in example 5 was taken and added into a 250ml three-neck flask, 72ml of a 5% pyridine hydrochloride methanol solution prepared in advance was uniformly stirred, 2.1g of 5% palladium carbon (containing 57.6% of water) was added, vacuum pumping and nitrogen gas pumping were carried out for three times, vacuum pumping and hydrogen gas pumping were carried out for three times, and hydrogen balloon hydrogenation was carried out. Heating in oil bath at 60 deg.C, reacting for 3.5 hr, sampling, HPLC detecting, and stopping stirring, wherein the raw material disappears and each intermediate is less than 2%. The solid is filtered off, and the filtrate is dried in a spinning mode to obtain 6.1g of goserelin crude peptide, 87.5 percent of HPLC and 6.0g of theoretical yield.
Example 8 deprotection to prepare crude buserelin peptide
9g (4.84mmol) of the fully protected buserelin crude peptide obtained in example 4 is taken and added into a 250ml three-neck flask, 90ml of a prepared 90% acetic acid aqueous solution is used for stirring uniformly, 2.1g of 5% palladium carbon (containing 57.6% of water) is added, the mixture is vacuumized and replaced by nitrogen gas for three times, the mixture is vacuumized and replaced by hydrogen gas for three times, and hydrogen is added by a hydrogen balloon for hydrogenation. Heating in oil bath at 61 deg.C, reacting for 3.5 hr, sampling, HPLC detecting, disappearance of raw materials, each intermediate less than 2%, and stopping stirring. Filtering out solid, wherein the filtrate is buserelin crude peptide acetic acid solution, HPLC 88.2%, and the acetic acid solution is directly prepared by high performance liquid purification.
Example 9 deprotection to give goserelin crude peptide
9g (4.76mmol) of the fully protected goserelin crude peptide obtained in example 5 is taken and added into a 250ml three-neck flask, 81ml of a prepared 90% acetic acid aqueous solution is used for stirring uniformly, 2.1g of 5% palladium carbon (containing 57.6% of water) is added, the mixture is vacuumized and replaced by nitrogen gas for three times, the mixture is vacuumized and replaced by hydrogen gas for three times, and hydrogen is added by a hydrogen balloon for hydrogenation. Heating in oil bath at 62 deg.C, reacting for 3.5 hr, sampling, HPLC detecting, and stopping stirring, wherein the raw material disappears and each intermediate is less than 2%. Filtering out solid, wherein the filtrate is goserelin crude peptide acetic acid solution, HPLC (high performance liquid chromatography) 90.1 percent, and the acetic acid solution is directly prepared by high performance liquid purification.
EXAMPLE 10 purification of buserelin
6.2g of the crude buserelin peptide obtained in example 6 was subjected to high performance liquid purification and freeze-drying to obtain 4.2g of buserelin refined peptide. HPLC purity > 99%, single impurity < 0.15%. The total yield was 64.3%.
EXAMPLE 11 purification of goserelin
The goserelin crude peptide acetic acid solution obtained in example 9 was subjected to high performance liquid purification and freeze-drying to obtain 4.3g of goserelin refined peptide. HPLC purity > 99%, single impurity < 0.15%. The total yield is 65.5%.
English abbreviation and Chinese meaning used in the invention
Claims (13)
1. A preparation method of buserelin or goserelin comprises the following steps:
1) preparing Fmoc-Pro-resin by using 2-CTC resin as a carrier;
2) the solid phase synthesis method is used for preparing the full protection 9 peptide resin Pyr-His (Trt) -Trp-Ser (Trt) -Tyr (Bzl) -D-Ser (tBu) -Leu-Arg (NO)2) -Pro-resin;
3) cracking the full-protection 9 peptide resin to obtain the full-protection 9 peptide Pyr-His (Trt) -Trp-Ser (Trt) -Tyr (Bzl) -D-Ser (tBu) -Leu-Arg (NO)2)-Pro-OH；
4) Fully-protected buserelin is obtained by fully-protected 9 peptide and monoethylamine hydrochloride under the action of a coupling agent, or fully-protected goserelin is obtained by fully-protected 9 peptide and semicarbazide hydrochloride under the action of the coupling agent;
5) carrying out hydrogenolysis reaction of palladium-carbon catalysis on the fully protected buserelin or the fully protected goserelin in a solvent Z, and filtering off palladium-carbon after the reaction is finished to obtain a buserelin solution or a goserelin solution;
6) purifying the buserelin solution or the goserelin solution, and freeze-drying to obtain buserelin or goserelin;
wherein the solvent Z in the step 5) is a methanol solution of 5% pyridine hydrochloride or an acetic acid aqueous solution of 85-95%;
the reaction temperature in the step 5) is 58-65 ℃; the reaction time is 2-5 hours.
2. The method of claim 1, wherein the Fmoc-Pro-resin in the step 1) is activated by Fmoc-Pro-OH and DIPEA, and then the activated Fmoc-Pro-OH and DIPEA are added to a 2-CTC resin with a substitution degree of 0.6-1.0 mmol/g for coupling, and the resin is blocked with methanol for 20 minutes after the reaction is completed.
3. The method according to any one of claims 1 to 2, wherein the solid phase synthesis method in step 2) is an Fmoc solid phase polypeptide synthesis method in which amino acids having an amino group protected with Fmos are individually synthesized.
4. The method of claim 3, wherein the coupling agent selected for Fmoc solid phase peptide synthesis is DIPCDI + A or DIPEA + A + B, wherein A is selected from HOBt, HOAt or a combination thereof, and B is selected from PyBOP, PyAOP, HATU, HBTU, TBTU or a combination of at least two thereof.
5. The process according to claim 4, wherein the coupling agent comprises DIPCDI (DiPCDI: A-1: 0.8-1.5, DIPEA, A: B ═ 2: 0.8-1.5: 0.8-1.5; the amino acid of the Fmoc protected amino group is Fmoc-Arg (NO)2) -OH, Fmoc-Leu-OH, Fmoc-D-Ser (tBu) -OH, Fmoc-Tyr (Bzl) -OH, Fmoc-Ser (Trt) -OH, Fmoc-Trp-OH, Fmoc-His (Trt) -OH and Pyr-OH.
6. The process of claim 5 wherein the coupling agent comprises DIPCDI and DIPEA and B in molar ratios of 1.2:1.1 to 2.0:1.1: 1.0.
7. The method according to any one of claims 1-2, wherein the reagent used in the step 3) is 1-3% TFA/DCM solution, and the cleavage time is 2-3 hours.
8. The method of claim 7, wherein the volume ratio of TFA to DCM is 1: 45-55.
9. The method of claim 7, wherein the volume ratio of TFA to DCM is 1: 48-50.
10. The method of claim 7, wherein the volume ratio of TFA to DCM is 1: 49.
11. the method of claim 7, further comprising the steps of precipitating with diethyl ether, separating the precipitate, and washing with diethyl ether after the completion of the cleavage.
12. The method according to any one of claims 1 to 2, wherein the coupling agent in step 4) is EDCI or NMM.
13. The production method according to any one of claims 1 to 2, wherein the purification method in step 6) is a high performance liquid phase method.
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| WO2023030278A1 (en) * | 2021-08-30 | 2023-03-09 | 湖南三太药业有限公司 | Full-liquid-phase synthesis method for reelin drug |
| CN113999289B (en) * | 2021-11-24 | 2024-05-07 | 杭州信海医药科技有限公司 | Preparation method of goserelin |
| CN116675741B (en) * | 2023-07-31 | 2023-10-31 | 杭州湃肽生化科技有限公司 | Application of intermediate in preparation of goserelin |
| CN116655745B (en) * | 2023-07-31 | 2023-10-13 | 杭州湃肽生化科技有限公司 | Application of intermediate in preparation of buserelin |
| CN118047836A (en) * | 2024-01-19 | 2024-05-17 | 中肽生化有限公司 | Preparation method of goserelin impurity E |
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| WO2006119388A2 (en) * | 2005-05-03 | 2006-11-09 | Novetide, Ltd. | Methods for the production of peptide having a c-terminal amide |
| CN102653555A (en) * | 2012-05-18 | 2012-09-05 | 深圳翰宇药业股份有限公司 | Method for preparing goserelin by solid phase |
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