WO2013098802A2 - Synthèse peptidique en phase solide par une fixation par chaîne latérale - Google Patents

Synthèse peptidique en phase solide par une fixation par chaîne latérale Download PDF

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Publication number
WO2013098802A2
WO2013098802A2 PCT/IB2013/051544 IB2013051544W WO2013098802A2 WO 2013098802 A2 WO2013098802 A2 WO 2013098802A2 IB 2013051544 W IB2013051544 W IB 2013051544W WO 2013098802 A2 WO2013098802 A2 WO 2013098802A2
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WIPO (PCT)
Prior art keywords
resin
trt
protecting group
group selected
peptide
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Application number
PCT/IB2013/051544
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English (en)
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WO2013098802A3 (fr
Inventor
Kleomenis K. Barlos
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Chemical & Biopharmaceutical Laboratories Of Patras S.A.
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Priority claimed from US13/772,793 external-priority patent/US9388212B2/en
Application filed by Chemical & Biopharmaceutical Laboratories Of Patras S.A. filed Critical Chemical & Biopharmaceutical Laboratories Of Patras S.A.
Publication of WO2013098802A2 publication Critical patent/WO2013098802A2/fr
Publication of WO2013098802A3 publication Critical patent/WO2013098802A3/fr

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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
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C07K1/042—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers characterised by the nature of the carrier

Definitions

  • Peptides and peptaibols of high purity were obtained by solid phase peptide synthesis using as the starting resin hydroxy amino acids, hydroxy amino acid amides, hydroxy amino alcohols or small peptides containing hydroxy amino acids attached to polymers through their side chain.
  • Hya or "hydroxyl amino acid(s)” means amino acids that contain a hydroxyl (-OH) group.
  • N-terminus or amino terminus is the first amino acid in a peptide chain.
  • C-terminus or carboxy terminus is the last amino acid in the peptide chain as shown below.
  • P or "solid support” or “resin” means an insoluble material containing a functional group(s) suitable to react and link with an amino acid or peptide.
  • the solid support or resins are well known in the art.
  • Alkyl such as Ci_ 10 alkyl or C 1-6 alkyl, means a branched or unbranched fully saturated acyclic aliphatic hydrocarbon group (i.e. composed of carbon and hydrogen containing no double or triple bonds).
  • alkyls may be substituted or unsubstituted.
  • Alkyls may include, but are not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like, and in some embodiment, each of which may be optionally substituted.
  • Nonexclusive alkyl substituents may include Ci_ 3 alkoxy, halo (F, CI, Br or I), nitro, amino, -SH and - OH.
  • Attachment means the linking of an amino acid or a peptide or peptide derivative to an insoluble support.
  • Hse means homoserine
  • Hnv means hydroxylnorvaline
  • SPPS solid phase peptide synthesis
  • NA means 4-nitro anilide
  • DME dimethoxy ethane
  • Acid sensitive resin means an insoluble material or resin containing a functional group(s) suitable to react and link with an amino acid or peptide, which may be cleaved from the peptide by acidic treatment.
  • Acid sensitive protecting group means a protecting group which may be cleaved from the amino acid or peptide or peptide derivative by acidic treatment or under acidic condition.
  • Phenaibol means a peptide which contain at its C-terminal position an amino alcohol instead of an amino acid or an amino acid amide.
  • Step-by-step means the method of peptide synthesis where any of the amino acids contained in the peptide chain is introduced individually and sequentially. The method may or may not involve an intermediate purification step.
  • Protected peptide means the peptide with all functional groups blocked or protected by protecting groups.
  • Partially protected peptide means the peptide which contains at least one functional group blocked or protected by a protecting group.
  • Solid phase peptide synthesis is traditionally performed by the attachment of the C- terminal amino acid through its a-carboxyl function on a suitable solid support and elongating the peptide chain towards the amino terminal of the peptide by adding sequentially the amino acid residues in the gradually growing peptide chain.
  • the peptides were produced very efficiently in high yield and purity by attaching a hydroxy amino acid through its amino acid side chain, or a small peptide which contain in its sequence a hydroxy amino acid on a resin of the trityl or benzhydryl-type, resulting in amino acid-resin conjugates or peptide resin conjugates of Fonnula I-IV, wherein P is a solid-phase support selected from the supports used in solid phase peptide synthesis, Pr 1 is H or an amino protecting group selected from Fmoc, Boc, Trt, Dde and Alloc, wherein Pr 2 is an acid sensitive hydroxyl protecting group selected from Trt, Clt, Mmt, Mtt, Dpm and tBu, wherein Hya is a hydroxy amino acid selected from D- or L-Ser, Thr, Tyr, Hse, Hyp, Hnv etc ., and A is OH, an acid sensitive alkoxy group selected from OTrt,
  • peptaibols such as octreotide
  • peptaibols were obtained by solid phase synthesis using the resin-bound amino alcohols of the Formula III- VI selected from amino alcohols which are derived from the naturally occurring hydroxy amino acids, wherem P, X, V, Z and Pr 1 are as defined above, wherein R 3 , R 4 are alkyl, aryl or aralkyl groups, and Pr 2 is an acid sensitive protecting group of the trityl, benzhydryl or benzyl type.
  • peptides prepared with the application of resins of the Formula I-IV may be cleaved from the resin by mild acidic treatment and wherein the side chain protecting groups of the tBu and benzyl-type remain intact.
  • the cleavage from the resin occurs by the treatment with 1-3 % acid solutions, such as TFA, diluted HC1 solutions, optionally adding scavengers, in a solvent.
  • the cleavage may be performed in a solvent such as DCM or acetone.
  • Such partially protected peptides have been found to be useful in the synthesis of longer peptides by fragment condensation in solution or on solid phase.
  • the present method expands the versatility of the application of the resins described herein, and also results in significantly improving the purity of the resulting pharmaceutical peptides, and at the same time, substantially reducing the cost of their synthesis.
  • Lanreotide was produced by solid phase synthesis using resin-bound Thr-amide as shown below:
  • the human insulin B chain was synthesized by SPPS.
  • the synthesis begins from the resin-bound Thr-t-butyl ester as described in the example, using the 4- methoxy benzhydryl resin.
  • the synthesis may also be performed on solid phase by condensing the 1-8 partially protected Boc-Phe-Val-Asn(Trt)-Gln(Trt)-His(Trt)-Leu-Cys(Trt)- Gly-OH fragment with the resin-bound 9-30 fragment; or after the selective cleavage of the partially protected 9-30 fragment from the resin with condensation in solution of the 1-8 and 9-30 fragments.
  • Salmon Calcitonin [0028] Optionally salmon calcitonin may be produced starting the synthesis from resin bound Fmoc-Thr-Pro-NH 2 . The peptide chain is then elongated using Fmoc-amino acids.
  • the resin-bound salmon calcitonin is produced by fragment condensation on the resin as shown above, for example, or in solution as shown below using 2-4 fragments.
  • octreotide was efficiently synthesized by the attachment of Fmoc-threoninol-OTrt to the 4-methoxybenzhydryl resin through the side chain of threoninol as shown below, followed by the octreotide chain assembly using Fmoc-amino acids and finally cleaving octreotide from the resin with subsequent or simultaneous Cys-oxidation.
  • Fmoc- threoninol-OTrt is much easier to be produced than the Fmoc-Thr(tBu)-ol which may be attached onto the resin through the hydroxymethyl group of threoninol on a suitable resin.
  • H-Thr(OtBu)-ol used as the starting material for the production of Fmoc-Thr(tBu)-ol, is much more difficult to be produced than Fmoc-threoninol-OTrt used in the attachment of threoninol through its side chain onto the resin.
  • Fmoc-Ser-NH 2 was attached through its side chain on trityl resin and used for the synthesis of exenatide.
  • the synthesis may be performed by the step-by-step manner or by fragment condensation in solution after cleavage a partially protected exenatide fragment from the resin by mild acidic treatment or on solid phase, as described below.
  • This method most impurities typically formed during the synthesis of many Pro and Gly residues containing peptides are completely avoided and peptides of high purity are obtained.
  • the method also allows the complete avoidance of impurities originating from the cleavage of peptides from peptide amide linkers using other methods known in the art, which significantly reduce the yields and purity of the peptide. : Fmoc-Ser(Resin)-NH 2
  • exenatide may be produced by cleavage of the partially protected peptide 12-39 from the resin and condensing it in solution as shown below with the partially protected 1- 11 fragment.
  • the condensation to obtain protected exenatide may be performed with the fragments 1-13 and 14-39.
  • the method is also highly effective in the production of amylin peptides.
  • the side chain attachment may be performed using one of the C-terminal Ser, Thr or Tyr residues of amylin or its derivatives such as pramlintide.
  • the synthesis may be performed in the step-by- step manner or by fragment condensation in solution or on solid phase.
  • pseudoprolines ⁇ , see Mutter et al, Peptide Res. (1995 8, 145) into the growing peptide chain, the synthesis is accelerated and the purity of the peptide obtained is improved.
  • the synthesis of pramlintide may be performed in liquid phase with equal success concerning the purity and the yield of the obtained pramlintide.
  • the protected peptide which is bound on the resin through the side chain of Fmoc-Tyr- H 2 may be quantitatively cleaved from the resin with the side chain protecting groups of the tBu-type remaining intact, using mild acidic treatment at various positions of the peptide chain.
  • the partially protected 1-10 fragment prepared on the 2-chlorotrityl resin in the step by step manner was condensed successfully with the partially protected 11-37 fragment amide.
  • Resin 2-chlorotrityl resin 1 %-TFA/DCM/TES
  • ACTH 1-24 was effectively prepared starting from resin-bound Fmoc-Tyr-Pro-OtBu by the step by step procedure or by condensing the 1-10 partially protected fragment in solution with the 11-24 fragment or with the resin-bound 1 1-24 fragment, as shown below.
  • bivalirudin was produced in high yield and high purity starting from resin-bound Fmoc-Tyr-Leu-OtBu, extending the peptide chain in the step-by-step manner with Fmoc-amino acids and finally deprotecting and cleaving the peptide from the resin as shown below.
  • bivalirudin was obtained by the condensation of protected fragments on the resin or by cleaving a partially protected peptide which contain 4-15 amino acid residues from the resin and condensing it in solution with a bivalirudin fragment which contain 5-16 amino acids. The bivalirudin synthesis by fragment condensation on the resin of the 1-10 partially protected bivalirudin fragment with the resin-bound 11-20 partially protected bivalirudin fragment is described below.
  • Trt-Thr-OMe prepared from H-Thr-OMe by its reaction with Trt-Cl/Me 3 SiCl and DIPEA following conventional methods were reacted with 20 g (30 mmol) of 4-methoxy 4'- polystyryl benzhydryl bromide resin (product of CBL-Patras) and 60 mmol DIPEA in 250 ml TUF for 10 h at RT. To the mixture were then added 60 mmol methanol and the mixture was shaken for additional 4 h.
  • the resin was filtered and washed 3X with THF/ eOH/DIPEA (85:10:5), 3X DCM, 3X 1% TFA in DCM, 4X THF, 3X lN-LiOH in THF/Water/Methanol (70: 15:15), 3X THF/Water (75:25) 4X DMF and then reacted for 2 h at RT with 60 mmol Fmoc- OSu and 30 mmol DIPEA, washed 3X DMF, 3X DCM and then reacted for 3h at RT with 50 mmol Trt-Cl and 50 mmol DIPEA, washed 4X DMF, 6X DEE and dried in vacuum to constant weight. 32.3 g of resin-bound Fmoc-Thr-OtBu were obtained with a loading of 0.78 mmol/g resin.
  • Trt-Thr-OMe prepared from H-Thr-OMe by its reaction with Trt-Cl/Me 3 SiCl and DIPEA following conventional methods were reacted with 20 g (30 mmol) of 4-methoxy 4'- polystyryl benzhydryl bromide resin (product of CBL-Patras) and 60 mmol DIPEA in 250 ml THF for 10 h at RT. To the mixture were then added 60 mmol methanol and the mixture was shaken for additional 4 h.
  • the resin was filtered and washed 3X with THF/MeOH/DIPEA (85: 10:5), 5X TFfF, and then reacted with 30 mmol L1BH 4 in THF.
  • the resin was then filtered and washed 6X THF, 4X DCM, 6X 1% TFA in DCM, 3X with DMF/DIPEA (97:3) and then reacted for 2 h at RT with 60 mmol Fmoc-OSu and 30 mmol DIPEA, washed 3X DMF, 3X DCM and then reacted for 3h at RT with 50 mmol Clt-Cl and 50 mmol DIPEA, washed 4X DMF, 6X IPA and 6X DEE and dried in vacuum to constant weight. 34.7 g of resin-bound Fmoc-Throl-O- Clt were obtained with a loading of 0.74 mmol/g resin.
  • Fmoc-Tyr-Pro-OtBu 50 mmols of Fmoc-Tyr-Pro-OtBu were prepared according to standard procedures known in the art, were dissolved in 0.5 liter of DCM. To the resulting solution 30 g of 2-chlorotrityl chloride resin (48 mmol) were added and 65 mmol DIPEA and the mixture was stirred for 12 h at RT. Then 25 ml methanol and 50 mmol DIPEA were added and the mixture was stirred for additional 2h at RT. The resin was then filtered and washed 3X with DCM/MeOH/DIPEA (90:5:5), 5X DMF, 4X IPA, 4X DEE and dried in vacuum to constant weight. 44.5 g of Fmoc- Tyr-Pro-OtBu containing resin with a loading of 0.64 mmol/g was obtained.
  • CTC-C1 2-Chlorotrityl chloride resin (1 0 g; loading 1.6 mmol/g) of CBL-Patras, is placed in a 2 L peptide synthesis reactor and is swollen with 700 mL dichloromethane
  • the resin is then washed four times with 500 mL DMF.
  • the resin is deswelled with 3 washes with 500 mL of isopropanol (EPA).
  • EPA isopropanol
  • the resin is dried to constant weight. On the resin was bound the 70-95% of the mmol of the used amino acid.
  • the resin was placed in a 15 ml reactor and treated twice with 7 mL NMP, followed by filtration.
  • Fmoc-amino acids Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn-OH, Fmoc-Asn(Trt)-OH, Fmoc-D- Cys(Trt)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Gln-OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Hyp(tBu)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc- Met-OH, Fmoc-D-Phe-OH, Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-
  • C General method for the acidic cleavage from the CTC- resin of peptides and of protected peptide segments, which contain Fmoc- or Boc-groups on their N-terminus.
  • Example 18 Salmon calcitonin
  • Example 22 Tetracosactide (ACTH 1-24)
  • Synthetic polypeptide Synonyms: Pramlintide; amylin analogue ⁇ 400> SEQUENCE: 17

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Analytical Chemistry (AREA)
  • Peptides Or Proteins (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne des peptides et des peptaibols de pureté élevée pouvant être obtenus par une synthèse peptidique en phase solide à l'aide, comme résine de départ, d'acides hydroxy aminés, des amides d'acides hydroxy aminés, des alcools hydroxy aminés ou de petits peptides contenant des acides hydroxy aminés fixés à des polymères par l'intermédiaire de leur chaîne latérale.
PCT/IB2013/051544 2011-12-29 2013-02-26 Synthèse peptidique en phase solide par une fixation par chaîne latérale WO2013098802A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201161581503P 2011-12-29 2011-12-29
US61/581,503 2011-12-29
US13/772,793 2013-02-21
US13/772,793 US9388212B2 (en) 2013-02-21 2013-02-21 Solid phase peptide synthesis via side chain attachment

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WO2013098802A2 true WO2013098802A2 (fr) 2013-07-04
WO2013098802A3 WO2013098802A3 (fr) 2014-02-27

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014203193A1 (fr) * 2013-06-19 2014-12-24 Chemical & Biopharmaceutical Laboratories Of Patras S.A. Conjugué peptide-résine et son utilisation
CN105713082A (zh) * 2014-12-04 2016-06-29 深圳翰宇药业股份有限公司 一种制备利西拉来的方法
WO2017178950A1 (fr) * 2016-04-11 2017-10-19 Emcure Pharmaceuticals Limited Procédé de préparation d'acétate de lanréotide
CN108059667A (zh) * 2018-02-10 2018-05-22 润辉生物技术（威海）有限公司 一种兰瑞肽的固相合成方法
CN108503687A (zh) * 2018-04-08 2018-09-07 南京医科大学 成胶因子的制备方法和水凝胶的制备方法以及应用
CN109912709A (zh) * 2019-04-15 2019-06-21 北京大学深圳研究生院 一种酸敏感离子通道抑制剂的制备方法
WO2019184089A1 (fr) * 2018-03-29 2019-10-03 深圳翰宇药业股份有限公司 Composé, son procédé de préparation et son utilisation
WO2020027737A1 (fr) * 2018-07-31 2020-02-06 Agency For Science, Technology And Research Acide aminé hydroxy supporté par un solide et alcool aminé supporté par un solide
CN111378009A (zh) * 2018-12-27 2020-07-07 江苏金斯瑞生物科技有限公司 一种奥曲肽的制备方法
WO2020170185A1 (fr) * 2019-02-21 2020-08-27 Dr. Reddy’S Laboratories Limited Lanréotide sensiblement pur ou son sel et méthode associée
CN111825742A (zh) * 2019-04-18 2020-10-27 陈铭 Ctpa作为特种偶合剂用于氨基酸离子液体的多肽固相合成
CN113135979A (zh) * 2020-01-18 2021-07-20 深圳市健翔生物制药有限公司 一种肽的固相合成方法
WO2022217395A1 (fr) * 2021-04-12 2022-10-20 南京汉欣医药科技有限公司 Corticotropine humaine de grande pureté ou analogue de celle-ci, et son procédé de préparation à grande échelle

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EP2270025A1 (fr) * 2009-06-29 2011-01-05 Centre National pour la Recherche Scientifique (CNRS) Synthèse de peptide en phase solide d'alcools peptidiques

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A. BERNHARDT; M. DREWELLO; M. SCHUTKOWSKI: "The solid-phase synthesis of side-chain-phosphorylated peptide-4-nitroanilides", J PEPTIDE RES., vol. 50, 1997, pages 143 - 152
C. CABRELE; M. LANGER; A. G. BECK-SICKINGER: "Amino Acid Side Chain Attachment Approach and Its Application to the Synthesis of Tyrosine-Containing Cyclic Peptides", J ORG. CHEM., vol. 64, 1999, pages 4353 - 4361, XP002258925, DOI: doi:10.1021/jo982402j
L. RIZZI; K. CENDIC; N. VAIANA; S. ROMEO: "Alcohols immobilization onto 2-chlorotritylchloride resin under microwave irradiation", TETRAHEDRON LETTERS, vol. 52, 2011, pages 2808 - 2811, XP028198985, DOI: doi:10.1016/j.tetlet.2011.03.113
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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014203193A1 (fr) * 2013-06-19 2014-12-24 Chemical & Biopharmaceutical Laboratories Of Patras S.A. Conjugué peptide-résine et son utilisation
CN105713082B (zh) * 2014-12-04 2020-12-01 深圳翰宇药业股份有限公司 一种制备利西拉来的方法
CN105713082A (zh) * 2014-12-04 2016-06-29 深圳翰宇药业股份有限公司 一种制备利西拉来的方法
WO2017178950A1 (fr) * 2016-04-11 2017-10-19 Emcure Pharmaceuticals Limited Procédé de préparation d'acétate de lanréotide
CN108059667A (zh) * 2018-02-10 2018-05-22 润辉生物技术（威海）有限公司 一种兰瑞肽的固相合成方法
CN110317188B (zh) * 2018-03-29 2023-01-17 深圳翰宇药业股份有限公司 化合物及其制备方法和应用
WO2019184089A1 (fr) * 2018-03-29 2019-10-03 深圳翰宇药业股份有限公司 Composé, son procédé de préparation et son utilisation
CN110317188A (zh) * 2018-03-29 2019-10-11 深圳翰宇药业股份有限公司 化合物及其制备方法和应用
CN108503687A (zh) * 2018-04-08 2018-09-07 南京医科大学 成胶因子的制备方法和水凝胶的制备方法以及应用
WO2020027737A1 (fr) * 2018-07-31 2020-02-06 Agency For Science, Technology And Research Acide aminé hydroxy supporté par un solide et alcool aminé supporté par un solide
CN111378009A (zh) * 2018-12-27 2020-07-07 江苏金斯瑞生物科技有限公司 一种奥曲肽的制备方法
WO2020170185A1 (fr) * 2019-02-21 2020-08-27 Dr. Reddy’S Laboratories Limited Lanréotide sensiblement pur ou son sel et méthode associée
CN109912709A (zh) * 2019-04-15 2019-06-21 北京大学深圳研究生院 一种酸敏感离子通道抑制剂的制备方法
CN109912709B (zh) * 2019-04-15 2023-07-14 北京大学深圳研究生院 一种酸敏感离子通道抑制剂的制备方法
CN111825742A (zh) * 2019-04-18 2020-10-27 陈铭 Ctpa作为特种偶合剂用于氨基酸离子液体的多肽固相合成
CN111825742B (zh) * 2019-04-18 2024-01-30 陈铭 Ctpa作为特种偶合剂用于氨基酸离子液体的多肽固相合成
CN113135979A (zh) * 2020-01-18 2021-07-20 深圳市健翔生物制药有限公司 一种肽的固相合成方法
WO2022217395A1 (fr) * 2021-04-12 2022-10-20 南京汉欣医药科技有限公司 Corticotropine humaine de grande pureté ou analogue de celle-ci, et son procédé de préparation à grande échelle

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