WO2017212390A1 - Procédé de préparation d'acétate de lanréotide - Google Patents

Procédé de préparation d'acétate de lanréotide Download PDF

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Publication number
WO2017212390A1
WO2017212390A1 PCT/IB2017/053302 IB2017053302W WO2017212390A1 WO 2017212390 A1 WO2017212390 A1 WO 2017212390A1 IB 2017053302 W IB2017053302 W IB 2017053302W WO 2017212390 A1 WO2017212390 A1 WO 2017212390A1
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cys
acm
boc
trp
tyr
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PCT/IB2017/053302
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English (en)
Inventor
Mukund Gurjar
Narendra TRIPATHY
Chinmoy PRAMANIK
Sanjay Deshmukh
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Emcure Pharmaceuticals Ltd,
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Publication of WO2017212390A1 publication Critical patent/WO2017212390A1/fr

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    • 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
    • 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
    • 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
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • 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
    • C07K5/0815—Tripeptides 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
    • 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

Definitions

  • the present invention relates to an improved process for the solution phase synthesis of an octapeptide, Lanreotide acetate and its key intermediates comprising coupling of suitably protected tetrapeptide fragments A and B, followed by deprotection, oxidation and acetic acid treatment to provide Lanreotide acetate (1) having desired purity.
  • Lanreotide acetate (1) chemically known as [cyclo S-S]-3-(2-naphthyl)-D-alanyl-L- cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-valyl-L-cysteinyl-L-threoninamide acetate salt (acetic acid ranges from 1.6 to 3.4) is a synthetic, cyclical octapeptide analog of the natural hormone, somatostatin.
  • the amino acid sequence for the octapeptide is represented as follows,
  • Lanreotide acetate is indicated for long-term treatment of acromegaly and in the treatment of patients with locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors.
  • Lanreotide acetate, developed by Ipsen with proprietary name Somatulin depot was first approved by USFDA on August 30, 2007 as an injection with strength of 60 mg/0.2 ml and 90 mg/0.3 ml.
  • Lanreotide acetate was first disclosed in US 4,853,371 wherein the synthetic process comprised treating benzhydryl amine -polystyrene resin (neutralized in the chloride ion form) with Boc-O-benzyl-threonine in presence of diisopropylcarbodiimide and the resulting amino acid resin is then coupled successively with Boc-S-methylbenzyl- Cys, Boc-Val, Boc-Ne-benzyloxycarbonyl-lysine, Boc-D-Trp, Boc-Tyr, Boc-S- methylbenzyl-Cys, and Boc-D- ⁇ -naphthylalanine.
  • the resultant octapeptide is iodinated using reagents such as Chloramine-T/ sodium iodide; Lactoperoxidase-glucose oxidase (LP-GO)/ sodium iodide; Iodine/ potassium iodide; Iodine monochloride etc. followed by purification using preparative HPLC.
  • reagents such as Chloramine-T/ sodium iodide; Lactoperoxidase-glucose oxidase (LP-GO)/ sodium iodide; Iodine/ potassium iodide; Iodine monochloride etc.
  • WO 2013098802 discloses a solid phase peptide synthesis of Lanreotide comprising use of resin-bound Thr-amide wherein the resin, Fmoc-Thr(Resin)- NH2 « DIPEA Fmoc-Thr-NH2 was subjected to seven cycles of sequential deprotection and coupling steps to give Boc-D-2-Nal-Cys(Acm)-Tyr(Clt)-D-Trp- Lys(Mtt)-Val-Cys(Acm)-Thr(Resin)-NH 2 which after the deprotection reaction followed by cleavage from the resin and simultaneous iodine oxidation yielded the desired compound.
  • CN 104497130 discloses a process wherein a combination of solid and liquid phase peptide synthesis methods was used to obtain Lanreotide.
  • Solid phase peptide synthesis methods comprise 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. These methods involve 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 isolation render these processes unsuitable for large scale industrial production of the product.
  • Solution phase synthetic methods for peptides comprises independent synthesis of amino acids segments or blocks having the desired sequence, followed by condensation of these segments in solution. Such processes are comparatively economical and hence more suited for synthesis on industrial scale.
  • the present inventors have developed an economical and convenient process for solution phase synthesis of Lanreotide acetate (1) which provides the desired molecule in good yield overcoming the problems faced in the prior art.
  • 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 lesser impurity formation, and consequently significant yield improvement as compared to prior art processes.
  • An objective of the present invention is to provide an industrially applicable, convenient process for solution phase synthesis of Lanreotide acetate (1), which avoids use of expensive resins, costly reagents in solid phase peptide synthesis and also lengthy reaction sequences and elaborate protection, deprotection, purification methods.
  • Another object of the invention relates to a 4+4 solution phase synthesis of Lanreotide acetate comprising mild reagents and facile, moderate reaction conditions for functional group protection and deprotection to provide the desired intermediates and subsequently, Lanreotide with desired purity.
  • An aspect of the invention relates to a 4+4 solution phase synthetic process for Lanreotide acetate (1) comprising coupling of two suitably protected tetrapeptide fragments, followed by deprotection, oxidation and acetic acid treatment to give Lanreotide acetate having desired purity.
  • Yet another aspect of the invention relates to synthesis of Lanreotide acetate comprising reaction of tetrapeptide H-Lys(Boc)-Val-Cys(Acm)-Thr-NH 2 (fragment A) with Boc-D-Nal-Cys(Acm)-Tyr-D-Trp-OH (fragment B) in presence of a suitable coupling agent, a base and in an organic solvent to give the octapeptide, which on subsequent deprotection, oxidation, followed by treatment with acetic acid gives Lanreotide acetate (1) having purity conforming to regulatory specifications.
  • the present strategy also comprises utilization of selective and specific, yet labile protecting groups at different stages, which are deprotected using mild acids, that do not adversely affect the chirality of the amino acids and intermediates in the synthetic sequence.
  • Fmoc Flourenylmethoxycarbonyl
  • Trt Triphenyl methyl (Trityl)
  • TIS Triisopropylsilane
  • PTSA p-toluene sulfonic acid
  • the water immiscible organic solvent was selected from ethers such as MTBE, diethyl ether, diisopropyl ether, halogenated hydrocarbons such as dichlorome thane, ethylene dichloride and esters such as ethyl acetate, butyl acetate.
  • ethers such as MTBE, diethyl ether, diisopropyl ether, halogenated hydrocarbons such as dichlorome thane, ethylene dichloride and esters such as ethyl acetate, butyl acetate.
  • compound (2) was coupled with Boc-Cys(Acm)-OH (3A) in an organic solvent in presence of a coupling agent and a base like NMM to give Boc- Cys(Acm)-Thr-NH 2 (4A).
  • Boc deprotection of (4A) using suitable acids such as trifluoroacetic acid, hydrochloric acid or mixtures of acids in organic solvents like acetonitrile, ethyl acetate or dichloromethane gave H-Cys(Acm)-Thr-NH 2 , compound (5).
  • Coupling of (5) with Boc-Val-OH (6) in an organic solvent in presence of a coupling agent gave Boc-Val-Cys(Acm)-Thr-NH 2 (7).
  • the reaction was carried out in the temperature range of 0 to 30°C. After completion, the reaction mass was quenched using mineral acid to precipitate the intermediate, which was filtered and treated with water and a hydrocarbon solvent prior to drying.
  • the hydrocarbon solvent was selected from pentane, n-hexane, cyclohexane, heptane, toluene and mixtures thereof.
  • Boc deprotection of (7) using suitable acids such as trifluoroacetic acid, hydrochloric acid either singular or in the form of acid mixtures like anhydrous HC1 in acetonitrile or ethyl acetate; or trifluoroacetic acid in an organic solvent such as dichlorome thane afforded H-Val-Cys (Acm)-Thr-NH 2 (8).
  • suitable acids such as trifluoroacetic acid, hydrochloric acid either singular or in the form of acid mixtures like anhydrous HC1 in acetonitrile or ethyl acetate; or trifluoroacetic acid in an organic solvent such as dichlorome thane afforded H-Val-Cys (Acm)-Thr-NH 2 (8).
  • the reaction was carried out in temperature range of 0 to 30°C. After completion, concentration of the reaction mixture provided a residue containing compound (8) as its HC1 salt.
  • D-Tryptophan (H-D-Trp-OH) was treated with allyl alcohol in presence of para toluene sulfonic acid in a hydrocarbon solvent such as toluene.
  • the reaction was carried out between 80 to 100°C. After completion of the reaction as monitored by HPLC, the reaction mass was cooled, and quenched with base like aqueous bicarbonate. Extraction with an organic solvent selected from MTBE, ethyl acetate etc. and concentration of the organic layer provided the desired allyl ester of D-Tryptophan, H-D-Trp-OAll (11).
  • Boc-Tyr-OH (12) was coupled with H-D-Trp-OAll (11) in presence of a coupling agent and a base such as NMM, and a suitable organic solvent selected from DMF, DMSO, DMAc etc., to give Boc-Tyr-D-Trp-OAll (13).
  • a coupling agent and a base such as NMM
  • a suitable organic solvent selected from DMF, DMSO, DMAc etc.
  • Boc deprotection of (13) using acid mixtures such as anhydrous HC1 in acetonitrile or ethyl acetate, or trifluoroacetic acid in dichloromethane afforded H-Tyr-D-Trp-OAll (14).
  • the reaction was carried out at ambient temperature using anhydrous HC1 in ethyl acetate and after completion, concentration of the reaction mixture provided a residue containing compound (14) as HC1 salt.
  • compound (14) was coupled with Boc-Cys(Acm)-OH (3 A) in an organic solvent in presence of a coupling agent and a base like NMM to give Boc- Cys(Acm)-Tyr-D-Trp-OAll (15 A).
  • Boc deprotection of (15A) using suitable acids such as trifluoroacetic acid, hydrochloric acid or mixtures of acids in organic solvents like acetonitrile, ethyl acetate or dichloromethane gave compound (16).
  • reaction mass was filtered, quenched with a mineral acid to precipitate the solid intermediate, which was filtered, treated with alkali solution, followed by optional treatment with hydrocarbon solvent selected from pentane, n-hexane, cyclohexane, heptane, toluene and mixtures thereof, Further removal of solvent and drying gave compound (18).
  • hydrocarbon solvent selected from pentane, n-hexane, cyclohexane, heptane, toluene and mixtures thereof, Further removal of solvent and drying gave compound (18).
  • allyl deprotection of (18) using the catalyst tetrakis(triphenylphosphine)palladium, morpholine and an organic solvent such as DMSO, DMF or DMAc at 0 to 30°C provided Boc-D-Nal-Cys (Acm)-Tyr-D-Trp- OH (Fragment B).
  • a hydrocarbon solvent such as toluene, cyclohexane and dried to provide fragment B.
  • the oily product obtained from reaction mass was treated with a mineral acid and the precipitated solid was filtered.
  • a solvent selected from ethers such as MTBE, diethyl ether, diisopropyl ether and mixtures thereof provided compound (19).
  • Compound (19) was dissolved in a halogenated hydrocarbon solvent like dichloromethane and was treated with TFA, in presence of anisole at 0 to 30°C to give (20).
  • concentration of the reaction mixture gave a residue which was further treated with ether solvent like MTBE to give a solid after filtration.
  • the solid was treated with aqueous acetic acid and iodine in presence of acetonitrile, followed by treatment with L- ascorbic acid to yield Lanreotide acetate (1).
  • the organic solvents were selected from the group comprising chlorinated hydrocarbons, aprotic solvents, ethers, esters and nitriles.
  • 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, 1 -Ethyl - 3-(3-dimethylaminopropyl) carbodiimide (ED AC), BOP(Benzotriazol-l-yloxy- tris(dimethylamino)-phosphonium hexafluorophosphate), PyBOP (Benzotriazol-1- yloxy-tripyrrolidino-phosphonium-hexafluoro phosphate), PyBrOP
  • substituted carbodiimides such as diisopropylcarbodiimide, dicyclohexylcarbodiimide, 1 -Ethyl - 3-(3-dimethylaminopropyl) carbodiimide (ED AC), BOP(Benzotriazol-l-yloxy- tris(dimethylamino)-phosphonium
  • 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 (433 ml) was added to the solution of (4, 200 g) in DMF (500 ml) and the reaction mass was stirred between 25 to 45 °C. After completion of the reaction, as monitored by TLC, the reaction mass was quenched by gradually adding IN hydrochloric acid. The mass was filtered and extracted with ethyl acetate. Neutralization of the aqueous layer followed by extraction with ethyl acetate, and separation, concentration of the organic layer gave H-Cys (Acm)-Thr-NH 2 (5).
  • N-methylmorpholine (41 ml) was added to the mixture of Fmoc-Lys(Boc)-OH (9, 129 g), in DMF (300 ml), HOBT (56 g), EDAC.HC1 (88 g) and the mixture was stirred at 0-10°C.
  • the residue containing (8) as obtained above in DMF (200 ml) was further added to the resulting mass and the reaction mixture was stirred at 20-40°C till completion of reaction, as monitored by TLC. After completion, the reaction mixture was quenched with dilute hydrochloric acid. Filtration of the precipitated solid, optional treatment with water, cyclohexane and drying gave Fmoc-Lys (Boc)- Val-Cys (Acm)-Thr-NH 2 (10).
  • Triethylamine (67 ml) was added to the mixture of (10, 50 g) in DMF (300 ml), and the mixture was stirred between 20 to 45°C. After completion of reaction, as monitored by TLC, the reaction mass was quenched by gradual addition of 1.0 N hydrochloric acid. The resulting mass was filtered, optionally washed with MTBE and the aqueous layer was neutralized using sodium bicarbonate. Extraction with DCM and concentration of the organic layer gave H-Lys(Boc)-Val-Cys(Acm)-Thr- NH 2 (Fragment A) as an oily mass.
  • Boc-Tyr-OH (12, 173 g) was added to the stirred mixture of H-D-Trp-OAll (11.150 g) and DMF (450 ml) at 25 to 35°C, followed by addition of HOBt (104 g). NMM (75 ml) and EDAC.HCl (142 g). The reaction mixture was stirred at 10 to 30°C, till completion, as monitored by TLC. After completion, the reaction mass was quenched with 0.5N HCl. The precipitated solid was filtered, treated with 5% aqueous sodium carbonate solution, filtered again and dried to give Boc-Tyr-D-Trp-OAll (13).
  • Triethylamine (277 ml) was added to the mixture of (15, 200 g) in DCM (2000 ml) and the reaction mass was stirred at 20 to 30°C till completion of the reaction, as monitored by TLC. After completion, the reaction mass was quenched with water and the organic layer was separated. Concentration of the organic layer, followed by treatment of resultant solid with toluene: cyclohexane mixture gave H-Cys (Acm)- Tyr-D-Trp-OAll (16).
  • Boc-D-Nal-OH (17, 70 g) was added to the stirred mixture of compound 16 as obtained above in DMF (600 ml) at 20-30°C, followed by addition of HOBT (46 g). EDAC.HCl (72 g ) was then added to the reaction mixture and stirring was continued at 0 to 30°C till completion of the reaction, as monitored by TLC. After completion, the reaction mixture was filtered, added to the cooled solution of 0.5M hydrochloric acid and stirred at 0 to 5°C.
  • Morpholine (45 g) and tetrakis (triphenylphosphine)palladium. (6.5g) were added to the mixture of (18, 100 g) in DMSO (400 ml).
  • the reaction mixture was stirred at 15 to 30°C, till completion of the reaction, as monitored by TLC.
  • the reaction mass was filtered and quenched with dilute hydrochloric acid.
  • the obtained solid was filtered, and the wet cake was treated with water, followed by treatment with toluene: cyclohexane mixture.
  • the solid so obtained was optionally treated with cyclohexane and dried to give Boc-D-Nal-Cys (Acm)-Tyr-D-Trp-OH (Fragment B).
  • Fragment A as obtained in example 4 in DMF (250 ml) was stirred at 0 -10°C and HOBt (l lg), EDAC.HC1 (17 g), were added to it with continued stirring.
  • Fragment B 50 g was added to the mixture and stirring was continued at 10-30°C till completion of the reaction, as monitored by TLC. After completion of the reaction, the mass was cooled to 0 to 5°C and quenched with DM water (50 vol) (The stirring was continued at 15-25°C and the precipitated solid was filtered The wet cake was washed with 5% dil.

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

L'invention concerne un procédé amélioré de synthèse en phase de solution 4+4 d'acétate de lanréotide (1), consistant à coupler deux fragments de tétrapeptide dûment protégés qui sont soumis à une déprotection, à une oxydation, puis à réaliser un traitement au moyen d'acide acétique afin d'obtenir de l'acétate de lanréotide (1) à une pureté souhaitée.
PCT/IB2017/053302 2016-06-06 2017-06-05 Procédé de préparation d'acétate de lanréotide WO2017212390A1 (fr)

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IN201621019405 2016-06-06
IN201621019405 2016-06-06

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WO2017212390A1 true WO2017212390A1 (fr) 2017-12-14

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MXPA01000969A (es) * 1998-07-30 2003-04-07 Scient Sas Soc De Conseils De Metodo de uso de un analogo de somatostatina.
WO2009071957A2 (fr) * 2007-12-05 2009-06-11 Biostatin Gyógyszerkutató-Fejlesztö Kft. Nouveaux peptides et dérivés d'acides aminés, compositions pharmaceutiques contenant ces derniers et utilisation desdits composés.
CN101541824A (zh) * 2006-11-21 2009-09-23 爱尔兰伊普森制造有限公司 Boc和Fmoc固相肽合成

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MXPA01000969A (es) * 1998-07-30 2003-04-07 Scient Sas Soc De Conseils De Metodo de uso de un analogo de somatostatina.
CN101541824A (zh) * 2006-11-21 2009-09-23 爱尔兰伊普森制造有限公司 Boc和Fmoc固相肽合成
WO2009071957A2 (fr) * 2007-12-05 2009-06-11 Biostatin Gyógyszerkutató-Fejlesztö Kft. Nouveaux peptides et dérivés d'acides aminés, compositions pharmaceutiques contenant ces derniers et utilisation desdits composés.

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