CN103641894A - Preparation method of polypeptide medicine for treating cushing disease - Google Patents

Preparation method of polypeptide medicine for treating cushing disease Download PDF

Info

Publication number
CN103641894A
CN103641894A CN201310656466.2A CN201310656466A CN103641894A CN 103641894 A CN103641894 A CN 103641894A CN 201310656466 A CN201310656466 A CN 201310656466A CN 103641894 A CN103641894 A CN 103641894A
Authority
CN
China
Prior art keywords
fmoc
boc
resin
lys
oall
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201310656466.2A
Other languages
Chinese (zh)
Other versions
CN103641894B (en
Inventor
宓鹏程
潘俊锋
马亚平
袁建成
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hybio Pharmaceutical Co Ltd
Original Assignee
Hybio Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hybio Pharmaceutical Co Ltd filed Critical Hybio Pharmaceutical Co Ltd
Priority to CN201310656466.2A priority Critical patent/CN103641894B/en
Publication of CN103641894A publication Critical patent/CN103641894A/en
Application granted granted Critical
Publication of CN103641894B publication Critical patent/CN103641894B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Peptides Or Proteins (AREA)

Abstract

The invention belongs to the technical field of medical chemistry, discloses a preparation method of a polypeptide medicine for treating the cushing disease, and in particular relates to a preparation method of pasireotide. The preparation method uses Fmoc-Lys-OAll as a raw material, and comprises the following steps: coupling by adopting a pure solid phase synthesizing method to obtain Fmoc-Pro(4-OH)-Phg-D-Trp(Boc)-Lys(C TC)-OAll; coupling with Boc-NH-C2H4-NH-COOH on the premise that the Fmoc protecting group is not removed to synthesize side chain amino acid; coupling the amino acid protected by Fmoc in sequence, removing the protecting group-All at C terminal, cyclizing to obtain pasireotide resin, and performing cracking purification to obtain pasireotide. Compared with the prior art, the preparation method is easily available in raw materials, few in reaction steps and high in pasireotide yield, and is suitable for large-scale production of pasireotide; the prepared pasireotide is high in purity.

Description

A kind of preparation method who treats the polypeptide drugs of hypercortisolism
Technical field
The invention belongs to pharmaceutical chemistry technical field, be specifically related to a kind of preparation method who treats the polypeptide drugs of hypercortisolism, relate in particular to a kind of preparation method of SOM230.
Background technology
Hypercortisolism is a kind of rare disease that jeopardizes patients ' lives, because stimulating, pituitary tumor cause thyroliberin (ACTH) to be secreted in a large number, thereby stimulate suprarenal gland growth and secrete a large amount of hydrocortisones, causing that patient occurs that body weight increases that (especially at face and neck), skin easily abrade, facial fine hair is heavy, the symptom such as muscle and bone dies down, elevation of blood pressure.Ocal resection is the effective ways for the treatment of hypercortisolism, but inoperable patient, and what do not get the Green Light before this specially controls medicine.The medicine of current many treatment hypercortisolisms all belongs to over adaptation card to be used.
SOM230, English pasireotide diaspartate by name, its structure is:
Figure BDA0000432235660000011
SOM230 is manufactured by Novartis Pharma Schweiz AG, is a kind of somatostatin analogue that can be combined with polyceptor, has high-bond with somatostatin receptor sst1～3 and sst5.SOM230 can suppress GHI, and the secretion of GF-I and ACTH points out it may be for the treatment of acromegaly and hypercortisolism.After wherein SOM230 and somatostatin receptor are given and closed, can stop the release of ACTH, thereby reduce the cortisol levels in blood, alleviate the symptom of hypercortisolism.Clinical study proves, by 900 μ g SOM230, has the cortisol levels in 41% patient urine at least to reduce by 50%; By 600 μ g SOM230, there is the cortisol levels in 34% patient urine at least to reduce by 50%.U.S. food Drug Administration (FDA) on November 14th, 2012 approval know clearly new " Orphan drug " Signifor (SOM230, pasireotide diaspartate) injection liquid be used for the treatment of can not be by operative treatment hypercortisolism (Cushing ' s disease) patient.Therefore SOM230 has very high pharmaceutical use and wide market outlook.
Publication number is in the patent of CN1446229A, to disclose the synthesis technique of SOM230, by first preparing special material Fmoc-Pro (4-OCO-NH-CH2-CH2-NH-BOC)-OH, then adopt solid phase method to carry out the synthetic of chain, last cracking, in liquid phase, carry out cyclisation, finally obtain SOM230.Yet aforesaid method needs pre-synthesis special material Fmoc-Pro (4-OCO-NH-CH2-CH2-NH-BOC)-OH, then by solid liquid phase combining method, synthesize, exist reactions steps many, technique is loaded down with trivial details, special material is not easy to obtain, and is unfavorable for the shortcomings such as scale operation.
Summary of the invention
In view of this, the object of the invention is the defect for prior art, a kind of preparation method of SOM230 is provided, the scale operation that described preparation method's step yield few, SOM230 is high, be suitable for SOM230, the SOM230 purity simultaneously making is high.
For realizing object of the present invention, the present invention adopts following technical scheme:
A preparation method for SOM230, comprising:
Step 1: by Fmoc-Lys-OAll and solid phase carrier coupling, obtain Fmoc-Lys (Resin)-OAll;
Step 2:Fmoc-Lys (Resin)-OAll is coupling Fmoc-D-Trp (Boc)-OH, Fmoc-Ph g-OH and Fmoc-Pro (4-OH)-OH one by one, obtains Fmoc-Pro (4-OH)-Phg-D-Trp (Boc)-Lys (CTC)-OAll;
Step 3:Fmoc-Pro (4-OH)-Phg-D-Trp (Boc)-Lys (Resin)-OAll and Boc-NH-C 2h 4-NH-COOH coupling obtains Fmoc-Pro (4-OCO-NH-C 2h 4-NH-Boc)-Phg-D-Trp (Boc)-Lys (CTC)-OAll;
Step 4:Fmoc-Pro (4-OCO-NH-C 2h 4-NH-Boc)-Phg-D-Trp (Boc)-Lys (CTC)-OAll successively coupling Fmoc-Phe-OH and Fmoc-Tyr (Bzl)-OH obtains NH 2-Tyr (Bzl)-Phe-Pro (4-OCO-NH-C 2h 4-NH-Boc)-Phg-D-Trp (Boc)-Lys (Resin)-OAll, remove the blocking group-All of C end after cyclisation obtain SOM230 resin;
Step 5: SOM230 pitch shake solution obtains the thick peptide of SOM230;
Step 6: the thick peptide purification of SOM230 obtains SOM230.
Preferably, described in step 1, solid phase carrier is Trt Resin or 2-CTC Resin.
Preferably, described in step 1, the substitution degree of Fmoc-Lys (Resin)-OAll is 0.4～0.6mmol/g.
Preferably, described in step 1, the coupling agent of coupling is diisopropylethylamine.
Preferably, described in step 2, the coupling agent of coupling is DIC/HOBt.
Preferably, described in step 3, be DIC/HOBt/DMAP with the coupling agent of Boc-NH-C2H4-NH-COOH coupling.
Preferably, described in step 4, the coupling agent of coupling is DIC/HOBt successively.
Preferably, to remove the reagent of the blocking group-All of C end be Pd (PPh3) 4/ phenyl silane to step 4.
Preferably, described in step 4, the cyclizing agent of cyclisation is a kind of in HBTU/HOBt/DIPEA, PyBOP/HOBt/DIPEA or TBTU/HOBt/DIPEA.
Preferably, described in step 5, the cracking agent of cracking is the mixing solutions of TFA, TIS and water.
First the preparation method of SOM230 of the present invention obtains Fmoc-Lys (Resin)-OAll by the solid phase carrier coupling of Fmoc-Lys-OAll and suitable substitution degree; coupling Fmoc-D-Trp (Boc)-OH, F moc-Phg-OH and Fmoc-Pro (4-OH)-OH obtain Fmoc-Pro (4-OH)-Phg-D-Trp (Boc)-Lys (CTC)-OAll one by one afterwards, then Fmoc-Pro (4-OH)-Phg-D-Trp (B oc)-Lys (CTC)-OAll elder generation and Boc-NH-C under the prerequisite that does not remove Fmoc protecting group 2h 4side chain amino acid is synthesized in-NH-COOH coupling, then coupling Fmoc-Phe-OH and Fmoc-Tyr (Bzl)-OH obtain NH successively 2-Tyr (Bzl)-Phe-Pro (4-OCO-NH-C 2h 4-NH-Boc)-Phg-D-Trp (Boc)-Lys (Resin)-OAll, finally remove the blocking group-All of C end after cyclisation obtain SOM230 resin, cracking obtains the thick peptide of SOM230, purifying obtains SOM230 sterling.Compared with prior art, preparation method of the present invention be take Fmoc-Lys-OAll as raw material, adopt the method for pure solid phase synthesis to prepare SOM230, raw material is easy to get, the scale operation that reactions steps is few, the yield of SOM230 is high, be suitable for SOM230, simultaneously first the side chain amino acid of synthetic SOM230 again solid phase coupling to obtain the impurity that the method for SOM230 resin produces few, the SOM230 purity making is high.
Embodiment
The embodiment of the invention discloses a kind of preparation method of SOM230.Those skilled in the art can use for reference content herein, suitably improve processing parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they are all deemed to be included in the present invention.Method of the present invention is described by preferred embodiment, and related personnel obviously can change method as herein described or suitably change and combination within not departing from content of the present invention, spirit and scope, realizes and apply the technology of the present invention.
For realizing object of the present invention, the present invention adopts following technical scheme:
A preparation method for SOM230, comprising:
Step 1: by Fmoc-Lys-OAll and solid phase carrier coupling, obtain Fmoc-Lys (Resin)-OAll;
Step 2:Fmoc-Lys (Resin)-OAll is coupling Fmoc-D-Trp (Boc)-OH, Fmoc-Ph g-OH and Fmoc-Pro (4-OH)-OH one by one, obtains Fmoc-Pro (4-OH)-Phg-D-Trp (Boc)-Lys (CTC)-OAll;
Step 3:Fmoc-Pro (4-OH)-Phg-D-Trp (Boc)-Lys (Resin)-OAll and Boc-NH-C 2h 4-NH-COOH coupling obtains Fmoc-Pro (4-OCO-NH-C 2h 4-NH-Boc)-Phg-D-Trp (Boc)-Lys (CTC)-OAll;
Step 4:Fmoc-Pro (4-OCO-NH-C 2h 4-NH-Boc)-Phg-D-Trp (Boc)-Lys (CTC)-OAll successively coupling Fmoc-Phe-OH and Fmoc-Tyr (Bzl)-OH obtains NH 2-Tyr (Bzl)-Phe-Pro (4-OCO-NH-C 2h 4-NH-Boc)-Phg-D-Trp (Boc)-Lys (Resin)-OAll, remove the blocking group-All of C end after cyclisation obtain SOM230 resin;
Step 5: SOM230 pitch shake solution obtains the thick peptide of SOM230;
Step 6: the thick peptide purification of SOM230 obtains SOM230.
The preparation method of SOM230 of the present invention adopts Fmoc/tBu synthesis strategy; first the solid phase carrier coupling of Fmoc-Lys-OAll and suitable substitution degree is obtained to Fmoc-Lys (Resin)-OAll; coupling Fmoc-D-Trp (Boc)-OH, Fmoc-Phg-OH and Fmoc-Pro (4-OH)-OH obtain Fmoc-Pro (4-O H)-Phg-D-Trp (Boc)-Lys (CTC)-OAll one by one afterwards, then Fmoc-Pro (4-OH)-Phg-D-Trp (Boc)-Lys (CTC)-OAll elder generation and Boc-NH-C under the prerequisite that does not remove Fmoc protecting group 2h 4side chain amino acid is synthesized in-NH-COOH coupling, then coupling Fmoc-Phe-OH and Fmoc-Tyr (Bzl)-OH obtain NH successively 2-Tyr (Bzl)-Phe-Pro (4-OCO-NH-C 2h 4-NH-Boc)-Phg-D-Trp (Boc)-Lys (Resin)-OAll, finally remove the blocking group-All of C end after cyclisation obtain SOM230 resin, cracking obtains the thick peptide of SOM230, purifying obtains SOM230 sterling.
First preparation method's step 1 of the present invention obtains Fmoc-Lys (Resin)-OAll by Fmoc-Lys-OAll and solid phase carrier coupling.
Wherein, preferred, solid phase carrier is Trt Resin or 2-CTC Resin described in step 1, can reduce resin cost.
Further, described in step 1, the initial substitution degree of solid phase carrier is preferably 0.4mmol/g～1.0mmol/g.1.0mmol/g more preferably.The substitution degree that described coupling obtains Fmoc-Lys (Resin)-OAll is preferably 0.4～0.6mmol/g.Being 0.4mmol/g in certain embodiments, is 0.5mmol/g in certain embodiments, is 0.6mmol/g in certain embodiments.
In the process of the amino acid of Fmoc blocking group and solid phase carrier coupling, usually need coupling agent, with activated amino acid.Preferably, described in step 1, the coupling agent of coupling is diisopropylethylamine (DIPEA).
Concrete, described Fmoc-Lys-OAll organic solvent dissolution, joins in solid state reaction post after adding DIPEA to activate under ice bath, carries out linked reaction with the prior solid phase carrier with organic solvent dissolution.
As preferably, the organic solvent of described dissolving Fmoc-Lys-OAll and solid phase carrier is DMF.
As preferably, the condition of linked reaction is room temperature reaction 60min.
Described in above-mentioned steps 1, linked reaction needs reaction solution to carry out purifying after finishing, and separation obtains Fmoc-Lys (Resin)-OAll.Described purification process concrete grammar for adding anhydrous methanol sealing in reaction solution, and with DMF and DCM washing, methyl alcohol shrinks to be drained, and obtains Fmoc-Lys (Resin)-OAll resin successively.
Preparation method's step 2 of the present invention adopts coupling one by one mode by polypeptide solid-state reaction method is coupled to F moc-D-Trp (Boc)-OH, Fmoc-Phg-OH and Fmoc-Pro (4-OH)-OH on Fmoc-Lys (Re sin)-OAll and obtains Fmoc-Pro (4-OH)-Phg-D-Trp (Boc)-Lys (CTC)-OAll.
Wherein, the coupling agent that described in step 2, coupling mode is one by one used is preferably DIC/HOBt.
Further, DIC described in above-mentioned coupling agent and HOBt mol ratio are preferably 1:1.
Described in step 2 coupling agent consumption be preferably excessive.In certain embodiments, described is 1:1.2 with the amino acid of Fmoc blocking group and the mol ratio of coupling agent.The mol ratio of described amino acid, DIC and HOBt with Fmoc blocking group is 1:1.2:1.2.
Further, described in step 2, in coupling mode one by one, before every step coupling, also comprise and remove Fmoc step.In certain embodiments, the reagent that removes Fmoc described in is DBLK(piperidines: DMF=1:4).
Concrete; amino acid Fmoc-D-Trp (the Boc)-OH of described Fmoc protection first mixes with HOBt; be dissolved in afterwards and in organic solvent, under ice bath, add DIC activation, then with in advance with organic solvent dissolution Fmoc-Lys (Resin)-OAll of removing Fmoc protection, carry out linked reaction.Fmoc-Phg-OH and the according to said method coupling one by one of Fmoc-Pro (4-OH)-OH of Fmoc protection.
As preferably, the amino acid of described dissolving Fmoc protection and the organic solvent of Fmoc-Lys (Resin)-OAll are DMF.
As preferably, described in remove Fmoc for to add DBLK solution room temperature stirring reaction with organic solvent dissolution Fmoc-Lys (Resin)-OAll.More preferably, add DBLK solution room temperature stirring reaction 5min, drain, repeat to add DBLK solution once, stirring at room reaction 7min.
As preferably, the condition of linked reaction is room temperature reaction 60min described in above-mentioned steps 2.
Described in above-mentioned steps 2, linked reaction detects the each linked reaction terminal of judgement with ninhydrin method.If resin water white transparency, represents to react completely; Resin colour developing, represents reaction not exclusively, needs linked reaction 1 hour again.
Preparation method's step 3 of the present invention is not removing under the prerequisite of Fmoc protecting group, Fmoc-Pro (4-OH)-Phg-D-Trp (Boc)-Lys (CTC)-OAll elder generation and Boc-NH-C 2h 4side chain amino acid is synthesized in-NH-COOH coupling, obtains Fmoc-Pro (4-OCO-NH-C 2h 4-NH-Boc)-Phg-D-Trp (Boc)-Lys (CTC)-OAll.
Wherein, described in step 3, the coupling agent of coupling is preferably DIC/HOBt/DMAP.
Further, DIC, HOBt described in above-mentioned coupling agent and DMAP mol ratio are preferably 1.2:1.2:1.In certain embodiments, described Boc-NH-C2H4-NH-COOH, DIC, HOBt and DMAP mol ratio are preferably 1:1.2:1.2:1.
Concrete, Fmoc-Pro (4-OH)-Phg-D-Trp (Boc)-Lys (Resin)-OAll elder generation and Boc-NH-C described in step 3 2h 4-NH-COOH linked reaction is specially described Boc-NH-C 2h 4-NH-COOH first mixes with HOBt and DMAP, be dissolved in afterwards and in organic solvent, under ice bath, add DIC activation, Fmoc-Pro (4-OH)-Phg-D-Trp (Boc)-Lys (the CTC)-OAll then obtaining with step 2 carries out linked reaction and obtains Fmoc-Pro (4-OCO-NH-C 2h 4-NH-Boc)-Phg-D-Trp (Boc)-Lys (CTC)-OAll.
As preferably, described organic solvent is DMF.
As preferably, the condition of linked reaction is room temperature reaction 12h described in above-mentioned steps 3.
Preparation method's step 4 of the present invention is first at Fmoc-Pro (4-OCO-NH-C 2h 4-NH-Boc)-Ph g-D-Trp (Boc)-Lys (CTC)-OAll successively coupling Fmoc-Phe-OH and Fmoc-Tyr (Bzl)-OH obtains NH 2-Tyr (Bzl)-Phe-Pro (4-OCO-NH-C 2h 4-NH-Boc)-Phg-D-Trp (Boc)-Lys (Resin)-O All.
Wherein, described in step 4 successively the coupling agent of coupling for being preferably DIC/HOBt.
As preferably, DIC described in above-mentioned coupling agent and HOBt mol ratio are 1:1.In certain embodiments, the mol ratio of the described amino acid with Fmoc blocking group, DIC and HOBt is 1:1.2:1.2.
Further, described in step 4 successively coupling with also comprising and remove Fmoc step before every step coupling in the amino acid whose reaction of Fmoc blocking group.In certain embodiments, the reagent that removes Fmoc described in is DBLK(piperidines: DMF=1:4).
Concrete; the amino acid Fmoc-Phe-OH that described in step 4, coupling is described Fmoc protection with the amino acid of Fmoc blocking group successively first mixes with HOBt; be dissolved in afterwards in organic solvent and under ice bath, add DIC activation, then with the Fmoc-Pro (4-OCO-NH-C that removes in advance Fmoc protection 2h 4-NH-Boc)-P hg-D-Trp (Boc)-Lys (CTC)-OAll(is Pro (4-OCO-NH-C2H4-NH-Boc)-Phg-D-Trp (B oc)-Lys (CTC)-OAll) carry out linked reaction.The according to said method coupling of Fmoc-Tyr (Bzl)-OH of Fmoc protection.
As preferably, the organic solvent of coupling is DMF successively described in above-mentioned steps 4.
As preferably, the condition of the linked reaction of coupling is room temperature reaction 2h successively described in above-mentioned steps 4.
Further, described in above-mentioned steps 4 successively coupling remove Fmoc for the resin with organic solvent dissolution Fmoc protection, add DBLK solution room temperature stirring reaction.More preferably, add DBLK solution room temperature stirring reaction 5min, drain, repeat to add DBLK solution once, stirring at room reaction 7min.
Further, described in above-mentioned steps 4, linked reaction detects the each linked reaction terminal of judgement with ninhydrin method successively.If resin water white transparency, represents to react completely; Resin colour developing, represents reaction not exclusively, needs linked reaction 1 hour again.
Preparation method's step 4 of the present invention is obtaining NH 2-Tyr (Bzl)-Phe-Pro (4-OCO-NH-C 2h 4-NH-Boc) after removing the blocking group-All of C end after-Phg-D-Trp (Boc)-Lys (Resin)-OAll, cyclisation obtains SOM230 resin.
Wherein, the reagent that removes the blocking group-All of C end described in step 4 is preferably Pd (PPh3) 4/ phenyl silane.
Further, Pd (PPh described in the reagent of the above-mentioned blocking group-All that removes C end 3) 4with the mol ratio of phenyl silane be 1:100.
Preferably, described in step 4, the cyclizing agent of cyclisation is a kind of in HBTU/HOBt/DIPEA, PyBOP/HOBt/DIPEA or TBTU/HOBt/DIPEA.
Further, PyBOP(or HBTU or TBTU described in above-mentioned cyclizing agent), the mol ratio of HOBt and DIPEA is 1:1.2:2.In certain embodiments, the mol ratio of PyBOP, HOBt and DIPEA is 1:1.2:2.In certain embodiments, the mol ratio of HBTU, HOBt and DIPEA is 1:1.2:2.In certain embodiments, the mol ratio of TBTU, HOBt and DIPEA is 1:1.2:2.
In certain embodiments, described NH 2-Tyr (Bzl)-Phe-Pro (4-OCO-NH-C 2h 4-NH-Boc) mol ratio of-P hg-D-Trp (Boc)-Lys (Resin)-O, PyBOP/HBTU/TBTU, HOBt and DIPEA is 1:1:1.2:2.
Concrete, removing cyclisation after the blocking group-All of C end described in step 4 is NH 2-Tyr (Bzl)-Phe-P ro (4-OCO-NH-C 2h 4-NH-Boc)-Phg-D-Trp (Boc)-Lys (Resin)-OAll linear peptides resin dissolves, in organic solvent, adds Pd (PPh subsequently 3) 4react the blocking group-All that removes C end with phenyl silane.Separately get a kind of and HOBt in PyBOP, HBTU or TBTU and be dissolved in organic solvent and under ice bath, add DIPEA activation, then with the above-mentioned resin (NH that removes All protection 2-Tyr (Bzl)-Phe-Pro (4-OCO-NH-C 2h 4-NH-Boc)-Phg-D-Trp (Boc)-Lys (Resin)-O) mix and carry out cyclization.
As preferably, the organic solvent that removes All protection and cyclisation described in above-mentioned steps 4 is DCM, DMF or NMP.In certain embodiments, the organic solvent that removes All protection is DCM, and the organic solvent of cyclisation is DMF.In certain embodiments, the organic solvent that removes All protection is DCM, and the organic solvent of cyclisation is NMP.
As preferably, the condition that removes the reaction of All protection described in above-mentioned steps 4 is NH 2-Tyr (Bzl)-Phe-Pro (4-OCO-NH-C 2h 4-NH-Boc)-Phg-D-Trp (Boc)-Lys (Resin)-OAll linear peptides resin first reacts with phenyl silane 3 minutes, then adds Pd (PPh 3) 4room temperature reaction 45 minutes.
As preferably, the condition of cyclization is room temperature reaction 2h described in above-mentioned steps 4.
Further, described in above-mentioned steps 4, cyclization detects judgement reaction end with ninhydrin method.If resin water white transparency.
Further, cyclization after finishing needs reaction solution to carry out purifying described in above-mentioned steps 4, and separation obtains SOM230 resin.Described purification process concrete grammar is that cyclization finishes the rear organic solvent washing of using, and methyl alcohol shrinks drains and obtain SOM230 resin.As preferably, described organic solvent is DMF.
Preparation method's step 5 of the present invention obtains the thick peptide of SOM230 by SOM230 pitch shake solution.
Wherein, described in step 5, cracking agent is preferably the mixing solutions of TFA, TIS and water.The mixing solutions that more preferably TFA, TIS and water volume ratio are 95:5:5.
Further, the add-on of cracking agent is preferably by mL/g and calculates described in step 5, and the ratio of cracking agent and peptide resin is 10:1.Be that every 1g peptide resin adds the above-mentioned cracking agent of 10mL.
Further, described in step 5, crack reacting condition is preferably stirring at room 2h.
In some embodiments, scission reaction after finishing needs reaction solution to carry out purifying described in above-mentioned steps 3, and separation obtains the thick peptide of SOM230.Described purification process concrete grammar is that reaction solution filters with sand core funnel, collects filtrate, and resin is again with a small amount of TFA washing, concentrating under reduced pressure after merging filtrate, add freezing anhydrous diethyl ether precipitation, anhydrous diethyl ether washing 3 times for collecting precipitation, vacuum-drying obtains the thick peptide of SOM230.Wherein TFA washing can wash out the product being adsorbed on resin of remnants as far as possible, to reduce the loss.
The SOM230 purifying crude that preparation method's step 6 of the present invention obtains cracking obtains SOM230 sterling, and wherein said purifying is preferably RPLC purifying.
RPLC, English name reversed phase high performance liquid chromatography, is called for short RP-HPLC, the liquid chromatography system being comprised of non-polar stationary phase and polarity moving phase.It is just in time contrary with the liquid chromatography system (normal-phase chromatography) being comprised of polar stationary phase and low-pole moving phase.RP-HPLC is the topmost clastotype of current liquid chromatography, almost can be used for all organic separation and purification that can be dissolved in polarity or weak polar solvent.The SOM230 crude product that preparation method of the present invention obtains step 5 cracking adopts reversed-phased high performace liquid chromatographic purifying to obtain SOM230 sterling.
Preferably, described reversed-phased high performace liquid chromatographic is specially: take anti-phase octadecylsilane or eight alkyl silane bonded silica gels is stationary phase, after the SOM230 crude product solution loading that cracking obtains, by 0.2%TFA/ acetonitrile moving phase, purifies, and collects object peak cut.
Further, after RPLC purifying, freeze-drying obtains SOM230.
In order further to understand the present invention, below in conjunction with embodiment, the present invention is described in detail.
The implication of the abbreviation of using in specification sheets and claims is listed in the following table:
Fmoc 9-fluorenylmethyloxycarbonyl
Boc Tertbutyloxycarbonyl
NMP N-Methyl pyrrolidone
DBLK 20% hexahydropyridine/DMF solution
DIPEA DIPEA
DMAP 4-dimethylamino pyridine
TBTU O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid
CTC?Resin 2-chlorine trityl chloride resin
Trt?Resin Trityl resin
Fmoc 9-fluorenylmethyloxycarbonyl
DIC DIC
HOBt I-hydroxybenzotriazole
HBTU Benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester
PyBOP Phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl phosphorus
TBTU O-benzotriazole-N, N, N, N-tetramethylurea (TMU) Tetrafluoroboric acid ester
DMF DMF
DCM Methylene dichloride
TFA Trifluoroacetic acid
TIS Tri isopropyl silane
Pd(PPh 3) 4 Four (triphenyl) phosphine palladium
Embodiment mono-: the preparation of the Fmoc-Lys that substitution degree is 0.4mmol/g (CTC)-OAll
Taking substitution degree is the 2-CTC resin 100g(100mmol of 1.0mmol/g), join in solid state reaction post, with DMF washing 2 times, with DMF swelling resin, after 30 minutes, get 19.6g(48mmol) Fmoc-Lys-OAll dissolves with 200mL DMF, under ice-water bath, adds 9.3g(72mmol) after DIPEA activation, add in the above-mentioned reaction column that resin is housed, after reaction 5min, again add 6.2g(48mmol) DIPEA, room temperature reaction 60min.In reaction solution, add 81mL anhydrous methanol sealing 30min.With DMF washing 3 times, DCM washes 3 times, and methyl alcohol shrinks to be drained, and obtains Fmoc-Lys (CTC)-OAll resin 115.7g, and detection substitution degree is 0.409mmol/g.
Embodiment bis-: the preparation of the Fmoc-Lys that substitution degree is 0.5mmol/g (CTC)-OAll
Taking substitution degree is the 2-CTC resin 100g(100mmol of 1.0mmol/g), join in solid state reaction post, with DMF washing 2 times, with DMF swelling resin, after 30 minutes, get 24.5g(60mmol) F moc-Lys-OAll dissolves with 200mL DMF, under ice-water bath, adds 11.6g(90mmol) after DIPEA activation, add in the above-mentioned reaction column that resin is housed, after reaction 5min, again add 7.7g(60m mol) DIPEA, room temperature reaction 60min.In reaction solution, add 81mL anhydrous methanol sealing 30min.With DMF washing 3 times, DCM washes 3 times, and methyl alcohol shrinks to be drained, and obtains Fmoc-Lys (CTC)-OAll resin 119.8g, and detection substitution degree is 0.512mmol/g.
Embodiment tri-: the preparation of the Fmoc-Lys that substitution degree is 0.6mmol/g (CTC)-OAll
Taking substitution degree is the 2-CTC resin 100g(100mmol of 1.0mmol/g), join in solid state reaction post, with DMF washing 2 times, with DMF swelling resin, after 30 minutes, get 29.4g(72mmol) F moc-Lys-OAll dissolves with 200mL DMF, under ice-water bath, adds 13.9g(108mmol) after DIPEA activation, add in the above-mentioned reaction column that resin is housed, after reaction 5min, again add 9.3g(72mmol) DIPEA, room temperature reaction 60min.In reaction solution, add 81mL anhydrous methanol sealing 30min.With DMF washing 3 times, DCM washes 3 times, and methyl alcohol shrinks to be drained, and obtains Fmoc-Lys (CTC)-OAll resin 126.5g, and detection substitution degree is 0.603mmol/g.
Embodiment tetra-: the preparation of the Fmoc-Lys that substitution degree is 0.4mmol/g (Trt)-OAll
Taking substitution degree is the Trt resin 100g(100mmol of 1.0mmol/g), join in solid state reaction post, with DMF washing 2 times, with DMF swelling resin, after 30 minutes, get 19.6g(48mmol) Fmoc-Lys-OAll dissolves with 200mL DMF, under ice-water bath, adds 9.3g(72mmol) after DIPEA activation, add in the above-mentioned reaction column that resin is housed, after reaction 5min, again add 6.2g(48mmol) DIPEA, room temperature reaction 60min.In reaction solution, add 81mL anhydrous methanol sealing 30min.With DMF washing 3 times, DCM washes 3 times, and methyl alcohol shrinks to be drained, and obtains Fmoc-Lys (Trt)-OAll resin 116.3g, and detection substitution degree is 0.401mmol/g.
Embodiment five: the preparation of the Fmoc-Lys that substitution degree is 0.5mmol/g (Trt)-OAll
Taking substitution degree is the Trt resin 100g(100mmol of 1.0mmol/g), join in solid state reaction post, with DMF washing 2 times, with DMF swelling resin, after 30 minutes, get 24.5g(60mmol) Fmoc-Lys-OAll dissolves with 200mL DMF, under ice-water bath, adds 11.6g(90mmol) after DIPEA activation, add in the above-mentioned reaction column that resin is housed, after reaction 5min, again add 7.7g(60mmol) DIPEA, room temperature reaction 60min.In reaction solution, add 81mL anhydrous methanol sealing 30min.With DMF washing 3 times, DCM washes 3 times, and methyl alcohol shrinks to be drained, and obtains Fmoc-Lys (Trt)-OAll resin 118.6g, and detection substitution degree is 0.504mmol/g.
Embodiment six: the preparation of the Fmoc-Lys that substitution degree is 0.6mmol/g (Trt)-OAll
Taking substitution degree is the Trt resin 100g(100mmol of 1.0mmol/g), join in solid state reaction post, with DMF washing 2 times, with DMF swelling resin, after 30 minutes, get 29.4g(72mmol) Fmoc-Lys-OAll dissolves with 200mL DMF, under ice-water bath, adds 13.9g(108mmol) after DIPEA activation, add in the above-mentioned reaction column that resin is housed, after reaction 5min, again add 9.3g(72mmol) DIPEA, room temperature reaction 60min.In reaction solution, add 81mL anhydrous methanol sealing 30min.With DMF washing 3 times, DCM washes 3 times, and methyl alcohol shrinks to be drained, and obtains Fmoc-Lys (Trt)-OAll resin 126.3g, and detection substitution degree is 0.608mmol/g.
Embodiment seven: the preparation of Fmoc-Pro (4-OH)-Phg-D-Trp (Boc)-Lys (CTC)-OAll
Get Fmoc-Lys in embodiment bis-(CTC)-OAll resin 97.7g(50mmol), with DMF washing 2 times, with DMF swelling resin, after 30 minutes, drain DMF.Add DBLK(piperidines: DMF=1:4) the about 300mL of solution is used for removing Fmoc, stirring at room reaction 5min, drains, and reaction repeated once, is reacted 7min.Then with DMF washing 6 times.Take 79.0g(150mmol) Fmoc-D-Trp (Boc)-OH, 24.3g(180mmol) HOBt, with 200mL DMF, dissolve, under ice-water bath, add 22.7g(180mmol) after DIC activation, add room temperature reaction 2h in resin.With ninhydrin method, detect judgement reaction end, if resin water white transparency represents to react completely; Resin colour developing, represents reaction not exclusively, needs linked reaction 1 hour again, and this judging criterion is applicable to ninhydrin method, detect judgement reaction end in subsequent content.Repeat the step that the above-mentioned Fmoc of removing protected and added corresponding amino acid coupling; coupling Fmoc-Phg-OH and Fmoc-Pro (4-OH)-OH successively; after the complete Fmoc-Pro of coupling (4-OH)-OH, do not need to remove N end Fmoc, obtain Fmoc-Pro (4-OH)-Phg-D-Trp (Boc)-Lys (CTC)-OAll.
Embodiment eight: Pro (4-OCO-NH-C 2h 4-NH-Boc) preparation of-Phg-D-Trp (Boc)-Lys (CTC)-OAll
Get 36.0g(150mmol) Boc-NH-C 2h 4-NH-COOH, 24.3g(180mmol) HOB t, 1.8g(15mmol) DMAP, dissolves with 250mL DMF, under ice bath, adds 22.7g(180mmol) after DIC activation, add in the resin of embodiment seven and react 12h.Drain reaction solution, with DMF washing 3 times.Add DBLK(piperidines: DMF=1:4) the about 300mL of solution is used for removing Fmoc, stirring at room reaction 5min, drains, and reaction repeated once, is reacted 7min.Then with DMF washing 6 times.Obtain Pro (4-OCO-NH-C 2h 4-NH-Boc)-Phg-D-Trp (Boc)-Lys (CTC)-OAll.
Embodiment nine: NH 2-Tyr (Bzl)-Phe-Pro (4-OCO-NH-C 2h 4-NH-Boc) preparation of-Phg-D-Trp (Boc)-Lys (Resin)-OAll
Take 58.1(150mmol) Fmoc-Phe-OH, 24.3g(180mmol) HOBt, with 200mLDMF, dissolve, under ice-water bath, add 22.7g(180mmol) after DIC activation, add room temperature reaction 2h in the resin of embodiment eight.With ninhydrin method, detect judgement reaction end, if resin water white transparency represents to react completely; Resin colour developing, represents reaction not exclusively, needs linked reaction 1 hour again, and this judging criterion is applicable to ninhydrin method, detect judgement reaction end in subsequent content.Repeat the step that the above-mentioned Fmoc of removing protected and added corresponding amino acid coupling, coupling Fmoc-Tyr (Bzl)-OH, removes Fmoc protecting group, D MF washing 6 times, and methyl alcohol shrinks to be drained, and obtains NH 2-Tyr (Bzl)-Phe-Pro (4-OCO-NH-C 2h 4-NH-Boc)-Phg-D-Trp (Boc)-Lys (Resin)-OAll peptide resin.
Embodiment ten: the preparation of Pasireotide peptide resin
Get NH 2-Tyr (Bzl)-Phe-Pro (4-OCO-NH-C 2h 4-NH-Boc)-Phg-D-Trp (Boc)-Lys (R esin)-OAll linear peptides resin (50mmol), after 30 minutes, drains swelling solution with DCM swelling resin.Rejoin 50mL methylene dichloride, then add 123.1mL phenyl silane (1000mmol), react 3 minutes, then add 7.0g Pd (PPh 3) 4(10mmol), room temperature reaction is 45 minutes.
Take PyBOP26.0g(50mmol), HOBt8.1g(60mmol), with 200mL DMF, dissolve, under ice-water bath, add 17.4mLDIPEA(100mmol) and activate 3 minutes, add reaction column reaction 2 hours, with ninhydrin method, detect judgement reaction end.With DMF washing 6 times, methyl alcohol shrinks to be drained, and obtains Pasireotide peptide resin 155.6g.
Embodiment 11: the preparation of Pasireotide peptide resin
Get NH 2-Tyr (Bzl)-Phe-Pro (4-OCO-NH-C 2h 4-NH-Boc)-Phg-D-Trp (Boc)-Lys (R esin)-OAll linear peptides resin (50mmol), after 30 minutes, drains swelling solution with DCM swelling resin.Rejoin 50mL methylene dichloride, then add 123.1mL phenyl silane (1000mmol), react 3 minutes, then add 7.0g Pd (PPh 3) 4(10mmol), room temperature reaction is 45 minutes.
Take HBTU19.0g(50mmol), HOBt8.1g(60mmol), with 200mL NMP, dissolve, under ice-water bath, add 17.4mLDIPEA(100mmol) and activate 3 minutes, add reaction column reaction 2 hours, with ninhydrin method, detect judgement reaction end.With DMF washing 6 times, methyl alcohol shrinks to be drained, and obtains Pasireotide peptide resin 153.9g.
Embodiment 12: the preparation of Pasireotide peptide resin
Get NH 2-Tyr (Bzl)-Phe-Pro (4-OCO-NH-C 2h 4-NH-Boc)-Phg-D-Trp (Boc)-Lys (R esin)-OAll linear peptides resin (50mmol), after 30 minutes, drains swelling solution with DCM swelling resin.Rejoin 50mL methylene dichloride, then add 123.1mL phenyl silane (1000mmol), react 3 minutes, then add 7.0g Pd (PPh 3) 4(10mmol), room temperature reaction is 45 minutes.
Take TBTU16.1g(50mmol), HOBt8.1g(60mmol), with 200mL NMP, dissolve, under ice-water bath, add 17.4mLDIPEA(100mmol) and activate 3 minutes, add reaction column reaction 2 hours, with ninhydrin method, detect judgement reaction end.With DMF washing 6 times, methyl alcohol shrinks to be drained, and obtains Pasireotide peptide resin 156.3g.
Embodiment 13: the preparation of the thick peptide of Pasireotide
The peptide resin of getting in embodiment ten to 12 preparation is placed in scission reaction wherein, with the ratio of 10mL/g resin, adds lytic reagent (TFA:TIS: water=90:5:5(V/V)), stirring at room 2h.Reactant filters with sand core funnel, collects filtrate, and resin is again with a small amount of TFA washing 3 times, concentrating under reduced pressure after merging filtrate.Add freezing anhydrous diethyl ether precipitation, with anhydrous diethyl ether washing 3 times, vacuum-drying obtains white powder solid, i.e. the thick peptide of Pasireotide, and weight yield is 95.1%～99.6%.HPLC purity is greater than 50%.Single mixing is less than 5%.
Embodiment 14: adopt Trt resin for the thick peptide of Pasireotide
Get Fmoc-Lys in embodiment five (Trt)-OAll resin 99.2g(50mmol), with DMF washing 2 times, with DMF swelling resin, after 30 minutes, drain DMF.Add DBLK(piperidines: DMF=1:4) the about 300mL of solution is used for removing Fmoc, stirring at room reaction 5min, drains, and reaction repeated once, is reacted 7min.Then with DMF washing 6 times.
Take 79.0g(150mmol) Fmoc-D-Trp (Boc)-OH, 24.3g(180mmol) HOBt, with 200mL DMF, dissolve, under ice-water bath, add 22.7g(180mmol) after DIC activation, add room temperature reaction 2h in resin.With ninhydrin method, detect judgement reaction end, if resin water white transparency represents to react completely; Resin colour developing, represents reaction not exclusively, needs linked reaction 1 hour again, and this judging criterion is applicable to ninhydrin method, detect judgement reaction end in subsequent content.Repeat the step that the above-mentioned Fmoc of removing protected and added corresponding amino acid coupling, coupling Fmoc-Phg-OH and Fmoc-Pro (4-OH)-OH, does not need to remove N end Fmoc after the complete Fmoc-Pro of coupling (4-OH)-OH successively.Get 36.0g(150mmol) Boc-NH-C 2h 4-NH-COOH, 24.3g(180mmol) HOBt, 1.8g(15mmol) DMAP, with 250mL DMF, dissolve, under ice bath, add 22.7g(180mmol) after DIC activation, add in the resin of embodiment seven and react 12h.Drain reaction solution, with DMF washing 3 times.Add DBLK(piperidines: DM F=1:4) the about 300mL of solution is used for removing Fmoc, stirring at room reaction 5min, drains, and reaction repeated once, is reacted 7min.Then with DMF washing 6 times.Take 58.1(150mmol) Fmoc-Phe-OH, 24.3g(180mmol) HOBt, with 200mL DMF, dissolve, under ice-water bath, add 22.7g(180mmol) after DIC activation, add room temperature reaction 2h in the resin of embodiment eight.With ninhydrin method, detect judgement reaction end, if resin water white transparency represents to react completely; Resin colour developing, represents reaction not exclusively, needs linked reaction 1 hour again, and this judging criterion is applicable to ninhydrin method, detect judgement reaction end in subsequent content.Repeat the step that the above-mentioned Fmoc of removing protected and added corresponding amino acid coupling, coupling Fmoc-Tyr (Bzl)-OH, removes Fmoc protecting group, DMF washing 6 times.Add 50mL methylene dichloride, then add 123.1mL phenyl silane (1000mmol), react 3 minutes, then add 7.0g Pd (PPh 3) 4(10mmol), room temperature reaction is 45 minutes.Take PyBOP26.0g(50mmol), HOBt8.1g(60mmol), with 200mL DMF, dissolve, under ice-water bath, add 17.4m LDIPEA(100mmol) and activate 3 minutes, add reaction column reaction 2 hours, with ninhydrin method, detect judgement reaction end.With DMF washing 6 times, methyl alcohol shrinks to be drained, and obtains Pasireotide peptide resin 162.8g
Get peptide resin and be placed in scission reaction wherein, with the ratio of 10mL/g resin, add lytic reagent (TFA:TIS: water=90:5:5(V/V)), stirring at room 2h.Reactant filters with sand core funnel, collects filtrate, and resin is again with a small amount of TFA washing 3 times, concentrating under reduced pressure after merging filtrate.Add freezing anhydrous diethyl ether precipitation, with anhydrous diethyl ether washing 3 times, vacuum-drying obtains white powder solid, i.e. the thick peptide of Pasireotide, and weight yield is 97.8%.HPLC purity 53.2%.Maximum single assorted 4.1%.
Embodiment 15: the preparation of Pasireotide essence peptide
Taking the thick peptide of any 30.0g Pasireotide in embodiment 13 to 14 uses after 1500mL water dissolution, adopt Waters2545RP-HPLC system, wavelength 230nm, chromatographic column is the anti-phase C18 post of 50 * 250mm, conventional 0.2%TFA/ acetonitrile moving phase purifying, collect object peak cut, obtain purity and be greater than 99.0% smart peptide.Rotary evaporation is concentrated, and freeze-drying obtains Pasireotide essence peptide 10.2g, and RP-HPLC purity is greater than 99.2%.
The explanation of above embodiment is just for helping to understand method of the present invention and core concept thereof.It should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improvement and modification also fall in the protection domain of the claims in the present invention.

Claims (10)

1. a preparation method for SOM230, is characterized in that, comprising:
Step 1: by Fmoc-Lys-OAll and solid phase carrier coupling, obtain Fmoc-Lys (Resin)-OAll;
Step 2:Fmoc-Lys (Resin)-OAll is coupling Fmoc-D-Trp (Boc)-OH, Fmoc-Ph g-OH and Fmoc-Pro (4-OH)-OH one by one, obtains Fmoc-Pro (4-OH)-Phg-D-Trp (Boc)-Lys (CTC)-OAll;
Step 3:Fmoc-Pro (4-OH)-Phg-D-Trp (Boc)-Lys (Resin)-OAll and Boc-NH-C 2h 4-NH-COOH coupling obtains Fmoc-Pro (4-OCO-NH-C 2h 4-NH-Boc)-Phg-D-Trp (Boc)-Lys (CTC)-OAll;
Step 4:Fmoc-Pro (4-OCO-NH-C 2h 4-NH-Boc)-Phg-D-Trp (Boc)-Lys (CTC)-OAll successively coupling Fmoc-Phe-OH and Fmoc-Tyr (Bzl)-OH obtains NH 2-Tyr (Bzl)-Phe-Pro (4-OCO-NH-C 2h 4-NH-Boc)-Phg-D-Trp (Boc)-Lys (Resin)-OAll, remove the blocking group-All of C end after cyclisation obtain SOM230 resin;
Step 5: SOM230 pitch shake solution obtains the thick peptide of SOM230;
Step 6: the thick peptide purification of SOM230 obtains SOM230.
2. preparation method according to claim 1, is characterized in that, solid phase carrier is Trt Resin or 2-CTC Resin described in step 1.
3. preparation method according to claim 1, is characterized in that, the substitution degree of Fmoc-Lys (Resin)-OAll is 0.4～0.6mmol/g described in step 1.
4. preparation method according to claim 1, is characterized in that, the coupling agent of coupling is diisopropylethylamine described in step 1.
5. preparation method according to claim 1, is characterized in that, the coupling agent of coupling is DIC/HOBt described in step 2.
6. preparation method according to claim 1, is characterized in that, described in step 3 with Boc-NH-C 2h 4the coupling agent of-NH-COOH coupling is DIC/HOBt/DMAP.
7. preparation method according to claim 1, is characterized in that, the coupling agent of coupling is DIC/HOBt successively described in step 4.
8. preparation method according to claim 1, is characterized in that, the reagent that step 4 removes the blocking group-All of C end is Pd (PPh3) 4/ phenyl silane.
9. preparation method according to claim 1, is characterized in that, the cyclizing agent of cyclisation is a kind of in HBTU/HOBt/DIPEA, PyBOP/HOBt/DIPEA or TBTU/HOBt/DIPEA described in step 4.
10. preparation method according to claim 1, is characterized in that, the cracking agent of cracking is the mixing solutions of TFA, TIS and water described in step 5.
CN201310656466.2A 2013-12-06 2013-12-06 A kind of preparation method treating the polypeptide drugs of hypercortisolism Expired - Fee Related CN103641894B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201310656466.2A CN103641894B (en) 2013-12-06 2013-12-06 A kind of preparation method treating the polypeptide drugs of hypercortisolism

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201310656466.2A CN103641894B (en) 2013-12-06 2013-12-06 A kind of preparation method treating the polypeptide drugs of hypercortisolism

Publications (2)

Publication Number Publication Date
CN103641894A true CN103641894A (en) 2014-03-19
CN103641894B CN103641894B (en) 2015-10-28

Family

ID=50247205

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201310656466.2A Expired - Fee Related CN103641894B (en) 2013-12-06 2013-12-06 A kind of preparation method treating the polypeptide drugs of hypercortisolism

Country Status (1)

Country Link
CN (1) CN103641894B (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104447962A (en) * 2014-12-29 2015-03-25 成都圣诺生物科技股份有限公司 Pasireotide preparation method
WO2016097962A1 (en) * 2014-12-19 2016-06-23 Auro Peptides Ltd A process for the preparation of pasireotide
WO2016207912A1 (en) * 2015-06-22 2016-12-29 Biophore India Pharmaceuticals Pvt. Ltd. Novel process for the preparation of pasireotide
CN113461775A (en) * 2021-08-23 2021-10-01 成都诺和晟泰生物科技有限公司 Preparation method of polypeptide compound

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1446229A (en) * 2000-08-01 2003-10-01 诺瓦提斯公司 Somatostatin analogues
WO2005014624A2 (en) * 2003-08-08 2005-02-17 Novartis Ag Preparation of somatostatin peptides
CN101883785A (en) * 2007-12-03 2010-11-10 意大利法尔马科有限公司 New non-selective somatostatin analogues

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1446229A (en) * 2000-08-01 2003-10-01 诺瓦提斯公司 Somatostatin analogues
WO2005014624A2 (en) * 2003-08-08 2005-02-17 Novartis Ag Preparation of somatostatin peptides
CN1832962A (en) * 2003-08-08 2006-09-13 诺瓦提斯公司 Preparation of somatostatin peptides
CN101883785A (en) * 2007-12-03 2010-11-10 意大利法尔马科有限公司 New non-selective somatostatin analogues

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016097962A1 (en) * 2014-12-19 2016-06-23 Auro Peptides Ltd A process for the preparation of pasireotide
CN104447962A (en) * 2014-12-29 2015-03-25 成都圣诺生物科技股份有限公司 Pasireotide preparation method
CN104447962B (en) * 2014-12-29 2018-07-17 成都圣诺生物科技股份有限公司 A method of synthesis parritide
WO2016207912A1 (en) * 2015-06-22 2016-12-29 Biophore India Pharmaceuticals Pvt. Ltd. Novel process for the preparation of pasireotide
US10556924B2 (en) 2015-06-22 2020-02-11 Biophore India Pharmaceuticals Pvt. Ltd. Process for the preparation of pasireotide
CN113461775A (en) * 2021-08-23 2021-10-01 成都诺和晟泰生物科技有限公司 Preparation method of polypeptide compound

Also Published As

Publication number Publication date
CN103641894B (en) 2015-10-28

Similar Documents

Publication Publication Date Title
CN102286092B (en) Solid-phase synthesis method of liraglutide
KR101904808B1 (en) Process for the manufacture of degarelix and its intermediates
JP2019503369A (en) Method for producing semaglutide
CN101935339B (en) Solid-phase preparation method for buserelin
CN102584945A (en) Preparation method for ganirelix acetate
CN103467575B (en) A kind of preparation method of Pa Xirui peptide
CN102408471A (en) Preparation method of Terlipressin
CN103641894B (en) A kind of preparation method treating the polypeptide drugs of hypercortisolism
CN104447962B (en) A method of synthesis parritide
CN106928313A (en) A kind of synthetic method of the terminal modified peptides of C-
CN102731643A (en) Method for preparing polypeptide used for treating osteoporosis
CN103087181A (en) Solid-phase synthesis method of liraglutide
CN101357938B (en) Method for synthesizing Exenatide from solid phase polypeptide
CN102952174A (en) Method for synthesizing degarelix
CN102532267B (en) Method for preparing icatibant
CN104418949A (en) Preparation method of teduglutide
CN103012563A (en) Solid-phase synthesis method of antibacterial peptide Iseganan
CN104177490B (en) Method for preparing salmon calcitonin acetate by fragment condensation
CN103242441A (en) Solid-phase synthesis method of Ziconotide
CN104004064A (en) Preparing method of buserelin
CN104817638B (en) A method of synthesis is for degree Shandong peptide
CN103265620B (en) Somatostatin and preparation method thereof
CN101857629A (en) Solid-phase synthesis method of Bremelanotide
CN102558298B (en) Method for synthesizing tetrapeptide isomers by using solid phase peptide synthesis method and applications of tetrapeptide isomers
CN108059667B (en) A kind of solid phase synthesis process of Lanreotide

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20151028