EP2013226A2 - Procédés de préparation d'octréotide - Google Patents

Procédés de préparation d'octréotide

Info

Publication number
EP2013226A2
EP2013226A2 EP07734124A EP07734124A EP2013226A2 EP 2013226 A2 EP2013226 A2 EP 2013226A2 EP 07734124 A EP07734124 A EP 07734124A EP 07734124 A EP07734124 A EP 07734124A EP 2013226 A2 EP2013226 A2 EP 2013226A2
Authority
EP
European Patent Office
Prior art keywords
octreotide
salt
acm
cys
preparation
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.)
Withdrawn
Application number
EP07734124A
Other languages
German (de)
English (en)
Inventor
Kumar Kamlesh Laxmi Singh
Siddiqui Mohammed Jaweed Mukarram
Deshpande Amol Ashok
Roy Anupam Badal Chandra
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.)
Wockhardt Ltd
Original Assignee
Wockhardt 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
Application filed by Wockhardt Ltd filed Critical Wockhardt Ltd
Publication of EP2013226A2 publication Critical patent/EP2013226A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/655—Somatostatins
    • C07K14/6555—Somatostatins at least 1 amino acid in D-form

Definitions

  • the field of the invention relates to processes for the preparation of pure octreotide or pharmaceutically acceptable salts thereof.
  • the invention also relates to an amorphous form of octreotide and processes for the preparation of amorphous form of octreotide or pharmaceutically acceptable salts thereof.
  • the invention also relates to pharmaceutical compositions that include the pure octreotide or the amorphous octreotide or pharmaceutically acceptable salts thereof.
  • Octreotide is a cyclic octapeptide. Chemically, octreotide is D-Phenylalanyl-L-cysteinyl- L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-iV- [2-hydroxy- 1 -(hydroxymethyl) propyl] -L-cysteinamide cyclic (2D7)-disulfide having the structural Formula I. It is a long-acting octapeptide with pharmacologic properties mimicking those of the natural hormone somatostatin. Octreotide is indicated to reduce blood levels of growth hormone and IGF-I in acromegaly patients. It is also indicated for the symptomatic treatment of patients with metastatic carcinoid tumors and Vasoactive Intestinal Peptide Tumors (VIPomas).
  • VIPomas Vasoactive Intestinal Peptide Tumors
  • a process for the preparation of R 1 -(D) Phe- Cys(Acm)-Phe-OH, wherein Ri is amino or suitable amino protecting group used in peptide chemistry includes the steps of: a) hydrolyzing R 1 -(D)PhC-CyS(ACm)-PhC-OMe in one or more solvents by maintaining a pH of about 9.0 to about 10 of reaction mass; b) acidifying the reaction mass after completion of hydrolysis; and c) isolating the R 1 -(D)PhB-CyS(ACm)-PlIe-OH from the reaction mass thereof.
  • Embodiment of the process may include one or more of the following features.
  • the hydrolysis may be carried out in the presence of one or more bases.
  • the bases include hydroxides, carbonates or bicarbonates of alkali or alkali earth metal compound.
  • the solvent may include one or more of lower alkanols.
  • the lower alkanol may include one or more of primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • the lower alkanol may include one or more of methanol, ethanol, n- propanol, and isopropanol.
  • the process may include protection of amino group with a suitable protecting group and deprotection of amino protecting group prior to isolating the R 1 -(D) Phe-Cys(Acm)-Phe- OH.
  • the process includes the steps of: a) treating L-Thr-OH with methanol and thionyl chloride at a temperature above
  • a process for removal of inorganic impurities (de-salting) OfR 1 -CyS(ACm)-ThT-OL wherein R 1 is amino or a suitable amino protecting group used in peptide chemistry.
  • the process includes the steps of: a) reducing R 1 -CyS(ACm)-ThT-OMe in one or more solvents in the presence of sodium borohydride; b) extracting the resultant mass in dichloromethane; and c) isolating the R 1 -CyS(ACm)-ThT-OL from the extract thereof.
  • the solvent may be, for example, one or more of lower alkanols, lower aliphatic acids, water, or mixtures thereof.
  • the lower alkanol may include one or more of methanol, ethanol, isopropanol and n-propanol.
  • the lower aliphatic acid may include formic acid, acetic acid, propionic acid, or mixtures thereof.
  • a process for the preparation of Cys (Acm)- Phe-OMe or a salt thereof includes the steps of: a) treating t-BOC-Cys(Acm)-Phe-OMe or a salt thereof with less than 15 moles of trifluoroacetic acid; b) removing the excess trifluoroacetic acid from reaction mass; and c) isolating the Cys(Acm)-Phe-OMe or a salt thereof from the reaction mass thereof.
  • a process for the preparation of Cys(Acm)- Thr-OL or a salt thereof includes the steps of: a) treating t-BOC-Cys(Acm)-Thr-OL or a salt thereof with less than 15 moles of trifluoroacetic acid; b) removing the excess trifluoroacetic acid from reaction mass; and c) isolating the Cys(Acm)-Thr-OL or a salt thereof from the reaction mass thereof.
  • Embodiment of the process may include one or more of the following features.
  • removing the excess trifluoroacetic acid may include distillation, distillation under vacuum and evaporation.
  • the process may also include non-polar solvent like ether, hexane or mixture thereof.
  • a process for the preparation of trifluoroacetate salt of 8P-OL includes the steps of: a) coupling t-BOC-6P-OH and Cys(Acm)-Thr-OL in one or more suitable organic solvent to give t-BOC-8P-OL; b) removing the t-BOC protection from the product t-BOC-8P-OL using trifluoroacetic acid to give trifluoroacetate salt of 8P-OL; c) extracting the trifluoroacetate salt of 8P-OL in water to get an aqueous solution; d) removing undissolved dicyclohexylcarbodiimide-urea complex from the aqueous solution; and e) isolating the trifluoroacetate salt of 8P-OL from the aqueous solution by lyophilization.
  • Embodiment of the process may include one or more of the following features.
  • suitable organic solvent may include polar aprotic solvent.
  • Polar aprotic solvent may include one or more of N, N-dimethylformamide, N,N-dimethylacetarnide, dimethylsulphoxide, N-methyl pyrrolidone, tetrahydrofuran or acetonitrile.
  • the process may include one or more catalysts and coupling reagents in the coupling reaction.
  • the catalyst may include 1-hydroxybenzotriazole (HOBt), and the like.
  • the coupling reagent may include dicyclohexylcarbodiimide (DCC), and the like.
  • the process may also include adding one or more scavengers at step (b) for deprotecting the t-BOC protection.
  • the scavengers may include thioanisole, anisole, mercaptoethanol, and the like.
  • the process may produce the trifluoroacetate salt of 8P-OL having less than 1% of dicyclohexylcarbodiimide -urea.
  • a process for the preparation of octreotide or a salt thereof includes the steps of: a) treating trifluoroacetate salt of 8P-OL in methanol with iodine; b) drying the resultant mixture; c) treating the resultant mass with one or more bases; d) acidifying the solution of step (c) with acetic acid; and e) isolating the octreotide mixture by desalting.
  • the base may include one or more of sodium hydroxide, potassium hydroxide, carbonates or bicarbonates of alkali or alkali earth metal compounds, and the like.
  • Octreotide or salts thereof so obtained may be further purified. It may be purified by preparative chromatography.
  • a process for the preparation of octreotide acetate by preparative chromatography includes the steps of: a) charging octreotide or a salt thereof over preparative chromatography column with 3% ammonium acetate and 1% acetic acid; b) collecting desired elute; c) concentrating the desired elute; and d) isolating the octreotide or a salt thereof from the elute.
  • the preparative chromatography may be performed by using YMC ODS-A column having length 50 x 500 mm and particle size 15 micron having 12nm pore size.
  • octreotide or salt or derivative with a purity of greater than about 98.5% by HPLC.
  • the amorphous form of octreotide acetate may have, for example, the X-ray diffraction pattern of Figure 1.
  • composition that includes a therapeutically effective amount of the amorphous form of octreotide acetate; and one or more pharmaceutically acceptable carriers, excipients or diluents.
  • a process for the preparation of amorphous form of octreotide acetate includes the steps of: a) charging octreotide or a salt thereof, wherein the salt is other than acetate, over preparative chromatography column; b) eluting the column with 0.1 to 4% ammonium acetate and 0.1-2% acetic acid; c) eluting the column with a mixture comprising of acetic acid and methanol to get desired fraction; d) concentrating the desired fraction; and e) isolating the octreotide acetate from the concentrate of step d).
  • the process may include further drying of the product obtained.
  • the process may include isolating the amorphous form of octreotide acetate by lyophilization.
  • the process may produce the amorphous form of the octreotide having the X-ray diffraction pattern of Figure 1.
  • Figure 1 is an X-Ray Diffraction Pattern of amorphous form of octreotide.
  • Figure 2 is a Fourier Transform Infrared (FTIR) spectrum of amorphous octreotide.
  • the inventors have developed processes for the preparation of pure octreotide . or pharmaceutically acceptable salts having a purity of more than 99% by HPLC.
  • the inventors also have developed processes for the preparation of intermediates of octreotide or pharmaceutically acceptable salts thereof.
  • the inventors have found a new form of octreotide acetate, the amorphous form and, in particular, the amorphous octreotide acetate.
  • the new form is characterized by its X-ray powder diffraction pattern and infrared spectrum as shown in Figures 1 and 2, respectively.
  • the inventors also have developed a process for the preparation of the pure amorphous form of octreotide acetate, from trifluoroacetate salt of H-(D)-PlIe 1 - Cys(Acm) 2 -Phe 3 -(D)-Trp 4 -Lys 5 -Thr 6 -Cys(Acm) 7 -Thr 8 -OL (i.e. 8P-OL).
  • the amorphous form of octreotide acetate offers several advantages in terms of enhanced solubility, greater stability and ease in incorporation to dosage form.
  • the inventors also have developed pharmaceutical compositions that contain the amorphous form of the octreotide acetate, in admixture with one or more solid or liquid pharmaceutical diluents, carriers, and/or excipients.
  • R 1 -(D)PhC-CyS(ACm)-PhC-OMe and L-Thr-OH can be prepared by any of the processes known in the art._Commercially available raw materials can also be employed. The treatment of L-Thr-OH with methanol and thionyl chloride at a temperature above 45 0 C facilitates the rate of reaction thus requiring less reaction time resulting in good yield and quality of the product. The earlier known processes operate on lower temperatures and therefore are more time consuming and the reaction do not go to completion.
  • R 1 -CyS(ACm)-ThT-OMe can also be prepared by the procedures well known to those skilled in peptide chemistry.
  • the t-BOC-Cys(Acm)-Phe-OMe can be prepared by the procedures well known to those skilled in the art of peptide chemistry.
  • the prior art uses 25 to 32 moles of trifluoroacetic acid for the preparation of Cys(Acm)-Phe-OMe but the present inventors have now found that when less than 10 moles of trifluoroacetic acid was employed, the impurities in the reaction mixture were greatly reduced and further helped to remove the product from the reaction mixture with greater ease.
  • the excess trifluoroacetic acid was removed from the reaction mixture after completion of the reaction by vacuum distillation and the residue was triturated with mixture of ether and hexane to get the product.
  • t-BOC-Cys(Acm)-Thr-OL can be prepared by the procedures well known to those skilled in the art of peptide chemistry. After the deprotection, the mass was concentrated under vacuum and the product was triturated with non-polar hydrocarbon solvent to get the desired product.
  • the present inventors have observed that when trifluoroacetate salt of 8P-OL remains in contact with urea, complete degradation of the product occurs in two to three days. However, removal of DCC-Urea complex from the crude trifluoroacetate salt of 8P-OL provides excellent stability to the product and the product remains stable for 55 days. The yield and the quality of the product was also improved. It was also noticed that if DCC- Urea complex was not removed at this stage, it continues in the next stages of the octreotide preparation till final purification of the product on preparative chromatography leading to damage of the costly separation columns.
  • the process further includes coupling of two starting materials t-BOC-6P-OH and Cys(Acm)-Thr-OL , which can be prepared by processes known in the art.
  • the two starting materials were coupled in the presence of DCC and 1-hydroxybenzotriazole (HOBt) in the presence of polar aprotic solvent such as N,N-dimethylformamide, N 5 N- dimethylacetamide, dimethylsulphoxide, N-mythylpyrrolidone, tetrahydrofuran, acetonitrile, and the like.
  • polar aprotic solvent such as N,N-dimethylformamide, N 5 N- dimethylacetamide, dimethylsulphoxide, N-mythylpyrrolidone, tetrahydrofuran, acetonitrile, and the like.
  • non-polar solvent such as ether, hexane etc.
  • the separated solids were filtered and extracted in ethyl acetate and the suspension
  • the product was treated with trifluoroacetic acid in dichloromethane in the presence of thioanisole, anisole and mercaptoethanol as scavengers. After completion of reaction, the mixture was concentrated and the residue was treated with ether. The separated product was filtered and suspended in water. The insoluble particles of DCC-Urea were filtered and the resultant aqueous solution was lyophilized to get the desired product.
  • the trifluoroacetate salt of 8P-OL can be prepared by the procedures well known to those skilled in the art.
  • Octreotide or salts or derivatives thereof can be prepared by treating trifluoroacetate salt of 8P-OL to the iodine containing alkanol at ambient temperature, further drying this resultant mixture, followed by basifying the reaction mixture with base or alkaline agents.
  • Suitable basifying agents can be selected from sodium hydroxide, potassium hydroxide, carbonate or bicarbonate of alkali or alkali earth metal compounds, and the like.
  • the resultant solution was treated with acetic acid and the crude octreotide was isolated by desalting.
  • the Preparative HPLC is an efficient tool for separation of one or several components from a complex mixture.
  • octreotide or salt or derivative thereof by preparative chromatography was performed by using YMC ODS-A column having length 50 x 500 mm and particle size 15 micron having 12nm pore size and 0.5% -10% ammonium acetate and 0.1%-5% acetic acid as solvent.
  • THF Tetrahydrofuran Powder XRD of the samples were determined by Rigaku X-Ray diffractometer model no. 2200-v Japan.
  • FT IR of the samples were determined by Perkin Elmer, Spectrum One FT-IR spectrometer in KBr pellets.
  • Lithium hydroxide solution 140 ml, IM was added drop wise to the solution of R 1 - (D)Phe-Cys(Acm)-Phe-OMe (112 g) in methanol (2500 ml) at 20- 25 0 C. The solution was stirred at 3O 0 C till completion of the reaction and the reaction was monitored by HPLC. The pH was brought to 2-3 by addition of hydrochloric acid (584 ml, IN) at 5- 1O 0 C. The solution was concentrated under vacuum. The concentrate was saturated with solid sodium chloride and diluted with ethyl acetate (1000 ml).
  • Example 4 Preparation of H-CysfAcmVPhe-OMe trifluroacetate salt t-BOC-Cys(Acm)-Phe-OMe (181 g) was suspended in dichloromethane (271 ml) and stirred at 5 0 C. It was followed by the addition of trifluoroacetic acid (245 ml). The resultant mass after completion of the reaction was distilled under vacuum to remove trifluoroacetic acid and dichloromethane. Ether (180 ml x 3) and hexane (360 ml x 3) was added to the residue, the mixture was triturated and allowed to settle under ice cooling.
  • the reaction mixture was cooled to 5 0 C and solution of sodium sulphite (135ml, IN) was added, followed by the addition of sodium hydroxide (45 ml, 4N) and acetic acid (19 ml).
  • the reaction mass was diluted with 0.5% acetic acid (5.5 lit) in water.
  • the solution was filtered through celite bed on sinter funnel and the bed was washed with 0.5% acetic acid (500ml) in water.
  • the clear solution so obtained was subjected to preparative HPLC for desalting and lyophilization.
  • the crude octreotide thus obtained was purified by preparative HPLC and converted into acetate salt with 3% ammonium acetate and 1% acetic acid.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biophysics (AREA)
  • Medicinal Chemistry (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • Toxicology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Endocrinology (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

La présente invention concerne des procédés de préparation d'octréotide pur ou de ses sels pharmaceutiquement acceptables. L'invention concerne également une forme amorphe d'octréotide et des procédés de préparation de la forme amorphe d'octréotide ou de ses sels pharmaceutiquement acceptables. L'invention concerne également des compositions pharmaceutiques qui comprennent l'octréotide pur ou l'octréotide amorphe ou leurs sels pharmaceutiquement acceptables.
EP07734124A 2006-03-28 2007-03-28 Procédés de préparation d'octréotide Withdrawn EP2013226A2 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
IN457MU2006 2006-03-28
IN454MU2006 2006-03-28
IN456MU2006 2006-03-28
IN455MU2006 2006-03-28
IN1382MU2006 2006-08-31
IN1372MU2006 2006-08-31
PCT/IB2007/000800 WO2007110765A2 (fr) 2006-03-28 2007-03-28 Procedes de preparation d'octreotide

Publications (1)

Publication Number Publication Date
EP2013226A2 true EP2013226A2 (fr) 2009-01-14

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EP07734124A Withdrawn EP2013226A2 (fr) 2006-03-28 2007-03-28 Procédés de préparation d'octréotide

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WO (1) WO2007110765A2 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013046233A2 (fr) 2011-09-30 2013-04-04 Mylan Laboratories Ltd Procédé de préparation d'acétate d'octréotide
WO2013132505A1 (fr) 2012-03-09 2013-09-12 Natco Pharma Limited Procédé amélioré pour la préparation d'octréotide par une synthèse peptidique en phase solution
CN104513293A (zh) * 2013-09-26 2015-04-15 深圳信立泰药业股份有限公司 一种多肽疫苗的盐及其制备方法和含有该盐的药物制品
WO2017175107A1 (fr) * 2016-04-04 2017-10-12 Emcure Pharmaceuticals Limited Procédé de préparation d'acétate d'octréotide

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE2512T1 (de) * 1979-11-27 1983-03-15 Sandoz Ag Polypeptide, verfahren zu ihrer herstellung, pharmazeutische zusammensetzungen, die diese polypeptide enthalten, und ihre verwendung.
US6987167B2 (en) * 2002-05-22 2006-01-17 Wockhardt Limited Process for production of the somatostatin analog, octreotide

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007110765A3 *

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WO2007110765A3 (fr) 2009-04-16
WO2007110765A2 (fr) 2007-10-04

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