WO2017175107A1 - Procédé de préparation d'acétate d'octréotide - Google Patents

Procédé de préparation d'acétate d'octréotide Download PDF

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Publication number
WO2017175107A1
WO2017175107A1 PCT/IB2017/051882 IB2017051882W WO2017175107A1 WO 2017175107 A1 WO2017175107 A1 WO 2017175107A1 IB 2017051882 W IB2017051882 W IB 2017051882W WO 2017175107 A1 WO2017175107 A1 WO 2017175107A1
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Prior art keywords
cys
trt
thr
phe
boc
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Ceased
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PCT/IB2017/051882
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English (en)
Inventor
Mukund Keshav Gurjar
Narendra Kumar Tripathy
Chinmoy Mriganka PRAMANIK
Sanjay Shankar Deshmukh
Ulhas Supadu MAHAJAN
Ashish Pramod DESHPANDE
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Emcure Pharmaceuticals Ltd
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Emcure Pharmaceuticals Ltd
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Publication of WO2017175107A1 publication Critical patent/WO2017175107A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
    • C07K1/026—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution by fragment condensation in solution
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/081—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1019—Tetrapeptides with the first amino acid being basic
    • 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
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids

Definitions

  • the present invention relates to an improved process for the solution phase synthesis of an octapeptide like octreotide acetate (1) and its key intermediates by a process comprising coupling of suitably protected tetrapeptide fragments, followed by deprotection, oxidation to provide the octapeptide acetate ( 1 ) of desired purity.
  • Octreotide acetate (1) chemically known as D-phenylalanyl-L-cysteinyl-L-phenylalanyl- D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy- l-(hydroxymethyl) propyl] -L-cysteinamide cyclic (2-7)-disulfide, is a cyclic octapeptide and a highly potent analog of somatostatin.
  • the peptide also represented as D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-Ol (Disulfide Bridge Cys2-Cys7); is a pharmacologically selective somatostatin analog which exhibits excellent in vitro and in vivo biological activity for inhibition of growth hormone for a longer duration. It is indicated for treating acromegaly for controlling and reducing the plasma level of growth hormone and for the symptomatic treatment of patients with metastatic carcinoid tumors and vasoactive intestinal peptide tumors.
  • Octreotide acetate developed by Novartis with proprietary name Sandostatin was first approved by USFDA on Oct. 21, 1988 as an injection with strength of 0.05-1.0mg base/ml. Later, octreotide acetate injection with a higher dose range of 10 to 30 mg base/vial was approved by USFDA on Nov. 25, 1998.
  • Solid phase synthesis comprises attachment of a C-terminal amino acid to resin, with a step by step building up of the peptide chain by utilizing pre- activated amino acids.
  • US 6346601, KR 2009074316, WO 20081087794, CN 1837232, CN 1699404, CN 1810829, CA 2511711, CN 1569890, TW 519545, US 6476186, WO 2002081499 disclose solid phase synthesis of octreotide
  • EP 953,577, US 5889146 disclose a method using 2-chlorotrityl resin and Fmoc -butyl protection.
  • Solid phase peptide synthesis involves use of expensive resins and Fmoc/tert-butyl protected amino acids in three to four fold excess, necessitating complex purification procedures to separate the product from the impurities. These additional steps before the isolation of desired product render these processes uneconomical and unsuitable for large scale industrial production of the product.
  • solution phase synthesis comprises synthesis of amino acids segments or blocks, followed by condensation in the desired sequence in solution. Such processes are comparatively economical and hence more suited for synthesis on industrial scale.
  • the process includes coupling of two tripeptide segments, Boc-D-Phe- Cys(Acm)-Phe-OMe and Z-D-Trp-Lys(Boc)-Thr-OMe to provide a hexapeptide Boc-D- Phe-Cys(Acm)-Phe-D-Trp-Lys(Boc)-Thr-OMe, which is further condensed with the dipeptide H-Cys(Acm)-Thr-OMe to yield the desired octapeptide.
  • phenylalanine methyl ester and acetamidomethyl (Acm) group for thiol protection in cysteine are the major drawback of the procedure. While a relatively non -bulky group like Acm does not ensure that the intermediates are isolated as solids, the methyl ester in phenylalanine causes racemization at the hydrolysis stage, severely affecting the enantiomeric purity of the intermediates. As a consequence, the process involves purification of segments by preparative HPLC, which increases process time, use of solvents and ultimately, the production cost.
  • WO 2013132505 also discloses a 6+2 strategy for preparation of the desired octapepeptide.
  • the synthesis involves use of bulky trityl moiety as a protecting group for cysteine, use of methyl ester of threonine is likely to result in epimerization and racemization and as already mentioned creates a negative impact on yield, and consequently, increases the project cost. It is now evident that most of the synthetic methods described in the aforementioned references resort to tedious synthesis of fragment blocks and their condensation involving expensive reagents and elaborate deprotection and separation procedures at various intermediate stages of synthesis.
  • the present inventors have developed an economical and convenient process for solution phase synthesis of octreotide acetate (1) which provides the desired molecule in good yield overcoming the problems faced in the prior art.
  • the inventors have found that employing 4+4 strategy comprising synthesis of two tetrapeptide fragments, clubbed with highly specific protection and deprotection methods and a facile condensation of the fragments facilitates in obtaining the desired molecule in fewer synthetic steps with significant yield improvement as compared to prior art processes.
  • An objective of the present invention is to provide an industrially viable, convenient process for synthesis of Octreotide acetate (1), which avoids use of lengthy reaction sequences and elaborate protection, deprotection and purification methods.
  • Another object of the invention relates to a 4+4 solution phase synthesis of Octreotide acetate comprising mild reagents and moderate reaction conditions to provide the desired purity.
  • An aspect of the invention relates to a 4+4 solution phase synthetic process for octreotide acetate (1) comprising coupling of two suitably protected tetrapeptide fragments, followed by deprotection and oxidation and acetic acid treatment to give octreotide acetate having desired purity.
  • Yet another aspect of the invention relates to solution phase synthesis of octreotide acetate (1), comprising reaction of H-Lys(Boc)-Thr(OtBu)-Cys(Trt)-Thr-01 (fragment A) with Boc-D-Phe-Cys(Trt)-Phe-D-Trp-OH (fragment B) in presence of a coupling agent, a base and in a solvent to give the octapeptide Boc-D-Phe-Cys(Trt)-Phe-D-Trp-Lys(Boc)- Thr(OtBu)-Cys(Trt)-Thr-01 (19) which on subsequent deprotection, oxidation, followed by treatment with acetic acid gives octreotide acetate (1), having desired purity.
  • the inventors also unexpectedly found that, owing to the specific protecting groups and nature of the peptide fragments, most of the intermediates in the said strategy were obtained as solids, which were purified easily with simple purification methods including recrystallization. Due to this, various laborious and cumbersome intermediate isolation and purification steps were avoided. This not only ensured notably higher yield for the desired octapeptide but also led to a convenient and economical synthetic process for octreotide which could easily be scaled up for commercial production.
  • the strategy also comprises selective and specific, yet labile protecting groups at different stages, which are deprotected using mild acids, that did not adversely affect the chirality of the amino acids and intermediates in the synthetic sequence.
  • Trt Triphenyl methyl (Trityl)
  • NMM N-methylmorpholine
  • HOBt 1 -Hydroxybenzotriazole
  • DIPEA Diisopropylethylamine
  • Fragment A Fragment B
  • L-Threoninol (2) was coupled with Fmoc-Cys (Trt)-OH (3) in a suitable solvent in presence of a coupling agent and a base such as NMM to give Fmoc-Cys(Trt)- Thr-Ol (4).
  • the coupling reaction was carried out in the temperature range of 0 to 30°C and in a solvent selected from polar aprotic solvents like DMSO, DMF, DMAc etc. After completion, the reaction mass was quenched using mineral acid selected from hydrochloric, nitric, sulfuric acid, preferably hydrochloric acid to precipitate the intermediate, which was filtered and optionally treated with water prior to drying.
  • Compound (4) was treated with a suitable base like TEA in an organic solvent for deprotection of the Fmoc group to afford H-Cys(Trt)-Thr-01 (5).
  • the solvent was selected from polar aprotic solvents like DMSO, DMF, and DMAc while the reaction was carried out in the temperature range of 0 to 30°C. After completion, the reaction mass was quenched using mineral acid, followed by addition of a water miscible organic solvent and treatment of the mixture with a water immiscible organic solvent.
  • the water miscible organic solvent was selected from DMF, DMSO, ACN, THF and the like whereas the water immiscible organic solvent were selected from ethers such as MTBE, diethyl ether, diisopropyl ether, halogenated hydrocarbons such as dichloromethane, ethylene dichloride and esters such as ethyl acetate, butyl acetate. Further basification of the separated aqueous layer, extraction with a suitable solvent and concentration provided H-Cys(Trt)-Thr-01 (5).
  • the water miscible organic solvent was selected from DMF, DMSO, ACN, THF and the like whereas the water immiscible organic solvent was selected from ethers such as MTBE, diethyl ether, diisopropyl ether etc., halogenated hydrocarbons such as dichloromethane, ethylene dichloride etc., esters such as ethyl acetate, butyl acetate etc. as well as mixtures thereof. Further basification of the separated aqueous layer, extraction with a suitable solvent and concentration provided H-Thr(OtBu)-Cys(Trt)-Thr- 01 (8).
  • the reaction was carried out in the temperature range of 0 to 30°C.
  • the solvent was selected from halogenated hydrocarbons such as dichloromethane, ethylene dichloride. After reaction completion, the reaction mass was quenched with water, organic layer was separated and concentrated. Further washing of the residue with a water immiscible organic solvent selected from a group of ethers such as MTBE, diethyl ether, diisopropyl ether or halogenated hydrocarbons such as dichloromethane, ethylene dichloride, or esters like ethyl acetate, butyl acetate or mixtures thereof, followed by treatment with hydrocarbon solvent or mixtures thereof provided a precipitate which was filtered and dried to give fragment A.
  • a water immiscible organic solvent selected from a group of ethers such as MTBE, diethyl ether, diisopropyl ether or halogenated hydrocarbons such as dichloromethane, ethylene dichloride, or esters like
  • the hydrocarbon solvent was selected from pentane, n-hexane, cyclohexane, heptane, toluene and mixtures thereof.
  • mixtures of toluene: cyclohexane in proportions ranging from 1: 1 to 1:4 were used.
  • D-Tryptophan i.e. H-D-Trp-OH (11) was treated with allyl alcohol in a hydrocarbon solvent such as toluene.
  • the reaction was carried out at 80 to 100°C. After completion, the reaction mass was quenched with mineral acid and a water miscible organic solvent selected from DMF, DMSO, DMAc etc. was added to it. Concentration of the reaction mixture, alkali treatment of the residue, followed by extraction with an organic solvent like methyl tert-butyl ether, ethyl acetate after concentration provided the desired allyl protected compound, H-D-Trp-OAll (12).
  • Boc deprotection of (14) using an acid mixture such as HC1 in acetonitrile or trifluoroacetic acid in dichloromethane afforded H-Phe-D-Trp-OAll (15).
  • the reaction was carried out at ambient temperature and after completion, concentration of the reaction mixture provided a residue containing compound (15).
  • allyl deprotection of (18) using an organic solvent such as dimethyl sulphoxide or dimethylformamide in presence of morpholine and a catalyst tetrakis(triphenylphosphine)palladium at 0 to 30°C provided Boc-D-Phe-Cys(Trt)-Phe-D- Trp-OH (Fragment B).
  • a catalyst tetrakis(triphenylphosphine)palladium at 0 to 30°C provided Boc-D-Phe-Cys(Trt)-Phe-D- Trp-OH (Fragment B).
  • filtration, followed by treatment of filtrate with a mineral acid gave a solid which, after filtration, was washed with a hydrocarbon solvent such as toluene, cyclohexane and dried to provide fragment B.
  • coupling of fragment A with fragment B was carried out in a suitable organic solvent like DMF in presence of a coupling agent at 0 to 30°C and in presence of a base such as N-methyl morpholine, furnished the octapeptide Boc-D-Phe- Cys(Trt)-Phe-D-Trp-Lys(Boc)-Thr(OtBu)-Cys(Trt)-Thr-01 (19). After completion, the reaction mass was treated with a mineral acid and the precipitated solid was filtered to provide (19).
  • Organic solvents that can be used were selected from the group comprising chlorinated hydrocarbons, aprotic solvents, ethers, esters and nitriles. Examples of these solvents are methylene chloride, chloroform, dichloroethane (EDC), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), ethyl acetate, N-methyl-2- pyrrolidinone (NMP), acetonitrile, and combinations thereof.
  • the coupling agent was selected from the group comprising substituted carbodiimides such as diisopropylcarbodiimide, dicyclohexylcarbodiimide, l-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (ED AC), BOP(Benzotriazol-l-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate), PyBOP (Benzotriazol-l-yloxy-tripyrrolidino-phosphonium- hexafluoro phosphate), PyBrOP (Bromotripyrrolidino phosphonium hexafluorophosphate), PyAOP (7-Aza-benzotriazol- 1 -yloxy-tripyrrolidinophosphonium hexafluorophosphate), DEPBT (3-(Diethoxyphosphoryloxy)-l,2,3-benzo[d]triazin-4(3H)-
  • the base was selected from the group comprising diisopropylethylamine (DIEA), N- methylmorpholine (NMM), triethyl amine (TEA), diethyl amine (DEA), piperidine, 1- methyl-2-pyrrolidinone (NMP).
  • the acid employed for deprotection was selected from the group comprising trifluoroacetic acid either neat or in dichloromethane (DCM), hydrogen chloride gas dissolved in ethyl acetate, acetonitrile or dioxane.
  • Triethylamine (71.7 ml) was added to the solution of compound (7) (75 g) in DMF (225 ml). The reaction mass was stirred at 25 to 30°C till completion of reaction, as monitored by TLC. After completion, the reaction mixture was quenched with 0.5N hydrochloric acid (1900 ml) and DMF (730 ml) was added to it, followed by treatment with MTBE. The aqueous layer was separated, basified using 10% aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was separated, and concentrated to give an oily residue containing H-Thr (OtBu)-Cys (Trt)-Thr-Ol (8).

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  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne une synthèse améliorée en phase de solution 4+4 d'acétate d'octréotide. Le procédé comprend le couplage de deux fragments tétrapeptidiques protégés de manière appropriée qui, par déprotection, oxydation et traitement avec de l'acide acétique, produit de l'acétate d'octréotide ayant une pureté souhaitée.
PCT/IB2017/051882 2016-04-04 2017-04-01 Procédé de préparation d'acétate d'octréotide Ceased WO2017175107A1 (fr)

Applications Claiming Priority (2)

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IN201621011904 2016-04-04
IN201621011904 2016-04-04

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109942678A (zh) * 2019-05-07 2019-06-28 上海上药第一生化药业有限公司 一种奥曲肽的精制方法
WO2025158194A1 (fr) * 2024-01-25 2025-07-31 Flowchem Pharma Private Limited Procédé de préparation d'acétate d'octréotide

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1355173A (zh) * 2000-11-29 2002-06-26 中国人民解放军军事医学科学院毒物药物研究所 醋酸奥曲肽的液相合成方法
WO2005087794A1 (fr) * 2004-03-12 2005-09-22 Dalton Chemical Laboratories Inc. Procede de synthese d'octreotide
WO2007110765A2 (fr) * 2006-03-28 2007-10-04 Wockhardt Ltd Procedes de preparation d'octreotide
WO2010089757A2 (fr) * 2008-11-07 2010-08-12 Usv Limited Procédé amélioré de synthèse d'un octapeptide cyclique
CN103102390A (zh) * 2011-11-09 2013-05-15 杭州华津允上医药有限公司 一种奥曲肽的制备方法
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

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1355173A (zh) * 2000-11-29 2002-06-26 中国人民解放军军事医学科学院毒物药物研究所 醋酸奥曲肽的液相合成方法
WO2005087794A1 (fr) * 2004-03-12 2005-09-22 Dalton Chemical Laboratories Inc. Procede de synthese d'octreotide
WO2007110765A2 (fr) * 2006-03-28 2007-10-04 Wockhardt Ltd Procedes de preparation d'octreotide
WO2010089757A2 (fr) * 2008-11-07 2010-08-12 Usv Limited Procédé amélioré de synthèse d'un octapeptide cyclique
CN103102390A (zh) * 2011-11-09 2013-05-15 杭州华津允上医药有限公司 一种奥曲肽的制备方法
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

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109942678A (zh) * 2019-05-07 2019-06-28 上海上药第一生化药业有限公司 一种奥曲肽的精制方法
WO2025158194A1 (fr) * 2024-01-25 2025-07-31 Flowchem Pharma Private Limited Procédé de préparation d'acétate d'octréotide

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