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WO2008044890A1 - Procédé permettant de préparer des peptides par synthèse en phase solide - Google Patents

Procédé permettant de préparer des peptides par synthèse en phase solide Download PDF

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Publication number
WO2008044890A1
WO2008044890A1 PCT/KR2007/004989 KR2007004989W WO2008044890A1 WO 2008044890 A1 WO2008044890 A1 WO 2008044890A1 KR 2007004989 W KR2007004989 W KR 2007004989W WO 2008044890 A1 WO2008044890 A1 WO 2008044890A1
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WO
WIPO (PCT)
Prior art keywords
fmoc
resin
group
peptide
leu
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.)
Ceased
Application number
PCT/KR2007/004989
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English (en)
Inventor
Kyoung Min Kim
Sun Jong Ryoo
Kyung Hoi Cha
Dae Sung Lim
Han Won Lee
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.)
Dong Kook Pharmaceutical Co Ltd
Original Assignee
Dong Kook 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
Priority claimed from KR1020070102700A external-priority patent/KR101046846B1/ko
Application filed by Dong Kook Pharmaceutical Co Ltd filed Critical Dong Kook Pharmaceutical Co Ltd
Publication of WO2008044890A1 publication Critical patent/WO2008044890A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/23—Luteinising hormone-releasing hormone [LHRH]; Related peptides

Definitions

  • the present invention relates to novel process for preparing goserelin, buserelin and leuprolide peptide having potent pharmacological activity.
  • Buserelin a synthetic gonadotropin-releasing hormone (GRH) agonist, specifically binds to GRH receptor presented at anter iorpituitary and increases or decreases the number of receptors in hypophysis through auto- regulation mechanism (G. Tolis et al., Tumor Growth Inhibition in Patients with Prostatic Carcinoma Treated with Luteinizing Hormone-Feleasing Hormone Agonists, Proc. Natl. Acad. Sci. , 79, pl658, 1982).
  • G. Tolis et al. Tumor Growth Inhibition in Patients with Prostatic Carcinoma Treated with Luteinizing Hormone-Feleasing Hormone Agonists, Proc. Natl. Acad. Sci. , 79, pl658, 1982.
  • Buserelin PyrHis-TrrSerTyrD-SerfiBiiJ-Leu-ArrPrO-NH-CHi-CHj (acetate salt)
  • amino acid derivatives disclosed herein comprises the derivatives protected by the protecting group at N-termina? group and side chain groups thereof selected from Boc UerHDutoxycarbonyl), Fmoc (9- fluorenylmethoxycarbonyl) or Cbz (benzy1oxycarbony1) group, preferably, Fmoc group.
  • the reaction temperature disclosed herein ranges from ⁇ about 0 to 70°C, preferably, about 20 to 50 ° C, and the reaction period disclosed herein ranges from 10 mins to 48 hours, preferably, 1 hour to 24 hours considering both of the reactivity of each reactants and the productivity of final product, but it dose not limited thereto. However, the reaction may be performed repeatedly, twice to five times to obtain purposed increased reaction yield.
  • the "link" group in the rink amide resin may be preferably rinkamide group having following chemical formulae (d); [Chemistry Figure 4] resin
  • the peptide of step 4 is released from the resin by adding weak acidic cleavage solution such as 2% TFA (trifluoroacetic acid)/DCM (dichloromethane) to the peptide resin in the 5 step; after adding hydrazine solution thereto, the side-chain protecting groups, i.e., benzyl group, nitro group, Cbz group etc are removed through catalyst hydrogen transfer reaction using by Pd/C and cyclohexadiene etc to obtain peptide and the peptide is performed to purification process using by reverse phase column chromatography and ion exchange resin to obtain purposed goserelin acetate salt in the 6 step.
  • weak acidic cleavage solution such as 2% TFA (trifluoroacetic acid)/DCM (dichloromethane)
  • the peptide of step 4 is released from the resin by adding weak acidic cleavage solution such as 2% TFA (trifluoroacetic acid)/DCM (dichloromethane) to the peptide resin to obtain peptide derivative, i.e., TFA (trifluoroacetic acid)/DCM (dichloromethane)
  • weak acidic cleavage solution such as 2% TFA (trifluoroacetic acid)/DCM (dichloromethane
  • the peptide of step 4 is released from the resin by adding weak acidic cleavage solution such as 2%-50% TFA (trifluoroacetic acid)/DCM (dichloromethane) to the peptide resin to obtain peptide derivative, i.e., Pyr-His-Try-Ser(Bzl)-Tyr(Bzl)-DLeu-Leu-Arg(N0 2 ) and then the derivative is reacted with PrO-NH-CH 2 CH 3 and coupling reagent to obtain Pyr-His-Try-
  • weak acidic cleavage solution such as 2%-50% TFA (trifluoroacetic acid)/DCM (dichloromethane
  • chain protecting groups i.e., benzyl group, nitro group etc are removed through catalytic hydrogen transfer reaction using by Pd/C and cyclohexadiene etc to obtain peptide and the peptide is performed to purification process using by reverse phase column chromatography and ion exchange resin to obtain purposed leuprolide acetate salt in the 6 step.
  • link 2-chlorotrityl chloride represented by following chemical formulae (e) can be preferably used as the "link" in the 2-chlorotrityl chloride type link-arginine type resin disclosed in the above-described synthetic methods for buserelin and leuprolide: [Chemistry Figure 5]
  • the coupling reaction of amino acid disclosed in above-described synthetic methods for buserelin and leuprolide can be performed using by at least one activator selected from the group consisting of; the activated ester of each amino acid, DCC (Dicyclohexyl carbodiimide), DIC (Diisopropyl carbodiimide), BOP (Benzotriazole-lyl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate) , PyBOP (Benzotriazol-1-yl-oxytripyrrol idinenophosphonium hexafluorophosphate), HBTU (0-Benzotriazole-N,N,N'N'tetramethyluronium hexafluorophosphate), TBTU (0-(Benzotriazol-lyl)-N,N,N'N'tetramethyluronium tetrafluoroborate), HATU (2-(lH
  • inventive method of the present invention characterized in coupling the amino acid derivatives of which amino-terminal group as well as all the side chains are protected, with high molecular support s.de-by side, can provide more favorable advantages over the conventionally known synthetic methods for goserelin, buserelin and leuprolide, for example, high yield and high purity etc. [Advantageous Effects]
  • ⁇ 70> Present invention related to the preparation method of goserelin, buserelin and leuprolide using by solid phase synthesis, specifically, reacting amino acid derivatives on rink amide linker introduced modified polystyrene resin side by side to obtain peptide resin and releasing the peptide from the resin to obtain purposed peptides. Accordingly, the inventive preparation methods exhibit more advantageous effects, such as easiness to synthesis, mass production, high yield, high purity of final product etc over the conventionally known synthetic methods showing unsolved problems, such as high cost, limitation to mass production etc.
  • the resulted resin - was treated with 20% piperidine to remove the Fmoc group and the reaction mixture mixed with 615 mg of Fmoc-Leu-0H (1.74 mmol) and 271 microliter of DIC (1.74 mmol) was added thereto to react together with a similar way to the above-described method.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc group and the reaction mixture mixed with 670 mg of Fmoc-D-Ser(tBu)-OH (1.74 mmol) and 271 microliter of DIC (1.74 mmol) was added thereto again to react together with a similar way to the above- described method.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc residue and the reaction mixture mixed with 859 mg of Fmoc-Tyr(OBzI)-OH (1.74 mmol) and 271 microliter of DIC (1.74 mmol) was added thereto again to react together with a similar way to the above-described method.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc group and the reaction mixture mixed with 726 mg of Fmoc-Ser(OBzI)-OH (1.74 mmol) and 271 microliter of DIC (1.74 mmol) was added thereto again to react together with a similar way to the above-described method.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc group and the reaction mixture mixed with 742 mg of Fmoc-Trp-0H (1.74 mmol) and 271 microliter of DIC (1.74 mmol) was added thereto again to react together with a similar way to the above-described method.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc group and the reaction mixture mixed with 1.078g of Fmoc-His(Fmoc)-0H (1.74 mmol) and 271 microliter of DIC (1.74 mmol) was added thereto again to react together with a similar way to the above-described method.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc group and the reaction mixture mixed with 244 mg of Pyr-OH (1.74 mmol) and 271 microliter of DIC (1.74 mmol) was added thereto again to react together with a similar way to the above- described method.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc residue and the reaction mixture mixed with 768 mg of Fmoc-Arg(N02)-0H (1.74 mM) and 271 microliter of DIC (1.74 mM) was added thereto to react together with a similar way to the above-described method. After washing the resin, the reaction mixture mixed with 384 mg of Fmoc-Arg(N02)-0H (0.87 mM) and 136 microliter of DIC (0.87 mM) was added thereto again to react together and the resin was washed again.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc residue and the reaction mixture mixed with 615 mg of Fmoc- Leu-OH (1.74 mM) and 271 microliter of DIC (1.74 mM) was added thereto to react together with a similar way to the above-described method.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc residue and the reaction mixture mixed with 670 mg of Fmoc-D- Ser (tBu)-OH (1.74 mM) and 271 microliter of DIC (1.74 mM) vas added thereto again to react together with a similar way to the above-described method.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc residue and the reaction mixture mixed with 859 mg of Fmoc-Tyr(OBzI)-OH (1.74 mM) and 271 microliter of DIC (1.74 mM) was added thereto again to react together with a similar way to the above-described method.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc residue and the reaction mixture mixed with 726 mg of Fmoc-Ser(OBzI)-OH (1.74 mM) and 271 microliter of DIC (1.74 mM) was added thereto again to react together with a similar way to the above- described method.
  • the resulted r.esin was treated with 20% piperidine to remove the Fmoc residue and the reaction mixture mixed with 742 mg of Fmoc-Trp-OH (1.74 mM) and 271 microliter of DIC (1.74 mM) was added thereto again to react together with a similar way to the above- described method.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc residue and the reaction mixture mixed with 1.13g of Fmoc-His(Mmt)-0H (1.74 mM) and 271 microliter of DIC (1.74 mM) was added thereto again to react together with a similar way to the above- described method.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc residue and the reaction mixture mixed with 244 mg of Pyr-OH (1.74 mM) and 271 microliter of DIC (174 mM) was added thereto again to react together with a similar way to the above-described method.
  • the benzyl group and Cbz group among the side chain protecting group in the peptide were removed through catalytic hydrogen transfer reaction using by Pd/C and cyclohexadiene in the presence of methanol.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc residue and the reaction mixture mixed with 670 mg of Fmoc-D- SeKtBu)-OH (1.74 mM) and 271 microliter of DIC (1.74 mM) was added thereto again to react together with a similar way to the above-described method.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc residue and the reaction mixture mixed with 859 mg of Fmoc-Tyr(OBzI)-OH (1.74 mM) and 271 microliter of DIC (1.74 mM) was added thereto again to react together with a similar way to the above-described method.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc residue and the reaction mixture mixed with 726 mg of Fmoc-Ser(OBzI)-OH (1.74 mM) and 271 microliter of DIC (1.74 mM) was added thereto again to react together with a similar way to the above- described method.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc residue and the reaction mixture mixed with 742 mg of Fmoc-Trp-0H (1.74 mM) and 271 microliter of DIC (1.74 mM) was added thereto again to react together with a similar way to the above- described method.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc residue and the reaction mixture mixed with 1.078g of Fmoc-His(Fmoc)-0H (1.74 mM) and 271 microliter of DIC (1.74 mM) was added thereto again to react together with a similar way to the above-described method.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc residue and the reaction mixture mixed with 244 mg of Pyr-OH (1.74 mM) and 271 microliter of DIC (1.74 mM) was added thereto again to react together with a similar way to the above-described method.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc residue and the reaction mixture mixed with 615 mg of Fmoc-D- Leu-0H (1.74 mM) and 271 microliter of DIC (1.74 mM) was added thereto again to react together with a similar way to the above-described method.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc residue and the reaction mixture mixed with 859 mg of Fmoc ⁇ TyKOBzI)-OH (1.74 mM) and 271 microliter of DIC (1.74 mM) was added thereto again to react together with a similar way to the above-described method.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc residue and the reaction mixture mixed with 726 mg of Fmoc-Ser(OBzI)-OH (1.74 mM) and 271 microliter of DIC (1.74 mM) was added thereto again to react together with a similar way to the above-described method.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc residue and the reaction mixture mixed with 742 mg of Fmoc-Trp-0H (1.74 mM) and 271 microliter of DIC (1.74 mM) was added thereto again to react together with a similar way to the above-described method.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc residue and the reaction mixture mixed with 1.078g of Fmoc-His(Fmoc)-0H (1.74 mM) and 271 microliter of DIC (1.74 mM) was added thereto again to react together with a similar way to the above- described method.
  • the resulted resin was treated with 20% piperidine to remove the Fmoc residue and the reaction mixture mixed with 244 mg of Pyr-OH (1.74 mM) and 271 microliter of DIC (1.74 mM) was added thereto again to react together with a similar way to the above-described method.
  • the novel method of the present invention related to the preparation method of goserelin, buserelin and leuprolide using by solid phase synthesis, specifically, reacting amino acid derivatives on rink amide linker introduced modified polystyrene resin side by side to obtain peptide resin and releasing the peptide from the resin to obtain purposed peptides.
  • the inventive preparation methods exhibit more advantageous effects, such as easiness to synthesis, mass production, high yield, high purity of final product etc over the conventionally known synthetic methods showing unsolved problems, such as high cost, limitation to mass production etc.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Endocrinology (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Cette invention concerne un procédé de préparation de goseréline, de buseréline et de leuprolide présentant des activités pharmacologiques. Plus particulièrement, cette invention concerne un procédé permettant de préparer des peptides, lequel procédé comprend les étapes qui consistent à coupler, pas à pas, les acides aminés sur un support solide à poids moléculaire élevé puis à libérer les acides aminés des supports de manière à obtenir les peptides avec un rendement élevé et une grande pureté.
PCT/KR2007/004989 2006-10-12 2007-10-12 Procédé permettant de préparer des peptides par synthèse en phase solide Ceased WO2008044890A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2006-0099224 2006-10-12
KR20060099224 2006-10-12
KR10-2007-0102700 2007-10-11
KR1020070102700A KR101046846B1 (ko) 2006-10-12 2007-10-11 고체상 합성법을 이용한 펩타이드의 제조방법

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WO2008044890A1 true WO2008044890A1 (fr) 2008-04-17

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010141276A1 (fr) * 2009-06-03 2010-12-09 Mallinckrodt Inc. Procédé de synthèse peptidique en phase solide pour la production de goséréline
CN102690329A (zh) * 2011-03-25 2012-09-26 杭州九源基因工程有限公司 一种戈舍瑞林多肽的纯化生产方法
CN102746383A (zh) * 2011-04-21 2012-10-24 杭州九源基因工程有限公司 一种戈舍瑞林的合成方法
CN103554229A (zh) * 2013-11-11 2014-02-05 宁波市三生药业有限公司 固相合成布舍瑞林的方法
CN103936849A (zh) * 2014-05-05 2014-07-23 承德医学院中药研究所 一种布舍瑞林的制备方法
US20150166602A1 (en) * 2013-12-18 2015-06-18 Scinopharm Taiwan, Ltd. Process for the preparation of leuprolide and its pharmaceutically acceptable salts
CN106432427A (zh) * 2016-10-24 2017-02-22 合肥国肽生物科技有限公司 特异性微波合成制备醋酸戈那瑞林的方法
US10087221B2 (en) 2013-03-21 2018-10-02 Sanofi-Aventis Deutschland Gmbh Synthesis of hydantoin containing peptide products
CN108892711A (zh) * 2018-06-29 2018-11-27 江苏吉泰肽业科技有限公司 一种纯化布舍瑞林的方法
CN109293736A (zh) * 2017-07-25 2019-02-01 齐鲁制药有限公司 一种用于合成瑞林类药物的二肽
US10450343B2 (en) 2013-03-21 2019-10-22 Sanofi-Aventis Deutschland Gmbh Synthesis of cyclic imide containing peptide products
CN114805486A (zh) * 2022-06-02 2022-07-29 杭州思诺达医药科技有限责任公司 一种醋酸亮丙瑞林杂质的合成方法
CN116655745A (zh) * 2023-07-31 2023-08-29 杭州湃肽生化科技有限公司 一种中间体在制备布舍瑞林中的用途
CN116675741A (zh) * 2023-07-31 2023-09-01 杭州湃肽生化科技有限公司 一种中间体在制备戈舍瑞林中的用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5212288A (en) * 1990-02-20 1993-05-18 Syntex (U.S.A.) Inc. Temporary minimal protection synthesis of serine-containing polypeptides
US5510460A (en) * 1991-06-14 1996-04-23 Zeneca Limited Peptide process
US5602231A (en) * 1991-06-14 1997-02-11 Zeneca Limited Process for making peptides
US6028172A (en) * 1997-02-11 2000-02-22 Mallinckrodt Inc. Reactor and method for solid phase peptide synthesis
US6897289B1 (en) * 1999-05-20 2005-05-24 Lipotec, S.A. Peptide synthesis procedure in solid phase

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5212288A (en) * 1990-02-20 1993-05-18 Syntex (U.S.A.) Inc. Temporary minimal protection synthesis of serine-containing polypeptides
US5510460A (en) * 1991-06-14 1996-04-23 Zeneca Limited Peptide process
US5602231A (en) * 1991-06-14 1997-02-11 Zeneca Limited Process for making peptides
US6028172A (en) * 1997-02-11 2000-02-22 Mallinckrodt Inc. Reactor and method for solid phase peptide synthesis
US6897289B1 (en) * 1999-05-20 2005-05-24 Lipotec, S.A. Peptide synthesis procedure in solid phase

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010141276A1 (fr) * 2009-06-03 2010-12-09 Mallinckrodt Inc. Procédé de synthèse peptidique en phase solide pour la production de goséréline
CN102690329A (zh) * 2011-03-25 2012-09-26 杭州九源基因工程有限公司 一种戈舍瑞林多肽的纯化生产方法
CN102746383A (zh) * 2011-04-21 2012-10-24 杭州九源基因工程有限公司 一种戈舍瑞林的合成方法
US10087221B2 (en) 2013-03-21 2018-10-02 Sanofi-Aventis Deutschland Gmbh Synthesis of hydantoin containing peptide products
US10450343B2 (en) 2013-03-21 2019-10-22 Sanofi-Aventis Deutschland Gmbh Synthesis of cyclic imide containing peptide products
CN103554229A (zh) * 2013-11-11 2014-02-05 宁波市三生药业有限公司 固相合成布舍瑞林的方法
CN103554229B (zh) * 2013-11-11 2016-01-06 宁波市三生药业有限公司 固相合成布舍瑞林的方法
US9150615B2 (en) * 2013-12-18 2015-10-06 Scinopharm Taiwan, Ltd. Process for the preparation of leuprolide and its pharmaceutically acceptable salts
US20150166602A1 (en) * 2013-12-18 2015-06-18 Scinopharm Taiwan, Ltd. Process for the preparation of leuprolide and its pharmaceutically acceptable salts
CN103936849A (zh) * 2014-05-05 2014-07-23 承德医学院中药研究所 一种布舍瑞林的制备方法
CN106432427A (zh) * 2016-10-24 2017-02-22 合肥国肽生物科技有限公司 特异性微波合成制备醋酸戈那瑞林的方法
CN109293736A (zh) * 2017-07-25 2019-02-01 齐鲁制药有限公司 一种用于合成瑞林类药物的二肽
CN109293736B (zh) * 2017-07-25 2023-06-06 齐鲁制药有限公司 一种用于合成瑞林类药物的二肽
CN108892711A (zh) * 2018-06-29 2018-11-27 江苏吉泰肽业科技有限公司 一种纯化布舍瑞林的方法
CN114805486A (zh) * 2022-06-02 2022-07-29 杭州思诺达医药科技有限责任公司 一种醋酸亮丙瑞林杂质的合成方法
CN114805486B (zh) * 2022-06-02 2024-03-19 杭州思诺达医药科技有限责任公司 一种醋酸亮丙瑞林杂质的合成方法
CN116655745A (zh) * 2023-07-31 2023-08-29 杭州湃肽生化科技有限公司 一种中间体在制备布舍瑞林中的用途
CN116675741A (zh) * 2023-07-31 2023-09-01 杭州湃肽生化科技有限公司 一种中间体在制备戈舍瑞林中的用途
CN116655745B (zh) * 2023-07-31 2023-10-13 杭州湃肽生化科技有限公司 一种中间体在制备布舍瑞林中的用途
CN116675741B (zh) * 2023-07-31 2023-10-31 杭州湃肽生化科技有限公司 一种中间体在制备戈舍瑞林中的用途

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