US20030018164A1 - Process for rapid solution synthesis of peptides - Google Patents
Process for rapid solution synthesis of peptides Download PDFInfo
- Publication number
- US20030018164A1 US20030018164A1 US10/199,805 US19980502A US2003018164A1 US 20030018164 A1 US20030018164 A1 US 20030018164A1 US 19980502 A US19980502 A US 19980502A US 2003018164 A1 US2003018164 A1 US 2003018164A1
- Authority
- US
- United States
- Prior art keywords
- scavenger
- extractions
- peptide
- deprotection
- anion
- 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.)
- Abandoned
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
Definitions
- the invention relates to a new and versatile process for rapid solution synthesis of peptides, wherein the growing peptide need not be isolated before the assembly of the desired sequence is completed.
- Peptides are synthesized either on a solid support or in solution. In both approaches coupling and deprotection steps repetitively alternate and may be separated by intermittent purifications.
- solid phase approach a sequence is assembled completely while attached to a solid support before it is eventually cleaved from said support. Removal of excess reagents and by-products takes place by filtration.
- Solid phase synthesis clearly has advantages: it is more or less generally applicable and easy to automate. However, it has also some serious drawbacks. For example, reactions are diffusion-controlled and are usually rather slow under the applied heterogeneous conditions: in order to avoid deletion sequences relatively large excesses of reagents are needed.
- Amines are usually applied as scavengers.
- the use of polyamines as scavengers leads to scavenged compounds which may be actively extracted into a—preferably acidic—aqueous phase, depending on their polarity [e.g. Kisfaludy, L. et al. (1974) Tetrahedron Lett. 19, 1785-1786].
- This extraction is usually performed before the deprotection step to avoid loss of the growing peptide into the aqueous phase.
- this procedure has in numerous cases been found to result in incomplete intermittent purification due to the hydrophobicity of the scavenged compound: the intrinsic hydrophobicity of the amino acyl part of the carboxylic component is enhanced by the still present amino-protecting group. Aqueous extraction is thus not completely effective.
- the new process according to this invention is a process for rapid solution synthesis of a peptide in an organic solvent or a mixture of organic solvents comprising repetitive cycles of steps (a)-(d):
- step (b′) characterised in that the process comprises at least one step (b), referred to as step (b′), in which an amine comprising a free anion or a latent anion is used as a scavenger of residual activated carboxylic functions.
- the growing peptide need not be isolated until the final peptide sequence (i.e. final product of the process of this invention) has been obtained. Therefore, the process is significantly less time-consuming than the classical solution phase processes and easy to scale up.
- the process of this invention allows for highly efficient removal of residual activated carboxylic component without encountering the hydrophobicity problems of other prior art processes in which polyamines are used as scavengers. Thus peptides of high purity are obtained.
- step (a) of the process of this invention the molar amounts of the reagents used are in decreasing order: carboxylic component, coupling additive>coupling reagent>amino component.
- step (a) a pre-activated carboxylic component is used.
- step (b′) an amine comprising a latent anion is used as the scavenger.
- the latent anion in the scavenging amine bears a temporary protecting group which can be selectively removed in the presence of any permanent protecting group attached to the growing peptide.
- the protecting group of the latent anion in the scavenging amine displays a lability similar to that of the temporary protecting group present at the N-terminus of the growing peptide. This allows the deprotection of the scavenger yielding the anion and the N-terminal deprotection of the growing peptide to take place in a single process step.
- the temporary protecting groups present at the N-terminus of the growing peptide and optionally present in the scavenger, are hydrogenolytically removable groups whereas the permanent protecting groups are acidolytically removable protecting groups.
- said temporary protecting groups are of the benzyl type, e.g. (substituted) benzyl and benzyloxycarbonyl groups.
- a preferred scavenger is a primary amine comprising a free anion or a latent anion, and in particular a C-terminally protected amino acid derivative.
- the scavenging amine may comprise other anionic functions such as—but not limited to—sulfonate, sulfate, phosphonate, phosphate or phenolate.
- a highly preferred amino acid for use as a scavenger is ⁇ -alanine or a derivative thereof (e.g. an ester or sily ester derivative).
- the most preferred scavenger is benzyl ⁇ -alaninate or a salt thereof.
- a thiol comprising a free or a latent anion may also be used as a scavenger instead of an amine comprising a free or a latent anion according to the process of this invention.
- the scavenger is preferably used in a two- to sixfold molar excess with respect to the residual active component that needs to be scavenged.
- hydrophilic scavenged compounds which may be actively extracted into a basic aqueous phase after the deprotection step: upon deprotection (if applicable), hydrophilicity is enhanced by the presence of both a free amino function and a free carboxylic function in the scavenged species.
- the process of this invention results in a very effective intermittent purification due to the possibility of actively extracting a hydrophilic scavenged compound.
- a possibly present excess of carboxylic component which was not activated and whose temporary protecting group was also removed during deprotection is extracted from the reaction mixture at the same time.
- At least one cycle, but possibly more cycles of the process comprise(s) a step (b′) wherein a free anion or a latent anion is used as a scavenger of residual activated carboxylic functions.
- the process may comprise also one or more cycles wherein in step (b) a polyamine, such as 3-dimethylamino-1-propylamine, is used as the scavenger.
- Another preferred process of this invention comprises one or more cycles wherein in step (b) deprotection does not occur (thus the circumstances are chosen such that the scavenger is only used for quenching, e.g. using the Z protecting group and an amine comprising a latent anion as a scavenger) and the subsequent step (c) comprises sequential basic, acidic and basic extractions, which are preferably performed in the presence of sodium chloride or potassium nitrate.
- This process comprises a subsequent step (d) which comprises deprotection and sequential basic and neutral extractions; these extractions are preferably performed in the presence of sodium chloride or potassium nitrate.
- Another preferred process of this invention comprises one or more cycles wherein in step (b) both quenching and deprotection occur (e.g. using the Bsmoc protecting group and a polyamine as a scavenger) and the subsequent step (c) comprises sequential basic and neutral extractions, which are preferably performed in the presence of sodium chloride or potassium nitrate.
- step (a) Also preferred is a process, wherein in the last cycle in step (a) the protecting groups of the carboxylic component display a similar lability to that of the permanent protecting groups of the amino component and in step (b) the scavenger is a polyamine.
- the process according to this invention may be performed in several organic solvents which are commonly used for the production of peptides.
- a highly preferred organic solvent is ethyl acetate.
- Also preferred are mixtures of ethyl acetate and other organic solvents, such as dichloromethane, 1-methyl-2-pyrrolidinone, N,N-dimethylformamide or tetrahydrofuran.
- the process of this invention may be performed at temperatures well known in the art for such steps in classical solution phase peptide synthesis. However, preferably the process is performed within a temperature range of 0 to 50° C., and in particular at ambient temperature.
- the process of this invention is very suitable for combinatorial synthesis of peptide libraries using the split and mix method. Couplings are performed separately while the individual coupling mixtures are combined for extractions and deprotections.
- the process of this invention is very suitable for automation since standard protocols are used.
- the new process of this invention is a highly efficient process which may conveniently be used in the production of oligo- and polypeptides of high purity.
- a suitable process according to the present invention is the coupling of an excess of a carboxylic component to an amino component, wherein the carboxylic function is pre-activated or activated in situ using a coupling reagent and, if desired, an additive.
- a coupling reagent and, if desired, an additive.
- residual activated carboxylic functions are scavenged by adding the scavenger to the reaction mixture and mixing, usually followed by aqueous extraction.
- temporary protecting groups are removed using suitable methods known in the art, usually followed by removal of the scavenged compound by aqueous extraction.
- amino component refers to a molecule comprising a free amino function.
- the amino component may be any amine, amino acid or oligopeptide which bears a free amino function and whose other functional groups are protected in such a manner that they do not interfere with the desired coupling reaction.
- the C-terminal function of the applied amino acid or oligopeptide may be protected as a substituted or unsubstituted amide or as an ester; examples of the latter include—but are not limited to—methyl, ethyl, t-butyl, benzyl, phenacyl, 3-(3-methyl)pentyl (Mpe), 2-(2-phenyl)propyl (Pp), 2-chlorotrityl (Clt), diphenyl(4-pyridyl)methyl (PyBzh), dicyclopropylmethyl (Dcpm), 9-fluorenylmethyl (Fm), allyl (All), 2-(trimethylsilyl)ethyl (Tmse), 4- ⁇ N-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]amino ⁇ benzyl (Dmab) esters and enzymatically cleavable esters
- t-butyl Functions of the t-butyl type or functions of similar lability are preferred for the permanent protection of other functional groups in the amino component; these include—but are not limited to—t-butyl ( t Bu) for the protection of the Asp, Glu, Ser, Thr and Tyr side chains, t-butoxycarbonyl (Boc) for the protection of the Lys and Trp side chains, trityl (Trt) for the protection of the Asn, Gln and His side chains and 2,2,5,7,8-pentamethylcliromane-6-sulfonyl (Pmc) or 2,2,4,6,7-pentamethyldihydrobenzofurane-5-sulfonyl (Pbf) for the protection of the Arg side chain [Barany, G.
- carboxylic component refers to a molecule comprising a free carboxylic function.
- the carboxylic component may be any carboxylic acid, amino acid or oligopeptide which bears a free carboxylic function and whose other functional groups are protected in such a manner that they do not interfere with the desired coupling reaction.
- the amino group of the applied amino acid or oligopeptide is temporarily protected by a benzyloxycarbonyl (Z) function; other examples include—but are not limited to—the Boc, Trt, fluoren-9-ylmethoxycarbonyl (Fmoc), 2-(methylsulfonyl)ethoxycarbonyl (Msc), allyloxycarbonyl (Alloc) functions, functions of the arylsulfonyl type, such as ortho-nitrobenzenesulfonyl (o-NBS) and enzymatically cleavable functions [Geiger, R. and König, W. (1981) in: ‘ The Peptides ’, vol. 3 (Gross, E.
- the carboxylic component may be preactivated as an active ester, preferably an -N-hydroxysuccinimide, benzotriazol-1-yl, pentafluorophenyl or 4-nitrophenyl ester, a halide, an N-carboxyaihydride or as a symmetric anliydride.
- an active ester preferably an -N-hydroxysuccinimide, benzotriazol-1-yl, pentafluorophenyl or 4-nitrophenyl ester, a halide, an N-carboxyaihydride or as a symmetric anliydride.
- the carboxylic component may be activated in situ as a mixed anhydride or using a coupling reagent, such as a carbodimide, preferably N,N′-dicyclohexylcarbodiimide (DCC) or 1-(3′-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), a uronium or a phosphonium salt in the possible presence of a coupling additive, preferably N-hydroxysuccinimide (HONSu), 1-hydroxybenzotriazole (HOBt), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBt), 1-hydroxy-7-azabenzotriazole (HOAt) or 6-chloro-1-hydroxybenzotriazole (Cl-HOBt) and if required in the presence of a tertiary amine [‘ The Peptides ’, vol. 1 (1979) (Gross, EMC),
- the temporary protecting group may be removed according to methods known in the art (vide supra).
- the Z function may be removed by hydrogenolysis using (standard) procedures that apply, e.g. hydrogen gas or formate as a hydrogen donor. During this proces all benzyl-type protecting groups are removed and protecting groups of the t-butyl type or functions of similar lability are maintained. The latter may be removed by acidolysis according to the methods known in the art.
- basic aqueous extractions are preferably performed using aqueous solutions of sodium hydrogencarbonate or sodium carbonate, if desired in the presence of sodium chloride or potassium nitrate.
- active aqueous extraction refers to an extraction in which either an amino component is extracted under acidic conditions in the protonated form (ammonium) or a carboxylic component is extracted under basic conditions in the deprotonated form (carboxylate).
- the mixture was stirred for another 30 minutes and was extracted with 5% NACO 3 /10% NaCI, 5% KHSO 4 /10% NaCl, 5% Na 2 CO 3 /10% NaCl, 30% NaCl and water.
- the organic layer was evaporated to dryness and the residue triturated with methyl tert-butyl ether and dried to give the desired protected tetrapeptide in 95% yield based on the starting material H-Ser( t Bu)-O t Bu. The process was completed within 6 hours.
- the extractions following scavenging were performed at 35° C.
- coupling was performed at 3° C., 1014 g of 1-hydroxybenzotriazole was replaced by 2561 g of 6-chloro-1-hydroxybenzotriazole and a supplementary portion of 132 g of 1-(3′-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added after 1 hour coupling.
- the extractions following hydrogenolysis were performed at 35° C.
- the organic layer was evaporated to dryness to give the desired protected nonapeptide in 73% yield based on the starting material H-Pro-O t Bu.HCI (i.e., on average 98% per chemical step).
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Analytical Chemistry (AREA)
- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/692,354 US20040082760A1 (en) | 2001-07-19 | 2003-10-22 | Process for rapid solution synthesis of peptides |
US10/693,802 US7435791B2 (en) | 2001-07-19 | 2003-10-23 | Process for rapid solution synthesis of peptides |
US10/693,123 US20060063918A1 (en) | 2001-07-19 | 2003-10-23 | Process for rapid solution synthesis of peptides |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP01202753.8 | 2001-07-19 | ||
EP01202753 | 2001-07-19 |
Related Child Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/692,354 Division US20040082760A1 (en) | 2001-07-19 | 2003-10-22 | Process for rapid solution synthesis of peptides |
US10/693,802 Division US7435791B2 (en) | 2001-07-19 | 2003-10-23 | Process for rapid solution synthesis of peptides |
US10/693,123 Division US20060063918A1 (en) | 2001-07-19 | 2003-10-23 | Process for rapid solution synthesis of peptides |
Publications (1)
Publication Number | Publication Date |
---|---|
US20030018164A1 true US20030018164A1 (en) | 2003-01-23 |
Family
ID=8180656
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/199,805 Abandoned US20030018164A1 (en) | 2001-07-19 | 2002-07-19 | Process for rapid solution synthesis of peptides |
US10/692,354 Abandoned US20040082760A1 (en) | 2001-07-19 | 2003-10-22 | Process for rapid solution synthesis of peptides |
US10/693,123 Abandoned US20060063918A1 (en) | 2001-07-19 | 2003-10-23 | Process for rapid solution synthesis of peptides |
US10/693,802 Expired - Lifetime US7435791B2 (en) | 2001-07-19 | 2003-10-23 | Process for rapid solution synthesis of peptides |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/692,354 Abandoned US20040082760A1 (en) | 2001-07-19 | 2003-10-22 | Process for rapid solution synthesis of peptides |
US10/693,123 Abandoned US20060063918A1 (en) | 2001-07-19 | 2003-10-23 | Process for rapid solution synthesis of peptides |
US10/693,802 Expired - Lifetime US7435791B2 (en) | 2001-07-19 | 2003-10-23 | Process for rapid solution synthesis of peptides |
Country Status (26)
Country | Link |
---|---|
US (4) | US20030018164A1 (xx) |
EP (1) | EP1291356B1 (xx) |
JP (1) | JP4142907B2 (xx) |
KR (1) | KR100861031B1 (xx) |
CN (1) | CN1254483C (xx) |
AR (1) | AR034869A1 (xx) |
AT (1) | ATE302792T1 (xx) |
BR (1) | BRPI0202783B1 (xx) |
CA (1) | CA2390358C (xx) |
DE (1) | DE60205693T2 (xx) |
DK (1) | DK1291356T3 (xx) |
EC (1) | ECSP024291A (xx) |
ES (1) | ES2248485T3 (xx) |
HK (1) | HK1050904A1 (xx) |
HR (1) | HRP20020609B1 (xx) |
HU (1) | HUP0202369A2 (xx) |
IL (1) | IL150601A (xx) |
MX (1) | MXPA02006998A (xx) |
NO (1) | NO324245B1 (xx) |
PE (1) | PE20030214A1 (xx) |
PL (1) | PL205559B1 (xx) |
PT (1) | PT1291356E (xx) |
RU (1) | RU2237673C2 (xx) |
SG (1) | SG119160A1 (xx) |
TW (1) | TWI247012B (xx) |
ZA (1) | ZA200205409B (xx) |
Cited By (9)
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WO2007059921A1 (en) | 2005-11-25 | 2007-05-31 | Nanokem S.A. | Solution-phase synthesis of leuprolide and its intermediates |
WO2007059922A1 (en) * | 2005-11-25 | 2007-05-31 | Synthacon Gmbh | Synthesis of carbon acid amides |
US20090069538A1 (en) * | 2006-03-01 | 2009-03-12 | Hiroshi Murao | Method of Producing Peptide |
US20090093016A1 (en) * | 2006-01-17 | 2009-04-09 | N.V. Organon | Selective Enzymatic Hydrolysis of C-Terminal Tert-Butyl Esters of Peptides |
EP2409982A3 (en) * | 2010-02-25 | 2012-02-08 | Corning Incorporated | Chemical processes generating solid(s) carried out continuously within microreactors |
US9334302B2 (en) | 2011-12-15 | 2016-05-10 | Ajinomoto Co., Inc. | Method for removing FMOC group |
US11098078B2 (en) | 2015-03-04 | 2021-08-24 | Jitsubo Co., Ltd. | Peptide synthesis method |
US11420997B2 (en) | 2018-04-13 | 2022-08-23 | Jitsubo Co., Ltd. | Peptide synthesis method |
US11827660B2 (en) | 2019-02-01 | 2023-11-28 | Sederma | Synthesis strategy for gap protecting group |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL150601A (en) * | 2001-07-19 | 2010-06-30 | Organon Nv | Process for rapid synthesis of peptides within a solution using the back of an activated carboxyl component and destruction of the residual activated carboxyl component |
US8124372B2 (en) | 2007-06-25 | 2012-02-28 | N.V. Organon | Selective enzymatic amidation of C-terminal esters or acids of peptides |
DK2167673T3 (da) * | 2007-06-25 | 2011-04-18 | Organon Nv | Fremgangsmåde til omdannelse af C-terminale peptidestere eller -syrer til amider under anvendelse af subtilisin i tilstedeværelsen af ammoniumsalte |
US9850274B2 (en) * | 2008-12-30 | 2017-12-26 | Gkl-Biotec Ag | Peptide combination |
KR101032399B1 (ko) * | 2010-02-11 | 2011-05-03 | 주식회사 이너트론 | 밴드패스필터의 철재하우징 및 그 제조방법 |
FR3090636B1 (fr) * | 2018-12-24 | 2021-01-01 | Strainchem | Procédé de synthèse de peptides |
US20230056969A1 (en) | 2019-12-27 | 2023-02-23 | Chugai Seiyaku Kabushiki Kaisha | Method for synthesizing peptide compound |
WO2021192488A1 (ja) * | 2020-03-27 | 2021-09-30 | 株式会社カネカ | アミド結合含有化合物の製造方法 |
JP7063408B1 (ja) | 2021-07-02 | 2022-05-09 | ペプチスター株式会社 | 液相ペプチド製造方法 |
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US5101059A (en) * | 1989-12-05 | 1992-03-31 | Research Corporation Technologies, Inc. | Amino acid protecting groups |
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US5516892A (en) | 1992-12-28 | 1996-05-14 | Indiana University Foundation | Polymer-bound mixed carboxylic anhdrides as a stable form of activated carboxylic acids |
US6310180B1 (en) * | 1993-06-21 | 2001-10-30 | Vanderbilt University | Method for synthesis of proteins |
US6001966A (en) | 1995-10-19 | 1999-12-14 | Proligo Llc | Method for solution phase synthesis of oligonucleotides and peptides |
US5698676A (en) | 1995-11-30 | 1997-12-16 | Abbott Laboratories | Use of propylene oxide as an acid scavenger in peptide synthesis |
US5849954A (en) * | 1996-01-18 | 1998-12-15 | Research Corporation Technologies, Inc. | Method of peptide synthesis |
CA2251700A1 (en) | 1996-05-03 | 1997-11-13 | Warner-Lambert Company | Rapid purification by polymer supported quench |
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- 2002-07-04 IL IL150601A patent/IL150601A/en active IP Right Grant
- 2002-07-04 TW TW091114832A patent/TWI247012B/zh not_active IP Right Cessation
- 2002-07-05 JP JP2002197550A patent/JP4142907B2/ja not_active Expired - Lifetime
- 2002-07-05 ZA ZA200205409A patent/ZA200205409B/xx unknown
- 2002-07-15 PT PT02077830T patent/PT1291356E/pt unknown
- 2002-07-15 ES ES02077830T patent/ES2248485T3/es not_active Expired - Lifetime
- 2002-07-15 DE DE60205693T patent/DE60205693T2/de not_active Expired - Lifetime
- 2002-07-15 SG SG200204298A patent/SG119160A1/en unknown
- 2002-07-15 EP EP02077830A patent/EP1291356B1/en not_active Expired - Lifetime
- 2002-07-15 AT AT02077830T patent/ATE302792T1/de active
- 2002-07-15 DK DK02077830T patent/DK1291356T3/da active
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- 2002-07-18 KR KR1020020041898A patent/KR100861031B1/ko not_active IP Right Cessation
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- 2002-07-18 AR ARP020102687A patent/AR034869A1/es active IP Right Grant
- 2002-07-18 CA CA002390358A patent/CA2390358C/en not_active Expired - Lifetime
- 2002-07-18 CN CNB021261911A patent/CN1254483C/zh not_active Expired - Lifetime
- 2002-07-18 HU HU0202369A patent/HUP0202369A2/hu unknown
- 2002-07-18 NO NO20023446A patent/NO324245B1/no not_active IP Right Cessation
- 2002-07-18 RU RU2002119630/04A patent/RU2237673C2/ru not_active IP Right Cessation
- 2002-07-19 PL PL355125A patent/PL205559B1/pl not_active IP Right Cessation
- 2002-07-19 EC EC2002004291A patent/ECSP024291A/es unknown
- 2002-07-19 HR HR20020609A patent/HRP20020609B1/xx not_active IP Right Cessation
- 2002-07-19 US US10/199,805 patent/US20030018164A1/en not_active Abandoned
-
2003
- 2003-04-29 HK HK03103037A patent/HK1050904A1/xx not_active IP Right Cessation
- 2003-10-22 US US10/692,354 patent/US20040082760A1/en not_active Abandoned
- 2003-10-23 US US10/693,123 patent/US20060063918A1/en not_active Abandoned
- 2003-10-23 US US10/693,802 patent/US7435791B2/en not_active Expired - Lifetime
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Cited By (15)
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US8013117B2 (en) | 2005-11-25 | 2011-09-06 | Nanokem S.A. | Solution-phase synthesis of leuprolide and its intermediates |
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