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WO2011066386A1 - Procédé de production de degarelix - Google Patents

Procédé de production de degarelix Download PDF

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Publication number
WO2011066386A1
WO2011066386A1 PCT/US2010/058004 US2010058004W WO2011066386A1 WO 2011066386 A1 WO2011066386 A1 WO 2011066386A1 US 2010058004 W US2010058004 W US 2010058004W WO 2011066386 A1 WO2011066386 A1 WO 2011066386A1
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WO
WIPO (PCT)
Prior art keywords
resin
degarelix
protected
4aph
fmoc
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PCT/US2010/058004
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English (en)
Inventor
Chaim Eidelman
Avi Tovi
Original Assignee
Novetide, Ltd.
Teva Pharmaceuticals Usa, Inc.
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Publication date
Application filed by Novetide, Ltd., Teva Pharmaceuticals Usa, Inc. filed Critical Novetide, Ltd.
Publication of WO2011066386A1 publication Critical patent/WO2011066386A1/fr

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    • 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 encompasses processes for the preparation and purification ofDegarelix. Background of the Invention
  • Gonadotropin-releasing hormone (GnRH) antagonists are used in protocols for ovulation induction and are recognized as potential drugs for the management of sex steroid-dependent pathophysiologies, such as hormoneresponsive prostate cancers and, in females, the management or treatment of breast and gynecological cancers,
  • Degarelix a third generation GnRH receptor antagonist (a GnRH blocker), has been developed as a new therapy for prostate cancer patients in need of androgen ablation therapy.
  • the aim of the Degarelix development has been to achieve testosterone suppression in the same range as for GnRH agonist therapy without any increase in testosterone levels after the initial dose.
  • Degarelix binds to GnRH receptors in the anterior pituitary gland resulting in a decreased secretion of LH and FSH, and subsequently decreased production of testosterone by the Leydig cells in the testes.
  • Testosterone suppression is achieved almost immediately after subcutaneous (s.c.) administration of Degarelix.
  • the degree and duration of testosterone suppression are related to plasma concentrations of Degarelix.
  • the formation of a depot following s.c. administration gives rise to sustained plasma concentrations of Degarelix, resulting in prolonged GnRH receptor-mediated suppression of testosterone levels.
  • Degarelix which is a third generation gonadotropin releasing hormone (GnRH) antagonist (blocker), is a synthetic linear decapeptide containing seven unnatural amino acids, five of which are D-amino acids.
  • Degarelix is a decapeptide and is chemically designated as D-Alaninamide, iV- acetyl-3-(2-naphmalenyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridinyl)-D-alanyl-L- seryl-4-[[[(45)-hexahydro-2,6-dioxo-4-pyrimidinyl]carbonyl]amino]-L-phenylalanyl-4- [(aminocarbonyl)amino]-D-phenylalanyl-L-leucyl-N6-(l-methylethyl)-L-lysyl-L-prolyl-.
  • Chlorophenylalanine, 3Pal is 3-Pyridylalanine, Hor is hydroorotyl, Lys(iPr) is N6- Isopropyllysine, 4Aph is 4-Aminophenylalanine, and Cbm is the carbamoyl group.
  • the rimary sequence of Degarelix is:
  • N-Boc-D-alanine (I) was coupled to the MBHA resin using diisopropyl carbodiimide and 1-hydroxybenzotriazole to afford resin (II). Subsequent cleavage of the Boc protecting group by means of trifluoroacetic acid (TFA) provided the D-alanine-bound resin (III).
  • US 6214798 Bl which describes a similar synthetic approach, suggests that classical peptide solution synthesis would be preferable for producing large quantities of product.
  • the purity of the final material obtained in US 6214798 Bl is estimated, therein, to be about 98%, yet J Med. Chem. 2005, 48, 4851-4860 describing the same preparation yields a purity as measured by capillary zone electrophoresis (CZE) of 98%, which corresponds to 96% according to HPLC analysis.
  • CZE capillary zone electrophoresis
  • Fmoc chemistry generally employs milder reaction conditions than the Boc chemistry, and thus can sometimes be less likely to cause the formation of by-products.
  • Fmoc chemistry does not employ hydrofluoric acid or other very strong acid (such as TFMSA or HBr/AcOH) is needed. Therefore these processes are much safer and environmentally friendly; factors that are important when engineering such a synthesis process on the large production scale.
  • stepwise SPPS at least two types of protection for reactive functionalities other than those involved in peptide bond formation are necessary: temporary protection of the alpha-amino group, removable after formation of each peptide bond; and, side chain protection removable after assembly of the complete peptide chain.
  • tBu protecting group When using Fmoc chemistry, a tBu protecting group is commonly used for the protection of the hydroxyl groups on Ser, Tyr and Thr residues. The tBu group is easily removed together with other side-chain protecting groups at the end of the peptide synthesis by using TFA.
  • WO2010121835 (*W0'835') describes the preparation of Degarelix using an Fmoc strategy and using tBu as the protecting group for the Ser residue.
  • WO'835 also teaches that, unusually severe cleavage conditions such as long reaction time and 100% TFA as cleavage cocktail were required to successfully complete the final deprotection.. Such severe conditions are commonly known to result in increased side reactions, increased degradation of the peptide, and accordingly production of a lower quality of the resulting product.
  • Trt acid labile protecting group for Ser
  • Trt acid labile protecting group for Ser
  • Trt acid labile protecting group for Ser
  • the Trt group is very bulky and hydrophobic, and is frequently used to increase .the "steric hindrance" effect. See, e.g. Chem. Lett. 27, 1999 and J Pept. Sci. 2010; 16: 364-374, which describes that using the Trt protecting group in an Fmoc peptide synthesis could prevent formation of the target peptide due to "steric hindrance.”
  • the Degarelix sequence is inherently very hydrophobic.
  • Ser(Trt)-OH would be added to extremely bulky 4Aph(L-Hor) [4-[[[(4S)-hexahydro-2,6- dioxo-4-pyrimidinyl]carbonyl] amino] -L-phenylalanyl] residue. Accordingly, the use of this protecting residue would likely be quite difficult due to "steric hindrance". These "steric effects" are known to be of great importance when two molecules or two groups are in a close approach resulting in van der Waals forces repulsive effect. The repulsive potential can become quite large if the nonbonded distances are sufficiently short.
  • the present invention provides a solid-phase peptide synthesis
  • SPPS Styrene-maleic anhydride
  • the present invention provides a combined SPPS and solution synthesis for obtaining Degarelix.
  • TFA cocktail containing various scavengers refers to TFA containing scavenger reagents including, but not limited to ethanedithiol (EDT), TIS (triisopropylsilane) and water.
  • Normal/regular cleavage conditions refer to cleavage which is performed under an acidic conditions comprising a relative ratio of acidic material to scavenger to water.
  • the ratio can be from about 85% to about 99% acidic material, from about 0.1% to about 15% scavenger, and from about 0.1% to about 15% water (by weight).
  • a preferred acidic composition comprises about 95% TFA, about 2.5% EDT, and about 2.5% water.
  • the cleavage can be done for a period of about 1 h, at room temperature.
  • the present invention is directed to several processes for production of Degarelix. We report here the use of mild Fmoc chemistry instead of previously reported Boc chemistry for preparing Degarelix.
  • the Degarelix sequence contains several unnatural amino acids and thus requires the availability of the suitably protected starting materials to be used in the production process.
  • One of these amino acids is D-4Aph(Cbm) [4-[(aminocarbonyl)amino]-D- phenylalanine].
  • This residue is commercially available as Fmoc-D-4Aph(Cbm) or as Fmoc-D-4Aph(Cbm/tBu) (non protected on the side chain and protected by tBu on the side chain).
  • Boc synthesis approach the tBu group is observed to be stable under repeated deprotection cycles with TFA and is removed under final HF
  • sequential synthesis refers to repeated steps of adding amino acids, according to peptide sequence.
  • acidic treatment such as TFA based cleavage cocktail
  • TFA based cleavage cocktail will detach the peptide from the solid support and remove all protecting groups leaving an unprotected Degarelix molecule.
  • An evaluation of the chromatographic profile at this stage shows clearly a main peak corresponding to a high purity product .
  • the product may be easily purified further by methods such as HPLC or other known methods to obtain a purified Degarelix in high purity.
  • HPLC high purity liquid crystal display
  • a high purity product is easily obtained in high yield without need for several recycling cycles that require large volumes of solvents, long operation time, and results in a lower purity and lower yield of the final product.
  • the present invention provides a solid-phase peptide synthesis (SPPS of Degarelix, using Fmoc chemistry, preferably wherein Ser is protected by Trt.
  • SPPS solid-phase peptide synthesis
  • Fmoc chemistry preferably wherein Ser is protected by Trt.
  • This synthesis is preferably a "sequential synthesis”.
  • the solid-phase peptide synthesis of the present invention comprises: a) preparing a protected peptide attached to a Rink amide type resin, in a sequential synthesis wherein the prepared peptide contains the complete amino acid sequence of Degarelix, of which all or most multi-functional amino acids are protected with acid labile protecting groups; b) reacting the protected peptide resin with an acidic composition to produce an unprotected peptide; c) isolating the peptide by precipitation, crystallization, extraction or chromatography; d) purifying the unprotected Degarelix by chromatography, e) replace its counter-ion with acetate, and f) drying to obtain a final material as dry powder of Degarelix acetate.
  • the acidic composition consists of a cleavage cocktail based on TFA and various scavengers.
  • sequential synthesis of Degarelix of the present invention comprises: a) Loading of the first Fmoc-protected amino acid, Fmoc-D-Ala-OH, on the resin, and washing and masking all active sites on the resin;
  • step (iii) Washing the product of step (iii) with at least one solvent to remove all soluble compounds from the resin;
  • the resin could be, but is not limited to, Rink amide resin, Rink amide AM resin, Rink amide MBHA resin, and the permanently stable protecting group should be compatible with Fmoc strategy.
  • the resin is Rink amide AM resin.
  • the final peptide can be purified by suitable methods to obtain a high purity peptide.
  • purification can be carried out using RP-FTPLC.
  • Step (iii) of the sequential synthesis described above are commercially available as protected amino acids that are stable to any reactions and modifications of the side chains during the synthesis that could result in derivatives of the constituent amino acids.
  • One specific embodiment comprises obtaining intermediate XVII from intermediate XII by introducing, at step (iii), 4-(2,6-dioxohexdiydropyrimidin-4(S)-ylcarboxamido)-L-phenylalanine to the terminal amino group residue attached to the resin.
  • One embodiment of the invention encompasses Degarelix having a purity of at least about 98.5% (by HPLC), more preferably at least about 99%.
  • the ser is protected with
  • the 4Aph(Cbm) can be unprotected on its side chain group.
  • the process of the present invention further encompasses preparing a peptide from amino residues by employing Fmoc as a protecting group for the amino residues, Trt for Ser, Boc for iPr-Lys and tBu for 4Aph(Cbm) [4Aph(Cbm) could be used also unprotected on its side chain group] .
  • the present invention encompasses these intermediates, as well as their use in a process for the manufacture of Degarelix.
  • the present invention provides a combined SPPS and solution synthesis for obtaining Degarelix.
  • fragments of the peptide are synthesized in a sequential synthesis, and further reacted in a solution to obtain Degarelix.
  • these processes can include synthesis via 9 + 1 fragments and synthesis via 3 + 6 +1 fragments.
  • the combined SPPS and solution synthesis for obtaining Degarelix going via the 9 + 1 fragment protocol comprise a) providing a protected peptide attached to a super acid-labile resin, wherein the peptide contains the almost complete amino acid sequence of Degarelix except the C-terminal D-Ala-NH 2 , wherein all or most multi-functional amino acids are protected with a strong acid labile protecting group; b) Cleaving the protected peptide intermediate from the resin using mild acidic composition; c) isolating the protected peptide by precipitation, crystallization, extraction or chromatography; d) treating the protected peptide obtained in step (c) with a coupling agent in the presence of D-Ala-NH 2 to produce a protected Degarelix; e) reacting the protected Degarelix with strong acidic composition, f) isolating the unprotected Degarelix, and g) purifying the unprotected Degarelix by chromatography.
  • the process further comprises neutralizing excess
  • the obtained Degarelix preferably has purity of a least above 98.5% (by HPLC), more preferably, at least above 99%.
  • the combined SPPS and solution synthesis for obtaining Degarelix acetate, going via a 9 + 1 fragment protocol comprises:
  • step (iii) Washing the product of step (iii) with at least one solvent to remove all soluble compounds from the resin;
  • Suitable resins for use in the process include, but are not limited to, super-acid labile resins such as chlorotrityl resins.
  • super-acid labile resins such as chlorotrityl resins.
  • a preferred super acid labile resin is 2-Cl-Trt-Cl resin.
  • the mild and strong acidic solutions consist of different concentrations of TFA.
  • the mild acidic solution may be, for example, 1% TFA in DCM
  • the strong acidic solution may be, for example, 95% TFA 5% water
  • the present invention encompasses these intermediates, as well as their use in a process for the manufacture of Degarelix.
  • the combined SPPS and solution synthesis for obtaining Degarelix going via the 3 + 6 +1 fragment protocol comprise: a) providing a protected peptide fragment attached to a super acid-labile resin, wherein the peptide contains six amino acid sequence of
  • Degarelix (Fmoc-Ser(Trt)-4Aph(L-Hor)-D-4Aph(Cbm-tBu)-Leu-Lys(iPr-Boc)-Pro-OH); b) Cleaving the protected peptide intermediate from the resin using mild acidic composition; c) isolating the protected peptide fragment by precipitation, crystallization, extraction or chromatography; d) treating the protected peptide fragment obtained in step (c) with a coupling agent in the presence of D-Ala-NH 2 to produce a protected C-terminal Degarelix fragment containing 7 amino acids (Fmoc-Ser(Trt)-4Aph(L-Hor)-D- 4Aph(Cbm-tBu)-Leu-Lys(iPr-Boc)-Pro-D-Ala-NH 2 ); e) isolating the protected peptide fragment by precipitation, crystallization, extraction or chromat
  • the N-terrninal fragment containing three amino acids can be purchased or can be obtained in any method known in the art, such as described in (2001 :880 SYNTHLINE).
  • the preparation of this fragment can also be according to the above described solid-phase peptide synthesis (SPPS), using Fmoc chemistry.
  • the obtained Degarelix preferably has purity of a least above 98.5% (by HPLC), more preferably, at least above 99%.
  • the combined SPPS and solution synthesis for obtaining Degarelix, going via a 3 + 6 +1 fragment protocol comprises:
  • step (iii) Washing the product of step (iii) with at least one solvent to remove all soluble compounds from the resin;
  • Suitable resins for use in the process include, but are not limited to, super-acid labile resins such as chlorotrityl resins.
  • super-acid labile resins such as chlorotrityl resins.
  • a preferred super acid labile resin is 2-Cl-Trt-Cl resin.
  • the mild and strong acidic solutions consist of different concentration of TFA.
  • the mild acidic solution may be, for example, 1% TFA in DCM
  • the strong acidic solution may be, for example, 95% TFA 5% water
  • the present invention encompasses these intermediates, as well as their use in a process for the manufacture of Degarelix.
  • Suitable coupling agents include, but are not limited to, 2-(lH-benzotriazole-l- yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU) or DIC
  • Suitable solvents for use in the washing steps of the process include, but are not limited to, dimethylformamide (DMF), dichloromethane (DCM), methanol (MeOFi), or isopropanol (IP A).
  • DMF dimethylformamide
  • DCM dichloromethane
  • MeOFi methanol
  • IP A isopropanol
  • the N-terminal amino acid residue protecting group is removed by any known method, such as reaction with piperidme solution in DMF. Although one of ordinary skill in the art may substitute the reagents with other suitable reagents depending on the nature of the protecting group. In the case of Fmoc, beside piperidine, other reagents could be used such as DBU, diethyl amine, piperazine, dimethylethylamine and etc.
  • the acidic composition is preferably based on an acidic material such as TFA, and contains scavenger reagents including, but not limited to, ethanedithiol (EDT), TIS (triisopropylsilane) and water.
  • scavenger reagents including, but not limited to, ethanedithiol (EDT), TIS (triisopropylsilane) and water.
  • the relative ratio of acidic material to scavenger to water may be from about 85% to about 99% acidic material, from about 0.1% to about 15% scavenger, and from about 0.1% to about 15% water by weight.
  • a preferred acidic composition comprises about 95% TFA, about 2.5% EDT, and about 2.5% water.
  • the crude peptide product may be purified by any known method.
  • the peptide is purified using HPLC on a reverse phase (RP) column.
  • RP reverse phase
  • the counter ion of the peptide may be exchanged by a suitable ion such as, but are not limited to, acetate ion.
  • the counter-ion exchange can be done by any suitable method such as HPLC or ion exchange.
  • Suitable HPLC method can be done for example by loading a solution of the peptide to the head of the column; washing the column by actate buffer to replace and remove TFA or other acids, after completion of washings the peptide is eluted from the column by addition of strong solvent such as acetonitrile to the acetate buffer;
  • the ion- exchange can be done by attaching the peptide to the ion exchange column as a salt of the functional acidic residues of the ion-exchange resin, washing the column to remove TFA or other acids, releasing the peptide by gradient salt concentration increase.
  • the resulting purified product is dried and may be lyophilized.
  • Triiunctional amino acids were side chain protected as follows: Ser(Trt) and Lys(iPr-Boc). D-4Aph(Cbm) was used as nonprotected on its side chain group. At the end of the synthesis the peptide-resin was washed with DMF, followed by MeOH, and dried under vacuum to obtain the dry peptide-resin.
  • the peptide, prepared as described above, was cleaved from the resin using a 95% TFA, 2.5% TIS, 2.5% EDT solution for 2 hours at room temperature.
  • the crude product was precipitated by the addition of 10 volumes of ether, filtering and drying in vacuum to obtain crude product.
  • the crude peptide was dissolved in an aqueous solution of acetonitrile.
  • the resulting solution was loaded on a C 18 RP-HPLC column and purified to obtain fractions containing Degarelix trifluoroacetate at a purity of >99.0%. After treatment to replace
  • Example 2 Comparative cleavage experiments and LC/MS analytics for synthesis of Degarelix using Fmoc-SerftBu or Fmoc-D-4Aph(Cbm/tBu
  • Synthesis of the protected peptide fragment (1 to 9) is carried out by a regular stepwise Fmoc SPPS (solid phase peptide synthesis) procedure starting from 2-Cl-Trt resin.
  • the first amino acid (Fmoc-Pro-OH) is loaded onto the resin in a preliminary step to provide loading of about 0.7 mmol/g.
  • a second amino acid (Fmoc-Lys(iPr-Boc)-OH) is introduced to start the first coupling step.
  • Fmoc protected amino acid is activated in situ using TBTU/HOBt and subsequently coupled to the resin for 50 minutes. Diisopropylethylamine or Collidine are used during coupling as an organic base.
  • the peptide, prepared as described above, is cleaved from the resin using a 1% TFA solution in DCM by three repeated washings (15 min each).
  • the acidic peptide solution is neutralized by DIPEA.
  • the solvent is evaporated under reduced pressure and the protected peptide is precipitated by the addition of 10 volumes of water, filtered and dried under vacuum. It is identified by MS as Ac-D-2Nal-D-4Cpa-D-3-Pal-Ser(Trt)- 4Aph(L-Hor)-D-4Aph(Cbm-tBu)-Leu-Lys(iPr-Boc)-Pro-OH.
  • Protected peptide fragment is reacted with D-Ala-NH 2 dissolved in DMF.
  • the activation of carboxyl group of the peptide is done in-situ by addition of TBTU/HOBt into reaction mixture.
  • Diisopropylethyl amine is used as organic base. Completion of the reaction is monitored by HPLC analysis. At the end of reaction the DMF solution is added slowly to water and crude protected peptide is precipitated as off-white solid.
  • the protecting groups are removed using a 95% TFA, 2.5% TIS, 2.5% EDT solution for 1 hour at about 45 °C.
  • the crude product is precipitated by the addition of 10 volumes of ether, filtered and dried in vacuum.
  • the crude peptide is dissolved in aqueous solution of acetonitrile.
  • the resulting solution is loaded on a C 18 RP-HPLC column and purified to obtain fractions containing Degarelix trifluoroacetate at a purity of >99.0%. After treatment to replace trifiuoroacetate by acetate, the fractions are collected and lyophilized to obtain final dry peptide >99.0% pure (by HPLC).
  • Synthesis of the protected peptide fragment (4 to 9) is carried out by a regular stepwise Fmoc SPPS (solid phase peptide synthesis) procedure starting from 2-Cl-Trt resin.
  • the first amino acid (Fmoc-Pro-OH) is loaded onto the resin in a preliminary step to provide loading of about 0.7 mmol/g.
  • a second amino acid (Fmoc-Lys(iPr-Boc)-OH) is introduced to start the first coupling step.
  • Fmoc protected amino acid is activated in situ using TBTU/HOBt and subsequently coupled to the resin for 50 minutes. Diisopropylethylamine or Collidine are used during coupling as an organic base.
  • the peptide, prepared as described above, is cleaved from the resin using a 1% TFA solution in DCM by three repeated washings (15 min each).
  • the acidic peptide solution is neutralized by DIPEA.
  • the solvent is evaporated under reduced pressure and the protected peptide is precipitated by the addition of 10 volumes of water, filtered and dried under vacuum. It is identified by MS as Fmoc-Ser(Trt)-4Aph(L-Hor)-D- 4Aph(Cbm-tBu)-Leu-Lys(iPr-Boc)-Pro-OH.
  • Protected peptide fragment is reacted with D-Ala-NH 2 dissolved in DMF.
  • the activation of carboxyl group of the peptide is done in-situ by addition of TBTU/HOBt into reaction mixture.
  • Diisopropylethyl amine is used as organic base. Completion of the reaction is monitored by HPLC analysis. At the end of reaction the DMF solution is added slowly to water and crude protected peptide is precipitated as off-white solid.
  • the peptide fragment is dissolved in DMF containing 20% piperidine. After 2 minutes the solvent is concentrated under reduced pressure and the peptide is precipitated by addition of water. The peptide is collected by filtration and dried.
  • Protected peptide fragment is reacted with Ac-D-Nal-D-4Cpa-D-3Pal-OH dissolved in DMF.
  • the activation of carboxyl group of the peptide is done in-situ by addition of TBTU/HOBt into reaction mixture.
  • Diisopropylethyl amine is used as organic base. Completion of the reaction is monitored by FTPLC analysis. At the end of reaction the DMF solution is added slowly to water and crude protected peptide is precipitated as off- white solid.
  • the protecting groups are removed using a 95% TFA, 2.5% TIS, 2.5% EDT solution for 1 hour at about 45 °C.
  • the crude product is precipitated by the addition of 10 volumes of ether, filtered and dried in vacuum.
  • the crude peptide is dissolved in aqueous solution of acetonitrile.
  • the resulting solution is loaded on a C 18 RP-HPLC column and purified to obtain fractions containing Degarelix trifluoroacetate at a purity of >99.0%. After treatment to replace trifluoroacetate by acetate, the fractions are collected and lyophilized to obtain final dry peptide >99.0% pure (by HPLC).

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Abstract

L'invention porte sur des procédés de préparation de Degarelix de pureté élevée et sur du Degarelix préparé par de tels procédés à une pureté élevée d'au moins 98,5 % (par HPCL).
PCT/US2010/058004 2009-11-25 2010-11-24 Procédé de production de degarelix WO2011066386A1 (fr)

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US40717510P 2010-10-27 2010-10-27
US61/407,175 2010-10-27

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Cited By (16)

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CN102329373A (zh) * 2011-09-29 2012-01-25 深圳翰宇药业股份有限公司 地加瑞克的固相合成工艺
CN103351428A (zh) * 2013-08-05 2013-10-16 海南双成药业股份有限公司 一种固相片段法合成地加瑞克
WO2013178788A2 (fr) 2012-06-01 2013-12-05 Ferring B.V. Fabrication de dégarélix
ITMI20121638A1 (it) * 2012-10-02 2014-04-03 Marco Sbracia Utilizzo di degarelix nel trattamento dell'endometriosi e di patologie ad essa correlate
CN103992378A (zh) * 2013-11-01 2014-08-20 杭州诺泰制药技术有限公司 一种制备醋酸地加瑞克的方法
CN103992392A (zh) * 2014-05-19 2014-08-20 泰州施美康多肽药物技术有限公司 一种地加瑞克的固相合成方法
CN107022002A (zh) * 2017-05-26 2017-08-08 济南康和医药科技有限公司 一种固液结合制备地加瑞克的方法
CN109575109A (zh) * 2018-12-27 2019-04-05 兰州大学 片段缩合制备地加瑞克的方法
CN109748954A (zh) * 2017-11-06 2019-05-14 正大天晴药业集团股份有限公司 一种地加瑞克的纯化方法
WO2019202613A1 (fr) * 2018-04-20 2019-10-24 Alaparthi Lakshmi Prasad Procédé amélioré de production d'acétate de dégarélix
US10729739B2 (en) 2008-02-11 2020-08-04 Ferring B.V. Methods of treating prostate cancer with GnRH antagonist
CN112125956A (zh) * 2019-06-25 2020-12-25 深圳市健元医药科技有限公司 一种地加瑞克的制备方法
CN112876541A (zh) * 2019-11-29 2021-06-01 深圳翰宇药业股份有限公司 一种地加瑞克的固相合成方法
US11168114B2 (en) 2015-12-17 2021-11-09 Fresenius Kabi iPSUM S.r.l Process for the manufacture of degarelix and its intermediates
US11332495B2 (en) 2019-09-21 2022-05-17 RK Pharma Solutions LLC Process for the preparation of Degarelix acetate and Degarelix acetate-mannitol premix
CN116284206A (zh) * 2023-05-18 2023-06-23 杭州湃肽生化科技有限公司 一种树脂材料的洗涤方法

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US11168114B2 (en) 2015-12-17 2021-11-09 Fresenius Kabi iPSUM S.r.l Process for the manufacture of degarelix and its intermediates
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