CN107540727A - The preparation method of Buserelin or Goserelin - Google Patents
The preparation method of Buserelin or Goserelin Download PDFInfo
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- CN107540727A CN107540727A CN201610485117.2A CN201610485117A CN107540727A CN 107540727 A CN107540727 A CN 107540727A CN 201610485117 A CN201610485117 A CN 201610485117A CN 107540727 A CN107540727 A CN 107540727A
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Abstract
The present invention relates to the preparation method of a kind of Buserelin or Goserelin, step are as follows:1) using 2 CTC resins as carrier, Fmoc Pro resins are prepared;2) peptide resin of full guard 9 is prepared with solid phase synthesis process;3) peptide resin of full guard 9 is cracked, obtains the peptide of full guard 9;4) peptide of full guard 9 and hydrochloric acid monoethyl amine are obtained into full guard Buserelin in the presence of coupling agent, or the peptide of full guard 9 and semicarbazide hydrochloride is obtained into full guard Goserelin in the presence of coupling agent;5) full guard Buserelin or full guard Goserelin are carried out to the hydrogenolysis of palladium carbon catalysis in solvent Z, filter out palladium carbon after completion of the reaction, obtains Buserelin solution or Goserelin solution;6) Buserelin solution or Goserelin solution are lyophilized to obtain Buserelin or Goserelin by purifying;Wherein, the solvent Z in step 5) is the methanol solution or 85~95% aqueous acetic acid of 5% pyridine hydrochloride.
Description
Technical field
The present invention relates to a kind of preparation method of compound, and in particular to the preparation method of Buserelin or Goserelin.
Background technology
Buserelin (Buserelin) and Goserelin (Goserelin) belong to gonadotropin-releasing hormone (GnRH)
Analog, its structure are expressed as with amino acid abbreviations:Pyr-His-Trp-Ser-Tyr-D-Ser (tBu)-Leu-Arg-Pro-R,
As R=Azgly-NH in R=NHEt in Buserelin, Goserelin2, structural formula is as follows:
The synthetic method of Buserelin and Goserelin includes solid-phase synthesis and liquid phase synthesizing method at present.Liquid phase synthesis side
Fado sees the document of early stage, such as WO97/48726 and EP1008656.But liquid phase synthesis complex operation, often synthesize a step all
Purified, it is not high to be unfavorable for industrial production, application value.Due to the D-Ser side chains tBu in Buserelin and Goserelin
It is incompatible with widely used Fmoc/tBu Preservation tactics in solid phase synthesis process, consolidated in document using improved Fmoc/tBu
It is prepared by phase reaction system.
It is mainly at present several domestic patents using the patent of synthesis in solid state, each patented method is around protection group strategy and takes off
Guard method, it is all first to synthesize a full guard peptide and then again by distinct methods deprotection base to summarize these patents.According to
There is His, Ser, Tyr and Arg side chain in structure, the site that may have protection group.Writing brush space medicine company prepares the patent (Shen of Buserelin
Number 201010256054.6) please be using His (Trt), Ser (Trt), Arg (HCl) Preservation tactics, deprotecting regent 5%
TFA dichloromethane solutions;Writing brush space medicine company prepare the patent (application number 201210155366.7) of Goserelin using His (Trt),
Ser(Trt)、Tyr(Bzl)、Arg(NO2) Preservation tactics, deprotection method is hydrogen transfer reaction;It is prepared by Ningbo three lives medicine company
The Preservation tactics that the patent (application number 201310557778.8) of Buserelin uses is His (Trt), Ser (Bzl), Tyr
(Bzl)、Arg(NO2) Preservation tactics, removing condition is palladium carbon catalytic hydrogenolysis in methanol or ethanol solution;Chengde Medical College's system
The Preservation tactics that the patent (application number 201410185283.1) of standby Buserelin uses is His (Trt), Tyr (Bzl), Arg
(NO2), deprotection is in two steps first using hydrogen transfer reaction removing Bzl and NO2, it is then molten with about 15%TFA dichloromethane again
Liquid removes Trt;Suzhou heavenly steed preparation prepares the Preservation tactics that the patent (application number 201510005951.2) of Goserelin uses
For His (Trt), Tyr (Bzl), Arg (NO2), deprotection method is also removed with 20%TFA dichloromethane solutions first in two steps
Trt, then Bzl and NO is removed using hydrogen transfer reaction2。
The His (Trt) in two patents is not as hydrogen transfer reaction removes afterwards, but is individually removed using TFA.
This matches with our specific experiment phenomenon.It was found that the Trt protection groups in His (Trt) are anti-using conventional hydrogen migration
Answer or catalytic hydrogenolysis is difficult that removing or reaction are very slow, although fast using can slightly improve reaction the methods of heating or pressurization
Degree, but can substantially increase the content of impurity.So taken off at present in actual production using TFA dichloromethane solution
Remove, but this method inevitably has two problems:(1) the tertiary butyl ether for the D-Ser for needing to retain in molecule is also to acid
Sensitive group, therefore have the side reaction generation for removing the tertiary butyl ether;(2) reaction dissolvent is being removed under reduced pressure after completion of the reaction
When, reaction system TFA proportion of composing can persistently be changed, and distillation time can also be influenceed by factors such as equipment states and be difficult to standard
Really control, and the side reaction that these can all influence to remove tertiary butyl ether, so as to cause production technology unstable, bring to actual production
It is uncertain.
In addition, in actual experiment, it has been found that the Buserelin and Goserelin of full guard are in methanol and ethanol
Solubility very little, the solvent that hydrogen transfer reaction and hydrogenolysis due to routine are commonly used are methanol and ethanol, therefore using conventional
Method removes Bzl and NO2The problem of during protection group due to solubility, make reaction very slow or catalyst amount is too big and bring very
More potential safety hazards.
Therefore, it is gentle to develop a kind of reaction condition, it is simple to operate, it is easy to accomplish industrialization production, high selectivity de-
Based method is protected, the amplification production for Buserelin and Goserelin is necessary.
The content of the invention
To overcome drawbacks described above, the present invention provides a kind of preparation method of Buserelin or Goserelin, and step is as follows:
1) using 2-CTC resins as carrier, Fmoc-Pro- resins are prepared;
2) with solid phase synthesis process prepare full guard 9 peptide resin Pyr-His (Trt)-Trp-Ser (Trt)-Tyr (Bzl)-
D-Ser (tBu)-Leu-Arg (NO2)-Pro- resins;
3) crack the peptide resin of full guard 9, obtain full guard 9 peptide Pyr-His (Trt)-Trp-Ser (Trt)-Tyr (Bzl)-
D-Ser(tBu)-Leu-Arg(NO2)-Pro-OH;
4) peptide of full guard 9 and hydrochloric acid monoethyl amine are obtained into full guard Buserelin in the presence of coupling agent, or by all risk insurance
Protect 9 peptides and full guard Goserelin is obtained in the presence of coupling agent with semicarbazide hydrochloride;
5) full guard Buserelin or full guard Goserelin are carried out to the hydrogenolysis of palladium carbon catalysis in solvent Z, instead
Palladium carbon is filtered out after answering, obtains Buserelin solution or Goserelin solution;
6) Buserelin solution or Goserelin solution are lyophilized to obtain Buserelin or Goserelin by purifying;
Wherein, the solvent Z in step 5) is the methanol solution or 85~95% aqueous acetic acid of 5% pyridine hydrochloride.
Wherein, the temperature of the reaction in step 5) is 58 DEG C -65 DEG C;Preferably, the reaction time is 2-5 hours.
Wherein, Fmoc-Pro- resins are activated by Fmoc-Pro-OH and DIPEA during prepared by step 1), then add substitution
Spend in 0.6~1.0mmol/g 2-CTC resins and be coupled, reaction finishes to be obtained for 20 minutes with methanol closing resin.
Wherein, the solid phase synthesis process described in step 2) is Fmoc solid-phase peptide synthesis, and amino is protected with Fmos
Amino acid synthesize one by one;
Preferably, the coupling agent that Fmoc solid-phase peptide synthesis are selected is DIPCDI+A or DIPEA+A+B, wherein, A
PyBOP, PyAOP, HATU, HBTU, TBTU or its at least two combination are selected from selected from HOBt, HOAt or its combination, B;
It is highly preferred that the ratio of each composition is calculated as DIPCDI with molar ratio in coupling agent: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 acid of Fmoc protection amino is
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 TFA/DCM solution that cracking agents useful for same is 1~3% in step 3), pyrolysis time are 2~3 hours;
Preferably, the volume ratio of the TFA and DCM are 1:45-55(1:48-50,1:49);
Precipitated it is highly preferred that also being included after the completion of cracking with glacial acetic acid, precipitation and separation, and the step washed with ether
Suddenly.
Wherein, the coupling agent in step 4) is EDCI and NMM.
Wherein, the purification process in step 6) is with high-efficient liquid phase technique.
Compared with the prior art, this technological reaction mild condition is simple to operate for beneficial effect, good, the thick peptide of gained of selectivity
Purity is high, high income, is advantageous to amplification production.
Buserelin synthetic route chart:
Embodiment
The synthesis of the full guard peptide resin of embodiment 1
The 2-CTC resins 55.0g (50mmol) that substitution degree is 0.91mmol/g is weighed, is added in solid phase reaction post, is used
DMF was washed 2 times, with DMF swellable resins 30 minutes.33.7g (100mmol) Fmoc-Pro-OH is weighed, adds appropriate DMF to dissolve, ice
12.9g (100mmol) DIPEA is added under water-bath, stirring is added in resin after 4~6 minutes, and coupling reaction is after 5 minutes, then mends
Add addition methanol 55ml, capping 20 minutes in 12.9g (100mmol) DIPEA, then 1 hour backward reaction solution of coupling reaction
Afterwards, reaction solution is extracted, DMF washings resin three times, obtains Fmoc-Pro-CTC resins
Add DBLK deprotection 5+7 minutes, DMF washings resin 6 times.Weigh 66.2g (150mmol) Fmoc-Arg (NO2)-
OH and 22.5g (165mmol) HOAt, dissolved with appropriate DMF.Addition 22.6g (180mmol) DICPDI under ice-water bath, stirring 4~
It is added in resin, reacts at room temperature 2 hours after 6 minutes, (is terminated instead if resin water white transparency with ninhydrin detection reaction end
Should;Extend reaction 1 hour if resin develops the color).Reaction terminates, and extracts reaction solution, DMF washings resin is three times.
According to coupling Fmoc-Arg (NO2) method same-OH is coupled Fmoc-Leu-OH, Fmoc-D-Ser successively
(tBu)-OH, Fmoc-Tyr (Bzl)-OH, Fmoc-Ser (Trt)-OH, Fmoc-Trp-OH, Fmoc-His (Trt)-OH and Pyr-
OH.Obtain full guard peptide resin.
Coupling finishes, and methanol shrinkage resin 3 times, drains solvent, vacuumizes overnight, obtains dry full guard peptide resin
138.9g, resin weightening 83.9g, theoretical weight gain 89.75, rate of body weight gain 93.5%.
The synthesis of the full guard peptide resin of embodiment 2
The 2-CTC resins 48.4g (30mmol) that substitution degree is 0.62mmol/g is weighed, is added in solid phase reaction post, is used
DMF was washed 2 times, with DMF swellable resins 30 minutes.20.2g (60mmol) Fmoc-Pro-OH is weighed, adds appropriate DMF to dissolve, ice
7.7g (60mmol) DIPEA is added under water-bath, stirring is added in resin after 4~6 minutes, and coupling reaction is after 5 minutes, then adds
Methanol 45ml is added in 7.7g (60mmol) DIPEA, then 1 hour backward reaction solution of coupling reaction, capping is taken out after 20 minutes
Except reaction solution, DMF washings resin three times, obtains Fmoc-Pro-CTC resins
Add DBLK deprotection 5+7 minutes, DMF washings resin 6 times.Weigh 39.7g (90mmol) Fmoc-Arg (NO2)-
OH and 13.5g (99mmol) HOAt, dissolved with appropriate DMF.13.6g (108mmol) DICPDI, stirring 4~6 are added under ice-water bath
It is added in resin, reacts at room temperature 2 hours after minute, (is terminated instead if resin water white transparency with ninhydrin detection reaction end
Should;Extend reaction 1 hour if resin develops the color).Reaction terminates, and extracts reaction solution, DMF washings resin is three times.
According to coupling Fmoc-Arg (NO2) method same-OH is coupled Fmoc-Leu-OH, Fmoc-D-Ser successively
(tBu)-OH, Fmoc-Tyr (Bzl)-OH, Fmoc-Ser (Trt)-OH, Fmoc-Trp-OH, Fmoc-His (Trt)-OH and Pyr-
OH.Obtain full guard peptide resin.
Coupling finishes, and methanol shrinkage resin 3 times, drains solvent, vacuumizes overnight, obtains dry full guard peptide resin
101.5g, increase weight 53.1g, theoretical weight gain 53.85g, rate of body weight gain 98.6%.
The cracking of embodiment 3 prepares the thick peptide of full guard
101.5 grams of the full guard peptide resin that embodiment 2 obtains is added in 2000ml round-bottomed flasks.Add and prepare in advance
Good TFA:DCM=2:98(V:V) 1015ml, react at room temperature 2.5 hours, filter resin, collect filtrate.Washed with a small amount of DCM
Resin, merging filtrate.Filtrate is slowly added to precipitate in 10.15L ice ether, centrifuged, then is washed 2 times with ether, is dried under reduced pressure
Obtain 50.2 grams of the thick peptide of full guard, HPLC purity 93.9%.Theoretical yield 55.0g, weight yield 91.4%.
Embodiment 4 prepares full guard Buserelin
The thick peptide of full guard for weighing the gained of 18.31g (10mmol) embodiment 3 is added in 500ml round-bottomed flasks, adds 183ml
DCM magnetic agitations dissolve.1.64g (20mmol) monoethyl amine hydrochloride is weighed, with adding reactant after~5ml DMF ultrasonic dissolutions
In system.Weigh again in 2.88g (15mmol) EDCI and 3.54g (35mmol) NMM addition systems, after being stirred at room temperature 16 hours.Instead
It should finish, reaction solution is poured into separatory funnel, and saturated nacl aqueous solution washs three times, and saturated sodium bicarbonate solution washed once,
Saturated nacl aqueous solution washed once again.The decompression rotation of gained organic phase removes organic solvent, obtains full guard Buserelin 18.68g.Reason
By yield 18.59g.
Embodiment 5 prepares full guard Goserelin
The thick peptide of full guard for weighing the gained of 18.31g (10mmol) embodiment 3 is added in 500ml round-bottomed flasks, adds 183ml
DCM magnetic agitations dissolve.2.23g (20mmol) semicarbazide hydrochloride is weighed, with adding reactant after~7ml DMF ultrasonic dissolutions
In system.Weigh again in 2.88g (15mmol) EDCI and 3.54g (35mmol) NMM addition systems, after being stirred at room temperature 16 hours.Instead
It should finish, reaction solution is poured into separatory funnel, and saturated nacl aqueous solution washs three times, and saturated sodium bicarbonate solution washed once,
Saturated nacl aqueous solution washed once again.The decompression rotation of gained organic phase removes organic solvent, obtains full guard Goserelin 19.05g.Reason
By yield 18.89g.
The deprotection of embodiment 6 prepares the thick peptide of Buserelin
The thick peptide 9g (4.84mmol) of the gained full guard Buserelin of Example 4 is added in 250ml three-necked flasks, with advance
The 5% pyridine hydrochloride methanol solution 81ml prepared is stirred, and adding 5% palladium carbon, (aqueous 57.6%) 2.1g, is vacuumized logical
Nitrogen displacement three times, then vacuumizes logical hydrogen displacement three times, hydrogen balloon hydrogenation.63 DEG C of oil bath heatings, after reacting 4 hours, sampling
HPLC is detected, and raw material disappears, each intermediate<2%, stop stirring.Solid is filtered out, filtrate is spin-dried for, and obtains the thick peptide 6.2g of Buserelin,
HPLC 89.5%, theoretical yield 6.0g.
The deprotection of embodiment 7 prepares the thick peptide of Goserelin
The thick peptide 9g (4.76mmol) of the gained full guard Goserelin of Example 5 is added in 250ml three-necked flasks, with advance
The 5% pyridine hydrochloride methanol solution 72ml prepared is stirred, and adding 5% palladium carbon, (aqueous 57.6%) 2.1g, is vacuumized logical
Nitrogen displacement three times, then vacuumizes logical hydrogen displacement three times, hydrogen balloon hydrogenation.60 DEG C of oil bath heatings, after reacting 3.5 hours, take
Sample HPLC is detected, and raw material disappears, each intermediate<2%, stop stirring.Solid is filtered out, filtrate is spin-dried for, and obtains the thick peptide of Goserelin
6.1g, HPLC 87.5%, theoretical yield 6.0g.
The deprotection of embodiment 8 prepares the thick peptide of Buserelin
The thick peptide 9g (4.84mmol) of the gained full guard Buserelin of Example 4 is added in 250ml three-necked flasks, with advance
The 90% acetic acid aqueous solution 90ml prepared stirs, and adding 5% palladium carbon, (aqueous 57.6%) 2.1g, vacuumizes logical nitrogen displacement
Three times, then logical hydrogen displacement is vacuumized three times, hydrogen balloon hydrogenation.61 DEG C of oil bath heatings, after reacting 3.5 hours, sampling HPLC inspections
Survey, raw material disappears, each intermediate<2%, stop stirring.Filter out solid, filtrate is the thick peptide acetum of Buserelin, HPLC
88.2%, the acetum directly carries out efficient liquid phase purifying and prepared.
The deprotection of embodiment 9 prepares the thick peptide of Goserelin
The thick peptide 9g (4.76mmol) of the gained full guard Goserelin of Example 5 is added in 250ml three-necked flasks, with advance
The 90% acetic acid aqueous solution 81ml prepared stirs, and adding 5% palladium carbon, (aqueous 57.6%) 2.1g, vacuumizes logical nitrogen displacement
Three times, then logical hydrogen displacement is vacuumized three times, hydrogen balloon hydrogenation.62 DEG C of oil bath heatings, after reacting 3.5 hours, sampling HPLC inspections
Survey, raw material disappears, each intermediate<2%, stop stirring.Filter out solid, filtrate is the thick peptide acetum of Goserelin, HPLC
90.1%, the acetum directly carries out efficient liquid phase purifying and prepared.
The purifying of embodiment 10 prepares Buserelin fine peptide
The thick peptide 6.2g of the gained Buserelin of embodiment 6 is purified by efficient liquid phase, be lyophilized, obtains 4.2g Buserelins essence
Peptide.HPLC purity>99%, it is single miscellaneous<0.15%.Total recovery 64.3%.
The purifying of embodiment 11 prepares Goserelin fine peptide
The thick peptide acetum of the gained Goserelin of embodiment 9 is purified by efficient liquid phase, be lyophilized, obtains 4.3g Ge Sherui
Woods fine peptide.HPLC purity>99%, it is single miscellaneous<0.15%.Total recovery 65.5%.
English abbreviation and Chinese implication used in the present invention
Claims (7)
1. the preparation method of a kind of Buserelin or Goserelin, step are as follows:
1) using 2-CTC resins as carrier, Fmoc-Pro- resins are prepared;
2) full guard 9 peptide resin Pyr-His (Trt)-Trp-Ser (Trt)-Tyr (Bzl)-D-Ser is prepared with solid phase synthesis process
(tBu)-Leu-Arg(NO2)-Pro- resins;
3) peptide resin of full guard 9 is cracked, obtains full guard 9 peptide Pyr-His (Trt)-Trp-Ser (Trt)-Tyr (Bzl)-D-Ser
(tBu)-Leu-Arg(NO2)-Pro-OH;
4) peptide of full guard 9 and hydrochloric acid monoethyl amine are obtained into full guard Buserelin in the presence of coupling agent, or by the peptide of full guard 9
Full guard Goserelin is obtained in the presence of coupling agent with semicarbazide hydrochloride;
5) full guard Buserelin or full guard Goserelin are carried out to the hydrogenolysis of palladium carbon catalysis in solvent Z, reacted
Palladium carbon is filtered out after finishing, obtains Buserelin solution or Goserelin solution;
6) Buserelin solution or Goserelin solution are lyophilized to obtain Buserelin or Goserelin by purifying;
Wherein, the solvent Z in step 5) is the methanol solution or 85~95% aqueous acetic acid of 5% pyridine hydrochloride.
2. preparation method according to claim 1, wherein, the temperature of the reaction in step 5) is 58 DEG C -65 DEG C;It is preferred that
Ground, reaction time are 2-5 hours.
3. according to the preparation method described in claim any one of 1-2, wherein, in prepared by step 1) Fmoc-Pro- resins be by
Fmoc-Pro-OH and DIPEA is activated, and is then added in 0.6~1.0mmol/g of substitution value 2-CTC resins and is coupled, and is reacted
Finish and obtained within 20 minutes with methanol closing resin.
4. according to the preparation method described in claim any one of 1-3, wherein, the solid phase synthesis process described in step 2) is
Fmoc solid-phase peptide synthesis, the amino acid for protecting amino with Fmos synthesize one by one;
Preferably, the coupling agent that Fmoc solid-phase peptide synthesis are selected is DIPCDI+A or DIPEA+A+B, wherein, A is selected from
HOBt, HOAt or its combination, B are selected from PyBOP, PyAOP, HATU, HBTU, TBTU or its at least two combination;
It is highly preferred that the ratio of each composition is calculated as DIPCDI with molar ratio in coupling agent: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 acid of the Fmoc protections amino is 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.
5. according to the preparation method described in claim any one of 1-4, wherein, cracking agents useful for same is 1~3% in step 3)
TFA/DCM solution, pyrolysis time are 2~3 hours;
Preferably, the volume ratio of the TFA and DCM are 1:45-55(1:48-50,1:49);
The step of being precipitated with ether it is highly preferred that also being included after the completion of cracking, precipitation and separation, and being washed with ether.
6. according to the preparation method described in claim any one of 1-5, wherein, the coupling agent in step 4) is EDCI and NMM.
7. according to the preparation method described in claim any one of 1-6, wherein, the purification process in step 6) is with efficient liquid phase
Method.
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CN113999289A (en) * | 2021-11-24 | 2022-02-01 | 杭州信海医药科技有限公司 | Preparation method of goserelin |
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 |
CN116655745A (en) * | 2023-07-31 | 2023-08-29 | 杭州湃肽生化科技有限公司 | Application of intermediate in preparation of buserelin |
CN116675741A (en) * | 2023-07-31 | 2023-09-01 | 杭州湃肽生化科技有限公司 | Application of intermediate in preparation of goserelin |
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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CN110128505A (en) * | 2019-05-21 | 2019-08-16 | 梯尔希(南京)药物研发有限公司 | A kind of synthetic method of Goserelin impurity |
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 |
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CN113999289B (en) * | 2021-11-24 | 2024-05-07 | 杭州信海医药科技有限公司 | Preparation method of goserelin |
CN116655745A (en) * | 2023-07-31 | 2023-08-29 | 杭州湃肽生化科技有限公司 | Application of intermediate in preparation of buserelin |
CN116675741A (en) * | 2023-07-31 | 2023-09-01 | 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 |
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 |
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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