WO2013167703A1 - Process for the manufacture of cyclic undecapeptides - Google Patents

Process for the manufacture of cyclic undecapeptides Download PDF

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Publication number
WO2013167703A1
WO2013167703A1 PCT/EP2013/059672 EP2013059672W WO2013167703A1 WO 2013167703 A1 WO2013167703 A1 WO 2013167703A1 EP 2013059672 W EP2013059672 W EP 2013059672W WO 2013167703 A1 WO2013167703 A1 WO 2013167703A1
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Prior art keywords
cyclosporin
methyl
compound
formula
ethyl
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PCT/EP2013/059672
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French (fr)
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WO2013167703A9 (en
Inventor
Fabrice Gallou
Bernard Riss
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Novartis Ag
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Priority to AU2013257989A priority Critical patent/AU2013257989A1/en
Priority to SG11201406303XA priority patent/SG11201406303XA/en
Priority to EA201492036A priority patent/EA024903B1/en
Priority to MX2014013613A priority patent/MX2014013613A/en
Priority to US14/399,261 priority patent/US20150087808A1/en
Priority to IN8483DEN2014 priority patent/IN2014DN08483A/en
Priority to JP2015510823A priority patent/JP2015517481A/en
Priority to CN201380023760.8A priority patent/CN104284902A/en
Priority to MA37498A priority patent/MA20150231A1/en
Application filed by Novartis Ag filed Critical Novartis Ag
Priority to KR1020147031112A priority patent/KR20150006435A/en
Priority to CA2868940A priority patent/CA2868940A1/en
Priority to BR112014027648A priority patent/BR112014027648A2/en
Priority to EP13722740.1A priority patent/EP2847211A1/en
Publication of WO2013167703A1 publication Critical patent/WO2013167703A1/en
Priority to TNP2014000411A priority patent/TN2014000411A1/en
Priority to IL235428A priority patent/IL235428A0/en
Priority to PH12014502499A priority patent/PH12014502499A1/en
Publication of WO2013167703A9 publication Critical patent/WO2013167703A9/en
Priority to HK15102858.0A priority patent/HK1202555A1/en
Priority to US15/198,152 priority patent/US9840534B2/en
Priority to AU2016222370A priority patent/AU2016222370B2/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K1/00General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/12General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by hydrolysis, i.e. solvolysis in general
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K1/00General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K7/00Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04Linear peptides containing only normal peptide links
    • C07K7/06Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K7/00Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64Cyclic peptides containing only normal peptide links
    • C07K7/645Cyclosporins; Related peptides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides

Definitions

  • the invention relates to novel process(es), novel process step(s) and novel intermediate(s) useful for the opening of Cyclosporin derivatives and subsequently for the preparation of cyclic polypeptides, more specifically, cyclic undecapeptides, such as alisporivir (also known as DEB025, Debio025, or Debio).
  • cyclic undecapeptides such as alisporivir (also known as DEB025, Debio025, or Debio).
  • the present invention relates to processes for the preparation of cyclic polypeptides, such as, for example, cyclic undecapeptides, such as alisporivir.
  • Alisporivir is a cyclophilin (Cyp) inhibitor used for the treatment of hepatitis C virus (HCV) infection or HCV induced disorders as described in WO 2006/038088. Furthermore,
  • WO2009/042892 describes methods for the use of alisporivir in the treatment of multiple sclerosis
  • WO2009/098577 describes methods for the use of alisporivir in the treatment of muscular dystrophy
  • WO2008/084368 describes methods for the use of alisporivir in the treatment of Ullrich congenital muscular dystrophy.
  • Alisporivir and a synthesis thereof are described in WO 00/01715. Alisporivir has been attributed the CAS Registry Number 254435-95-5.
  • AXX1 MeBmt, Bmt, MeLeu, Desoxy-MeBmt, Methylaminooctanoic acid
  • AXX2 Abu, Ala, Thr, Val, Nva
  • AXX10 MeLeu, Leu
  • AXX1 1 MeVal, Val, D-MeVal
  • Cyclic undecapeptides may be obtained bystrain selection, however obtaining most un-natural derivatives requires a chemical transformation which relies on opening of the cyclic polypeptide, for example, of Formula (la) or of Formula (lb) and subsequent amino acid replacement.
  • cyclic polypeptide for example of Formula (la) are opened in a highly selective process and an amino acid residue is removed via the Edman degradation to access the opened cyclic polypeptide as a key intermediate (Wenger, R. M. In Peptides 1996; Ramage, R.; Epton, R., Eds.; The European Peptides Society, 1996; pp. 173; Wenger, R. M. et al. Tetrahedron Letters 2000, 41, 7193.). Numerous scientists and companies have used this reliable and selective strategy wherein pure cyclosporin A and purification by column chromatography have been used to obtain cyclic undecapeptides.
  • purification of products involve several steps of purification by liquid chromatography on silica. Beside the moderate overall obtained yield, the major drawback of this purification scheme is the very high costs for the chromatography steps.
  • Large-scale purification processes of such products derived from cyclosporin A or its structural analogues described in the literature generally involve a chromatographic purification or at least a pre-purification by adsorption chromatography. Such pre-purification may be followed, for instance, by extraction, counterflow extraction, and/or supercritical fluid extraction.
  • pre-purification may be followed, for instance, by extraction, counterflow extraction, and/or supercritical fluid extraction.
  • none of these techniques appear to be fully satisfactory for obtaining the key opened intermediates with the desired quality requirements, with an acceptable overall yield, and at an acceptable cost for an industrial scale production, as costly precursors of high quality were required.
  • dimethoxycarbenium ions (described in Novartis patent application EP 0 908 461 A1 for the methylation of Cephalosporine derivatives), do the same chemistry as oxonium ions (trimethyl or triethyloxonium Meerwein salts) in the opening of the macrocyclic polypeptide.
  • the new conditions can advantageously be prepared in situ, thus avoiding the handling of hazardous and hygroscopic substance, can proceed in a variety of solvents such as for example toluene, xylene, anisole, by-passing the need for using the undesirable chlorinated solvents such as dichloromethane or dichloroethane, and avoid the use of oxonium Meerwein salts originating from the genotoxic epichlorhydrin.
  • Either the dedicated carbenium tetrafluoroborate salt or the in situ generated reactive species made by the reaction of boron trifluoride and an orthoester derivative, preferably trimethyl orthoformate, will result in the desired opened polypeptides such as compound 3 below.
  • undecapeptides such as alisporivir.
  • the process according to the present disclosure may also be applied to other cyclosporins that can be opened via the same sequence. It was found that opened cyclosporin salts, such as hydrochloric acid (HCI), fluoroboric acid (HBF 4) , or hexafluorophosphoric acid (HPF 6 ), can be formed at several stages.
  • HCI hydrochloric acid
  • HHF 4 fluoroboric acid
  • HPF 6 hexafluorophosphoric acid
  • the present invention provides novel crystalline intermediates, such as cylosporine esters, such as acetate, pivaloate, and opened cyclosporin A, cyclosporin B, cyclosporin D or cyclosporin G salts such as the HCI salt, the HBF 4 salt, or the HPF 6 salt, and processes to generate them.
  • novel crystalline intermediates such as cylosporine esters, such as acetate, pivaloate, and opened cyclosporin A, cyclosporin B, cyclosporin D or cyclosporin G salts such as the HCI salt, the HBF 4 salt, or the HPF 6 salt
  • the method includes the steps of acylation of cyclosporin A, to form acetyl-Cyclosporin A; ring opening of the acetyl- Cyclosporin A; and crystallizing the ring opened acetyl-Cyclosporin A to obtain the compound of formula 3.
  • R is methyl, ethyl, propyl or phenyl and R' is methyl or ethyl.
  • the method includes the steps of Edman degradation of compound of formula 3; and then crystallizing the compound to obtain the compound of formula 4.
  • a process for preparing a compound of formula 4 or a salt thereof is provided,
  • the method includes the steps of: acylation of cyclosporin A to form acetyl-Cyclosporin A; ring opening of the acetyl- Cyclosporin A; and crystallizing the ring opened acetyl-Cyclosporin A to obtain the compound of formula 3
  • R is methyl, ethyl, propyl or phenyl and R' is methyl or ethyl.
  • R is methyl, ethyl, propyl or phenyl and R' is methyl or ethyl.
  • Figure 1 is a proton NMR spectra for compound 3.
  • Figure 2 is a proton NMR spectra for compound 4.
  • R 2 is:
  • alisporivir can be made by converting cyclosporin A (compound (1) wherein R 2 is ethyl) into a compound of formula 4 as shown above by acylation of cyclosporin A, to form acetyl-Cyclosporin A (2); ring opening; crystallization to obtain a compound 3, Edman degradation of compound 3; crystallization to obtain a compound 4 and then cyclizing compound 4 to form alisporivir (as shown below).
  • the invention specially relates to the processes described in each section.
  • the invention likewise relates, independently, to every single step described in a process sequence within the corresponding section. Therefore, each and every single step of any process, consisting of a sequence of steps, described herein is itself a preferred embodiment of the present invention.
  • the invention also relates to those embodiments of the process, according to which a compound obtainable as an intermediate in any step of the process is used as a starting material.
  • the invention also relates to intermediates which have been specifically developed for the preparation of the compounds according to the invention, to their use and to processes for their preparation. It is noted that in the present application, explanations made in one section may also be applicable for other sections, unless otherwise stated.
  • Cyclosporin A, cyclosporin B, cyclosporin D or cyclosporin G or salts thereof, may be prepared, for example by fermentation.
  • the present invention relates to a method for preparing compound of formula 3, comprising the steps of acylation of cyclosporin A, cyclosporin B, cyclosporin D or cyclosporin G to form acetyl-Cyclosporin A, B, D, or G; ring opening; and crystallization.
  • the present invention relates to a method for preparing compound of formula 4 or a salt thereof, comprising Edman degradation, a reaction well known in the art, of a compound of formula 3 and crystallization thereof to obtain compound of formula 4.
  • Another embodiment of the present invention relates to a method for preparing a compound of formula 3 or formula 4 wherein the purity of the Cyclosporin A starting material is >80% by weight
  • Another embodiment of the present invention relates to a method for preparing a compound of formula 3 or formula 4 wherein the purity of the Cyclosporin A starting material is >85% by weight.
  • Another embodiment of the present invention relates to a method for preparing a compound of formula 3 or formula 4 wherein the purity of the Cyclosporin A starting material is 60 to 80%, weight % assay.
  • R is methyl, ethyl, propyl or phenyl
  • R' is methyl or ethyl
  • R 2 is methyl, ethyl, or propyl
  • R is methyl, ethyl, propyl or phenyl
  • R' is methyl or ethyl
  • R 2 is methyl, ethyl, or propyl
  • R is methyl, ethyl, propyl or phenyl and R' is methyl or ethyl.
  • Acetyl-Cyclosporin A (100g as is) was reacted with trimethyloxonium tetrafluoroborate (32 g) at 20-25*0 in dichloromethane (180 mL). After 20 h, acetonitrile (200 mL) and water (650 mL) were added to perform the hydrolysis. After 3 h, at 20-25°C, the phases were separated and the reaction mixture was dried by azeotropic distillation with 2-Methy!-Tetrahydrofuran (solvent exchange dichloromethane 1 2-Methyl-Tetrahydrofuran).
  • the "undecapeptide amino acid" precursor (5 to 13% to the overall end mass) dissolved in dichloromethane and the DCC dissolved into dichloromethane were added continuously in parallel in ca. 10 h to a mixture of CI-HOBT, and NMM in dichloromethane at 40 °C. At the end of the addition, the mixture was stirred for an additional 2h, filtered to remove the DCU salt and concentrated to give Alisporivir as a crude product.

Abstract

The present invention relates to processes and intermediates useful for the manufacture of cyclic undecapeptides, such as Alisporivir, a non-immunosuppressive cyclosporine A derivative. The cyclosporin is acylated on the butenyl-methyl-threonine side chain and then subjected to a ring-opening reaction (the ring opens between the sarcosine and the N-methyl-leucine residues). This linear peptide intermediate is subjected to Edman degradation (removal of the N-terminal residue) as to give the second linear decapeptide intermediate, e.g. of sequence Val-N(Me)Leu-Ala-Ala-N(Me)Leu-N(Me) Leu-N(Me)Val-N(Me)Bmt-Abu-Sar when starting from CsA.

Description

Process for the Manufacture of Cyclic Undecapeptides
Field of the invention
The invention relates to novel process(es), novel process step(s) and novel intermediate(s) useful for the opening of Cyclosporin derivatives and subsequently for the preparation of cyclic polypeptides, more specifically, cyclic undecapeptides, such as alisporivir (also known as DEB025, Debio025, or Debio).
Background of the invention
The present invention relates to processes for the preparation of cyclic polypeptides, such as, for example, cyclic undecapeptides, such as alisporivir.
Alisporivir is a cyclophilin (Cyp) inhibitor used for the treatment of hepatitis C virus (HCV) infection or HCV induced disorders as described in WO 2006/038088. Furthermore,
WO2009/042892 describes methods for the use of alisporivir in the treatment of multiple sclerosis; WO2009/098577 describes methods for the use of alisporivir in the treatment of muscular dystrophy; WO2008/084368 describes methods for the use of alisporivir in the treatment of Ullrich congenital muscular dystrophy.
Alisporivir and a synthesis thereof are described in WO 00/01715. Alisporivir has been attributed the CAS Registry Number 254435-95-5.
Processes for the preparation of Alisporivir on laboratory scale are described by J.F. Guichoux in "De nouveaux analogues de Cycloposrine A comme agent anti-HIV-1 " PhD thesis, Faculte des Sciences de L'Universite de Lausanne, 2002, in WO2006/038088, and in WO2008/084368.
Cyclic undecapeptides, as represented below, are cyclic polypeptides of Formula (la), wherein n=2.
Alisporivir (Formula I) is a cyclic undecapeptide of Formula (lb) wherein n=2, aa1 is D-MeAla and aa2 is EtVal.
Figure imgf000003_0001
CYCLIC POLYPEPTIDES CYCLIC UNDECAPEPTIDES
A= Alkyl substituent A= Alkyl substituent
aan= amino acids aan= amino acid
(Formula la) (Formula lb)
Figure imgf000003_0002
ALISPORIVIR
n = 2, aai = D-MeAla, aa2= EtVal
(Formula I)
GENERIC FORMULA:
Cyclo-(AXX1-AXX2-AXX3-AXX4-AXX5-AXX6-AXX-7-AXX8-AXX9-AXX10-AXX1 1 ), should cover examples from case WO2010/052559 A1 as fragmentation made at key Sar fragment
AXX1 = MeBmt, Bmt, MeLeu, Desoxy-MeBmt, Methylaminooctanoic acid
AXX2= Abu, Ala, Thr, Val, Nva
AXX3= Sar
AXX4= MeLeu, Val AXX5= Val, Nva
AXX6= MeLeu, Leu
AXX7= Ala, Abu
AXX8= D-Ala
AXX9= MeLeu, Leu
AXX10= MeLeu, Leu
AXX1 1 = MeVal, Val, D-MeVal
And all other combinations covered in WO 2010/052559 A1
Over the last several years, cyclosporin A (CyA) has been used as a raw material for a variety of synthetic cyclic undecapeptides which are useful for the treatment of inflammatory or viral diseases. Cyclic undecapeptides may be obtained bystrain selection, however obtaining most un-natural derivatives requires a chemical transformation which relies on opening of the cyclic polypeptide, for example, of Formula (la) or of Formula (lb) and subsequent amino acid replacement.
Traditionally, cyclic polypeptide, for example of Formula (la) are opened in a highly selective process and an amino acid residue is removed via the Edman degradation to access the opened cyclic polypeptide as a key intermediate (Wenger, R. M. In Peptides 1996; Ramage, R.; Epton, R., Eds.; The European Peptides Society, 1996; pp. 173; Wenger, R. M. et al. Tetrahedron Letters 2000, 41, 7193.). Numerous scientists and companies have used this reliable and selective strategy wherein pure cyclosporin A and purification by column chromatography have been used to obtain cyclic undecapeptides.
Furthermore, purification of products, such as opened cyclosporin A, involve several steps of purification by liquid chromatography on silica. Beside the moderate overall obtained yield, the major drawback of this purification scheme is the very high costs for the chromatography steps. Large-scale purification processes of such products derived from cyclosporin A or its structural analogues described in the literature generally involve a chromatographic purification or at least a pre-purification by adsorption chromatography. Such pre-purification may be followed, for instance, by extraction, counterflow extraction, and/or supercritical fluid extraction. However, none of these techniques appear to be fully satisfactory for obtaining the key opened intermediates with the desired quality requirements, with an acceptable overall yield, and at an acceptable cost for an industrial scale production, as costly precursors of high quality were required.
We identified that dimethoxycarbenium ions (described in Novartis patent application EP 0 908 461 A1 for the methylation of Cephalosporine derivatives), do the same chemistry as oxonium ions (trimethyl or triethyloxonium Meerwein salts) in the opening of the macrocyclic polypeptide. The new conditions can advantageously be prepared in situ, thus avoiding the handling of hazardous and hygroscopic substance, can proceed in a variety of solvents such as for example toluene, xylene, anisole, by-passing the need for using the undesirable chlorinated solvents such as dichloromethane or dichloroethane, and avoid the use of oxonium Meerwein salts originating from the genotoxic epichlorhydrin. Either the dedicated carbenium tetrafluoroborate salt or the in situ generated reactive species made by the reaction of boron trifluoride and an orthoester derivative, preferably trimethyl orthoformate, will result in the desired opened polypeptides such as compound 3 below.
We identified an improved process which maintains the advantage of a highly selective Edman degradation strategy while taking full advantage of newly identified crystalline intermediates.
The following disclosure presents newly isolated and crystalline intermediates derived from the
opening of cyclosporin A
Figure imgf000005_0001
Figure imgf000006_0001
and a process to generate and purify them, via methods such as crystallizations. This approach allows for a rapid, practical and much more effective access to opened cyclosporin A, cyclosporin B, cyclosporin D or cyclosporin G and can be used to produce cyclic
undecapeptides, such as alisporivir. Furthermore, the process according to the present disclosure may also be applied to other cyclosporins that can be opened via the same sequence. It was found that opened cyclosporin salts, such as hydrochloric acid (HCI), fluoroboric acid (HBF4), or hexafluorophosphoric acid (HPF6), can be formed at several stages.
The present invention provides novel crystalline intermediates, such as cylosporine esters, such as acetate, pivaloate, and opened cyclosporin A, cyclosporin B, cyclosporin D or cyclosporin G salts such as the HCI salt, the HBF4 salt, or the HPF6 salt, and processes to generate them.
Summary of the Invention
A process for preparing a compound of formula 3 or a salt thereof is provided,
Figure imgf000007_0001
(3)
wherein R is methyl, ethyl, propyl or phenyl and R' is methyl or ethyl. The method includes the steps of acylation of cyclosporin A, to form acetyl-Cyclosporin A; ring opening of the acetyl- Cyclosporin A; and crystallizing the ring opened acetyl-Cyclosporin A to obtain the compound of formula 3.
A process for preparing a compound of formula 4 or a salt thereof is provided,
Figure imgf000007_0002
wherein R is methyl, ethyl, propyl or phenyl and R' is methyl or ethyl. The method includes the steps of Edman degradation of compound of formula 3; and then crystallizing the compound to obtain the compound of formula 4. A process for preparing a compound of formula 4 or a salt thereof is provided,
Figure imgf000008_0001
(4)
wherein R is methyl, ethyl, propyl or phenyl and R' is methyl or ethyl. The method includes the steps of: acylation of cyclosporin A to form acetyl-Cyclosporin A; ring opening of the acetyl- Cyclosporin A; and crystallizing the ring opened acetyl-Cyclosporin A to obtain the compound of formula 3
Figure imgf000008_0002
(3)
Edman degradation of the compound of formula 3; and then crystallizing the compound to obtain the compound of formula 4 or a salt thereof.
rovided
Figure imgf000009_0001
(3)
wherein R is methyl, ethyl, propyl or phenyl and R' is methyl or ethyl. is provided
Figure imgf000009_0002
(4)
wherein R is methyl, ethyl, propyl or phenyl and R' is methyl or ethyl.
Brief Description of the Drawings
Figure 1 is a proton NMR spectra for compound 3.
Figure 2 is a proton NMR spectra for compound 4.
Detailed Description of the Invention
The general process according to the present invention for producing cyclic polypeptides, more specifically, cyclic undecapeptides, such as Alisporivir, is shown in the scheme below; however, this general scheme can also be used io make cyclic polypeptides, more specifically, cyclic
Figure imgf000010_0001
wherein R2 is:
ethyl for Cydosporin A
(2)
(1) mefliyl for Cyclosporin B
propyl for Cyclosporin G
isopropyl for Cyclosporin D
Figure imgf000010_0002
Figure imgf000010_0003
Specifically, alisporivir can be made by converting cyclosporin A (compound (1) wherein R2 is ethyl) into a compound of formula 4 as shown above by acylation of cyclosporin A, to form acetyl-Cyclosporin A (2); ring opening; crystallization to obtain a compound 3, Edman degradation of compound 3; crystallization to obtain a compound 4 and then cyclizing compound 4 to form alisporivir (as shown below).
Figure imgf000011_0001
ALISPO IVI
The invention specially relates to the processes described in each section. The invention likewise relates, independently, to every single step described in a process sequence within the corresponding section. Therefore, each and every single step of any process, consisting of a sequence of steps, described herein is itself a preferred embodiment of the present invention. Thus, the invention also relates to those embodiments of the process, according to which a compound obtainable as an intermediate in any step of the process is used as a starting material.
The invention also relates to intermediates which have been specifically developed for the preparation of the compounds according to the invention, to their use and to processes for their preparation. It is noted that in the present application, explanations made in one section may also be applicable for other sections, unless otherwise stated.
Cyclosporin A, cyclosporin B, cyclosporin D or cyclosporin G or salts thereof, may be prepared, for example by fermentation.
In one embodiment the present invention relates to a method for preparing compound of formula 3, comprising the steps of acylation of cyclosporin A, cyclosporin B, cyclosporin D or cyclosporin G to form acetyl-Cyclosporin A, B, D, or G; ring opening; and crystallization.
In one embodiment the present invention relates to a method for preparing compound of formula 4 or a salt thereof, comprising Edman degradation, a reaction well known in the art, of a compound of formula 3 and crystallization thereof to obtain compound of formula 4.
Another embodiment of the present invention relates to a method for preparing a compound of formula 3 or formula 4 wherein the purity of the Cyclosporin A starting material is >80% by weight
Another embodiment of the present invention relates to a method for preparing a compound of formula 3 or formula 4 wherein the purity of the Cyclosporin A starting material is >85% by weight.
Another embodiment of the present invention relates to a method for preparing a compound of formula 3 or formula 4 wherein the purity of the Cyclosporin A starting material is 60 to 80%, weight % assay.
In the processes shown above, novel. and inventive compounds are involved. Consequently, further subjects of the present invention are the compounds shown below.
Compounds of formula 3 or salts thereof,
Figure imgf000013_0001
(3)
wherein R is methyl, ethyl, propyl or phenyl, R' is methyl or ethyl, and R2 is methyl, ethyl, or propyl.
Compounds of formula 4 or salts thereof,
Figure imgf000013_0002
(4>
wherein R is methyl, ethyl, propyl or phenyl, R' is methyl or ethyl, and R2 is methyl, ethyl, or propyl.
Compounds of formula 3 or salts thereof,
(3) wherein R is methyl, ethyl, propyl or phenyl and R' is methyl or ethyl. Compounds of formula 4 or salts thereof,
Figure imgf000014_0002
(4)
wherein R is methyl, ethyl, propyl or phenyl and R' is methyl or ethyl.
The following Examples represent preferred embodiments of the reaction steps, intermediates and/or the process of the present invention and serve to illustrate the invention without limiting the scope thereof.
Preparation of Compound 3 HBF* Salt with erwein Salt
Acetyl-Cyclosporin A (100g as is) was reacted with trimethyloxonium tetrafluoroborate (32 g) at 20-25*0 in dichloromethane (180 mL). After 20 h, acetonitrile (200 mL) and water (650 mL) were added to perform the hydrolysis. After 3 h, at 20-25°C, the phases were separated and the reaction mixture was dried by azeotropic distillation with 2-Methy!-Tetrahydrofuran (solvent exchange dichloromethane 1 2-Methyl-Tetrahydrofuran). The desired product was then crystallized from 2-Methyl-Tetrahydrofuran (900 mL) and 2- ethoxy-2-methylpropane (400 mL) to provide compound 3 HBF4 as a white crystalline powder (63.9 g, after drying, purity >92%). 0.69, (3H,d,J=6.6Hz); 0.71 , (3H,d,J=6.5Hz); 0.81, (6H,m); [0.82 .. 0.89], (24H,m); 0.90, (3H,d,J=6.6Hz); 0.93, (3H,d,J=6.6Hz); 1.16, (6H,m); [1.23 .. 1.50], (4H,m); 1.52, (1H,m); [1.32 .. 1.73], (8H,m); 1.59, (3H,d,J=6.0Hz); 1.65, (2H,m); 1.65, 2.13, (2H,m); 1.93, 1.94, (3H,s); 2.03, (1H,m); 2.19, (1 H,m); 2.45, (3H,s); 2.72, <3H,s); 2.84, (3H,s); 2.86, (3H,s); 2.99, (3H,s); 3.02, (3H,s); 3.06, (3H,s); 3.62, 3.68, (3H,s); 3.78, (1H,m); 3.87, 4.53, (1 H,d,J=17.2Hz,18.6Hz); 4.10, 4,26, (1 H,d(J=18.6Hz,16.8Hz); 4.23, (1H,m); 4.60, (1H,m); 4.62, (1H,m); 4.66, (1 H,m); 5.02, (1H,m); 5.13, (1 H,dd,J=11.3Hz,4.7Hz); 5.26, (1 H,m); 5.29, (1 H,m); 5.32, (1 H,m); 5.36, (1 H,m); 5.39, (2H,m); 7.72, (1 H,d,J=7.3Hz); 8.14, (1 H,d,J=7.3Hz); 8.21, 8.35, (1H,d, J=7.3Hz,8.1 Hz); 8.85, (2H,s,br); 8.96, (1 H,d,J=8.4Hz).
Preparation of Compound 3 HBFj Salt with Use of Triroethylorthoforroate and
Borontrifluoride Etherate
A solution of Acetyl-Cyclosporin A (10g) in dichloromethane (20 mL) was added at -15°C to a slurry of dimethoxycarbenium teirafluoroborate generate at -20°C by a slow addition of borontrifluoride (2ml) to a solution of trimethylorthoformate (2ml) in dichloromethane (20 mL). After the addition, the slurry was allowed to warm up to room temperature and was kept stirring for 20 h. Afterward, Acetonitrile (10 ml) and water (10 ml) were added. After 2 h stirring at 0°C, phases were split. Then, after having washed the organic phase with water, solvent switched to 2-Methyl-Tetrahydrofuran and saturation with 2-Methoxy-2-methylpropane, compound 3 was obtained as a white solid which was dried under vacuum (5.1 g, >90 % purity) (see Figure 1)
Preparation of Compound HBF Salt:
The previously prepared salt of compound 3 (34.62 g) was charged to a reactor along with sodium carbonate (4.8 g), Toluene (50 mL) and water (50 mL). The resulting mixture was stirred at 20-25°C for 30 minutes, and the phases were separated. Phenylisothiocyanate (3.81 g) was added drop wise in 1 h at 20-25°C and the resulting reaction mixture was stirred until completion. Then methanol (20 mL), and 48% fluoroboric acid in water (2.5 g) was added and the mixture was stirred for an additional 1h. Then water (25 mL) was added, and the phases were split. The aqueous layers were extracted once more with toluene (50 mL) and then extracted with 2-Methyl-Tetrahydrofuran (100 mL). The organic extract was dried azeotropically and the desired product was crystallized from 2-Methyl-Tetrahydrofuran (100 mL) and 2- Methoxy-2-methylpropane (50 mL) to provide compound 4 HBF„ as a white crystalline powder (ca. 30 g, after drying, >93% purity), (see Figure 2)
0.69,
Figure imgf000016_0001
0.73, (3H,d,J=7.0Hz); 0.81, (3H,t, J=7.3Hz, 7.3Hz); 0.82, (3H,m); 0.85, (9H,m); 0.88, (6H,m); 0.91 , (3H,d,'J=7.0Hz); 0.93, (3H,d.,J=6.6Hz); 0.99, (3H,d,J=7.0Hz); 1.17, (6H,d,J=6.6Hz); [1.30 .. 1.55], (9H,m); 1.60, (3H,d,J=5.5Hz); [1.56 .. 172], (4H,m); 1.93, 1.95 (3H,s); 2.09, (1 H,m); 2.14, (1H,m); 2.20, (1 H,m); 2.74, (3H,s); 2.82, 3.06, (3H,s); 2.84, (3H,s); 2.87, (3H,s); 2.94, (3H,s); 3.02, (3H,s); 3.63, 3.68, (3H,s); 3.88, 4.52, (1H,d,J=17.2Hz, 18.6Hz); 4.10, 4.24, (1
Figure imgf000016_0002
4.24, (2H,m); 4.39, 4.62, (1H,m); 4.66, (1 H,m); 5.02, (1H,m); 5.08, (1 H,m); 5.26, (2H,m); 5.32, (1 H,m); 5.37, (1 H,m); 5.39, (2H,m); 7.84, 8.51 (1 H,d,J=7.3Hz, 8.1Hz); 7.98, (3H,s,br); 8.07, 8.18 (1 H,d,J=7.7Hz, 7.3Hz); 8.13, 8.27, (1H,d,J=7.3Hz,8.1 Hz).
The "undecapeptide amino acid" precursor (5 to 13% to the overall end mass) dissolved in dichloromethane and the DCC dissolved into dichloromethane were added continuously in parallel in ca. 10 h to a mixture of CI-HOBT, and NMM in dichloromethane at 40 °C. At the end of the addition, the mixture was stirred for an additional 2h, filtered to remove the DCU salt and concentrated to give Alisporivir as a crude product.

Claims

Claims:
1. A process for preparing a compound of formula 3 or a salt thereof,
Figure imgf000018_0001
(3)
wherein R is methyl, ethyl, propyl or phenyl and R' is methyl or ethyl, the method comprising the steps of acylation of cyclosporin A, to form acetyl-Cyclosporin A;
ring opening of the acetyl-Cyclosporin A ; and
crystallizing the ring opened acetyl-Cyclosporin A to obtain a compound of formula 3.
2. A process according to claim 1 for preparing a compound of formula 4 or a salt thereof,
Figure imgf000018_0002
(4)
wherein R is methyl, ethyl, propyl or phenyl and R' is methyl or ethyl, the method comprising the steps of Edman degradation of compound of formula 3; and then
crystallizing the compound to obtain a compound of formula 4.
3. A process for preparing a compound of formula 4 or a salt thereof,
Figure imgf000019_0001
(4)
wherein R is methyl, ethyl, propyl or phenyl and R' is methyl or ethyl, the method comprising the steps of:
i) acylation of cyclosporin A to form acetyl-Cyclosporin A;
ii) ring opening of the acetyl-Cyclosporin A; and ;
iii) crystallizing the ring opened acetyl-Cyclosporin A to obtain a compound of formula 3
Figure imgf000019_0002
(3) or salt thereof; iv) Edman degradation of the compound of formula 3; and then
v) crystallizing the compound to obtain a compound of formula 4 or a salt thereof.
4. A compound of formula 3 or a salt thereof
Figure imgf000020_0001
(3) wherein R is methyl, ethyl, propyl or phenyl and R' is methyl or ethyl.
5. A compound of formula 4 or a salt thereof
Figure imgf000020_0002
(4)
wherein R is methyl, ethyl, propyl or phenyl and R' is methyl or ethyl.
6. A process according to claim 1 or 3 wherein the purity of the starting material is >80%, by weight, Cyclosporin A.
7. A process according to claim 6 wherein the purity of the starting material is >85%, by weight, Cyclosporin A.
8. A process according to claim 7 wherein the purity of the starting material is 60 to 80%, weight % assay, of Cyclosporin A).
9. A process for preparing a compound of formula 3 or a salt thereof from from Cyclosporin or from Cyclosporin G,
Figure imgf000021_0001
(3)
wherein R is methyl, ethyl, propyl or phenyl, R' is methyl or ethyl, and R2 is methyl, ethyl, or propyl, the method comprising the steps of acylation of cyclosporin A , B, D, or G, to form acetyl- Cyclosporin A, B, D, or G;
ring opening of the acetyl-Cyclosporin A, B, D, or G; and
crystallizing the ring opened acetyl-Cyclosporin A, B, D, or G to obtain a compound of formula 3.
10. A process according to claim 9 for preparing a compound of formula 4 or a salt thereof,
Figure imgf000021_0002
(4)
wherein R is methyl, ethyl, propyl or phenyl, R' is methyl or ethyl, and R2 is methyl, ethyl, or propyl, the method comprising the steps of Edman degradation of compound of formula 3; and then
crystallizing the compound to obtain a compound of formula 4.
1 1 . A process for preparing a compound of formula 4 or a salt thereof,
Figure imgf000022_0001
(4) wherein R is methyl, ethyl, propyl or phenyl, R' is methyl or ethyl, and R2 is methyl, ethyl, or propyl, the method comprising the steps of:
vi) acylation of cyclosporin A , B, D, or G, to form acetyl-Cyclosporin A, B, D, or G;
vii) ring opening of the acetyl-Cyclosporin A, B, D, or G; and
viii) crystallizing the ring opened acetyl-Cyclosporin A, B, D, or G to obtain a compound of formula 3 or salt thereof
Figure imgf000022_0002
ix) Edman degradation of compound of formula 3; and then
x) crystallizing the compound to obtain a compound of formula 4 or a salt thereof.
12. A process according to claim 9 or 1 1 wherein the purity of the starting material is >90%, by weight, Cyclosporin A.
13. A process according to claim 12 wherein the purity of the starting material is >92%, by weight, Cyclosporin A.
14. A process according to claim 13 wherein the purity of the starting material is 60 to 80%, weight % assay, of Cyclosporin A).
15. A compound of formula 3 or a salt thereof
Figure imgf000023_0001
(3) wherein R is methyl, ethyl, propyl or phenyl, R' is methyl or ethyl, and R2 is methyl, ethyl, or propyl.
Figure imgf000024_0001
(4)
wherein R is methyl, ethyl, propyl or phenyl, R' is methyl or ethyl, and R2 is methyl, ethyl, or propyl.
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