CN101747426A - Method for synthesizing pramlintide - Google Patents
Method for synthesizing pramlintide Download PDFInfo
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- CN101747426A CN101747426A CN200910189086A CN200910189086A CN101747426A CN 101747426 A CN101747426 A CN 101747426A CN 200910189086 A CN200910189086 A CN 200910189086A CN 200910189086 A CN200910189086 A CN 200910189086A CN 101747426 A CN101747426 A CN 101747426A
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- resin
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- amylin
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- 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
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- 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
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Abstract
The invention discloses a method for preparing pramlintide through solid-phase synthesis. The method comprises the following steps: 1) using Fmoc-Tyr(tBu)-OH and amino resin with a substituted ratio of 0.3-1.5mmol/g to obtain Fmoc-Tyr(tBu)-amino resin; progressively coupling Fmoc-Tyr(tBu)-amino resin with residual protective amino acids according to the peptide sequence; 3) performing solid phase oxidation with iodine to ensure sulphydryl groups to form rings; 4) cracking pramlintide-resin to obtain crude pramlintide; and 5) purifying to obtain pramlintide. The technology of the invention adopts Fmoc solid phase synthesis strategy, utilizes coupling method of multiple coupling agent systems and dipeptide fragments, uses solid phase oxidation, is characterized by easy reaction operation, low cost and high yield, and is applicable to mass production.
Description
Technical field
The present invention relates to a kind of synthetic method of synthetic polypeptide, relate in particular to the solid phase synthesis process of blood sugar lowing polypeptide medicine.
Background technology
At first, people have found a kind of polypeptide that can slow down food in the small intestine absorption rate, the i.e. polypeptide hormone that is made of 37 amino-acid residues (amylin) from the β emiocytosis thing of pancreas islet.This polypeptide hormone reduces patient's appetite by suppressing the generation that hyperglycemia usually reduces glycogen, assists body blood sugar regulation level, but this polypeptide hormone is also unstable in solution, facile hydrolysis, and toughness is big, and easily the agglomerative characteristic is not suitable for making medicine and is used for the treatment of.Through artificial screening, carry out structure of modification, synthesized a kind of stable analogue, the difference between aforementioned polypeptides hormone and the synthetic analogue is that the former is replaced by proline(Pro) by the 25th, 28 and 29 upper amino acid, this synthetic analogue is exactly a tripro-amylin.
Tripro-amylin is used for assisting therapy I type and type ii diabetes, and be mainly used in list and use Regular Insulin, and combined utilization Regular Insulin and the invalid patient of sulfonylurea drugs.
The chemical molecular formula of tripro-amylin is:
Summary of the invention
The present invention proposes a more suitable route, easy to operate, the time is shorter, yield is higher, be fit to large-scale production.
For achieving the above object, the invention provides a kind of method of synthesizing pramlintide, may further comprise the steps:
1) is the aminoresin of 0.3-1.5mmol/g with solid phase synthesis process by Fmoc-Tyr (tBu)-OH and substitution value, obtains Fmoc-Tyr (tBu)-aminoresin;
2) with Fmoc-Tyr (tBu)-aminoresin according to the peptide preface remaining protection amino acid of coupling progressively;
3) two cysteine sulfydryl Side chain protective groups are removed, utilize iodine to carry out phase oxidative;
4) cracking tripro-amylin-resin obtains the thick peptide of tripro-amylin;
5) obtain tripro-amylin through purifying.
Fmoc-Tyr in the described step 1) (tBu)-aminoresin substitution value scope is preferably 0.3-0.5mmol/g at 0.3-1.5mmol/g.Solid phase synthesis process refers in particular to the solid-phase synthesis of polypeptide.Aminoresin is generally Rink Amide mbha resin, Sieber resin, Rink AmideAM resin, Rink Amide resin or Rink Amide bha resin, preferred Rink Amide resin.
Described step 2) " protection amino acid " is meant that C end adopts the amino acid of Fmoc protection in, some amino acid as, Lys, Cys; Asn, Thr, Gln, Arg; His, Ser, Tyr also need other protecting group protection, " the synthetic method signal of the present invention " that vide infra in detail.Wherein, the amino acid coupling system is one or two among solid phase coupling system: DIC or the DIEA, with among HOBT, HOAT, Cl-HOBT, HBTU, HATU, PyBOP or the PyAOP any one or more than one, form coupling system.For example: DIC+HOAT, DIEA+HBTU, DIEA+HOAT+HBTU or DIEA+HOBT+PyBOP etc.
Coupling system preferably is combined as: any one among HOBT, HOAT, the Cl-HOBT or make up with DIC more than; For example: HOBT+DIC, Cl-HOBT+DIC or HOBT+Cl-HOBT+DIC;
Or coupling system preferably is combined as: any one among DIEA and HOBT, HOAT or the Cl-HOBT or more than one with HBTU, HATU, PyBOP or PyAOP in any one or form the polycomponent coupling system more than one.For example: DIEA+HOBT+HBTU, DIEA+HOAT+HATU, DIEA+HOBT+HOAT+PyAOP, DIEA+HOBT+HATU+PyBOP, DIEA+Cl-HOBT+PyBOP or DIEA+HOBT+HOAT+HBTU+PyAOP.Wherein said " polycomponent coupling agent " can be 3 component coupling agents, 4 component coupling agents, 5 component coupling agents, 6 component coupling agents, 7 component coupling agents or 8 component coupling agents.
Experiment is found, adopts multiple coupling agent system of the present invention, can significantly improve reaction efficiency.
Step 2 furtherly) synthetic C holds the 4th amino acids, C to hold the coupling of the 5th amino acids to adopt Fmoc-Gly-Ser (Ψ Me, Me pro)-OH.Select for use Fmoc-Gly-Ser (Ψ Me, Mepro)-the OH effect is better than and selects Fmoc-Ser (tBu)-OH and Fmoc-Gly-OH separately for use.Fmoc-Gly-Ser (Ψ Me, Me pro)-OH protects 2 peptide fragment for being subjected to Fmoc.Wherein Fmoc-Gly-Ser (Ψ Me, Me pro) is Fmoc-Gly-Ser (psiMe Me pro)-OH, and Shanghai office of Merck ﹠ Co., Inc. brand trademark is by name: Novabiochem, product article No.: 05-20-1127-1GM.
Experiment is found, is subjected to Fmoc to protect two peptide fragment solvabilities good, is easy to coupling, compares with Fmoc-Gly-OH with selecting Fmoc-Ser (tBu)-OH separately for use, and reaction can be more complete, and the by product that obtains is few; Help purifying, and can improve yield greatly;
Described step 3) utilizes iodine to carry out phase oxidative, and purpose is to make sulfydryl Cheng Huan.The iodine amount ranges is 5-20 a times of tripro-amylin mol ratio, preferred 15 times; The oxidization time scope is 4-16 hour, preferred 6 hours.The solid-phase oxidation method reaction times is shorter, handled easily, and control easily, low for equipment requirements, cost is low, is fit to large-scale production;
Described step 4) lytic reagent is: cutting reagent is trifluoroacetic acid (TFA), and capture agent is one or more combination of reagent such as water, tri isopropyl silane, triethyl silicane, thioanisole, methyl-phenoxide and dithioglycol.Preferred TFA/ thioanisole/dithioglycol/the methyl-phenoxide volume ratio is 90/5/3/2, and reaction is 2-3 hour under the room temperature, and wherein dithioglycol is meant 1.The lysate consumption is 10-12 a times of peptide resin weight, and sedimentation ether consumption is 10-12 a times of lysate volume.
Step 5) obtains tripro-amylin through reversed phase high efficiency liquid phase purifying.
Process using Fmoc solid phase strategy of the present invention synthesizes long peptide; two peptide fragment are adopted but not common coupling method one by one in the centre; utilize phase oxidative simultaneously; have that operation is simple, cost is low and yield than characteristics such as height; the total recovery of reaction can reach 20%; be fit to large-scale production, have considerable economical and practical value, be with a wide range of applications in the synthetic field of polypeptide drugs design simultaneously.
Synthetic method of the present invention is schematically as follows:
Wherein:
Fmoc-Tyr (R1)-OH representative: N-fluorenylmethyloxycarbonyl-side chain R1 protects tyrosine
Fmoc-Thr (R1)-OH representative: N-fluorenylmethyloxycarbonyl-side chain R1 protects Threonine
Fmoc-Asn (R2)-OH representative: N-fluorenylmethyloxycarbonyl-side chain R2 protects l-asparagine
Fmoc-Ser (R2)-OH representative: N-fluorenylmethyloxycarbonyl-side chain R2 protects Serine
Fmoc-Gly-OH representative: N-fluorenylmethyloxycarbonyl glycine
Fmoc-Val-OH representative: N-fluorenylmethyloxycarbonyl Xie Ansuan
Fmoc-Pro-OH representative: N-fluorenylmethyloxycarbonyl proline(Pro)
Fmoc-Leu-OH representative: N-fluorenylmethyloxycarbonyl leucine
Fmoc-Ile-OH representative: N-fluorenylmethyloxycarbonyl Isoleucine
Fmoc-Phe-OH representative: N-fluorenylmethyloxycarbonyl phenylalanine
Fmoc-Ser (R
1)-OH representative: N-fluorenylmethyloxycarbonyl-side chain R
1The protection Serine
Fmoc-His (R
2)-OH representative: N-fluorenylmethyloxycarbonyl-side chain R
2The protection Histidine
Fmoc-Ala-OH representative: N-fluorenylmethyloxycarbonyl L-Ala
Fmoc-Arg (R
3)-OH representative: N-fluorenylmethyloxycarbonyl-side chain R
4The protection arginine
Fmoc-Gln (R
2)-OH representative: N-fluorenylmethyloxycarbonyl-side chain R
2The protection glutamine
Fmoc-Cys (R
2)-OH representative: N-fluorenylmethyloxycarbonyl-side chain R
2The protection halfcystine
Boc-Lys (R
4)-OH representative: N-tertbutyloxycarbonyl-side chain R
4Protection Methionin
DICPDI representative: DIC
PyBOP representative: phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl phosphorus
HOBt representative: 1-hydroxy benzo triazole
TFA representative: trifluoroacetic acid
DIPEA representative: diisopropylethylamine, i.e. DIEA
DCM representative: methylene dichloride
DMF representative: N, N '-dimethyl formamide
DBLK representative: the DMF solution of piperidines
R1 representative: tBu (tertiary butyl);
R
2Representative: Trt (trityl group);
R
3Representative: Pbf (2,2,4,6,7-pentamethyl-benzo furans-5-alkylsulfonyl);
R
4Representative: Boc (tertbutyloxycarbonyl);
The aminoresin polymer carrier is Rink Amide resin, Rink Amide-MBHA resin, Rink Amide-BHA resin, Rink Amide-AM resin or Sieber resin.
The RinkAmide-MBHA resin
The RinkAmide-BHA resin
The RinkAmide-AM resin
Embodiment
Embodiment 1, Fmoc-Tyr (tBu)-Rink Amide Resin's is synthetic
In the reaction column of 500ml, add 30 gram Rink Amide Resin (Sub=0.8mmol/g), add the DMF washed twice, each 5 minutes, used the DMF swelling again 30 minutes.Remove the Fmoc protecting group of Rink Amide Resin with 20%DBLK, removing finishes washes 4 times with DMF, and DCM washes twice, and detects with the triketohydrindene hydrate detection method.Take by weighing Fmoc-Tyr (tBu)-OH (2.89g, 6.3mmol), HOBt (1.02g, 7.56mmol), HBTU (2.37g, 6.24mmol), after all mixing, add DMF (30ml), DCM (30ml), ice bath adds DIEA (2.14ml, 12.6mmol) down and stirs 5min, activate the back and added reaction column, begun reaction.Finish reaction after 2 hours, washing finishes, sampling detects substitution degree, measure in diacetyl oxide (16.2ml, 180mmol), pyridine (13.8ml, 180mmol) the adding reaction column and seal, sealed two hours, the triketohydrindene hydrate detection method detects, resin is colourless, can stop sealing, wash, it is 0.4mmol/g that sampling records substitution value.
--Rink Amide bha resin, Fmoc-Tyr (the tBu)--aminoresin such as Rink Amide AM resin that utilize same strategy can obtain Fmoc-Tyr (tBu)-Sieber resin, Fmoc-Tyr (tBu) respectively;
Synthesizing of embodiment 2, Fmoc-Thr (tBu)-Tyr (tBu)-Rink Amide resin and AA1-35-Thr (tBu)-Tyr (tBu)-Rink Amide resin.Wherein AA1-35-Thr (tBu)-Tyr (tBu) is meant full guard line style tripro-amylin.
After Fmoc-Tyr (tBu)-Rink Amide mbha resin usefulness DMF washes clean, remove the Fmoc protecting group with 20%DBLK, remove the back that finishes and wash four times with DMF, DCM washes twice, and detects with the triketohydrindene hydrate detection method.(7.15g, 18mmol), (2.91g 21.6mmol), after all mixing, adds DMF (30ml), DCM (30ml) to HOBt, and ice bath adds DIC (4.2ml, 27mmol) down, has activated the back and has added reaction column, begins reaction to take by weighing Fmoc-Thr (tBu)-OH.Reacted 2 hours, and detected with the triketohydrindene hydrate detection method, resin transparent then continues reaction again and finishes reaction after 0.5 hour, gives a baby a bath on the third day after its birth time with DMF.Repeat above-mentioned steps according to the next protection of peptide preface coupling amino acid.Obtain full guard line style tripro-amylin-Rink Amide mbha resin.
Utilize same strategy can obtain full guard line style tripro-amylin respectively--Rink Amide resin, full guard line style tripro-amylin-Rink Amide bha resin, full guard line style tripro-amylin-Rink Amide AM resin and full guard line style tripro-amylin-Sieber resin.
The phase oxidative of embodiment 3, tripro-amylin
Take by weighing iodine (15.24g, 60mmol), be dissolved among the DMF (100ml), add reaction column after dissolving finishes, the beginning oxidizing reaction.Oxidation finished reaction in 4 hours.The DMF washing, each 100ml is washed till resin and recovers light yellow, washs 100ml with DCM again, washes twice.The methyl alcohol shrinkage resin obtains full guard tripro-amylin-aminoresin.
The phase oxidative of embodiment 4, tripro-amylin
Take by weighing iodine (7.6g, 30mmol), be dissolved among the DMF (100ml), add reaction column after dissolving finishes, the beginning oxidizing reaction.Oxidation finished reaction in 6 hours.The DMF washing, each 100ml is washed till resin and recovers light yellow, washs 100ml with DCM again, washes twice.The methyl alcohol shrinkage resin obtains full guard tripro-amylin-aminoresin
Embodiment 5, (22.84g 90mmol) is dissolved among the DMF (100ml), and the dissolving back that finishes adds reaction column, the beginning oxidizing reaction to take by weighing iodine.Oxidation finished reaction in 16 hours.The DMF washing, each 100ml is washed till resin and recovers light yellow, washs 100ml with DCM again, washes twice.The methyl alcohol shrinkage resin obtains full guard tripro-amylin-aminoresin
The cracking of embodiment 6, tripro-amylin
Take by weighing 50g full guard tripro-amylin-aminoresin to the 1L round-bottomed flask.The lysate that adding prepares (trifluoroacetic acid: thioanisole: dithioglycol: methyl-phenoxide 90: 5: 3 by volume: 2), ice bath, stirring 2h.After reaction finished, separation resin and lysate were poured lysate in the ready chilled ethyl ether into, separate thick peptide with whizzer, and chilled ethyl ether is washed 3 times, obtains the thick peptide of tripro-amylin.Thick peptide obtains the smart peptide of tripro-amylin through purifying.Purity＞97%, total recovery 20%.
In sum; the present invention adopts Fmoc solid phase strategy synthesizing pramlintide; utilize two fragments of peptides to replace the one by one method of coupling and phase oxidative of amino acid commonly used; operation is simple, post processing is easy, yield is high, the low characteristics such as large-scale production that are suitable for of cost, has considerable economical and practical value and application prospect widely.
Claims (10)
1. the method for a synthesizing pramlintide is characterized in that, may further comprise the steps:
1) is the aminoresin of 0.3-1.5mmol/g with solid phase synthesis process by Fmoc-Tyr (tBu)-OH and substitution value, obtains Fmoc-Tyr (tBu)-aminoresin;
2) with Fmoc-Tyr (tBu)-aminoresin according to the peptide preface remaining protection amino acid of coupling progressively
3) two cysteine sulfydryl Side chain protective groups are removed, utilize iodine to carry out phase oxidative;
4) cracking tripro-amylin-resin obtains the thick peptide of tripro-amylin;
5) obtain tripro-amylin through purifying;
Wherein, aminoresin is Rink Amide mbha resin in the described step 1), Sieber resin, Rink Amide AM resin, Rink Amide resin or Rink Amide bha resin.
2. the method for claim 1 is characterized in that, the substitution value of aminoresin is 0.3-0.5mmol/g in the described step 1).
3. the method for claim 1, it is characterized in that, described step 2) adopt the amino acid coupling system to carry out progressively coupling in, coupling system is: one or two among DIC or the DIEA, with among HOBT, HOAT, Cl-HOBT, HBTU, HATU, PyBOP or the PyAOP any one or more than one, form coupling system.
4. method as claimed in claim 3 is characterized in that, described coupling system is: any one among HOBT, HOAT, the Cl-HOBT or more than and DIC; Among DIEA and HOBT, HOAT or the Cl-HOBT any one or more than one with HBTU, HATU, PyBOP or PyAOP in any one or form coupling system more than one.
5. the method for claim 1 is characterized in that, described step 2) synthetic C holds the 4th amino acids, C to hold the coupling of the 5th amino acids to adopt Fmoc-Gly-Ser (Ψ Me, Me pro)-OH.
6. as claim 1,2,3 or 5 any described methods, it is characterized in that the 5-20 that described step 3) iodine consumption is the tripro-amylin mol ratio times, oxidization time is 4 to 16 hours.
7. as claim 1,2,3 or 5 any described methods, it is characterized in that the lytic reagent that described step 4) cracking tripro-amylin-resin adopts is: TFA/ thioanisole/dithioglycol/methyl-phenoxide volume ratio is 90/5/3/2.
8. method as claimed in claim 6 is characterized in that, the lytic reagent that described step 4) cracking tripro-amylin-resin adopts is: TFA/ thioanisole/dithioglycol/methyl-phenoxide, volume ratio are 90/5/3/2.
9. as claim 1,2,3 or 5 any described methods, it is characterized in that the lysate consumption in the described step 4) is 10-12 a times of peptide resin weight, sedimentation ether consumption is 10-12 a times of lysate volume.
10. method as claimed in claim 8 is characterized in that, the lysate consumption in the described step 4) is 10-12 a times of peptide resin weight, and sedimentation ether consumption is 10-12 a times of lysate volume.
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| CN2009101890866A CN101747426B (en) | 2009-12-18 | 2009-12-18 | Method for synthesizing pramlintide |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102206266A (en) * | 2010-03-31 | 2011-10-05 | 上海医药工业研究院 | Preparation method for pramlintide |
| CN103304624A (en) * | 2013-06-18 | 2013-09-18 | 深圳翰宇药业股份有限公司 | Method for preparing polypeptide |
| CN103467566A (en) * | 2013-09-13 | 2013-12-25 | 苏州维泰生物技术有限公司 | Method for synthesizing novel pseudo dipeptide at kilogram level |
| CN104356221A (en) * | 2014-10-24 | 2015-02-18 | 杭州阿德莱诺泰制药技术有限公司 | Preparation method of pexiganan |
| CN105273077A (en) * | 2014-07-18 | 2016-01-27 | 杭州诺泰制药技术有限公司 | Pramlintide preparation method |
| CN105777892A (en) * | 2014-12-17 | 2016-07-20 | 深圳翰宇药业股份有限公司 | Pramlintide polyethylene glycol derivative, and preparation method and application thereof |
| CN106519009A (en) * | 2016-10-26 | 2017-03-22 | 杭州固拓生物科技有限公司 | Method for preparing ularitide |
| CN106554405A (en) * | 2015-09-30 | 2017-04-05 | 深圳翰宇药业股份有限公司 | A kind of polypeptide and application thereof, preparation method |
| CN111892650A (en) * | 2020-07-06 | 2020-11-06 | 辽宁药联制药有限公司 | Solid-phase synthesis method of liraglutide |
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| US20100179131A1 (en) * | 2006-09-07 | 2010-07-15 | Nycomed Gmbh | Combination treatment for diabetes mellitus |
| CN101790535A (en) * | 2007-06-29 | 2010-07-28 | 隆萨股份公司 | The method for preparing tripro-amylin |
| CN101413009B (en) * | 2008-10-22 | 2011-05-04 | 广东暨大基因药物工程研究中心有限公司 | Preparation of human amylin mutant-pramlintide with modified structure |
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- 2009-12-18 CN CN2009101890866A patent/CN101747426B/en not_active Expired - Fee Related
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| CN102206266A (en) * | 2010-03-31 | 2011-10-05 | 上海医药工业研究院 | Preparation method for pramlintide |
| CN102206266B (en) * | 2010-03-31 | 2013-07-03 | 上海医药工业研究院 | Preparation method for pramlintide |
| CN103304624A (en) * | 2013-06-18 | 2013-09-18 | 深圳翰宇药业股份有限公司 | Method for preparing polypeptide |
| CN103467566A (en) * | 2013-09-13 | 2013-12-25 | 苏州维泰生物技术有限公司 | Method for synthesizing novel pseudo dipeptide at kilogram level |
| CN105273077B (en) * | 2014-07-18 | 2019-03-19 | 杭州阿诺生物医药科技有限公司 | A method of preparing pramlintide |
| CN105273077A (en) * | 2014-07-18 | 2016-01-27 | 杭州诺泰制药技术有限公司 | Pramlintide preparation method |
| CN104356221A (en) * | 2014-10-24 | 2015-02-18 | 杭州阿德莱诺泰制药技术有限公司 | Preparation method of pexiganan |
| CN105777892A (en) * | 2014-12-17 | 2016-07-20 | 深圳翰宇药业股份有限公司 | Pramlintide polyethylene glycol derivative, and preparation method and application thereof |
| CN106554405A (en) * | 2015-09-30 | 2017-04-05 | 深圳翰宇药业股份有限公司 | A kind of polypeptide and application thereof, preparation method |
| CN106554405B (en) * | 2015-09-30 | 2020-04-24 | 深圳翰宇药业股份有限公司 | Polypeptide and application and preparation method thereof |
| CN106519009A (en) * | 2016-10-26 | 2017-03-22 | 杭州固拓生物科技有限公司 | Method for preparing ularitide |
| CN106519009B (en) * | 2016-10-26 | 2019-08-27 | 杭州固拓生物科技有限公司 | A kind of preparation method of Ularitide |
| CN111892650A (en) * | 2020-07-06 | 2020-11-06 | 辽宁药联制药有限公司 | Solid-phase synthesis method of liraglutide |
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